Principles and Practice

of Brachytherapy
using afterloading systems
Edited by

C.A. Joslin
Emeritus Professor of Radiotherapy, Leeds University,
Tunbridge Building, Regional Cancer Treatment
Centre, Cookridge Hospital, Leeds, UK

A. Flynn
Head of Brachytherapy Physics, Department of
Medical Physics and Engineering, Cookridge Hospital,
Leeds, UK

and

E.J. Hall
Professor of Biophysics, Radiology and Radiation
Oncology, Director-Center for Radiological Research,
Department of Radiation Oncology, Columbia
University, New York, USA

A member of the Hodder Headline Group

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Contents

Contributors v

Preface viii

PART I THE PHYSICS OF BRACHYTHERAPY 1

1 Sources in brachytherapy Edwin Aird 3

2 Source specification and dosimetry J.M.Wilkinson 11

3 Calibration of sources Colin H.Jones 19

4 Systems of dosimetry Anne Welsh and Karen D'Amico 35

5 Computers in brachytherapy dosimetry Robert van der Laarse and Robert W. Luthmann 49

6 Dose specification and reporting: the ICRU recommendations Andre Wambersie and Jan J. Battermann 81

7 Afterloading systems A. Flynn 103

8 Quality assurance in low dose-rate afterloading Eric D. Slessinger 112

9 Quality assurance in high dose-rate afterloading Colin H. Jones 133

10 Radiation protection in brachytherapy A.M. Bidmead 147

PART II THE RADIOBIOLOGY OF BRACHYTHERAPY 159

11 The radiobiology of low dose-rate and fractionated irradiation Joel S. Bedford 161

12 Dose-rate effects with human cells G. Gordon Steel and John H. Peacock 180

13 Radiobiology of high dose-rate, low dose-rate, and pulsed dose-rate brachytherapy

David J. Brenner, Roger Dale, Colin Orton, and Jack Fowler 189

14 Predictive assays for radiation oncology John A. Cook and James B. Mitchell 205

15 Principles of the dose-rate effect derived from clinical data Eric J. Hall and David J. Brenner 215

PART III CLINICAL PRACTICE 223

16 Endobronchial brachytherapy in the treatment of lung cancer Burton L Speiser 225

17 Brachytherapy in cancer of the esophagus A.D. Flores 243

18 High dose-rate afterloading brachytherapy for prostate cancer P.J. Hoskin 257

19 Low dose-rate brachytherapy for breast cancer Julia R. White and J. Frank Wilson 266

20 Brachytherapy in the treatment of head and neck cancer A. Gerbaulet and M. Maher 284
iv Contents

21 High dose-rate interstitial and endocavitary brachytherapy in cancer of the head and neck
Peter Levendag, Connie de Pan, Dick Sipkema, Andries Visser, Inger-Karine Kolkman, and Peter Jansen 296

22 Brachytherapy in the treatment of pancreas and bile duct cancer Dattatreyudu Nori, Suhrid Parikh,
Srinath Sundararaman, and Margot Heffernan 317

23 Brachytherapy for treating endometrial cancer H.A. Ladner, A. Pfleiderer, S. Ladner, and U. Karck 333

24 Low dose-rate brachytherapy for treating cervix cancer: changing dose rate R.D. Hunter and S.E. Davidson 343

25 High dose-rate brachytherapy for treating cervix cancer C.A Joslin 354

26 Brachytherapy for brain tumors Maarten C.C.M. Hulshof and Jan J. Battermann 373

27 Interstitial brachytherapy in the treatment of carcinoma of the cervix A.M. Nisar Syed and
Ajmel A. Puthawala 379

28 Interstitial brachytherapy in the treatment of carcinoma of the anorectum Ajmel A. Puthawala and
A.M. Nisar Syed 387

29 High dose-rate brachytherapy in the treatment of skin tumors C.A. Joslin and A. Flynn 393

30 Hyperthermia and brachytherapy Peter M. Corry, Elwood P. Armour, David B. Gersten,

Michael J. Borrelli, and Alvaro Martinez 400

31 The costs of brachytherapy Graham Read 410

32 Quality management: clinical aspects C.A. Joslin 423

33 Safe practice and prevention of accidents in afterloading brachytherapy A. Flynn, S.E. Griffiths, and
C.A. Joslin 433

34 Pulsed low dose-rate brachytherapy in clinical practice Patrick S. Swift 443

Index 451
Contributors

Edwin Aird S.E. Davidson

Medical Physics Department, Mount Vernon Hospital, The Christie Hospital NHS Trust, Manchester, UK
Middlesex, UK
Connie de Pan
Elwood P. Armour Department of Radiation Oncology, Dr Daniel den Hoed
Department of Radiation Oncology, William Beaumont Cancer Centre, Rotterdam, The Netherlands
Hospital, Michigan, USA
A.D. Flores
Jan J. Battermann 7955 E, Chaparral Unit 125, Scottsdale, Arizona 85250, USA
Department of Radiation Oncology, Academisch Ziekenuis
Utrecht, The Netherlands A. Flynn
Medical Physics Department, Cookridge Hospital, Leeds, UK
Joel S. Bedford
Department of Radiological Health Sciences, Colorado State Jack Fowler
University, Colorado, USA Department of Human Oncology K4/336, University of
Wisconsin Cancer Center, Wisconsin, USA
A.M. Bidmead
Physics Department, Royal Marsden NHS Trust Hospital, A. Gerbaulet
London, UK Brachytherapy Department, Institut Gustave-Roussy, Villejuif,
France
Michael J. Borrelli
Department of Radiation Oncology, William Beaumont David B. Gersten
Hospital, Michigan, USA Department of Radiation Oncology, William Beaumont
Hospital, Michigan, USA
David J. Brenner
Center for Radiological Research, Columbia University, New S.E. Griffiths
York, USA Department of Radiotherapy, Regional Cancer Treatment
Centre, Cookridge Hospital, Leeds, UK
John A. Cook
Radiation Biology Branch, National Cancer Institute, National Eric J. Hall
Institutes of Health, Maryland, USA College of Physicians and Surgeons Center for Radiological
Research, Columbia University, New York, USA
Peter M. Corry
Department of Radiation Oncology, William Beaumont Margot Heffernan
Hospital, Michigan, USA Tumor Registry, New York Hospital Medical Center of Queens,
New York, USA
Roger Dale
District Department of Medical Physics, Charing Cross P.J. Hoskin
Hospital, London, UK Marie Curie Research Wing, Mount Vernon Hospital,
Middlesex, UK
Karen D'Amico
Medical Physics Department, Cheltenham General Hospital, Maarten C.C.M. Hulshof
Cheltenham, UK Academisch Medisch Centrum, Amsterdam, The Netherlands
vi Contributors

R.D. Hunter Suhrid Parikh

The Christie Hospital NHS Trust, Manchester, UK
Peter Jansen
Department of Radiation Oncology, Dr Daniel den Hoed
Cancer Centre, Rotterdam, The Netherlands
Colin H. Jones
Radiation Oncology, New York Hospital Medical Center -
Cornell, New York, USA and New York Hospital Medical Center
of Queens, New York, USA
John H. Peacock
Radiotherapy Research Unit, Institute of Cancer Research,
Surrey, UK

Physics Department, Royal Marsden NHS Trust, London, UK

A. Pfleiderer
University Hospital for Women, Freiburg, Germany
C.A. Joslin
Leeds University, Department of Radiotherapy, Regional
Ajmel A. Puthawala
Cancer Treatment Centre, Cookridge Hospital, Leeds, UK
Department of Radiation Oncology, Long Beach Memorial
Medical Center, California, USA
U. Karck
University Hospital for Women, Freiburg, Germany
Graham Read
Oncology Services, Royal Preston Hospital, Preston, UK
Inger-Karine Kolkman
Department of Radiation Oncology, Dr Daniel den Hoed Dick Sipkema
Cancer Centre, Rotterdam, The Netherlands Department of Radiation Oncology, Dr Daniel den Hoed
Cancer Centre, Rotterdam, The Netherlands
H.A.Ladner
University Hospital for Women, Freiburg, Germany Eric D. Slessinger
Regional Cancer Center, Community Hospital Indianapolis,
S. Ladner Indiana, USA
University Hospital for Women, Freiburg, Germany
Burton L Speiser
Peter Levendag St Joseph's Hospital and Medical Center, Department of
Department of Radiation Oncology, Dr Daniel den Hoed Radiation Oncology, Arizona, USA
Cancer Centre, Rotterdam, The Netherlands
G. Gordon Steel
Radiotherapy Research Unit, Institute of Cancer Research,
Robert W. Luthmann
Surrey, UK
St Vincent's Medical Center, Department of Radiation
Oncology, Florida, USA
Srinath Sundararaman
Radiation Oncology, New York Hospital Medical Center of
M. Maher
Queens, New York, USA
Radiotherapy Department, Mater Private Hospital, Dublin,
Ireland
Patrick S. Swift
Radiation Oncology, Alta Bates Comprehensive Cancer Center,
Alvaro Martinez
California, USA
Department of Radiation Oncology, William Beaumont
Hospital, Michigan, USA A.M. Nisar Syed
Department of Radiation Oncology, Long Beach Memorial
James B. Mitchell Medical Center, California, USA
Radiation Biology Branch, National Cancer Institute, National
Institutes of Health, Maryland, USA Robert van der Laarse
Nucletron BV, Veenendaal, The Netherlands
Dattatreyudu Nori
Radiation Oncology, New York Hospital Medical Center - Andries Visser
Cornell, New York, USA and New York Hospital Medical Center Department of Radiation Oncology, Dr Daniel den Hoed
of Queens, New York, USA Cancer Centre, Rotterdam, The Netherlands

Colin Orton Andre Wambersie

Gershenson Radiation Oncology Center, Harper Hospital and Unite de Radiobiologie et de Radioprotection, Faculte de
Wayne State University, Michigan, USA Medecine, Universite Catholiquede Louvain, Bruxelles, Belgium
 Contributors vii

Anne Welsh J.M. Wilkinson

Medical Physics Department, Cheltenham General Hospital, North Western Medical Physics, Christie Hospital, Manchester,
Cheltenham, UK UK

Julia R. White J. Frank Wilson

Medical College of Wisconsin, Wisconsin, USA Medical College of Wisconsin, Wisconsin, USA
Preface
Brachytherapy was for many years in a state of decline,
principally because of the radiation hazards to users and
those associated with the management of patients. The
introduction of afterloading machines in the 1960s pro-
vided the means to control the movement and position of
individual radioactive sources and greatly reduced the
radiation exposure to staff. As a result, brachytherapy
underwent a renaissance and provided the necessary stim-
ulus to promote the development of afterloading
brachytherapy techniques. These developments have been
further supported by the availability of nuclides, particu-
larly cobalt-60, cesium-137, and iridium-192 and, more
recently, radioactive seeds of iodine-125 and palladium -
105. In parallel with the technological advances in after-
loading machines, there have been major developments in
imaging techniques and computerized planning.
Cancer management generally has undergone major
advances since the 1960s and brachytherapy has played
an increasingly important role. The optimal manage-
ment of cancer patients requires expert teams who spe-
cialize in certain cancer sites within which brachytherapy
may have a specific place. Much of this work is now
being provided on an outpatient or day-care basis and
prolonged hospital stay is proving to be unnecessary.
Clinical training is largely obtained by observation of
and training from one's peers and also from supervised
hands-on experience. In parallel with the development
of clinical experience, an understanding of the principles
of radiobiology and physics is of great importance. It is
also prudent that clinical radiation oncologists continue
to update their state of knowledge with respect to cur-
rent practice.
The purpose of this book is not only to present to the
trainee clinical oncologist the scientific background and
principles of brachytherapy afterloading techniques, but
also to update those who specialize in brachytherapy.
The book is presented in three sections: physics, radiobi-
ology, and clinical treatment. The sections attempt to
cover the scientific principles, technical procedures, and
clinical applications of'afterloaded' brachytherapy.
The editors have aimed at a consistent presentation
for the various chapters without attempting to interfere
with the different styles of the individual authors. Some
chapters will be found to be more extensive than others,
which is mainly a reflection of the widespread applica-
tion of brachytherapy techniques within the subject of
those chapters.
We hope that readers of this textbook will find the
contents helpful in their work.
The editors would like to express their appreciation to
all authors for their well-prepared manuscripts and for
their tolerance during the book's production.
C.A. Joslin, A. Flynn, and Eric J. Hall
 PART
I
The physics of brachytherapy

1 Sources in brachytherapy 3
2 Source specification and dosimetry 11
3 Calibration of sources 19
4 Systems of dosimetry 35
5 Computers in brachytherapy dosimetry 49
6 Dose specification and reporting: the ICRU
recommendations 81
7 Afterloading systems 103
8 Quality assurance in low dose-rate afterloading 112
9 Quality assurance in high dose-rate afterloading 133
10 Radiation protection in brachytherapy 147
This page intentionally left blank

Sources in brachytherapy
EDWIN AIRD
1.1 INTRODUCTION
1.1.1 Radium
Radium was discovered by Marie Curie in 1898. Within
3 years of this discovery the first patients were treated
with radium implanted into their tumors.
In the UK, St Bartholomew's Hospital received its first
radium for clinical use in 1906. Early clinical experience
with these sources led to radiation necrosis and it
became clear that this was due, in part, to the intense
beta-ray dose from the radium. It was not until 1920 that
successful filtration of the beta-rays was achieved.
Radium was then used extensively throughout the
world. Physicists in the major clinical centers developed
dosimetry systems for interstitial and intracavity
brachytherapy. The Manchester and Paris systems are
probably still the most widely used for interstitial ther-
apy. However, in general radium has been replaced by
other radionuclides because, although it has a long half-
life, it has several disadvantages:
Radium and several of its daughter products,
including radon, are alpha emitters. Radon is a noble
gas which is soluble in tissue. This gas could escape
through a hairline crack - not easily detected by a
visual check - in the radium capsule. If an implanted
radium source were to be ruptured within the
patient's body, radium and its daughter products may
become deposited more or less permanently in the
bone.
There is also the possibility of damage - by
incineration or mechanical means - when the sources
are lost or while they are being processed, with the
subsequent release of toxic radioactivity to the
environment.
1
The gamma radiation from a radium source is of
higher energy than is necessary for brachytherapy.
Radiation protection for these sources requires large
thicknesses of lead, which can cause problems when it
comes to:
transporting sources in heavy containers
using very heavy protective screens around the
patient
the need for a heavy rectal shield in applicators used
for gynecological treatment.
The practical maximum activity concentration (the
specific activity) of radium salt is low (approximately
50 MBq mm~3 of active volume). Sources of higher
activity are therefore bulky and not suitable for
afterloading systems.
1.1.2 Radium substitutes
This was the phrase used to describe the first set of new
(artificial) radionuclides which were found useful for
brachytherapy from about 1950 onwards, though it is only
very recently that most radiotherapy centers have stopped
using radium. It was found that there were very few
radionuclides with the appropriate properties of the ideal
brachytherapy source. These properties are as follows:
(A full discussion of these points may be found in the
British Journal of Radiology Supplement 21 (1987); an
abbreviated set is stated here.)
Photon energy should be low to medium (0.03-0.5
MeV) to minimize radiation protection problems
(with the proviso that low-energy radionuclides
should not be used near bone because of the
enhanced dose to bone at these energies).
For permanent stock, a long half-life is desirable such
that the radioactive decay within the practical lifetime
4 Sources in brachytherapy
of the source and its container (typically 10 years) is
small.
For permanent implantation, a fairly short half-life is
essential in order to minimize the time over which
special precautions, towards relatives of a radioactive
patient and members of the public, need to be in
place.
The nuclide should be available at high specific
activity.
There should be no gaseous disintegration product.
The nuclide should be available in a form which does
not powder or otherwise disperse if the source is
damaged or incinerated.
The first sources to be used as alternatives to radium
were cobalt-60, gold-198, cesium-137 and iridium-192.
These are all described briefly below. The most com-
monly used sources at this time are cesium-137 and
iridium-192, both of which are used in after-loading
systems. Iridium-192 has the possibility of high specific
activity, which allows it to be used as a high dose-rate
(HDR) source.
1.1.3 New sources
The newer sources are not known as radium substitutes,
mainly because they have very different properties from
radium, namely very much higher specific activity (for
example the HDR iridium-192 source) and very differ-
ent energy. The only new source that has been accepted
into routine clinical use in certain centers throughout
the world is iodine-125. Palladium-103 is also now avail-
able as a standard commercial source.
The other sources that are still at the research stage of
development, to find out whether they can be of use clin-
ically, are samarium-145, americium-241, and ytter-
bium-169.
1.2 PRODUCTION OF RADIONUCLIDES
The most common method of producing the radio-
nuclides used in brachytherapy, apart from cesium-137
(which is a fission product), is by neutron bombardment
in a nuclear reactor. The reaction is that of neutron cap-
ture, normally in the stable isotope of the element
required (except for iodine-125, see below). Thus, for
iridum the reaction is:
For cobalt-60 the reaction is:
This method of production has the disadvantage that
the radioactive isotope cannot be separated from the
stable isotope and limits the specific activity possible.
However, for iodine-125, the reaction proceeds in two
stages, with xenon as the initial target element:
The radioactive xenon decays by beta emission, with a
half-life of 8 days, to the required125/53I,which can then be
chemically extracted as a pure radioisotope.
To estimate the yield of a given radionuclude, it is pos-
sible to use the simple form (for short irradiation time
and low fluxes) of the yield equation given in The
Radiochemical Manual [ 1 ]:
where s is the reaction cross-section; (j is the neutron
flux; n0 is number of atoms in target (=N 0 wq/A, where w
is target mass, q is the isotopic abundance of the nuclide
of interest in the target element, and A is the atomic mass
of the target element, N0 = Avogadro's number); t =
bombardment time; l = decay constant of the product
element.
The specific activity, S, of the target nuclide may be
approximated to:
For long irradiation times:
and S Ssat, the maximum activity possible for a given
neutron flux.
Example. For indium-191, the neutron capture cross-
section is 910 barns. (This is very high, compared with
cobalt-60, for example, which has a cross-section of 43
barns.) If the neutron flux is high (typically 1013 rt.cm-2S-1),
using the above equations, it is possible to show that the
maximum theoretical specific activity for iridium-192 is
about 29 TBq g-1, which equates to about 2.5 TBq for an
HDR source of 0.086 g.
In practice, although the neutron flux is probably
higher:
The irradiation times are shorter, so that only a fraction
of Ssat is reached. The typical specific activity produced
for HDR sources is 4.3 TBq g-1 (for a 370 GBq source).
It is interesting to compare the specific activities (in
terms of activity per unit length) available for the differ-
ent radionuclides used now in brachytherapy with those
in the older sources.
Iridium wire 37 MBq mm-1
Iridium HDR source 74 GBq mm-1 actual source
length
 Brachytherapy sources used in afterloading systems 5

Cesium miniature 333 MBq mm -1 actual Table 1.2 Examples of source trains suitable for Manchester
cylindrical source length (for manual System
afterloading source
trains)
Cobalt-60 beads 592 MBq mm-1 actual
source length (in a set of
active beads) Medium vaginal ovoid 3 1.7 127
Compared with radium 50 mg in 13.5 mm active Medium intrauterine 5 2.1 158
length, 20 mm actual Medium tandem 11 5.4 412
length, equates to 92.5 a
The nominal output is expressed in terms of air kerma rate (AKR) at
MBq mnT-1 actual length 1 m from the center of the source.

13 BRACHYTHERAPY SOURCES USED IN

AFTERLOADING SYSTEMS

Except where otherwise stated, reference data concerning

sources come from the Amersham Catalogue of Radiation Image Not Available
Source for Oncology.

13.1 Cesium-137 (Table 1.1)

FORMS FOR MANUAL AFTERLOADING

Miniature cylindrical sources (Figure 1.1) contain
cesium-137 glass beads encapsulated in stainless steel. Figure 1.1 Cylindrical cesium-137 sources as used in the
They are used in source trains in machine and manual Amersham afterloading source train. (Reproduced by kind
afterloading systems for gynecological brachytherapy. permission of Nycomed Amersham plc.)

AMERSHAM MANUAL AFTERLOADING SYSTEM

In the Amersham Manual Afterloading System (Figure
1.2) a source train consists of a flexible stainless-steel
holder containing miniature cylindrical sources sepa-
rated by spherical steel spacers 1.8 mm in diameter. The

Table 1,1 Properties of cesium-137

Production A fission product
Small quantities (less than 1%
cesium-134 present [2], which
decays with a half-life of about 2 Image Not Available
years)
Half-life 30.17 years
Decay scheme
Beta energies Emission probability-betas*
0.512 MeV 94.6%
1.173MeV 5.4%
Photon energies Emission probability - photons
0.662 MeV 90.1%
Barium X-rays
0.032-0.038 MeV -7%
Beta filtration 0.5 mm of platinum or stainless
steel
Figure 1.2 Source train used in the Amersham afterloading
Half value layer in lead 6.5mm
system. (Reproduced by kind permission of Nycomed Amersham
* Data from The Radiochemical Manual [1]. Pic.)
6 Sources in brachytherapy

sources and spacers are retained in the holder by a steel
spring, secured by a screwed-in end plug. They are
designed to locate in the Amersham manual afterloading
plastic applicators. The standard set of 11 source trains is
suitable for the Manchester System of Gynecological
tube dosage. Some examples are given in Table 1.2.
WALSTAM-TYPE SOURCES [3]
These are short, cylindrical sources with hemispherical
ends. They consist of cesium-137 in a ceramic matrix con-
tained in a welded stainless-steel capsule. They are used in
dome or cylindrical gynecological applicators. The sources
approximate a point source of activity higher than that
used in the Amersham (Manchester) System (Table 1.3).
Table 1.3 Waktnm-tvnr snurrtx;
CESIUM-137 SOURCES FOR BUCKLER* AFTERLOADING
These are cylindrical sources used in the fixed ovoids of
the Buchler Gynaecological System. The sources vary
from 10.1 GBq with active dimensions 2 mm x 3.5 mm
to fit applicators 6 mm diameter for low dose rates
(LDRs), to 148 GBq with active dimensions 4.1 mm x
11.5 mm to fit applicators 8 mm diameter for HDRs.
CESIUM-137 SOURCES FOR CURIETRON
These are cylindrical sources that are very similar to
those of the Amersham Manual Afterloading System, but
for use in a remote afterloading system in which the
source trains are attached to a cable drive.
1.3,2 Cobalt-60 (Table 1.4)
FORM OF SOURCE

Although used in various forms in the past, the most

common form in recent years is in 'bead' form, with a
0.37-74 GBq 28.5-570.0 mGy h-1
design very similar to that used for cesium-137 beads in
the Selectron unit. However, the activity of cobalt-60
beads is higher and they are used for HDR brachy-
therapy.
REMOTE AFTERLOADING CESIUM-137 SOURCES

Spherical Sources
Spherical sources are used in the Selectron (Nucletron
BV) afterloading system (Figure 1.3). The cesium-137 is Table 1.4 Properties of cobalt-60
incorporated into a glass bead and encapsulated in stain-
Production By neutron activation of the stable
less-steel ball bearings (referred to as 'beads' or 'pellets')
isotope cobalt-59
which, together with inactive spacer beads, can be pneu-
matically loaded from the intermediate safe into a Half-life 5.27 years

patient applicator along a plastic tube (nominal activity Decay scheme

1.48 GBq per bead, air kerma rate 112mGyh-1m2). Beta energies Emission probability - beta
0.318 MeV 99.9%
Photon energies Emission probability - photon
1.17 MeV 99.9%
1.33 MeV 100.0%*
Beta filtration Typical source wall thickness
Half value layer in lead 10mm

* Data from The Radiochemical Manual [1].

Image Not Available

133 lridium-192 (Table 1.5)

FORMS OF IRIDIUM-192
Wire
In Europe, platinum-covered iridium-192 wire is sup-
plied in 500 mm length coils. The wire consists of an
active iridio-platinum core, 0.1 mm thick, encased in a
sheath of platinum, 0.1 mm thick.

Figure 1.3 Spherical cesium-137 source as used in the Selectron

afterloading system. (Reproduced by kind permission of
Nucletron BV.) * Buchler GmbH, Braunschweig, Germany.
 Brachytherapy sources used in afterloading systems 7

Table 1.5 Properties of iridium-192

Production By neutron activation of the stable isotope iridium-191; the process also produces quantities of
iridium-194 (from the activation of iridium-193); because this has a half-life of only 17 h, it
does not contribute a significant dose by the time the source is used in the patient
Half-life 73.83 days
Decay scheme
Beta energies Emission probability-betas
0.079-0.672 MeV 0.1-48.1%
Photon energies Emission probability-photons Effective photon energy
Range 0.2-1.06 MeV 0.37 MeV (unencapsulated)
0.4 MeV (encapsulated)
Significant photon energies (>10%) for those greater than 10%
0.296 MeV 28.7%
0.308 MeV 29.8%
0.316 MeV 83.0%
0.468 MeV 47.7%
Beta filtration 0.1 mm platinum
Half value layer in lead 4.5mm

Data from The Radiochemical Manual [1].

Iridium-192 wire is not classified as a 'sealed radiation
source.' Because it is activated by neutron irradiation, its
cladding remains slightly active. This is not significant in
its clinical use. For radiation protection purposes, irid-
ium wire is know as a 'closed radiation source.'
Available source strength is shown in Table 1.6.
Table 1.6 Available source strength of indium wire
1.11-37.00 MBqmnr 126 nGy h-1 mm-1-4.19 mGy h-1
mm-1
Wire is cut to the required lengths and loaded into
plastic tubes or hypodermic needles.
Hairpins (Figure 1.4)
Platinum-covered iridium wire is supplied in the form of
'hairpin' or 'single-pin' shapes. The wire has a diameter
of 0.6 mm to give it added strength; the beta filtration
remains at 0.1 mm platinum. Hairpins are 131 mm over-
all length, with leg length 60 mm nominally (the legs can
be cut to the required length) and with a range of source
strength (Table 1.7).

Image Not Available

Figure 1.4 Platinum-covered iridium-192 wire hairpin (a) and slotted hairpin guide needles (b) as supplied by Nycomed Amersham
pic. (Reproduced by kind permission of Nycomed Amersham plc.)
8 Sources in brachytherapy

Table 1.7 Available source strength of iridium hairpins 13.4 lodine-125(Table1.8[5])

FORMS OF SEED (Figure 1.6a, b)
1.48-11.10 MBq mm-1 168-1257 m G y - 1 mm-1
Type 6711 seeds (Nycomed Amersham plc, Amersham,
UK) are used for permanent implant. Each seed consists
Single pins are 73 mm overall length with a nominal of a welded titanium capsule containing iodine-125
leg length of 60 mm and with a range of source strength adsorbed onto a silver rod (which also acts as X-ray
the same as the hairpins. marker). The active length is 3.0mm and diameter
Slotted stainless-steel guides are used for implanting 0.5mm. The overall length is 4.5mm and diameter
hairpins and single pins. 0.8 mm. Sources are available with air kerma rates at 1 m
of 0.13-7.58 [mGyh-1.
lridium-192 'seeds'
The seeds are used with special applicators to intro-
In the USA these are used instead of wire. Two seed styles
duce them into the patient a fixed distance apart. A new
are commercially available:
type of absorbable suture called Rapid Strand (Figure
1. 0.1 mm diameter core of active wire (30% iridium, 1.7), from Nycomed Amersham plc, has become avail-
70% platinum) surrounded by 0.2 mm cladding of able that encases ten seeds at a fixed distance apart
stainless steel (Best Industries, Springfield, VA). (1cm) in tissue until the suture dissolves (5mm or
2. 0.3 mm diameter core (10% iridium, 90% platinum) 15 mm is also available in this form). The suture mater-
surrounded by 0.1 mm cladding of platinum ial is braided Vicryl which is stiffened thermally and ster-
(Alpha-Omega, Bellflower, CA). ilized by ethylene oxide gas. It eventually dissolves in
tissue. These seeds also emit silver characteristic X-rays
Both seeds are 3 mm active length and are supplied
inside strands of nylon of 0.8 mm outside diameter.
Normal spacing is 1 cm, but other spacings are available. Table 1.8 Properties of iodine-125
Maximum overall length is about 18 cm.
Air kerma strengths range from 120 to 650 MBq per Production Neutron activation of xenon-124
seed. to xenon-125, which then
decays to iodine-125
Miniature iridium-192 sources for high dose rate
Half-life 59.4 days
There is a variety of types of these sources, ranging from
0.2 to 1.3 mm diameter and 1 to 20 mm active length, Decay scheme Iodine-125 decays by electron
capture to the first excited state
with typically up to 370 GBq activity (air kerma rate
of tellurium-125, which
42 mGy h-1).
undergoes internal conversion
Figure 1.5 shows the HDR sources in use throughout 93% of the time; the other 7% is
the world at the present time. They are always perma- occupied by the production of a
nently attached to a cable drive. gamma ray photon of 35.5 keV.
The active wire is encased in stainless steel. There is The electron capture and internal conversion processes give
now a 'new design source' for the Nucletron BV rise to characteristic X-rays as follows:
microSelectron-HDR machine [4] with slightly smaller
(X-ray) Photon energy Decay photons emitted
dimensions (4.95 mm length, 0.90 mm diameter) and 27.4 keV 15%
similar dose distribution, except for some improvement 31.4keV 25%
near the source tip and in the shadow of the cable
Tenth value layer in lead 0.01 mm
assembly.

Image Not Available

Figure 1.5 MicroSelection iridium-192 HDR sources. (Reproduced by kind permission of Nucletron BV)
 Brachytherapy sources used in afterloading systems 9

Image Not Available Image Not Available

Figure 1.6 (a) Type 6777 iodine-125 seed, (b) Type 6702 iodine-
Figure 1.7 Rapid Strand. (Courtesy Nycomed Amersham plc.)
125 seed. (Reproduced by kind permission of Nycomed
Amersham plc.)

of 22.1 and 25.5 keV. The average photon energy is taken

to be 27.4 keV.
Type 6702 seeds are used for temporary interstitial
implants. These consist of a welded titanium capsule
containing three resin spheres onto which the iodine- 13.5 Palladium-103 sources (Table 1.9)
125 is adsorbed by an ion exchange.
Sources are available with air kerma rates at 1 m of FORMS OF SEEDS
6.4-51.9 (mGyh-1. The effective energy of the photons The active material is coated onto two graphite pellets
from this seed is taken to be 28.5 keV. 0.9 mm long and 0.6 mm in diameter. Between these is a
A further type of iodine-125 seed is available in North 1 mm long lead marker for radiography. These seeds are
America from Best Industries. The Model 2300 contains encapsulated in a 0.05 mm thick titanium tube, laser
radioactive iodine adsorbed on a tungsten wire that is welded, that is 4.5 mm long and 0.8 mm diameter (the
encapsulated by two walls of titanium. This source offers same dimension as the iodine-125 seed).
the following advantages:
Because it contains radioactive iodine on the ends as
well as on the surface of the tungsten, it produces a Table 1.9 Properties of palladium-103 sources ,
more isostropic dose distribution than the other
Production Palladium-103 is formed when
sources [6].
stable palladium-102 absorbs a
It is available in a wide range of source strengths and
neutron
therefore suitable for both temporary and
Half-life 16.97 days
permanent implantation.
The tungsten wire acts as a radiographic marker. Decay scheme By electron capture, mostly to
The double-walled encapsulation reduces the risk of the first and second excited
states of ruthenium-103
radioactive leakage.
An excitation is almost totally by internal conversion, leading
There is another new source of iodine-125 seeds on the to the production of characteristic X-rays:
US market, designated as MED 3631-A/S and manufac- Photon energy Photons em itted
tured by North America Scientific Incorporated, North 20.1 keV 65.6%
Hollywood, California [7], This source has now been 23.0 keV 12.5%
reconfigured (MED 3631-A/M) with the intent of pro- Effective energy 21 keV
viding greater facility for radiographic source identifica-
Tenth value layer in lead 0.03mm
tion while achieving reduced isotropy [8].
10 Sources in brachytherapy
13.6 Other proposed sources [9,11]
The properties of other proposed sources are shown in
Tables 1.10, 1.11, and 1.12.
Table 1.10 Properties of samarium-145
Photon energy range
Mean photon energy
Half-life
Maximum specific activity
Tenth value layer in lead
Purpose
Table 1.11 Properties of ameridum-241
Photon energy range
Mean photon energy
Half-life
Maximum specific activity
Tenth value layer in lead
Purpose
Disadvantages
Table 1.12 Properties of ytterbium-169 [10]
Photon energy range
Mean photon energy
Half-life
Maximum specific activity
Tenth value layer in lead
Seed dimensions
Purpose
REFERENCES
1. Longworth, G. (ed.) (1998) The Radiochemical Manual.
Harwell, UK, AEA Technology plc.
2. Godden, T.J. (1988) Physical Aspects of Brachytherapy,
Medical Physics Handbooks 19. Bristol, Adam Hilger.
38.2-61.4 keV 3. Walstram, R. (1965) Studies in therapeutic short distance
41keV and intracavitary gamma beam techniques. Physical
340 days considerations with special reference to radiation pro-
tection. Acta Radial., Supplement 236,1-129.
73 GBq mm-3 (compared with
370 GBqmm-1for iodine-125) 4. Daskalov, G.M., Loffler, E. and Williamson, J.F. (1998)
Monte Carlo-aided dosimetry of a new high dose-rate
0.2mm
brachytherapy source. Med. Phys., 25, 2200-8.
To improve dose distribution 5. Nath, R., Anderson, L.L, Luxton, G., Weaverk, A.,
and shelf-life compared with
Williamson, J.F. and Meigooni, A.S. (1995) Dosimetry of
iodine-125; in addition, it is
interstitial brachytherapy sources: recommendations of
noted that the photon energy
emitted allowssensitization of the AAPM Radiation Therapy Committee Task Group
biological cells to radiation No.43. Med. Phys., 22, 209-34.
damage by the addition of 6. Nath, R. and Melillo, A. (1993) Dosimetric characteristics
iodinated deoxyuridine; there of a double wall 1-125 source for interstitial brachy-
are no commercially available therapy. Med. Phys., 20,1475-83.
sources at the present time 7. Wallace, R.E. and Fan, J.J. (1998) Evaluation of a new
brachytherapy iodine-125 source by AAPM TG43 formal-
ism. Med. Phys., 25, 2190-6.
8. Wallace, R.E. (1999) Report on the dosimetry of a new
13.9-125 keV (but dominated by design iodine-125 brachytherapy source. Med. Phys., 26,
59.5 keV) 1925-31.
GOkeV 9. Battista, J.J. and Mason, D.L.D. (1994) New radionuclides
432 years for brachytherapy. In Brachytherapy from Radium to
0.34 GBq mm-3 Optimization, ed. R.F. Mould, J.J. Battermann, A.A.
Martinez and B.L Speiser. Veenendaal, The Netherlands,
0.42 mm
Nucletron International, 373-84.
Could be used as an alternative
10. Mason, D.L.D., Battista, J.J., Barnett, R.B. and Porter, A.T.
to cesium-137 for cancers of the
(1992) Ytterbium-159: calculated physical properties of
cervix and endometrium
a new radiation source for brachytherapy. Med. Phys.,
An a emitter
19, 695-703.
Only low specific activity
11. Williamson, J.F. (1995) Recent developments in basic
available
brachytherapy physics. In Radiation Therapy Physics, ed.
A.R. Smith. New York, Springer-Verlag, 247-302.
50-308 keV
93keV
32.0 days
340 GBq mm-3
1.6mm
Similarto iodine-125
Possible benefit-less
attenuation in tissue than
iodine-125 or palladium-153
and higher specific activity
 2
Source specification and dosimetry

J.M.WILKINSON

2.1 SOURCE SPECIFICATION BY CONTENT quially as the 'k' factor, and an assumed knowledge of the
attenuating properties of the materials used in the source
construction. The specific gamma ray constant for radium
2.1.1 Radium and radium mass was defined as the product of the exposure rate, in roent-
gen per hour, and the square of the distance, in cm2, from
Early brachytherapy was practiced with two radio- a 1 mg point source, encapsulated in a platinum sheath of
nuclides from the uranium/radium series, namely 0.5 mm thickness. Early workers adopted a value of 8.4
radium-226 and its immediate daughter, radon-222. Rh-1cm-2mg-1 for this constant, but subsequently this was
Both exist in equilibrium with later radionuclides in the revised to what is now the generally accepted value of 8.25
series, and indeed their usefulness as brachytherapy Rh-1cm-2mg-1. To determine the exposure rate at a point
sources arises from the gamma emissions that occur in near to a line source required an evaluation of the Sievert
the transitions from lead-214 (referred to at one time as Integral [1]. This was originally expressed as an angular
radium B) to bismum-214 (radium C), and from integration, as illustrated in Figure 2.1, and the integral
bismuth-214 to polonium-214 (radium C'). Both itself is that given in equation 2.1:
radium and radon require heavy metal screenage (at
least 0.5 mm of platinum or gold) to remove the partic-
ulate emissions, leaving practical brachytherapy sources
with almost identical gamma spectra. Radium-226
sources were specified in terms of the mass of radium
element, in milligrams, that each contained, and, given
the very long half-life for the decay of radium, 5.85 x 105
days, it was usually regarded as unnecessary to correct
the mass specification during a period of less than about
20 years, that is to say, during the normal working life of
the source.

2.1.2 The Sievert Integral

It was anticipated that the degree of radiation damage in

tissue would be closely related to the magnitude of the
exposure. The exposure rate at a point outside a radium
source was determined by using a calculated value of the Figure 2.1 The exposure rate at point P is obtained by the
specific gamma ray constant, sometimes referred to collo- angular integration of the Sievert Integral from f1 to f2.
12 Source specification and dosimetry
where dX/dt is the exposure rate at the point P, M is the
radium mass, k0 is the specific gamma ray constant cor-
rected back to zero filtration, m, is an appropriate filtra-
tion coefficient, and the other symbols are as indicated
in Figure 2.1. There is no analytic solution to the inte-
gral, but tabulated values have been published (see, for
example, reference 2). This approach is not too unrea-
sonable at relatively high gamma energies, but in fact
represents a considerable simplification of the true
physical problem, which becomes apparent when doses
in the vicinity of a source are calculated by Monte
Carlo techniques [3]. The classical Sievert Integral
assumes that increased scattering at short distances will
compensate for attenuation in the irradiated medium
to within the precision tolerances required for practical
brachytherapy work. Furthermore, there is no
allowance for internal absorption in the source material
itself and there is no obvious way to determine an
appropriate value for the filtration coefficient for the
sheathing material. Early workers used a single value of
0.2 mm-1 for filtration of radium gammas in platinum
[4], but Whyte [5] suggested that a better approxima-
tion could be achieved by using decreasing values with
increasing thicknesses to counter the hardening of the
energy spectrum.
2*13 The milligram-hour concept
Systems of brachytherapy dosimetry for radium appli-
cations were devised which dictated the relative distrib-
ution of active material for different treatment
geometries. Of these, the best known were the
Manchester System [4, 6-9] and the Quimby System
[10-12]. Such 'systems' recognized that, for a predeter-
mined geometry and predetermined relative distribu-
tion of active material, the exposure rate at any point
was proportional to the total amount of radium used,
and that, for a complete treatment, the total exposure
was proportional to the product of the amount (speci-
fied as radium mass in milligrams) and the duration
(specified as time in hours). Hence the milligram-hour
(which was the name given to both the quantity and its
unit) became a key parameter in early brachytherapy
dosimetry. It was assumed that this product would
have to remain constant, for any particular source
geometry, in order to achieve consistency in the
observed clinical result. It is interesting to note that this
assumption was, in effect, challenged at a very early
stage by the use of time factor corrections [13, 14], but
the application of such corrections, now generally
called dose rate corrections, remains the subject of
much debate. Brachytherapy systems are discussed in
more detail in Chapter 4. They are introduced here to
demonstrate how the radium mass specification was a
fundamental component of these early clinical dosime-
try procedures.
2.1.4 Radon and radium mass equivalent
A radon source was specified, at any particular instant in
time, by its radium mass equivalent, defined as that mass
of radium, encapsulated by a 0.5 mm thickness of plat-
inum, which would give the same exposure rate at 1 cm
from the axis of the source. Radon-222 has a half-life of
3.83 days and so both the radium mass equivalent and
the exposure rate at any defined reference point decrease
during an application. Radon seeds were used both for
superficial mould treatments and for permanent
implantation. The total exposure for an application was
calculated by multiplying the initial exposure rate by an
'effective' treatment time, determined by integrating the
area under the exponential decay curve. The generalized
expression for 'effective' treatment time, teff, is that in
equation 2.2, where l, is the decay constant and t is the
duration of the application:
For a permanent implant of radon seeds, this reduced to
teff = half-life/loge2, or 132.5 h.
The use of radium and radon has now generally been
discontinued due to radiation safety considerations.
Radionuclides that have subsequently been substituted
for radium and radon, for example cesium-137 or gold-
198, have also been specified in terms of the radium mass
equivalent as this facilitates their use with the established
radium systems that use the milligram-hour concept.
However, such nuclides have different gamma emission
spectra and may be encapsulated in different materials.
Hence the dose distribution around a substitute source
may be different from that around a radium or radon
source of similar physical dimensions. In practice, the
radium mass equivalent was frequently determined by
comparing the source in question with a similar-sized
radium source, of known mass content, in a well-type
ionization chamber. This appears to have been satisfac-
tory and there is no evidence to suggest that clinical
results have been adversely affected by such practice.
2.1.5 Specification by activity content
An alternative quantity for specification by content is the
activity of the radionuclide that is encapsulated in the
source. The activity, A, of an amount of radioactive
nuclide, in a particular energy state and at a given time,
is defined by equation:
where dN is the expectation value of the number of
spontaneous nuclear transitions from that energy state
in the time interval dt [15].
The early unit of activity, the curie (Ci), was originally
defined as the activity of 1 g of radium, or approximately

3.7 x 1010 transitions per second. A subsequent redefini-
tion of the curie made it exactly this figure. The curie is
now obsolete as the unit of activity and has been
replaced by the SI unit the becquerel (Bq). One becquerel
is one transition per second.
In order to calculate exposure rate at a point external
to a source specified by its activity content, it was again
necessary to assume a knowledge of the attenuating
properties of the source and source encapsulation mate-
rial, and also, now, to know the value of the exposure rate
constant, Gd. This latter quantity replaces the specific
gamma ray constant. The two constants are very similar
in concept and for many nuclides are assigned the same
value. However, the specific gamma ray constant does
not allow for possible contributions from internal con-
version X-rays, and these may be significant for low
energy emitters. The definition of the exposure rate con-
stant, as given in reference 16, is the quotient:
where(dX/dt)Gdis the exposure rate due to photons of
energy greater than 5, at a distance / from a point source
of a nuclide containing activity A.
The exposure rate constant is characteristic of the par-
ticular radionuclide. For radium and radon, d is deter-
mined for a point source with a filter thickness of 0.5
mm platinum and hence is numerically equal to the spe-
cific gamma ray constant. For all other radionuclides, the
constant is determined for unfiltered emissions and
hence a correction is required to allow for source encap-
sulation.
2.1.6 Equivalent activity
In practice, it was difficult to determine the activity con-
tent of an existing source and so the equivalent activity,
A eq , was often used in its place [17]. This was calculated
by determining the exposure rate external to the source,
and then using the exposure rate constant to obtain the
activity of a hypothetical, unfiltered, point source that
would give the same result. There is scope here for much
confusion and possible error, particularly if those com-
mercial computer systems that offer a brachytherapy
dosimetry package fail to specify clearly whether it is the
true activity content, or the equivalent activity, that is
required when entering source data.
2.2 SPECIFICATION BY EMISSION
2.2.1 Air kerma strength
As an alternative to using a content quantity, such as
radium mass, radium mass equivalent, or activity, a
brachytherapy source may be specified directly in terms
Specification by emission 13
of an emission property, so avoiding errors due to uncer-
tainties in the exposure rate constant or any other simi-
lar parameter. At the same time dosimetry errors that
may be made when allowing for the encapsulation mate-
rial will be reduced. The benefits of this approach are
summarized by Jayaraman et al. [18]. Specification in
terms of a reference exposure rate was proposed by
Wambersie et al. [19], and in the following year this was
the subject of a formal recommendation by the National
Council on Radiation Protection and Measurements
[20]. However, as exposure rate has now been replaced
by air kerma rate in many aspects of fundamental radia-
tion dosimetry, specification quantities that are based on
air kerma rate are now being recommended instead. The
French Committee on Measurements of Ionising
Radiations (CFMRI) [21] and the American Association
of Physicists in Medicine (AAPM) [22,23] have each
independently recommended a quantity that is defined
as the product of the air kerma rate at a distance /, mea-
sured along the transverse bisector of the source, and the
square of the distance /. The distance / must be large
enough that both the source and the detector may be
treated mathematically as points. The CFMRI called the
quantity le debit de kerma normal, and the AAPM use the
term air kerma strength. The latter term will be used in
this chapter, but an international readership must be
wary not to translate strength as force, which is the dic-
tionary translation for some European languages. The
AAPM have assigned the symbol U to the unit of air
kerma strength, where, for a point source:
2.2.2 Reference air kerma rate
Various other national and international organizations
[24-27] have defined an air kerma specification quantity
as the air kerma rate at a reference distance of 1 m from
the center of the source. The precise wording of the def-
inition differs slightly in the different publications, but
the quantity is, in practice, the same, and several of the
reports and recommendations assign the name reference
air kerma rate. The definition given in the BIR/IPSM rec-
ommendations [27] is that the reference air kerma rate is
the kerma rate to air, in vacuo, at a reference point which
is 1 m from the center of the source, and that for needles,
tubes, and other similar rigid sources, the direction from
source center to the reference point is that at right-angles
to the long axis of the source. It was recognized by the
authors of the report that measurements at 1 m, in
vacua, and in scatter-free conditions, would not be pos-
sible, and that the magnitude of the reference air kerma
rate for any given source would have to be derived from
measurements made in other conditions, the most likely
being ionization measurements made in air, and con-
ceivably at distances of less than 1 m. In deriving the
14 Source specification and dosimetry
reference air kerma rate from such measurements, it will
be necessary to convert the measured charge released to
a statement of energy released by using a calculated value
of the average energy required to produce one unit of
ionization in air. It will also, in principle, be necessary to
correct for attenuation and scattering in air, for the
response of any detector that cannot be regarded as a
point detector, and for any deviation from the inverse
square law when extrapolating from the actual measure-
ment distance to 1 m. Other techniques of measurement,
and other methods of deriving the magnitude of the
specification quantity from such measurements,
although very unlikely, are not excluded by the
BIR/IPSM definition.
The recommended units for the reference air kerma
rate are mGy h-1 for low dose-rate sources, i.e., those used
in applications where treatment durations are quoted in
hours, progressing to mGy min-1 and mGy s-1 where the
treatment durations would be expressed in minutes or
seconds respectively. The air kerma strength of a source,
expressed in U, and the reference air kerma rate,
expressed in (mGy h-1, although dimensionally different,
will be numerically the same for all practical brachyther-
apy purposes. The discussions that follow on the rela-
tionship between the older content specifications and
reference air kerma rate will therefore be equally applic-
able to air kerma strength.
2.2.3 Radium mass equivalent and
reference air kerma rate
All advocates of source specification by emission recom-
mend that the practice of source specification by content
should be discontinued. However, there is a practical
problem here in that many commercial software pack-
ages, and some source suppliers, continue to use content
quantities. It is therefore necessary, at least during a tran-
sition period, to convert from reference air kerma rate to
milligram radium equivalent or to equivalent activity.
Using a specific gamma ray constant of 8.25 Rh-1cm2
mg~' for radium with 0.5 mm platinum filtration, the
average energy per unit charge released by ionization in
air of 33.97 J C-1 [28], and taking the charge released per
unit mass of air by one roentgen of exposure to be
2.58X 104 C kg-1 [15], then a point source containing
1 mg radium equivalent will give an air kerma rate of
7.23 mGy h-1 at 1 m.
2.2.4 Equivalent activity and reference air
kerma rate
To convert between reference air kerma rate and equiva-
lent activity requires knowledge of the appropriate air
kerma rate constant. With the demise of the quantities
exposure and exposure rate, the air kerma rate constant
has replaced the exposure rate constant in modern radi-
ation dosimetry. Unfortunately, the ICRU has assigned
the same symbol Gd to both constants. The air kerma rate
constant is defined by the quotient:
where (dK/dt)d is the air kerma rate due to photons of
energy greater than 8, at a distance / from a point source
of the nuclide containing activity A [15].
The weakness of this approach is that different parties
may adopt different values for the air kerma rate con-
stant. For iridium-192 several values have been
proposed; for example, Godden [29] recommends
0.111 LlGyrr'm'MBq-1, whereas Dutreix et al. [30] sug-
gest 0.1157 mGyh-1m2MBq-1. Clearly, great care is
required to avoid significant systematic error.
2*3 DOSE-RATE CALCULATION FROM A
REFERENCE AIR KERMA RATE SPECIFICATION
2*3*1 Reference air kerma rate and
spherical sources with isotropic emission
For small spherical sources with isotropic emission, the
most commonly used expression for calculating the dose
rate to water in water, dD(r)water/dt, at radial distance, r, is:
where (dfCair/dt)ref is the reference air kerma rate specifi-
cation for the source, f(r) is a radial function describing
the net effect of attenuation and scattering in water, the
term in square brackets is the ratio of the mass energy
absorption coefficient for water to the mass energy
transfer coefficient for air, and (djr)2 gives inverse square
scaling from the reference distance dr, (df equals 100
when r is in cm). The value of absorption coefficient to
transfer coefficient ratio may be calculated from the data
published by Hubbell [31], and for photon energies
between 150 keV and 1.5 MeV is in the range
1.107-1.112. Hence a single value of 1.11 may be
adopted without incurring serious error for most of the
commonly used brachytherapy radionuclides. Strictly
speaking, however, this ratio is a function of photon
energy and care must be exercised when using this
approach with nuclides of low energy emissions and
where the energy spectrum will be further significantly
degraded by scatter. Inverse square scaling will also break
down when very close to a finite-sized source, but this
has no practical dosimetric consequences.
2*3*2 Attenuation and scattering in the
irradiated medium
The net effect of attenuation and scattering in water has
been investigated both experimentally and by Monte

Carlo techniques. Meisberger et al. [32] summarize the
earlier work and recommend values for coefficients of
third-order polynomials for the function f(r). The
Meisberger polynomials became the most common cor-
rection method, but early Monte Carlo calculations [33]
suggested that these polynomials were suspect. However,
more recent Monte Carlo work, for example Sakelliou et
al. [34], is in much closer agreement. The BIR/IPSM
report [27] recommends polynomials based on
Sakelliou's work. Klevenhagen [35] demonstrated that
the polynomial approximation must break down both at
very small and at very large distances, but, as the correc-
tion is usually very small when using the common
radionuclides at short distances, this may be ignored in
practice.
233 Seed sources
Small seeds containing, originally, radon, but more
recently gold-198 or iridium-192, should strictly be con-
sidered as cylindrical sources. However, where a large
number of such seeds are randomly orientated in a per-
manent implant, a more practical approach is to treat
them as point sources but to include an anisotropy cor-
rection giving the average emissions over all angles.
Anisotropy corrections may not be applicable, however,
when the seeds are arranged in more controlled geome-
tries, such as on a plaque for a superficial treatment.
2.3.4 Reference air kerma rate and
cylindrical line sources
For a line source the BIR/IPSM recommendations [27]
advocate an adaptation of the Sievert Integral evaluated
by a summation of the contributions to the total dose
rate from N contiguous line source elements, each no
more than 1 mm in length.
Each line element is subjected to a different inverse
square scaling, to a different water absorption and scat-
tering correction, and to oblique filtration corrections
for both the source encapsulation material and also for
the source material itself. With reference to Figure 2.2,
the expression for the dose rate at radial distance r and
angle 0 is:
where ts(qi) is the thickness of the encapsulation mater-
ial at angle qi, and ta(qi) is the thickness of source mater-
ial at the same angle measured from the source axis; ms
and ma are the corresponding filtration correction coeffi-
cients. The ratio of water absorption coefficient to air
transfer coefficient has been given the value 1.11, assum-
ing that the source will be one of the higher energy emit-
ters. The other symbols are as for the spherical source
The AAPM recommendations 15
Figure 2.2 Intregral evaluated as the sum of the dose
contributions from many small contiguous line source elements.
expression (equation 2.7). The angle convention in the
above equation has been changed from the original
BIR/IPSM publication so as to be consistent with the
AAPM formalism, which will be described later in this
chapter.
The BIR/IPSM approach represents an improvement
over the original Sievert Integral in as far as there is now
an allowance for self-absorption in the source material,
and in that water attenuation and scattering are
included, but there remains the problem of choosing
appropriate values for the filtration coefficients. The
BIR/IPSM report recommends the use of the linear
absorption coefficients, as opposed to the linear attenu-
ation coefficients, for the mean photon energy of the
radionuclide concerned. For the higher energy emitters
with stainless-steel encapsulation, this will be a good
approximation, but will be less good when there is a low
energy component and when significant thicknesses of
high-density, high atomic number materials are
involved. For iridium-192 sources, for example, there
will be moderately large errors in local dose calculations
at points close to the axis where the oblique filtration
thicknesses in the source material itself are relatively
large [36]. However, this is of academic interest only and
will not significantly affect the calculation of treatment
times for clinical applications.
2.4 THE AAPM RECOMMENDATIONS
2.4.1 Low energy emitters and the
general AAPM formalism
As indicated in the previous section, the BIR/IPSM
approach is not satisfactory with low energy emitters,
and indeed is starting to be suspect with iridium-192. In
North America, most interstitial brachytherapy is done
using seeds of either iridium-192 or the very low energy
emitter iodine-125. Two other low energy emitters,
palladium-103 and ytterbium-169, have also been
16 Source specification and dosimetry

metry, at 1 cm from the center of a unit air kerma rate

source of that type. Thus:

It is an absolute quantity which includes considera-

tion of the source geometry, the spatial distribution of
the active material within the source, self-absorption of
the radiation and scattering within the source material,
attenuation and scattering within the encapsulation
material, and attenuation and scattering within the water
medium. As the quantity is inversely proportional to the
air kerma strength, any future systematic change in the
Figure 2.3 The geometry pertaining to the formalism
air kerma strength specification for a particular source
recommended by the MPM Radiation Therapy Task Group.
type, such as may arise from a change in calibration tech-
nique, must be accompanied by an equal and opposite
investigated for brachytherapy applications (see, for change in the value of the dose rate constant. The other
example, Meigooni et al. [37], or Chiu-Tsao and terms in the formalism are all relative quantities and
Anderson [38] for palladium, and Perera et al. [39] or normalize to unity at r=l cm and 0=71/2.
MacPherson and Battista [40] for ytterbium). The for-
malism recommended by the AAPM [23] attempts to
solve the problem by incorporating 'a direct use of mea-
sured or measurable dose distributions produced by a
2.4.3 The geometry factor, G(r,q)
source in a water equivalent medium.' However, the dif-
The geometry factor is included in the formalism to
ficulties associated with measuring low dose rates, in
enhance the accuracy of interpolation between tabulated
very high dose gradients, and with finite-sized detectors
discrete values of both the radial dose function and the
which may or may not be energy dependent, should not
anisotropy function in regions of very high dose gradi-
be underestimated, and anyone attempting to imple-
ent. Its purpose is to remove the effects of the inverse
ment this protocol should only use data that have been
square law on the dose distribution, and its use is per-
validated and approved by the appropriate AAPM task
haps most easily understood when considering the case
group. In practice, it would appear that much reliance is
of a small, spherical source with isotropic emission (i.e.,
being placed on Monte Carlo calculations. A critical
when F(r,q) is unity for all values of r and 9). In such a
review of published work on Monte Carlo calculations
case, the geometry factor takes the value of 1/r2 for all
and dose distribution measurements for those
angles, leaving the radial dose function, g(r), as a very
brachytherapy sources commonly used in interstitial
slowly varying function of radial distance describing
treatments in North America has been included with the
only the net effect on the dose rate of attenuation and
published AAPM recommendations [23]. The geometry
scattering in water.
for the AAPM formalism is shown in Figure 2.3.
For a line source it takes the value of the Sievert
In addition to the source specification quantity, air
Integral for zero filter thickness, thus:
kerma strength, symbol Sk, the general formalism intro-
duces several other new quantities. These are the dose
rate constant, A; the geometry factor, G(r,q); the radial
dose function, g(r); and the anisotropy function, -F(r,q).
For cylindrically symmetric sources, the expression for
calculating the dose rate by this formalism, is: 2.4.4 The radial dose function, g(r)

The radial dose function describes the relative variations

The symbol dD(r,q)water/dt, for dose rate to water in water
at radial distance r and angle q, has been retained so as to
maintain consistency with the previous notation in this
chapter.
2.4.2 The dose-rate constant, A
The dose-rate constant for a particular source type is the
dose rate to water in water, in the radial plane of sym-
in the dose to water in water along the transverse axis of
the source (i.e., in the radial plane of symmetry only). It
excludes the effect of inverse square fall off, but includes
the net effect of absorption and scattering in the
medium and, for points close to the line source, any
effects of oblique filtration in both the source and the
source encapsulation materials. It may be defined math-
ematically as:
g(r) = [dD(r,p/2) water /dfG(r = l,p/2)]/[dD(r =l,p/2)water/dtG(r,p/2)] (2.12)

2.4.5 The anisotropy function, F(r,jq)
The two-dimensional anisotropy function describes the
relative variations in dose at points away from the trans-
verse axis of the source. It may be defined mathemati-
cally as:
It allows for the effects of oblique filtration in both the
source material and the sheathing material, the effects of
internal scattering within the source, and the effects of
attenuation and scattering in the surrounding water
medium.
2.4.6 Anisotropy factor, q an (r) t and
anisotropy constant, f)an
The complete formalism using the anisotropy function
describes the dose distribution around individual line
sources. In practical cases where there are a large number
of randomly orientated small seed sources, and where
the distances involved are generally greater than the
source dimensions, it may be more convenient to use a
point source approximation. The formalism may then be
simplified as follows:
where f an (r) is the so-called anisotropy factor. It gives the
averaged dose rate over all angles at radial distance r, rel-
ative to the dose rate at the same radial distance, r, on the
transverse axis. For the more common seed sources it is
possible to replace the anisotropy factor with a distance-
independent anisotropy constant without any significant
loss in accuracy. Typical values of the anisotropy con-
stant range between 0.9 and 0.98, depending on the
radionuclide concerned and details of the source con-
struction. It should be noted, therefore, that when using
this simplified formalism the calculated dose rates will
be typically 2-10% less than those on the transverse axis,
and this could result in significant error in techniques
where the source orientation is controlled.
2.5 SUMMARY
It is unfortunate that two authoritative, but apparently
contradictory, formalisms for brachytherapy dosimetry
are currently being recommended. It is particularly
unfortunate that there are two air kerma specification
quantities, which have different names and different unit
dimensions, but which, for practical purposes, are inter-
changeable. A recent European publication [41] uses the
American formalism in conjunction with a reference air
kerma rate specification, and perhaps this hybrid
References 17
approach will become more generally accepted in the
future. The BIR/IPSM formalism may be used with con-
fidence for steel-encapsulated cesium-137 sources, and
will give very acceptable results for clinical dosimetry
when using high dose-rate iridium-192 stepping sources,
and for iridium wires and iridium seeds in ribbons.
However, the Sievert Integral approach is certainly not
satisfactory with the lower energy emitters and a formal-
ism based on measured parameters has its attractions,
but the difficulties encountered in making precise and
accurate dose rate measurements in the immediate
vicinity of low activity sources are considerable.
Confidence in Monte Carlo calculations in brachyther-
apy suffered a setback when early attempts were sub-
jected to criticism and revision, but the more recent code
should be better and, when used in conjunction with
measurements, offers a reasonable method of determin-
ing the parameters for use in the AAPM formalism.
REFERENCES
1. Sievert, R. (1921) Die Intensitatsverteilung der primaren
Gammastrahlung in der Nahe medizinischer
Radiumpraparate. Acta Radial., 1,89-128.
2. Shalek, R.J. and Stovall, M. (1990) Brachytherapy
dosimetry. In The Dosimetry of Ionizing Radiations, Vol. Ill,
ed. K.R. Kase, B.E. Bjarngard and F.H. Attix. San Diego,
Academic Press.
3. Williamson, J.F., Morin, R.L and Khan, F.M. (1983) Monte
Carlo evaluation of Sievert Integral for brachytherapy
dosimetry. Phys. Med. Biol., 28,1021-32.
4. Paterson, R. and Parker, H.M. (1938) A dosage system for
interstitial radium therapy. Br.J. Radiol., 1,252-340.
5. Whyte, G.N. (1955) Attenuation of radium gamma
radiation in cylindrical geometry. Br.J. Radiol., 28,635-6.
6. Paterson, R. and Parker, H.M. (1934) A dosage system for
gamma ray therapy. Br.J. Radiol., 7, 592-632.
7. Tod, M.C. and Meredith, W.J. (1938) A dosage system for
use in the treatment of cancer of the uterine cervix. Br. J.
Radiol.,11,809-24.
8. Tod, M.C. and Meredith, W.J. (1953) Treatment of cancer of
the cervix uteri - a revised Manchester method. Br. J.
Radiol., 26,252-7.
9. Meredith, W.J. (ed.) (1967) Radium Dosage: the Manchester
System, 2nd edn. Edinburgh, Livingstone.
10. Quimby, E.H. (1932) The grouping of radium tubes and
packs to produce the desired distribution of radiation.
Am.J. Roentgenol. Radium Ther., 27,18-38.
11. Quimby, E.H. (1935) Physical factors in interstitial radium
therapy. Am.J. Roentgenol. Radium Ther., 33, 306-16.
12. Quimby, E.H. (1947) Radium dosage in radium therapy.
Am.J. Roentgenol. Radium Ther., 57,622-7.
13. Cowell, MAC. (1937) Research into time factors in
radiotherapy. 14th Annual Report of the British Empire
Cancer Campaign. London, British Empire Cancer
Campaign, 97-103.
18 Source specification and dosimetry
14. Paterson, R. (1948) The Treatment of Malignant Disease by
Radium and X-rays. London, Edward Arnold.
15. ICRU (1980) ICRU Report 33. Radiation Quantities and
Units. Washington, DC, International Commission on
Radiation Units and Measurements.
16. ICRU (1971) ICRU Report 19. Radiation Quantities and
Units. Washington, DC, International Commission on
Radiation Units and Measurements.
17. ICRU (1962) ICRU Report 10c. Radioactivity. Washington,
DC, International Commission on Radiation Units and
Measurements.
18. Jayaraman, S., Lanzl, LH. and Agarawal, S.K. (1983) An
overview of errors in line source dosimetry for gamma-ray
brachytherapy. Med. Phys., 10,871-975.
19. Wambersie, A., Prignot, A. and Gueulette, J. (1973) A
propos du remplacement du radium par le caesium-137
en Curietherapie. y. Radiol. d'Electrol. Med. Nud., 54,
261-70.
20. NCRP (1974) Report No. 41. Specification of Gamma Ray
Brachytherapy Sources. Washington, DC, National Council
on Radiation Protection and Measurements.
21. CFM Rl (1983) Recommendations pour la Determination des
Doses Absorbees en Curietherapie. Rapport du Comite
Francais'Mesuredes Rayonnements lonisants' No. 1.
Paris, Bureau National de Metrologie.
22. AAPM (1987) Specification of Brachytherapy Source
Strength. Report 21. Task Group 32 of the American
Association of Physicists in Medicine. New York, American
Institute of Physics.
23. Nath, R., Anderson, LL, Luxton, G. et al. (1995) Dosimetry
of interstitial brachytherapy sources: recommendations of
the AAPM Radiation Therapy Committee Task Group No.
43. Med. Phys., 22,209-34.
24. BCRU (1984) Specification of brachytherapy source.
Memorandum from the British Committee on Radiation
Units and Measurements. Br.J. Radiol., 57,941-2.
25. ICRU (1985) ICRU Report 38. Dose and Volume Specification
for Reporting Intracavitary Therapy in Gynecology.
Bethesda, Maryland, USA. International Commission on
Radiation Units and Measurements.
26. NCORD (1991) Recommendations for Dosimetry and
Quality Control of Radioactive Sources used in
Brachytherapy. Amsterdam, Netherlands Commission on
Radiation Dosimetry.
27. Bl R/l PSM (1993) Recommendations for Brachytherapy
Dosimetry. Report of a Joint Working Party of the British
Institute of Radiology and the Institute of Physical
Sciences in Medicine. London, British Institute of
Radiology.
28. Moretti, C.J. (1992) Changes in the National Physical
Laboratory standard for X-ray exposure and air kerma.
Phys. Med. Biol., 37,1181-3.
29. Godden, T.J. (1986) Physical Aspects of Brachytherapy.
Bristol, Adam-Hilger. Philadelphia.
30. Dutreix, A., Marinello, G. and Wambersie, A. (1982)
Dosimetrieen Curietherapie. Paris, Masson.
31. HubbellJ.H. (1982) Photon mass energy absorption
coefficients from 1 keV to 20 MeV. Int.J. Appl. Radial Isot.,
33,1269-90.
32. Meisberger, LL, Keller, K.J. and Shalek, R.J. (1968) The
effective attenuation in water of the gamma rays of gold-
198, iridium-192, caesium-137, radium-226 and cobalt-
60. Radiology, 90, 953-7.
33. Webb, S. and Fox, R.A. (1979) The dose in water
surrounding point isotropicgamma emitters. Br.J.
Radiol., 52,482-4.
34. Sakelliou, L, Sakellariou, K., Sarigiannis, K. et al. (1992)
Dose rate distributions around Co-60, Cs-137, Au-198,
Ir-192, Am-241,1-125 (models 6702 and 6711)
brachytherapy sources and the nuclide Tc-99m. Phys. Med.
Biol., 37,1859-72.
35. Klevenhagen, S.C. (1993) Oral presentation at the British
Institute of Radiology, London.
36. Williamson, J.F. (1996) The Sievert Integral revisited:
evaluation and extension to 1251,169Yb, and 192lr
brachytherapy sources. Int.J. Radial Oncol. Biol. Phys.,
36,1239-50.
37. Meigooni, A.S., Sabnis, S. and Nath, R. (1990) Dosimetry of
103
Pd brachytherapy sources for permanent implant.
Endocuriether. Hypertherm. Oncol., 6,107-17.
38. Chiu-Tsao, S.T. and Anderson, LL (1991)
Thermoluminescent dosimetry for 103Pd (model 200) in a
solid water phantom. Med. Phys., 18,449-52.
39. Perera, H., Williamson, J.F., Li, Z., Mishra, V. and Meigooni,
A.S. (1994) Dosimetric characteristics, air kerma strength
calibration and verification of Monte Carlo simulation for
a newytterbium-169 brachytherapy source. Int.J. Radial
Oncol. Biol. Phys., 28,953-70.
40. MacPherson, M.S. and Battista, J.J. (1995) Dose
distribution and dose rate constant for new ytterbium-169
brachytherapy seeds. Med. Phys., 22,89-96.
41. Permattei, A., Azario, L, Rossi, G. etal. (1995) Dosimetry of
169
Yb seed model X1267. Phys. Med. Biol., 40, 1317-30.

Calibration of sources
COLIN H.JONES
3.1 INTRODUCTION
Although commercial suppliers of brachytherapy
sources provide a measure of source strength, it is unwise
to rely solely on this value for patient dose calculations.
Manufacturers usually specify source strengths within a
broad range of activity. Most departments planning to
provide brachytherapy should have the ability to verify
source strengths independently and to improve the over-
all precision of the measurement.
The radiation characteristics of an encapsulated
source are strongly dependent upon the chemical com-
position of the radionuclide, the inert filler material,
their distribution within the source, and the details of
the source encapsulation. Also in relation to source cali-
bration, the presence of radioactive impurities may
require a storage period after initial production to allow
for the decay of short half-life isotopes. Details of the
construction of sources are given in Chapter 1. Such
information is important, because attenuation in the
source capsule may significantly alter the dose distribu-
tion around the source and affect the dose calibration in
a variety of ways, especially when measurements are
made with re-entrant ionization chambers. It is possible
for two sources of different construction to have the
same source strengths but significantly different radia-
tion distributions close to the sources. The possibility
that such differences might influence calibration mea-
surements must be taken into account.
Source specification is considered in Chapter 2. In
summary, the source strength is specified as the air
kerma rate, in air, at a reference distance of 1 m, cor-
rected for attenuation and scatter in air. The unit to use
for low dose-rate brachytherapy sources is (mGy tr1 and
3
mGys-1for high dose-rate (HDR) applications. The spec-
ification quantity is called the reference air kerma rate
(RAKR), which is the name used by the ICRU [1].
3.2 REFERENCE STANDARDS AND
TRACEABILITY
The calibration of sources is traceable to national or
international standards at various levels [2]. Direct
traceability is established when a source or calibrator has
been calibrated at a national standards laboratory or an
accredited dosimetry calibration laboratory.
Secondary traceability is established when the source
is calibrated in comparison with a source of the same
design and comparable strength which has direct trace-
ability or when the source is calibrated using an instru-
ment with direct traceability.
Secondary traceability by statistical inference is a term
that is used for multiple sources of the same activity
from which a suitable random sample has been cali-
brated with secondary traceability.
Remote traceability occurs if the user relies upon the
manufacturer's calibration as the only standard, which
may, or may not, be traceable to a national or interna-
tional standard.
Ideally, brachytherapy sources used clinically should
have calibrations with direct or secondary traceability to
national standards.
In the UK, the traceability routes for the calibration of
brachytherapy sources supplied by Nycomed Amersham
plc have been summarized by Rossiter [3]. The first line
of traceability for this supplier's cobalt-60 sources is in
terms of the quantity 'activity.' Reference sources were
20 Calibration of sources

compared with a base standard of cobalt-60 whose activ-
ity was measured by absolute counting at the National
Physical Laboratory (NPL). The air kerma rate of the
base standard was calculated from the measured activity
and associated energy fluence, making allowances for
gamma ray absorption in the capsule, in the material
itself, and in air. Radium-226 sources have been treated
similarly, the activity being determined by comparison
with the British National Radium Standard. Two addi-
tional methods have been used to confirm traceability to
national standards of source air kerma rates. The first,
used for both cobalt-60 and cesium-137, involved iono-
metric comparisons with a standard radium-226 source,
and the second the measurement of the exposure rate of
sources in a scatter-free area at NPL by a large volume
chamber (200 mm diameter) directly calibrated against
the national primary standard [4]. This work was
repeated by Rossiter et al. [5] for cobalt-60, cesium-137,
and radium-226, and extended to include iridium-192
wire sources. The results, shown in Tables 3.1 and 3.2,
indicate good agreement between NPL and Amersham
source output measurements and provide assurance on
source air kerma rate figures provided by this major
source supplier and which are based on a traceability
route to standards of activity.
In the USA, the National Institute of Standards and
Technology (NIST) maintains air kerma strength stan-
dards for sealed sources of iodine-125, iridium-192, and
cesium-137. It should be noted, however, that the
strength specification of sealed sources is in terms of air
kerma strength (Sk), which is defined as the product of
air kerma rate in free space, K(d), measured along the
transverse bisector of the source, and the square of the
measurement distance d:
The distance d must be large enough that both source
and detector may be treated as mathematical points.
Such standardization measurements are performed in
air using air-attenuation corrections if needed. Sk has
units of mGy m2 h-1 and these units are denoted by the

Table 3.1 Comparison of air kerma rate values in vacuo at1 m distance. (Rossiter, Williams, and Bass, 1991 [5].j

137
Cs(1802MC) 18.7.89 78.70 77.79 1.012
60
Co(HR117) 18.7.89 88.71 87.77a 1.011
88.1 7b 1.006
226Ra (S5) 18.7.89 36.56 36.52 1.001
192
lr(A49945) 13.3.90 29.44 29.25 1.006
192
lr(A49946) 13.3.90 29.39 29.22 1.006

' Comparison with60Coreference source.

b
Comparison with 226Ra reference source.
NPL= National Physical Laboratory.

Table 3.2 Air kerma rate measurement uncertainties. (Rossiter, Williams and Bass, 1991 [5].)

60
Co, 137Cs, 226Ra Random Determination of secondary standard calibration factor 0.4
Source measurements 0.4
Non-random Determination of secondary standard calibration factor (all energies) 1.2
Measurement of pressure 0.1
Measurement of temperature 0.2
Measurement of distance 0.1
Air attenuation correction 0.2
Correction for finite chamber size 0.2
2.5(60Co)
Overalla 1.4 1.8(137Cs)
0.9 (226Ra)
192| r Uncertainties as above 1.4
Non-random Weighting procedure for secondary standard factor 0.4
Overalla 1.5
aQuadrature sum.
NPL= National Physical Laboratory.

symbol U. A set of equations has been developed for
unambiguously converting source strength estimates
and renormalizing published dose-rate tables, which
assume traditional quantities and units, into forms con-
sistent with air kerma strength [6]. These authors list the
factors to convert source strength of a selection of
nuclides from apparent millicuries (mCi) to air kerma
strength. The factors are independent of source geome-
try, but depend on the nominal exposure rate constant
value selected by the vendor. Conversion factors applic-
able to mass of radium or true activity depend upon
both source geometry and radionuclide identity. It
should be noted that because many of these conversion
factors depend upon vendor choices of physical con-
stants and exposure rate constants, users should review
source strength specification practices employed by the
vendor. This is a requirement even when an independent
calibration is made, because a comparison of the mea-
sured source strength with that provided by the vendor
is a useful and necessary quality assurance procedure.
Although an institution might accept the manufac-
turer's calibration, it is the responsibility of the institu-
tion to verify that the manufacturer's stated value is
correct. If the measured source strength disagrees with
the manufacturer's data by more than 5%, the source of
disagreement should be investigated and any unresolved
disparity should be reported to the manufacturer. In the
case of a batch of sources, a 3% tolerance is probably
more applicable, because individual sources may differ
from the mean by a greater amount. Discrepancies
greater than the accuracy limits specified by the manu-
facturer should always be explored further. For further
reading on this subject, the reader is referred to refer-
ence 7.
33 CALIBRATION METHODS
There are three principal methods of calibrating brachy-
therapy sources. The most frequently used method
employs a calibrated re-entrant ionization chamber. The
second method makes use of an ionization chamber to
measure the air kerma rate at a known distance from the
source. In the former method, calibration of the re-
entrant chamber is actually achieved by use of a radia-
tion source, the air kerma strength of which has been
previously measured in air. The third method uses a
solid phantom into which source(s) and ion chamber
can be introduced in a convenient and reproducible way.
In addition, experiments have been conducted on novel
dosimetry methods [8], but are not suitable for routine
calibrations at the present time.
Re-entrant chambers are preferred for the calibration
of conventional low-strength brachytherapy sources
[9,10], and ionization chambers measuring the air
kerma rate at a distance are preferred for HDR sources
Calibration methods 21
[11,12]. However, ionization chambers have been used
successfully for conventional dose-rate sources [13], and
re-entrant chambers can be used for HDR sources [14].
Baltas et al. [15] report on a comparison of different
calibration methods for HDR sources, and conclude that
satisfactory results can be obtained by both re-entrant
chambers and phantom methods.
3.3.1 Re-entrant ionization chambers
These instruments are characterized by a cylindrical well
and an ion collection volume, which surrounds the
source approximating at 4p measurement geometry. The
re-entrant (well-type) ionization chamber should
respond linearly throughout its measuring range; its
energy response must be known and care must be taken
to ensure that when measuring high activities there is no
drop in sensitivity. The response of the chamber will be
dependent upon the geometric configuration of the
source, its filtration, and encapsulation. The use of such
an instrument for intercomparison of sources requires
great care and it is advisable for potential users to ascer-
tain the characteristics of the chamber before embarking
on measurements. The report of AAPM Radiation
Therapy Committee Task Group 40 [2] describes the
physical characteristics of a suitable calibrator. It is rec-
ommended that the reproducibility of the calibrator
should be better than 2% and the signal-to-noise ratio
greater than 100:1. The response of the chamber is
dependent on the orientation of the source and its posi-
tion in the well [16], so it is essential to devise a source
holder that will reproduce the source positioning. It is
also recommended that the scale factor and linearity of
each scale used on the electrometer be determined and
monitored. The collection efficiency should be better
than 99% for commercial well chambers using conven-
tional brachytherapy sources. The sensitivity of re-
entrant ionization chambers depends on the energy of
the photons, thus a calibrated source of one radionuclide
cannot be used to determine the source strength of
another radionuclide. Similarly, because of dose
anisotropy about the source, the relative orientation of
the source axis is important for any calibrator. The
source should be moved through the active volume of
the chamber to verify and quantitate the extent of the
change in sensitivity with source position. Figure 3.1
illustrates a typical re-entrant chamber and Figure 3.2
shows the variation of sensitivity with source location in
the chamber well. The source-length dependence of the
chamber should also be investigated: this is best achieved
by determining the chamber response for wire sources of
different lengths. The source-length dependence may
also be a function of the radionuclide. Williamson et al.
[16] showed that a calibrated source of one encapsula-
tion may not be reliable for determining the strength of
a source of the same radionuclide but different encapsu-
22 Calibration of sources

Figure 3.1 Selectron Source Dosimetry System (SDS): PTW-Freiburg re-entrant (well-type) chamber with Perspex holders for LDR/MDR
Selectron sources and HDR microSelectron sources.

Figure 3.2 Relative response of SDS (PTW-Freiburg) chamber with iridium-192 source inserted at various depths.

lation. For example, two cesium-137 sources of equal
strength and of similar size but encapsulated in platinum
and stainless steel, respectively, might cause different
chamber responses. In practice, it is usual to use a posi-
tioning device to assure reproducible positioning of the
source close to the longitudinal chamber axis and where
the chamber sensitivity is high but least dependent upon
geometrical positioning of the source.
AAPM Report 13 [17] describes the use of re-entrant
(well-type) ionization chambers for measuring different
types of brachytherapy sources.
Long-lived sources (cesium-137, cobalt-60 etc.)
1. For each radionuclide (and encapsulation) to be
measured, one source should be identified as the
standard source. The source should be marked or
otherwise identified so that it can be recognized
at a later date. It is appropriate to ensure that the
source selected is typical of other sources in the
batch.
2. The standard source should be sent to an
appropriate calibration laboratory for calibration.
3. The standard may be used to calibrate all other
similar sources by sequential placement of the
standard source and the sources to be calibrated
in the same geometry within the chamber and

comparing readings. By correcting for decay of
the source, it is also possible to use the standard
source to check for long-term chamber stability
and chamber malfunction.
Short-lived sources (iridium-192, gold-198 etc.)
1. Identify a long-lived source as the reference
source. This source may be a standard source for
another radionuclide.
2. Obtain a standard source of the appropriate
short-lived isotope and compare this with the
reference source. This intercomparison will be
used to establish a baseline comparison of the
relative sensitivity of the system to the two
sources.
3. Submit the standard source to a suitable
calibration laboratory for calibration.
4. There are two methods that can be used to
transfer the calibration:
(a) The chamber is calibrated with the short-
lived standard source, and the reference
source is used to check that the chamber is
functioning properly. This requires
temperature and pressure corrections to be
made if unpressurized ambient air chambers
are used.
(b) A correction factor defined as the ratio of
two measurements of chamber response
using the standard source is calculated. The
correction factor relates the response of the
chamber to the short-lived standard source
in terms of the response to the reference
source.
5. Whichever method is used, the reference source is
measured every time the chamber is used to
calibrate the short-lived sources.
6. After decay of the standard source, the reference
source is used for subsequent calibrations.
Ideally, every radioactive source that is to be used in a
patient should be calibrated. In practice, this is not
always possible. For short half-life sources such as
iodine-125 and iridium-192 seeds, traceability by statis-
tical inference may be appropriate, depending upon the
number of ribbons or seeds in the designated strength
groupings under consideration. Kutcher et al. [2] recom-
mend that if the grouping contains only a few seeds or
ribbons, all seeds should be calibrated. For groupings
with a large number of loose seeds, it is recommended
that a random sample containing at least 10% of the
seeds be calibrated. For a large number of seeds in rib-
bons, a minimum of 10% or two ribbons (whichever is
larger) should be calibrated. For sources purchased in a
sterile configuration, the report recommends purchasing
and calibrating a single (non-sterile) seed for each desig-
nated strength grouping.
The calibration of iodine-125 seeds is traceable to a
calibration at the NIST. The dosimetry is more complex
Calibration methods 23
than other brachytherapy sources as the nuclide decays
principally by electron capture emitting characteristic
X-rays at energies from 27.2 to 31.8 keV and 35.5 keV
gamma rays. The construction of the source affects the
mean energy of the emitted radiation and any calibra-
tion must be made with a calibrated source of the same
design as the sources being investigated.
All long half-life sources should be calibrated.
The use of re-entrant chambers is illustrated further
in the following sections, where specific calibration pro-
cedures are described.
3.3.2 In-air' method using ionization
chambers
The 'in-air' measurement technique is the primary
method of determining the strength of a brachytherapy
source. Unfortunately, the method has several inherent
problems and, consequently, with the exception of the
calibration of strong sources (used for HDR afterload-
ing), its use is confined largely to specially equipped
laboratories. For a low strength source, the air kerma
rate at a large distance from the source will be low and
difficult to measure; scattering from surroundings is
also a problem, for which allowance must be made.
Measurements can be made closer to the source, but as
the measurement distance is decreased, the significance
of the physical dimensions of both the source and the
ion chamber increase. Positioning uncertainty also
becomes a problem for shorter distances. In the absence
of a calibrated re-entrant chamber, the 'in-air' ion
chamber method is a convenient means of checking the
relative strengths of individual sources by comparing
the signal strength for the unknown source against that
for a reference source of known air kerma strength
[13]. The method is less dependent upon the effects of
differences in encapsulation than for re-entrant cham-
ber measurements.
To measure low air kerma rates requires large volume
chambers to achieve a signal-to-noise ratio better than
100:1 and a wide range of chamber types have been
employed. One of the corrections that has to be applied
to the electrometer reading is to allow for the dose gra-
dient across the chamber response, which causes the
chamber response to differ from that of a point detector.
This effect depends upon the relative position of the
chamber with respect to the source and the physical
dimensions of the chamber. It has been analyzed by Tolli
[18], who provides a means of calculating a factor to cor-
rect for the gradient effect. This factor is referred to in
more detail when the calibration of HDR sources is
described.
The ideal jig for reproducible 'in-air' calibrations
should provide mechanical rigidity without contributing
scatter to the chamber. Mechanical devices are suitable
for shorter distances of 100-200 mm, but for measure-
24 Calibration of sources
ments made at much longer distances, some form of
optical alignment might be more appropriate. It is some-
times possible to make use of radiotherapy machine laser
alignment devices for this purpose. Corrections for
room-scattered radiation can be made by making mea-
surements at various distances. Room scatter, which can
be assumed to be constant over the distances measured,
can be determined from examination of the data, assum-
ing that the dose data set after correction for room scat-
ter should comply with the inverse-square-law.
The ion chamber and electrometer used for calibra-
tion purposes should have a traceable calibration for
radiation of the same energy that is being investigated
and preferably be relatively insensitive to changes in
photon energy over a wide range.
333 Source calibrations in solid phantoms
The third method of calibrating sources employs a solid
acrylic phantom, which contains a centrally placed ion
chamber with two or more cavities for source catheters
positioned radially around the chamber. Source mea-
surements in a solid phantom are more reproducible and
straightforward than 'in-air' measurements. In practice,
however, for reference air kerma rate measurements,
allowance has to be made for phantom attenuation and
scatter. Furthermore, at the point of measurement, it is
necessary to take into account the replacement of the
phantom material by the ionization chamber. These fac-
tors, which are characteristic of the measurement set-up,
are difficult to determine with precision, so the overall
accuracy of the measurement is reduced. Even so, once a
solid phantom has been calibrated satisfactorily, the high
reproducibility of the technique and its convenience
make it very useful for routine quality assurance-type
source measurements.
Some phantoms are designed to be filled with water:
this simplifies attenuation corrections, but the need for
scatter and chamber displacement factors still applies.
3.4 CALIBRATION OF SOURCES USED IN
REMOTE AFTERLOADING SYSTEMS
The following source types are considered:
Low dose-rate (LDR) sources in the form of wires or
ribbons (such as those used in the Nucletron
microSelectron).
Low dose-rate preloaded cesium-137 source trains
(similar to those used in the CIS Curietron machine).
Multiple low dose-rate cesium-137 sources of similar
strengths (such as those used in the LDR/MDR
Nucletron Selectron).
Multiple high dose-rate cobalt-60 sources of similar
source strengths (such as those used in the HDR
Nucletron Selectron).
Single HDR sources (similar to those used in the HDR
Nucletron microSelectron, the Gammamed HDR
system, the CIS Curietron 192 HDR, and the Varian
Varisource HDR remote afterloader).
Pulse dose-rate (PDR) sources.
It is good working practice when calibrating sources
used in remote after-loading brachytherapy equipment
for a written procedure to be drawn up and followed.
Measurements and observations must be fully docu-
mented. Whenever possible, the definitive calibration
should be derived from two independent sets of mea-
surements made by two physicists experienced in radio-
therapy, using different dose instruments. The
calibration measurement should be compared with the
supplier's certificate of calibration. When necessary, data
from the certificate of calibration should be re-calculated
using the same units and conversion factors as those
employed in the definitive calibration. Any difference
between the corrected data and the definitive calibration
must be reconciled. Using the clinical data calculated
from these measurements, the response of a suitable
dosimeter must be calculated for a different treatment
time from that used in the calibration. In the case of
equipment into which a value of source strength can be
programmed, it is recommended that the calculated
treatment time should be based on the displayed source
strength. The definitive calibration is confirmed if the
predicted reading is obtained within the limits of exper-
imental uncertainty. In some situations an allowance will
have to be made for any dose that is delivered during
transit of the source.
In practice, to comply with the above recommenda-
tions it is useful to have sufficient instrumentation to
facilitate measurements with a calibrated re-entrant ion-
ization chamber and also either an 'in-air' or phantom-
type calibration measurement.
It is appropriate to note that, despite international
agreement that source strength should be specified in
terms of the reference air kerma rate, it is recognized that
some commercially supplied computer software requires
source information in terms of activity. The use of such
software requires great care in converting an RAKR spec-
ification to an effective content specification. An equiva-
lent activity may be determined from the RAKR by using
the following expression:
where Aeq is the equivalent activity, and 10-6 is the mGy to
Gy conversion factor.
Ft is a constant and equal to 1/3600,1/60 or 1 depend-
ing on whether the RAKR is in mGy h-1, mGy min-1 or
mGy s-1, respectively; dr is the distance at which the RAKR
is defined and is unity; and Gg is an appropriate air kerma
rate constant in m2 GyBq-1s-l.

3.4.1 Low dose-rate sources in the form of
wires or ribbons
Remote afterloaders that are designed to treat intersti-
tially with wire sources or catheters loaded with radioac-
tive ribbons are equipped with up to 20 or so channels.
These may be connected to flexible or rigid implants
using iridium-192 wires, or ribbons of cesium-137
microseeds. A re-entrant-type chamber can be used to
determine the activity of the individual seeds. In the case
of the wire sources, it might be necessary to measure the
source strength per unit length along the wire. Special
scanning devices have been developed for this purpose;
generally, these devices are collimated detectors that can
be used to scan the length of the wire, which may be up
to 135 mm. Usually, for calibration, a re-entrant ioniza-
tion chamber is the instrument of choice. This is best
achieved by using wire that has been measured at a
national standards laboratory. The measurement of this
wire provides a baseline value, which can be compared
against a source with a longer half-life; this reference
source can be used to monitor chamber response over
the long time periods in-between the definitive source
calibrations. With long wire sources, it is particularly
important to use an appropriate source holder in order
to maintain the source centrally in the chamber well: off-
axis displacement can increase the chamber signal by up
to 20%. As part of the calibration procedure, a reference
curve should be constructed that shows the dependence
of the chamber output upon the length of the source.
This may be achieved by using a 10 mm piece of wire to
measure the response for different positions of wire
inside a thin, straight tube which is positioned precisely
along the axis of the well. The characteristics of well-type
chambers vary according to commercial design, but a
typical response with a 10 mm wire source should be
within about 2% over a 100 mm length [19]. Calibration
measurements should be made on all sources after wires
have been cut to length and sealed in catheters.
Steggerda and Mijnheer [20] make reference to the use
of a solid phantom in which a 0.6 cm3 Farmer-type ion-
ization chamber is used for dose rate measurements. The
Perspex phantom (see section 3.4.3) is 20 cm in diame-
ter and 15 cm high. Three stainless-steel afterloading
catheters are positioned in the phantom at a distance of
5.0 cm from the axis of the cylindrical phantom and at
120 angles. Although the phantom was designed origi-
nally for measuring Selectron sources, it can also be used
for calibrating iridium-192 line sources and cesium-137
microseed trains.
3.4.2 Low dose-rate preloaded cesium-137
source trains
A preloaded source train consists of one or more
cesium-137 sources in the form of small source capsules
Calibration of sources used in remote afterloading systems 25
separated by inactive spacers (usually small ball bear-
ings), all of which are contained in a flexible, stainless-
steel spring catheter. Before being used clinically, the
location of individual capsules in the source train should
be ascertained. One method of achieving this is by
autoradiography and by densitometric scanning of the
autoradiograph to locate the center of each source. The
calibration of individual source capsules is not easily
accomplished, especially when sources are very close to
each other. It is important for potential users of pre-
loaded source trains to liaise fully with manufacturers
before source trains are made up. The manufacturer
should be able to guarantee that the strength of each
source loaded into the source train does not differ by
more than 5% from that stated. It is useful to purchase
one or more source capsules for reference purposes,
which can be used to study the effect of the steel spring
and also to examine the response of the re-entrant cali-
bration chamber when the source is moved along its lon-
gitudinal axis. Individual sources encapsulated within a
flexible spring can be measured satisfactorily against a
reference source either in air using an ion chamber or in
a re-entrant chamber. Source trains with multiple
sources are more difficult to measure with high preci-
sion. The manufacturer is better placed to obtain infor-
mation about the strength of individual sources prior to
fabrication of the source trains. The user can check the
relative distribution of activity by film dosimetry, ther-
moluminescent dosimetry (TLD), and by judicious use
of a re-entrant chamber, but overall it is better to obtain
as much information as possible about the strength of
individual sources prior to loading of the source trains.
The location and relative strength of individual
sources in a source train can also be recorded by means
of a device employing a highly collimated detector.
3.43 Multiple low dose-rate sources of
similar strengths
To calibrate cesium-137 sources such as those used in the
Nucletron LDR/MDR Selectron machine, it is necessary
to measure the strength of each source. This is best
achieved with a suitably calibrated re-entrant ionization
chamber. The sources are cesium-137 glass beads encap-
sulated in a 2.5 mm diameter stainless-steel pellet; a
machine can take up to 48 pellets. The pellets are not
readily identifiable and are used effectively in a random
manner. Ideally, all pellets would have the same strength,
but in practice this is not the case. Figure 3.3 shows two
typical sets of source strength measurements. A re-
entrant chamber is usually calibrated in terms of the
source strength (mGy h-1 at 1 m), which produces a cur-
rent of a n A. When a chamber has not been suitably cal-
ibrated, an alternative method of determining source
strength must be used.
26 Calibration of sources
Figure 3.3 Source-strength frequency distribution for two
batches of cesium-137 LDR/MDR Selectron sources.
Aukett [21] has described a method in which a Farmer
ionization chamber is used for the direct measurement
of the air kerma rate in air for small, spherical cesium-
137 sources at distances of 35-70 mm. A 2 mm Perspex
build-up cap was used on the chamber, which was sup-
ported centrally, in air, equidistant from three stainless-
steel applicator tubes, each carrying six sources.
Geometry correction factors were calculated for each
group of sources. The resultant measurement was found
to differ from expected values by 4.4%.
An alternative method has been described by
Meertens [22]. The method is based on the use of a
phantom consisting of three parallel Perspex catheters
with a wall thickness of 0.11 cm, fixed together in a
cylindrical geometry at 120 angles. A Perspex support
for a 0.6 cm3 graphite-walled Farmer-type NE 2505/3A
ionization chamber was mounted between the three
catheters parallel to their axes; the distance between each
of the catheters and the chamber centre was 5 cm. The
catheters and the ionization chamber were placed in a 36
x 32 x 20 cm (full scatter) water phantom. The tech-
nique was designed to position sources in all three
catheters simultaneously in such a configuration that the
dose gradients through the chamber volume were mini-
mized. By using multiple sources (ten sources in each
catheter), the dose rate was high enough to measure sat-
isfactorily and, by eliminating dose gradients, the need to
apply a correction factor for the finite size of the cham-
ber is overcome. To obtain a uniform dose rate at the
point of measurement, the ten sources in each catheter
were distributed in two batches (2 x 5), separated by
50 mm above and below the level of the chamber center.
The procedure designed to measure the mean source
strength of a set of sources is as follows.
1. The air kerma rate in water at a point about 5.5 cm
distance from a number of sources is measured.
2. The air kerma rate in water at the same point for the
same set of sources is calculated for a reference air
kerma rate of 100 (mGy h-1 at 1 m in free air for each
source.
3. From the ratio of the measured and calculated air
kerma rates in water, the mean actual reference air
kerma rate of the set of sources can be determined.
Meertens [22] gives the following details about the air
kerma measurements and calculations.
KERMA RATE MEASUREMENTS IN WATER
The air kerma rate in water, km, was determined from
readings obtained with the ionization chamber and an
electrometer using the following formula [23]:
Where M is the corrected instrument reading:
M= MuncorPtPpPhum
Muncor is the uncorrected instrument reading; Pt> Pp, Phum
are the air temperature, pressure, and humidity correc-
tion factors respectively; Pion is the ion recombination
correction factor; and Ppol is the correction factor for
polarity effects. The last three correction factors were
assumed to be unity.
Nk (Jkg-1) is the air kerma factor. The product of the
correction factors pki (0.989) is given by:
where katt (0.990) is a correction for attenuation in the
wall and build-up cap of the ionization chamber; km
(0.999) is a correction for the difference in composition
between the wall plus build-up cap and air; kst (1.000) is
a correction for the stem effect for the employed field
size; and kce (1.000) is a correction for the effect of the
central electrode on the response of the chamber during
calibration.
The product of the correction factors ppi (0.972) to be
applied to the measurement in water for cesium-137
photons is given by:
where pwall (1.002) corrects for the difference in composi-
tion between the ionization chamber wall and water; pd
(0.970) is the displacement direction factor that corrects
for the displacement of the effective center of the ioniza-
tion chamber and is a function of the photon energy, the
source to chamber distance, and the size of the ioniza-
tion chamber. This value 0.970 for the 0.6 cm3 (0.3 cm
radius) Farmer chamber was estimated from prelimi-
nary results of experiments with ionization chambers
with radii ranging from 0.1 to 0.8 cm, Pce (1.000) corrects
for the effect of the central electrode on the response of
the chamber during the measurements in the water
phantom. The integration time, t, applied for the ioniza-
tion current measurements was 0.033 h (120 s).
 Calibration of sources used in remote afterloading systems 27

KERMA RATE CALCULATIONS IN WATER
The contribution of one point source with a given refer-
ence air kerma rate, Ktefy in mGyh-1 at 1 m free air to the
calculated air kerma rate Kc, in cGylr1 in water at a dis-
tance, d, in cm from the point source was calculated
according to the following formula:
where S(d) is the absorption and scatter correction fac-
tor according to Meisberger et al. [24].
and A0 = 1.0091, B0 = -9.015 x 10-3 cnr-1, C0 = -3.459 x
10-4 cm-2, and D0 = -2.817 x 10-5 cm-3.
Kc in the calibration point of the water phantom for
sources in the three catheters, each with a KKf value of
100 mGyhr1.
Meertens [22] also reports on the use of a Perspex cal-
ibration phantom smaller than the water phantom but of
a similar design. From experiments, it was determined
that the cylindrical Perspex phantom 20 cm diameter
and 15 cm high gave results 4% lower than those
obtained with the water phantom. The measurements in
water had a reproducibility of 0.3% (1 SD), with an
uncertainty that could not be evaluated by statistical
methods of about 1.2%.
Perspex phantoms similar to the one described ensure
good reproducibility of set-up and, once an appropriate
factor relating measurements made in Perspex to those
in water has been determined, the smaller solid phantom
can be used for routine calibration purposes.
The method has also been used by Jones [25] with a
different source configuration. Figures 3.4 and 3.5 show
the water phantom and the resultant distribution using
eight sets of five sources with a 40 mm separation
between each set of sources.
straight applicator and measure the air kerma rate with
the Farmer-type chamber at a distance of 500 mm. This
method has been described and used by Chenery et al
[26] and Messina et al. [27]. The chamber used should
have a calibration traceable to a national calibration lab-
oratory; it should be used with a build-up cap for cobalt-
60. For reproducible measurements, some form of
fixation device should be used to ensure that the appli-
cator and the ion chamber are parallel and held so that
the applicator is not displaced by transfer of the sources.
The applicator can be metal or plastic as long as it is
rigid. If both types are available, measurements can be
made to determine the attenuation effect of the metal
applicator. Both applicator and ionization chamber
should be at least 1 m from the floor, the walls, or any
other large scattering medium. Room scatter will be
characteristic of the local environment and an estimate
should be made of its magnitude. In most situations it is
likely to be between 3% and 4% for the source-chamber
geometry described. The principal error is likely to be
associated with the position of the sources inside the
applicator: they are not constrained to lie perfectly on
the axis of the applicator, but tend to zigzag, with dis-
placements of over 0.5 mm occurring 16% of the time
[26]. The positional errors, including those associated
with the measurement of the applicator-chamber sepa-
ration, produce an uncertainty in the measured dose rate

3.4.4 Multiple high dose-rate cobalt-60

sources of similar source strengths

The cobalt-60 sources used in the Nucletron remote

afterloading machine consist of 1.5 x 1.5 mm cylinders
encapsulated in titanium spheres 2.5 mm diameter;
there are 20 sources in each machine. The relative
strength of each source may be determined with a re-
entrant ionization chamber. If the chamber has not been
calibrated for these sources, a Farmer-type 0.6 cm3 ion
chamber can be used. A measurement device and source
configuration similar to that described in the preceding
section might be used, replacing the set of four sources
by a single source so that the chamber would be exposed Figure 3.4 Perspex/water calibration phantom with central
to eight sources simultaneously. cavity for Farmer chamber and four stainless-steel catheters
An alternative method is to use all 20 sources in a distributed radially at 50 mm.
28 Calibration of sources

Figure 3.5 IGE (Target) computer calculation of dose distribution of four straight Selectron catheters each loaded with 2x5
LDR/MDR Selectron pellets with 40 mm separation between each set of pellets (1.4 GBq per pellet). The calibration chamber is
positioned centrally in the region of low dose gradient. Units of distribution are cGyh-1; magnification factor (%) = WO.

of less than 1%. It should be noted that chamber leakage
should be measured, for which an appropriate correc-
tion might be made. This leakage should not be greater
that 0.1-0.2%.
3.4.5 Single high dose-rate sources
High dose-rate remote afterloading devices, such as
those listed above (section 3.4), make use of an iridium-
192 source with an activity of up to 370 GBq.
The source is typically in the form of a small pellet
(0.5 mm diameter, 4 mm active length, with a 0.3 mm
stainless-steel wall), connected to a wire that pushes and
pulls it through a plastic catheter to guide it to the
desired location. The half-life of iridium-192 is 73.83
days so source replacement is relatively frequent. The
principal supplier of these sources is Mallinckrodt
Diagnostica in the Netherlands, which provides a cali-
bration certificate with each new source that states the
overall uncertainty in activity to be 5%. An indepen-
dent recalibration is required after installation of a
source before the machine is used to treat patients.
There are three methods of calibrating a single HDR
source: 'in-air' measurements with a calibrated ion
chamber positioned at a distance of 10-20 cm from the
source; measurements with a re-entrant ionization
chamber that has a calibration traceable to a national
standards laboratory; and measurements with an ion
chamber and a solid phantom (or water phantom).
IN-AIR'CALIBRATIONS
A Joint Working Party of the BIR and IPSM recom-
mended that iridium-192 HDR sources should be cali-
brated in air with a Farmer-type 0.6 cm3 ion chamber
held at a distance of 100 mm from the source [28], and
that the traceability route for such measurements should
be through the external-beam standard. The recom-
mended method has the advantage of being widely
applicable and experience suggests that the method pro-
duces very reproducible results. It also has the advantage
that the purchase of additional calibration instrumenta-
tion is not required. However, although the procedure is
straightforward, a number of interrelated factors have to
be taken into consideration. These include the effects of
ion chamber geometry, source-chamber distance, posi-
tioning reproducibility, dose gradient, signal strength,
and room scatter. Furthermore, because national calibra-
tion laboratories do not offer calibration of ionization
 Calibration of sources used in remote afterloading systems 29

chambers with the gamma ray spectrum of iridium-192,

some form of procedure must be employed to determine
an appropriate factor for the ion chamber used in the
measurement procedure. These matters have been con-
sidered comprehensively by Ezzell [29], Goetsch et al.
[12], Piermattei [30], Grimbergen and van Dijk [31],
and Biiermann et al. [32].
At a source-chamber distance of 100 mm, the correc-
tion required to allow for the fluence gradient across the
Farmer (0.6 cm3) ion chamber is 0.9% [18]. For shorter
distances, the positioning becomes more critical and a
larger factor will be required to correct for the finite
chamber size (Table 3.3). With a suitable measurement
jig, it is possible to restrict dose errors due to positional
uncertainties to less than 0.5%. Both source and detector
need to be mounted well above floor level and well away
from walls or other large structures so as to reduce the
effects of room scatter to negligible levels. Several devices
have been described in the literature, two of which are
shown in Figure 3.6. The ideal jig for reproducible 'in-
air' calibrations would provide mechanical rigidity with-
out contributing scatter to the chamber. In practice, a
small correction will be required to allow for room scat-
ter, including any scatter that might arise from the jig
itself. If it is assumed that the air kerma rate at the point
of measurement caused by room scatter does not depend
on the distance from the source, then:

where d = distance from the source to the point of mea-

surement; d0 = distance from the source to a reference
point; X = total exposure at the point of measurement;
X0 = primary exposure at the reference distance; and Xs
= room scatter exposure (assumed constant for all d).
Figure 3.6 Two 'in-air' calibration jigs: (a) Nucletron device,
The value for the room scatter correction factor at the
and (b) 'Royal Marsden Hospital device. Both jigs are shown with
distance d is then given by:
Farmer chamber without build-up cap.

Since X and d are measurable quantities and d0 is an

arbitrarily chosen distance, the values for X0 and Xs may
be determined by fitting a line to data relating X to d.
Table 3.3 Dose gradient correction factors for NE 2571 Farmer Ezzell [29] used this method and obtained data at 200,
0.6 cm3 ion chamber as a function of distance from a point 300, 400, and 500 mm from the source. The average
source to chamber center. reading at each point was corrected for leakage and timer
error and the reference distance was chosen to be
200 mm. The four data points fell on a straight line with
a correlation coefficient of unity. The author concluded
1.0 1.342 that, for the calibration jig used and at a reference dis-
2.0 1.116 tance of 200 mm, room scatter was 0.6% of the mea-
5.0 1.026 sured dose.
10.0 1.009 A similar series of measurements was made by
15.0 1.005 Goetsch et al [12] using an Exradin A3 spherical cham-
20.0 1.004
ber of 3.6 cm3 with air-equivalent plastic walls (includ-
(T6lli,1997,[18].) ing cap) at nominal distances from 100 mm to
30 Calibration of sources
396.4 mm from an iridium-192 source. The room scatter
at a source-chamber distance of 200 mm was found to
be 0.63%. Table 3.4 summarizes both sets of measure-
ments. For relatively large distances, and in the typical
hospital laboratory, room scatter may introduce errors
that are not negligible. As an extended time period will
be required to collect sufficient charge for acceptable
precision, it is important that leakage for the electrome-
ter system is measured and, if necessary, an appropriate
correction made.
Iridium-192 has a very complex emission spectrum
which includes approximately 24 lines occurring in the
energy range 9-885 keV. The lowest energy emissions
are attenuated by the source capsule and do not influ-
ence measurements. The exposure-weighted average of
the remaining lines is 397 keV, which falls approximately
halfway between the cesium-137 gamma ray energy of
662 keV and the average energy (146 keV) of a 250 kVP
medium-filtration X-ray beam (half value thickness =
3.2 mm Cu). For a beam of this radiation quality, the
choice of calibration factor and choice of build-up cap
are not straightforward. There are three factors to con-
sider. First of all, Goetsch et al. [12] have demonstrated
that for in-air measurements at short distances, it is nec-
essary to exclude high-energy photoelectrons emitted
from the source capsule. This can be achieved either by
placing a build-up cap over the ion chamber or by intro-
ducing the source itself into a narrow-bore Perspex tube
where a wall thickness of 1 mm will be sufficient to
remove the electron contamination. Secondly, Goetsch et
al [12] have also suggested that iridium-192 measure-
ments require that the ionization chamber's wall thick-
ness must be sufficient to provide charged particle
equilibrium for the highest energy secondary electrons
present. These authors conclude, from measurements
made with ion chambers that have graphite caps of var-
ious thicknesses, that the total thickness of wall and cap
should be at least 0.3 g cm-2 to assure charged particle
equilibrium: a Farmer-type chamber has a wall of
0.065 g cm-2.
The third consideration concerns the instrument cali-
bration factor. There are two components: an intercom-
5.0 1.00
10.0 0.999 0.999
15.0 0.997 0.997
20.0 0.994 0.994
30.0 0.988 0.986
40.0 - 0.975
50.0 0.966 - bration factors. It was found that for both chambers the
' For local conditions as described by Ezzell (1989) [29], and Goetsch et
a I. (1991) [12].
parison ratio between the field instrument and a sec-
ondary standard, and a calibration factor for the sec-
ondary standard appropriate to this energy. The former
component may be determined using an iridium source
at sufficiently large distance to ensure that the correction
for finite chamber size will be the same for the two detec-
tors. The second component is more difficult to estab-
lish. The reason for this is that there is an absence of
primary standards for radiation from iridium-192
sources and the calibration factor of the chamber has to
be obtained by other means. In the UK, no factor for cal-
ibration against the primary standard is normally avail-
able between that for heavily filtered 280 kVP X-rays (for
use with measurements made without a build-up cap)
and that for 2 MV X-rays (for use with measurements
made with a build-up cap). In the USA and in some
European laboratories, a factor for calibration against
cesium-137 (gamma ray energy of 662 keV) is also avail-
able. The subject has been discussed comprehensively by
Grimbergen and van Dijk [31] and Goetsch et al. [12].
The method described by Goetsch is a linear interpo-
lation between a medium filtered 250 kV X-ray quality
and cesium-13 7, with correction for differences in wall
attenuation between X-rays, cesium-137, and iridium-
192 radiation. The correction factor was derived from
wall attenuation measurements with one type of ioniza-
tion chamber. This method is used extensively in the
USA and forms the basis of calibrating iridium-192
sources that are subsequently used in the calibration of
re-entrant ionization chambers.
Grimbergen and van Dijk describe the air kerma cali-
bration procedure that can be provided by the
Netherlands Measurements Institute (NMI), which is
based on weighting the chamber response according to the
air kerma spectrum of the iridium-192 source [5]. This
'energy response curve' method is probably the most accu-
rate, but is time consuming and expensive to realize. The
authors calculated the photon spectrum of iridium-192
source-type used in the microSelectron HDR afterloading
equipment using the EGS4 Monte Carlo System. The
energy response was calculated for two widely used ion
chambers: the NE 2561, which is used in the UK as a sec-
ondary standard, and the NE 2571, which is used as a field
instrument. The calibration of the chambers was per-
formed against the primary standards in beams of X-rays,
cesium-137, and cobalt-60 gamma radiation; during the
measurements the chambers were fitted with build-up
caps. To determine the chamber response at the energy of
each iridium-192 spectrum line, a polynomial was fitted
through the chamber calibration data (see Figures 3.7 and
3.8). A comparison was then made for each chamber: a cal-
ibration factor was derived using the 'energy response
curve' method and also one was derived using the average
of the medium filtered 250 kV X-ray and cesium-137 cali-
two-point method results in a 0.3% lower value than that
derived by matching the energy response curves. The

Image Not Available
Figure 3.7 Energy response (E) of the NE2561 (S/N 051) with
build-up cap. The error bars indicate two standard deviations.
The line is the polynomial fit used to determine the response at
the iridium-192 spectrum energies. (Reproduced with permission
from Grimbergen and van Dijk, 1995 [31].)
Image Not Available
Figure 3.8 Energy response (E) of the NE 2571 (S/N 1436) with
build-up cap. The error bars indicate two standard deviations.
The line is the polynomial fit used to determine the response at
the iridium-192 spectrum energies. (Reproduced with permission
from Grimbergen and van Dijk, 1995 [31].)
uncertainty in the calibration factor for iridium-192
determined with the energy response curve method was
estimatedat l%fortheNE2561 and l.l%for the NE 2571.
It is concluded by Grimbergen and van Dijk [ 31 ] that, with
respect to the chambers considered, the two-point
method is a reasonable alternative to the energy response
method. More recently, Ferreira et al. [33] have performed
Monte Carlo calculations of chamber wall correction fac-
tors for 51 commercially available ionization chambers
Calibration of sources used in remote afterloading systems 31
and build-up caps. These data are also presented in IAEA-
TECDOC1079 [7] together with a description of an in-air
calibration using the method based on the technique by
Goetsch et al, [12]. The principle of the method for cali-
brating an 192Ir HDR source, is to calibrate it at an appro-
priate X-ray quality and at 137Cs, or in 60Co if a 137Cs beam is
not available. With the knowledge of the air kerma calibra-
tion factors at these two energies, the air kerma calibration
factor for 192Ir is obtained by interpolation making use of
the wall correction factors. This method requires the total
wall thickness to be the same at each quality that the cham-
ber is calibrated.
In the UK, a Joint BIR and IPSM Working Party [28]
set up to report on brachymerapy dosimetry recom-
mended that the calibration for use with iridium should
be that for the highest available kilovoltage quality, that
is, the factor for heavily filtered 280 kV X-rays. This rec-
ommendation was made in the absence of a primary cal-
ibration for iridium-192. It was also suggested that the
measurements should be made with an NE 2 MV build-
up cap, or a Perspex sheath around the source to remove
photoelectrons emitted from the source capsule. The
recommended values for electron filter corrections are
1.017 for the NE 2 MV build-up cap, or 1.004 for a 1 mm
thick Perspex sheath around the source; more generally,
for small thicknesses of low atomic number filter mater-
ial, the recommended correction is 3% g-1 cm-2.
It is estimated that, whichever method is used to
ascertain the chamber factor, the difference between the
'energy response curve' method, the two-point method,
or the simpler 250 kV factor method is less than 1%.
Typical exposure times for an 'in-air' calibration at
100 mm using a nominal 10 mGy s-1 source will be about
300 s. If the mean reading is R then the RAKR, Kr in
mGy s-1 is derived as follows:
Fc is the air kerma calibration factor for the secondary
standard;
F.c is the intercomparison ratio between the field
instrument and the secondary standard;
Ftp is the temperature/pressure correction factor
(= TIP x 1013/293.2), where T is the temperature
in Kelvin and P the pressure in millibar;
Fs is the correction for room scatter and scatter
produced in the jig and its support (= 0.998 for the
Royal Marsden jig and support system);
Fg is the dose gradient correction factor for the ion
chamber (= 1.009 for a 0.6 cm3 Farmer-type
chamber at 100 mm);
Fe is the electron filter correction (= 1.017 for an NE
build-up cap);
Fis is the inverse square scaling from 100 mm to 1 m
(= 10-2);
Fm is the gray to microgray conversion (= 106);
t is the time, in seconds, for each reading.
32 Calibration of sources
In principle, there should also be corrections for air
attenuation and scattering and for the source transit
time, but both of these are taken as unity.
RE-ENTRANT IONIZATION CHAMBER
MEASUREMENTS
The most convenient means of measuring the strength
of an HDR iridium-192 source is to use a re-entrant ion-
ization chamber. The Standard Imaging HDR 1000 Ion
Chamber is designed specifically for high strength
sources [14]. The well of the chamber consists of a
35 mm diameter x 122 mm deep cavity into which a
holder can be inserted to carry a catheter or rigid appli-
cator for positioning the radioactive source. The respon-
sivity of the chamber is affected by source position, but
the variation is only 0.5% over a range of 25 mm near
to the center of the chamber axis.
Jones [34] used a modified Standard Imaging cham-
ber with an NE 2571/1 electrometer as part of a quality-
assurance programme for checking iridium-192 source
strengths. The chamber measurements were found to
correlate well with 'in-air' calibration measurements
made over a 3-month source-decay period; the maxi-
mum discrepancy between the 'in-air' measurement and
the re-entrant chamber measurement was 0.9% (Figure
3.9). A further investigation with a Nucletron Source
Dosimetry System (PTW-Freiburg re-entrant ion cham-
ber) calibrated at NIST and a modified Standard
Imaging chamber showed that, over a 4-month period,
13 comparative measurements made with both cham-
bers were found to be within 0.18% (1 SD). The air
kerma strength measured using the NIST traceable
Nucletron PTW chamber was found to agree within
0.3% of the 'in-air' calibration measurement.
Goetsch et al. [29] also report measurements using
three re-entrant ionization chambers manufactured by
Figure 3.9 The relative source strength of an iridium-192
source as a function of time measured with a modified standard
imaging HDR WOO chamber over a 3-month period. The line
corresponds to the decay curve; the points correspond to
chamber measurements [34].
three different manufacturers. Agreement was found to
be within 1%.
In order to obtain maximum reproducibility, mea-
surements in a re-entrant chamber should be made with
the aid of a Perspex insert. For definitive calibration
measurements, the chamber should be located away
from objects that might cause radiation scatter (such as
a laboratory wall). Consistent readings are obtained best
when the chamber is used each time in the same position
and in a reproducible manner.
SOLID PHANTOM (OR WATER PHANTOM)
MEASUREMENTS
The underlying principle of this type of measurement
has been described in section 3.4.3, except that in the
case of a single HDR source, the dose gradient through
the centrally placed ion chamber has to be corrected for
[18]. The method has been described by Ezzell [29], and
Krieger [35].
Measurements in a phantom require corrections to be
made for attenuation and scatter. Usually, the effective
distance between the source and the attenuation is deter-
mined using a formula that applies to the condition of
full scatter. Generally, the small dimensions of the solid
(acrylic) phantom do not fulfil this requirement and a
correction factor has to be applied to compensate for this
lack of scatter. Ezzell [29] measured this to be 1.079 for a
130 mm diameter x 130 mm long acrylic cylinder.
3.4.6. Pulse dose-rate sources
Pulse dose-rate (PDR) sources are of lower activity than
HDR sources and are of different physical construction.
PDR sources are typically 18-37 GBq in activity. In the
case of iridium-192, the active length of a 37 GBq PDR
source is 0.5 mm. The most convenient method of cali-
brating such a source is to use a re-entrant ion chamber.
It will be necessary to ensure that the chamber has been
calibrated for PDR sources rather than, or as well as,
HDR sources.
The strength of the source is such that an 'in-air' calibra-
tion with a 0.6 cm3 Farmer ion chamber is achieved best at
a distance of about 50 mm; greater distances would
require extended exposures. At this short distance, it is
important to ensure precise alignment between the source
and the chamber center. The location of the source center
should be ascertained (by autoradiography) so that align-
ment can be achieved reproducibly. It is necessary to use a
build-up cap (or a Perspex sheath over the source), as
described in the section on HDR source calibration, to
remove electrons emitted from the source capsule. A cor-
rection for the finite size of the chamber must be applied:
this increases significantly at short distances. Tolli [18] has
shown that, for a chamber of the same dimensions as a
0.6 cm3 Farmer chamber, the correction factor is 1.026.
Exposure times to accumulate sufficient charge will be

long (typically 0.5 h) and an allowance must be made for
any chamber leakage that occurs during the measurement
period.
REFERENCES
1. International Commission on Radiation Units and
Measurements (1985) Dose and Volume Specification for
Reporting Intracavitary Therapy in Gynaecology, Report
38. Bethesda, Maryland, ICRU.
2. Kutcher, G.J., Cola, L, Gillin, M. etal. (1994)
Comprehensive QA for radiation oncology: Report of
AAPM Radiation Therapy Committee Task Group 40. Med.
P/7ys.,21(4),581-618.
3. Rossiter, M.J. (1990) The traceability of brachytherapy
sources supplied byAmersham International. Br.J.
Radiol., 63,663.
4. Read, L.R., Burns, J.E. and Liquorish, R.A.C. (1978)
Exposure-rate calibration of small radioactive sources of
cobalt-60, radium-226and caesium-137. IntJ.Appl.
Radial /sof.,29,21-7.
5. Rossiter, M.J., Williams, T.T. and Bass, G.A. (1991) Air
kerma rate calibrations of small sources of cobalt-60,
caesium-137, radium-226and iridium-192. Phys. Med.
fi/o/., 36(2), 279-84.
6. Williamson, J.F. and Nath, R. (1991) Clinical
implementation of AAPM Task Group 32
recommendations on brachytherapy source strength
specification. Med. Phys., 18(3), 439-48.
7. IAEA-TECDOC-1079 (1999) Calibration of Brachytherapy
Sources. Vienna, International Atomic Energy Agency.
8. Mcjury, M., Tapper, P.D., Cosgrove, V.P. et al. (1999)
Experimental 3-D dosimetry around a high dose rate 192lr
source using a polyacrylamide gel (PAG) dosimeter. Phys.
Med. fi/o/., 44(10), 2431-44.
9. Berkley, L.W., Hanson, W.F., and Shalck, R.J. (1981)
Discussion of the characteristics and results of
measurements with a portable well-ionisation chamber
for calibration of brachytherapy sources. In Recent
Advances in Brachytherapy Physics, ed. D.R. Shearer,
Monograph No. 7. New York, AAPM, 38-48.
10. Weaver, K.A., Anderson, LL and MeliJ.A. (1990) Source
calibration. In Interstitial Brachytherapy: a Report by the
Interstitial Collaborative Working Group, ed. L.L.
Anderson, New York, Raven Press.
11. Flynn, A. and Workman, G. (1991) Calibration of a
microSelectron HDR iridium-192 source. Br.J. Radiol., 64,
734-9.
12. Goetsch, S.J., Attix, F.H., Pearson, D.W. and Thomadsen,
B.R. (1991) Calibration of Ir192 high dose rate afterloading
systems. Med. Phys., 18,462-7.
13. Jones, C.H. (1988) Quality assurance in gynaecological
brachytherapy. In Dosimetry in Radiotherapy Vol. 1,
Vienna, IAEA, 275-90.
14. Goetsch, S.J., Attix, F.H., Dewerd, LA. and Thomadsen,
B.R. (1992) A new re-entrant ionisation chamber for the
References 33
calibration of iridium-192 high dose rate sources. Int. J.
Radial Onc. Bio/. Phys., 24,167-70.
15. Baltas, D., Geramani, K., lonaddis, G.T. et al. (1999)
Comparison of calibration procedures for 192lr high dose
rate brachytherapy sources. Int.J. Radial Oncol. Bio/.
Phys., 1,43(3), 653-61.
16. Williamson, J.F., Morin, R.L and Khan, F.M. (1983) Dose
calibrator response to brachytherapy sources: a Monte
Carlo and analytic evaluation. Med. Phys., 10(2), 135-40.
17. AAPM Report No. 13 (1984) Brachytherapy. In Physical
Aspects of Quality Assurance in Radiation Therapy. New
York, American Institute of Physics, 38-9.
18. Tb'lli, H. (1997) Ionisation chamber dosimetry for
brachytherapy. Doctoral dissertation. University of
Goleborg, 15-31.
19. Schaeken, B., Vanneste, F., Bouiller, A. et al. (1992) 192Tr
brachytherapy sources in Belgian hospitals. Nucl. Insl
Methods Phys. Res., A312,251 -6.
20. Steggerda, M.J. and Mijnheer B. (1994) Replacement
corrections of a Farmer-type ionisation chamber for the
calibration of Cs-137and lr-192 sources in a solid
phantom. Radiother. Oncol., 31,76-84.
21. Aukett, R.J. (1991) A technique for the local measurement
of air kerma rate from small caesium-137 sources, fir. J.
Radiol., 64,918-22.
22. Meertens, H. (1990) In-phantom calibration of Selectron-
LDR sources. Radiother. Oncol., 17,369-78.
23. Mijnheer, B.J., Aalbers, A.H.L, Visser, A.G. and
Wittkamper, F.W. (1986) Consistency and simplicity in the
determination of absorbed dose to water in high-energy
photon beams: a new code of practice. Radiother. Oncol.,
7,371-84.
24. Meisberger, LL, Keller, R.J. and Shalek, R.J. (1968) The
effective attenuation in water of the gamma rays of gold
198, iridium 192, cesium 137, radium 226, and cobalt 60.
Radiology, 90,953-7.
25. Jones, C.H. (1991) Quality assurance in brachytherapy
using the Selectron-LDR/MDR and microSelectron-HDR.
Activity, 5(4), 12-15. Leersum, The Netherlands,
Nucletron BV.
26. Chenery, S.G.A., Pla, M. and Podgorsak, E.B. (1985)
Physical characteristics of the Selectron high dose rate
intracavitaryafterloader. Br.J. Radiol., 58,735-40.
27. Messina, C.F., Ezzell, G.A., Campbell, J.M. and Orton, C.G.
(1988) Commissioning the Selectron HDR cobalt-60.
Activity, 2, 5-10. Leersum, The Netherlands, Nucletron.
28. Aird,E.GA, Jones, C.H.,Joslin,C.A.F.efo/. (1993)
Recommendations for brachytherapy dosimetry: Report of
a Joint Working Party of the BIR and IPSM. London, BIR,
1-17.
29. Ezzell, G. (1989) Evaluation of calibration techniques for
the microSelectron HDR. In Brachytherapy2, ed. R.F.
Mould. Leersum, The Netherlands, Nucletron, 61 -9.
30. Piermattei, A., Azario, L, Soriani,A. et al. (1995) Reference
air kerma rate determination for iridium-192
brachytherapy sources. Phys. Med. 9-15.
31. Grimbergen, T.W.M. and van Dijk, E. (1995) Comparison of
34 Calibration of sources
methods for derivation of iridium-192 calibration factors
for NE2561 and NE2571 ionisation chambers. Activity,
Special Report No. 7, 52-6. Leersum, The Netherlands,
Nucletron BV.
32. Biiermann, L, Kramer, H.M. and Selbach, H.J. (1995)
Reference Air Kerma Rate Determination of an Iridium-192
Brachytherapy Source. Activity: Special Report No. 7.
Nucletron-Oldelft, Leersum, The Netherlands, 43-47.
33. Ferreira, I.H., Marre, D., Bridier, A., Marechal, M.H. and de
Almeida, C.E. (1999) Personal communication.
34. Jones, C.H. (1995) HDR microSelectron quality-assurance
studies using a well-type ion chamber. Phys. Med. Biol.,
40,95-101.
35. Krieger, H. (1991) Messungder Kenndosisleistung
punktund linien-formiger HDR iridium-192
Afterloadingstrahlermiteinem PMMA-
Zylinderphantom.Ze/f. Med. Physik., 1,38-41.
 4
Systems of dosimetry

ANNE WELSH AND KAREN D'AMICO

4.1 INTRODUCTION 4.2 NON-GYNECOLOGICAL TREATMENT

SYSTEMS
Brachytherapists have always aimed to deliver the opti-
mum treatment to the patients in their care. In order to 4.2.1 The Paris System
achieve this ideal, the introduction of brachytherapy was
soon followed by the development of dosimetry systems BASIC PRINCIPLES
which were based on clinical experience. A paper on the
The first account of this system was published in 1966
physics of brachytherapy was published in 1923 by
[5] and was followed by several more detailed publica-
Coliez [ 1 ] and this was followed by many other publica-
tions, e.g., in 1978 and 1987 [6,7].
tions.
The Paris System is designed for modern sources,
The well-known Manchester System [2] was pub-
particularly iridium-192 wires, which have narrow
lished in 1934, followed by the Quimby System in 1944
diameter, are flexible, and may be formed to any length
and 1953 [3,4]. The early systems were designed for
required. The system requires the brachytherapist to
radium. Subsequently, the Paris System [5,6] was pub-
distribute sources over a predetermined target volume in
lished as a modern dosimetry system which allows the
accordance with the system rules. Dose rates are then
brachytherapist to take full advantage of the technologi-
calculated at defined points, known as basal dose-rate
cal improvement in source production, in particular the
points, within the target volume. The isodose that closely
use of iridium-192 flexible wire sources.
envelopes the target volume may be found by calculating
The aim of all the published dosimetry systems is sim-
85% of the average basal dose rate.
ple: to provide a set of guidelines for the brachytherapist
The basic rules for positioning the sources are as fol-
which, if followed, enable a prescribed dose to be deliv-
lows:
ered to the patient as accurately as possible.
This chapter contains brief descriptions of the systems Each source must be implanted parallel to the others.
most commonly used and some sample data to enable a Each source must be equidistant from adjacent
limited number of practical calculations to be per- sources.
formed. It is recommended that the original works The reference air kerma per unit length of source is
describing the dosimetry systems are consulted before constant for all the sources used in the implant.
any of the systems described are set up for clinical use for Ideally, the centers of all the sources are contained in a
the first time. single plane which perpendicularly bisects the
36 Systems of dosimetry

sources. This plane is called the central plane of the

implant. If such a plane cannot be defined, the central
plane is that plane perpendicular to the sources which
passes as closely as possible to the source centers.
The perpendicular distance between two adjacent
sources is referred to as the source separation in this
chapter. The source separation must lie in the range 8-15
mm for short wires (i.e., 50 mm or less) and 8-22 mm
for long wires (greater than 70 mm). If the source sepa-
ration exceeds the maximum permitted, there will be an
unacceptably large high dose area around each source.
This is illustrated in Figure 4.1. If the wire separations
are less than 8 mm, it is difficult to implant the wires in
a parallel fashion and the implant may not conform to
the requirements of the Paris System. Figure 4.1 Two implants each showing the area receiving the
prescribed dose and twice the prescribed dose. The diameter of

POSITIONING THE SOURCES the high dose area is considerably larger for the implant with
the greater wire separation.
The first planning consideration is the size of the target
volume. The target volume has three dimensions, which
are usually referred to, in the Paris System, as the length,
the width, and the thickness (Figure 4.2). The sources are
positioned parallel to the length dimension and may be
implanted in one or more planes, depending on the
thickness of the treatment volume.
Practical planning commences by determining the
number of source planes and the source separation nec-
essary for the satisfactory treatment of the patient.
For a single plane containing only two sources, the
source separation is given approximately by:
wire separation = thickness x 2.0
Figure 4.2 The relationship between the wire positions, the
For a single plane implant containing three or more safety margins, and the target volume dimensions.
sources, the source separation is given approximately
by:
wire separation = thickness x 1.7
edge of their planned volume. The safety margin then
The number of sources needed to implant a target vol- fulfils the purpose of its name and provides a small addi-
ume can then be calculated from: tional margin around the volume.
If the calculated wire separation exceeds the maxi-
width = wire separation x (number of wires - 1) + safety margin x 2
mum permitted value, the implant cannot be carried out
The safety margins for the different wire arrange- as a single plane of sources and two or more planes must
ments are summarized in Table 4.1. Some brachythera- be implanted. In multi-plane implants the sources may
pists prefer to omit the safety margin from their be implanted on a square lattice ('in squares') or an equi-
planning calculations and implant the sources up to the lateral triangular lattice ('in triangles') (Figure 4.3).

Table 4.1 Safety margins as fractions of wire separations for implants planned in accordance with the Paris
System rules

0.37 0.27 0.15

 Non-gynecological treatment systems 37

source length = 1.4 x target volume length

All the formulae given above are approximate, but are
sufficiently accurate for clinical use. Detailed tables may
be found in reference [7].

CALCULATION OF THE DOSE

The isodose that encloses the target volume is known as

Figure 4.3 Cross-sections through two double-plane implants,
one implanted 'in triangles' and one implanted 'in squares'. The
dots indicate the wire positions and the crosses indicate the
basal dose points.
For an implant in squares, the wire separation can be
calculated from:
thickness = wire separation + safety margin x 2
For an implant in triangles, the wire separation can be
calculated from:
thickness = wire separation x 0.87 + safety margin x 2
The width of an implant in squares is given by:
width = number of squares x source separation +
safety margin x 2
The width of an implant in triangles is given by:
width = number of triangles x source separation x
0.5 + lateral safety margin x 2
The length of the sources required to treat a target vol-
ume is almost independent of the other parameters and
is given approximately by the expression:
the reference isodose. It is calculated from the basal dose-
rates, which are the lowest dose rates found within the
central plane. For a single-plane implant, the basal dose-
rate points are positioned at the midpoint of each gap
between the sources. The basal dose-rate points for an
implant in squares are at the center of the squares, and
for implants in triangles the basal dose rates are calcu-
lated at the points where the perpendicular bisectors of
the sides of the triangles intersect.
The dose rates can be calculated by entering the source
position data into a suitable computer program, which is
likely to be available in most oncology centers, or by
hand calculation using graphs or tables of dose rate
against distance from the source for unit activity. The
dose rates taken from graphs or tables must be corrected
to values for the actual mid-implant source strength.
This will involve obtaining the source strength from the
supplier's measurement certificate and correcting it for
radioactive decay to the date of the middle of the
implant. Sample data are given in Tables 4.2a and 4.2b. A
simple example of an application of the Paris System is
shown below.
EXAMPLE
A target volume 55 mm long, 8 mm thick, and 35 mm
wide is to be given a dose of 30 Gy. Calculate the source
lengths required and the dose rate assuming an air kerma
rate source strength of 800 nGy h-1 mm-1 at 1 m halfway
through the implant.

Table 4.2a Sample dose rates for iridium-192, 0.3 mm diameter wire sources, calculated according to the recommendations of the
Joint BIR/IPSM Brachytherapy Working Party [8]

20 100

10 350 104 48.0 27.7 12.5 7.1 4.5 3.1 1.7 1.0
20 489 176 88.3 52.4 24.3 13.9 8.9 6.2 3.4 2.0
30 547 219 118 72.6 35.0 20.3 13.2 9.2 5.1 3.1
40 577 246 138 88.4 44.4 26.3 17.2 12.0 6.7 4.1
50 595 262 153 101 52.3 31.6 20.9 14.7 8.2 5.1
60 606 275 164 110 59.1 36.3 24.3 17.3 9.3 6.1
80 619 290 179 124 69.5 44.2 30.3 21.8 12.6 7.9
100 627 299 188 132 76.9 50.2 35.1 25.7 15.1 9.6
120 631 305 194 138 82.3 54.9 39.0 28.9 17.3 11.1
Dose rates a re in mGyh-1 for an air kerma rate source strength of 1 mGy h-1 mm-1 at 1 m. All the dose rates are for crossline = 0, i.e., in the plane
through the center of the wire and perpendicular to it.
38 Systems of dosimetry

Table 4.2b Sample dose rates for iridium-192, 0.3 mm diameter wire sources, calculated according to the recommendations of the
Joint BIR/IPSM Brachytherapy Working Party [8]

50 0 595 262 153 101 52.3 31.6 20.9 14.7 8.2 5.1
50 10 581 251 145 95.2 49.9 30.4 20.3 14.4 8.1 5.1
50 20 487 200 116 78.0 43.0 27.2 18.7 13.5 7.8 4.9
50 30 139 98.9 71.4 53.9 22.7 22.8 12.1 9.3 7.3 4.7
100 0 627 299 188 132 76.9 50.2 35.1 25.7 15.1 9.6
100 30 606 278 170 117 66.9 43.8 30.9 22.9 13.8 8.9
100 50 319 157 103 74.9 46.8 32.7 24.2 18.6 11.8 7.9
Dose-rates are in mGy h-1 for source strengths of 1 u.Gy h-1 mm-1 at 1 m. The dose rates are for different crosslines, i.e., in different planes
perpendicular to the wire and at the crossline distance from the wire center.

Single plane implant. Treatment time may be calculated from this dose rate
and the prescribed dose.
Source separation = 1.7 x thickness
= 1.7x8 = 14 mm
Width =2 x 0.37 x 14 +14 x (number of
wires -1)
= 2 x .37 x 14 + 14 x 2 = 38 mm
The isodose distribution for this implant is shown in
This is the closest width to the required value and
Figure 4.4.
requires three wires to be used.
Wire length = 1.4 x 55 = 77 mm - use 80 mm. PROBLEMS
The details of the distances and dose rate calculations for It is unlikely that an implant that conforms perfectly
this calculation are given in Table 4.3. with the Paris rules can be achieved without the use of
The mean basal dose rate for a source strength of 1 a template to aid the source positioning. If the implant
1-iGy h-1 mm-1 at 1 m, from Table 4.3, is does not comply precisely with the rules, the Paris
System may still be used providing none of the indi-
0.5 x (943 + 943) = 943 mGy h-1
vidual basal dose rates differs from the mean basal dose
Correcting this to true source strength available for use: rate by more than 10% and if, when using the triangu-
lar formation of sources, none of the triangles is obtuse
(Figure 4.5). Further information on dealing with
variants in source position which may be needed in
practice may be found in the book Modern Brachy-
therapy [7].

_ 85
Reference dose rate average basal dose rate
~100 X

Table 4.3 Dose rates calculation for sample iridium-192

imnlnnt

1 7 412
2 7 412
3 21 119
943
Dose rates in mGy h-1 calculated for wire of air kerma rate source Figure 4.4 The dose distribution for the example of the Paris
strength 1 mGy h-1 mm-1 at 1 m. implant showing isodoses of 60 Gy, 30 Gy, 22.5 Gy, and 15 Gy.
 Non-gynecological treatment systems 39

4.2.2 The Manchester System

The first widely available set of rules that could be used

to deliver a uniform dose to a target volume is often
referred to as the Manchester System, after its place of
origin and is fully described in the book Radium Dosage,
The Manchester System [9]. Excluding gynecological
treatments, three different types of brachytherapy
implant were considered: moulds, interstitial planar
implants, and volume implants. The systems used to dis-
tribute sources and calculate treatment times need to be
discussed separately for each of these cases.

MOULDS

The term mould is used to describe the situation in

which the radioactive sources are positioned external to
the patient, usually at a distance from the patient's skin
known as the treatment distance and represented by the
letter d (Figure 4.6). The treatment dose is prescribed to
the plane which is at distance d from the sources and the
dose in this plane will be delivered with a 10% accuracy
if the rules are followed. The sources may be arranged
over the treatment area in circles or squares, circles being
the preferred arrangement. In both cases the target area
should be bounded with radioactive sources arranged in
the required shape. Ideally, the sources should be laid in
a continuous line around the periphery, but gaps not
exceeding d are acceptable.
For small circular treatment areas, the sources around
the periphery will treat the target area adequately, but
large circles may require additional sources in the inte-
rior. A circle may be deemed to be small if the ratio of the
Figure 4.6 Source arrangement for a Manchester-type mould
arrangement. Source positions are indicated by dots on the
cross-section and lines on the wire positions viewed from above.
circle diameter to the treatment distance (d) is less than
3. The distributions required for larger circles are given
in Table 4.4.
Squares will be adequately treated by the peripheral
sources only if the side of the square does not exceed
twice the distance d. If the square does not meet this
requirement, supplementary lines of sources, parallel to
the side of the square, will be needed in the interior. The
distance between the lines of sources must not exceed
twice the distance d. If only one additional line of

Table 4.4 Distribution of total source activity for circular moulds

Ratio of Diameter to Treatment Distance <3 3-6 6 7.5 10

Percentage of total source activity on outer circle 100 95 80 75 70

Percentage of total source activity on a circle of
diameter half that of the outer circle - - 17 22 27
Central spot - 5 3 3 3

For small values of d

Percentage of total source activity on outer circle 100 95 90 80
Central spot - 5 10 20
40 Systems of dosimetry

sources is required, the linear source strength of the inte-
rior sources should be half that of the periphery. If there
are two or more additional lines, the linear strength of
the interior sources should be two-thirds of the periph-
eral value.
If the target area is rectangular rather than square,
treatment times calculated for sources should be
increased. Details of this increase are given in Table 4.5.
Once the sources have been arranged and the total
source strengths used are known, the treatment time can
be calculated by looking up, in Table 4.6, the total prod-
uct of total source strength and treatment time for the
area in use and the treatment distance. Table 4.6 gives
values necessary to deliver a dose of 1 Gy to the treat-
ment plane, and the value looked up should be adjusted
proportionately for the dose actually prescribed. The
treatment time may then be calculated as follows:
table value for total source strength x
treatment time
Treatment time for n Gy = n x
total source strength used
The dosage table is based on the original Manchester
data, updated to allow for current values of the calcula-
tion parameters [10,11] and converted into SI units.
EXAMPLE
A circular area is to be treated to a dose of 30 Gy with
source of strength 1200 nGy h-1 mm-1 at 1 m. The treat-
ment distance is 10 mm.
Table 4.5 Percentage increase to square implant treatment
times for rectangular implants
Treat with a single circle 25 mm in diameter (from
Table 4.4)
Area = 5 cm2
Total source strength x treatment time is 237
microgray-hours at 1 m from Table 4.6.
Total source strength is 25 x p x 1200 nGy h-1 at 1 m
= 94.3 (mGy h-1 at 1 m.
INTERSTITIAL PLANAR IMPLANTS
The interstitial rules are based on those for moulds, but
simplified to allow for the technical difficulties of
implanting the sources into the patient's tissue. The
implant can be effected most easily using the square or
rectangular arrangement described for moulds. Parallel
lines of sources are implanted through the center of the
volume and across the ends of the target volume. The
simplified distribution rules are given in Table 4.7. The
treatment time for a treatment volume 10 mm thick may
be obtained from Table 4.6 using a treatment distance of
5 mm.
The target volume extends for 5 mm either side of the
plane containing the wires and is thus 10 mm thick.
If it is desired to sandwich the target volume between
two parallel planes, the sources may be arranged in the
same manner as for a single plane and the product of
total source activity and treatment is again obtained for
a treatment distance of 5 mm. The treatment time is
then increased by the factors given in Table 4.8, which
are dependent upon the separation of the two planes.

Ratio of side to base for rectangle 2:1 3:1 4:1

Percentage to increase treatment time 5 9 12 Table 4.7 Distribution of total source activity between
periphery and interior for planar implants

Table 4.6 Dose table for area planned according to the

Manchester System interior

0-25 67 33
25-100 50 50
>100 33 67
0 23 92 207 368
5 124 237 385 572
8 159 297 463 661
10 182 335 506 714 Table 4.8 Factor by which treatment times for two-plane
15 234 423 610 838 implants calculated for 5 mm treatment distance (e.g. from
20 285 496 704 947 Table 4.6, column 2) must be increased for plane separations
30 379 615 883 1150 greater than 10mm
40 466 722 1041 1339
50 545 829 1177 1514
60 619 932 1301 1686
80 758 1473 1520 1981
100 893 1327 1730 2235 10 1.0
15 1.25
Total air kerma source strength is expressed in mGy h-1 at 1 m and 20 1.40
treatment time is in hours. The table gives the product of total source 25 1.50
strength used and treatment time to deliver a dose of one Gy.
 Non-gynecological treatment systems 41

The dose will be low in the plane halfway between the 4.2.3 The Quimby System
source planes for separations which exceed 20 mm.
It is often impractical in an afterloaded implant to This system was developed by Edith Quimby from work
have two rows of sources perpendicular to the principal she originally carried out in the 1930s [12]. The system
implanted direction. If it is not possible to cross the ends is essentially an adaptation of the Manchester System
of the implant, the implanted area may be considered to and is described in her later works [3,4].
be decreased by 10% for each uncrossed end. The lines of The Manchester System made severe demands upon
implanted sources then extend 10% of their length the radium stocks available in the USA. In general, the
beyond the ends of the target volume for each uncrossed activities were higher than those which could be obtained
end. in the UK and the range of available activities was smaller.
This made it difficult for oncologists to fulfil the require-
VOLUME IMPLANTS ments of the Manchester System for sources in the inte-
Volumes may be considered to be spherical, cylindrical, rior of the implants to have a lower linear source strength
or cuboid. Sources must be distributed throughout the than those in the periphery. It was also difficult to achieve
volume in accordance with the rules given in Table 4.9. the required spacing of the sources within the implant
In general, volumes are considered to consist of an outer without substantially changing the proportions of activ-
shell and an inner core. Within the shells and cores the ity that the Manchester System assigned to the periphery
source activity should be distributed as evenly as possi- and interior of the implant.
ble in compliance with the distribution rules, and gaps The Quimby System is based on relaxing the
between sources should ideally be less than 15 mm. Manchester System distribution rules so that uniform
The treatment times can then be determined from the linear source strength sources may be used and the activ-
volume dosage in Table 4.10 in a manner analogous to ity is distributed uniformly throughout the treatment
that for the moulds and planar implants. volume. The homogeneity of dose within the treated vol-
Again, as for planar implants, it may well be impossi- ume is not as good as that achieved by the Manchester
ble to afterload sources which are positioned perpendic- System, but the inhomogeneity was considered to be
ularly to the main direction of implantation, and acceptable in clinical practice.
cylindrical volumes should be reduced by 7.5% for each Among the possibilities that Quimby considered were:
uncrossed end. 1. Using uniform-strength needles throughout the
target volume, and achieving the desired proportions
of activity on the periphery and interior of the
implant by increasing the source separations within
Table 4.9 Distribution of source activity for volume implants
the implant beyond that allowed by the Manchester
planned in accordance with the Manchester rules
System.
2. Using uniform-strength needles throughout and
maintaining the source separations recommended by
Sphere Shell: 6 parts Core: 2 parts the Manchester System and thus altering the
Cylinder Belt: 4 parts Core: 2 parts Each end: 1 part proportions of activity allocated to the interior and
Cuboid Each side: 1 part Core: 2 parts Each end: 1 part
periphery of the implant.
Gaps between the needles should not exceed 10-15 mm.
Planar implant tables based on the Quimby system,
with the sources spread uniformly across the target, have
Table 4.10 Dose table for volumes planned according to the
been calculated as for the Manchester System, and a sam-
Quimby and Manchester systems
ple set of data (Table 4.11) is included here, based on the
work of Godden [13] and converted to SI units, in accor-
dance with the recommendations of the BIR/IPSM
Working Party report. The tables are for the number of
5 78 152 mGy total source strength multiplied by treatment time in
10 123 244 hours required to deliver a dose of 1 Gy to the target area.
20 195 335
The source strength is specified in mGy h-1 at 1 m. These
40 310 472
80 491 663
tables are analogous to the Manchester System tables,
100 570 762 which were originally published in the units of milligram-
125 662 853 hours of radium required to deliver a dose of 1000 R, but
150 747 952 have been corrected to the currently recommended SI
units and current values of calculation parameters.
Total air kerma source strength is expressed in mGy h-1 at 1 m and
treatment time is in hours. The table gives the product of total source The Quimby System deals with uncrossed ends in the
strength used and treatment time to deliver a dose of 1 Gy for sources same manner as the Manchester System, reducing the
with a filtration equivalent to 0.5 mm of platinum. treated area by 10% for each end of the target volume not
42 Systems of dosimetry

Table 4.11 Sample dosage table for implanted areas planned Initially, the total implanted activity in millicuries was
according to the Quimby System simply taken to be five times the average dimension in
centimeters, the average dimension simply being the
Square applicators
mean of the length, width, and thickness of the target
volume. The factor 5 was based on previous clinical
experience.
10 35 107 224 381 It was expected that this system would result in a
20 61 143 263 434 patient dose that varied inversely as the sixth root of the
50 190 309 457 652 volume. Clinically, it is well known that small volumes
can tolerate higher doses than large volumes, so this slow
Rectangular applicators reduction of treatment dose was thought to correspond
well to clinical need. In practice, it was found that the
dose varied more rapidly than the sixth root of the vol-
ume and this was attributed to absorption of the low-
10x15 39 112 227 385 energy iodine-125 emissions by tissue. Tissue scatter and
40x60 218 324 475 666 absorption are not usually clinically significant for the
60x90 434 553 720 944 radionuclides used in the classical dose systems. The
average dimension method was thus modified to
Circular applicators
increase the amount of activity used in larger volume
implants.
The factor 5 was replaced as follows:
10 34 104 215 378 factor = 5 average dimension < 2.4 cm
30 79 167 305 462 factor = 3.87 (average 2.4 < average dimension < 3.24
60 228 345 519 699 dimension + 1.0)1293
Total air kerma source strength is expressed in mGy h-1 at 1 m and factor = 2.76 (average average dimension > 3.23
treatment time is in hours. The table gives the product of total source dimension + 1.0)1581
strength used and treatment time to deliver a dose of 1 Gy for sources
with a filtration equivalent to 0.5 mm of platinum.
PRACTICAL USE

To simplify the calculations of activity required for an

bounded by sources. The sources should thus extend well
beyond the boundary of the target volume if it is not pos-
sible to place sources across the ends of the target volume.
When considering volume implants, Quimby exam-
ined the effects of distributing the source activity uni-
formly throughout the volume. She published tables of
total source strength multiplied by treatment time to
deliver a treatment dose to the periphery of the target
volume for volume implants, assuming the activity is
uniformly distributed. Some data are reproduced in
Table 4.10, corrected for modern units. The quantity
total source strength multiplied by treatment time differs
substantially from the Manchester System because these
tables deliver a minimum treatment dose rather than an
average dose to a plane.
4.2.4 Modern seed implantation, average
dimension method
BASIC PRINCIPLES
This method is usually employed to deliver a required
dose to a small-volume permanent implant afterloaded
with iodine-125 seeds. A substantial part of the early
work was done at the Memorial Sloan-Kettering Cancer
Center, New York, and was based on clinical experience
with prostatic cancer [14].
implant, a nomogram was produced which allowed the
brachytherapist to calculate the necessary number of
seeds and seed strength for a particular volume. The
brachytherapist measures the dimensions of the volume
to be implanted in the coronal, sagittal, and transverse
planes and calculates the average dimension. A nomo-
gram is then used to determine the number of seeds
which should be implanted for the seed activity avail-
able. The activity is then spread uniformly throughout
the volume in a three-dimensional matrix. Practical con-
siderations usually constrain the separation of the
columns of seeds to 'round' number separations, e.g.,
10 mm, 15 mm, etc., and the nomogram will indicate the
most appropriate seed spacing within the column.
Modern practice, although based on the above general
principles, dispenses with nomograms for prostatic can-
cer and is computer based. The seeds are positioned in
the prostate under ultrasound guidance using a tem-
plate. The use of the template restricts the seed positions;
it usually has holes for placing columns of seeds every 5
mm. Typical implant spacing is 10 mm. The seeds must
be positioned out to the edges of the treatment for a sat-
isfactory implant. The expected seed position data are
entered into a treatment planning computer and source
activity is calculated to deliver the prescribed dose to the
isodose which enclosed the target volume. Many com-
puter programs used the data of Krishnaswamy [15] for

this purpose. Recommendations for calculating the dose
distribution around iodine-125 seeds have been pub-
lished by the American Association of Physicists in
Medicine (AAPM) brachytherapy working group [16].
These are the best current sources of data. The matched
peripheral dose for implants, that is, the dose that
encloses a volume of the dimensions to be treated, is
normally in the range 100 to more than 200 Gy. The dose
within the target volume will be considerably higher
than this. Further discussion of the dose distribution and
optimization techniques are discussed by Yang et al. [17].
4.2.5 Other dosimetric methods
THE 'NO SYSTEM' METHOD
It is possible to implant a patient without following any
rigid dosimetric system such as those described previ-
ously. The brachytherapist may position the radioactive
sources to cover the target volume as he or she thinks fit.
The source catheter positions may then be calculated
using orthogonal radiographs, isocentric films, or any
other appropriate method available. The dose distribu-
tion is then calculated either by hand, using published
data for the sources in use, or, more usually, with the aid
of a computer program. Suitable programs are available
in most radiotherapy departments. The brachytherapist
then prescribes the treatment dose to the isodose that
most appropriately covers the target volume.
There are considerable dangers in this system, which
may cause the unwary practitioner to give a considerable
overdose to parts of the treatment volume. There is a
very steep dose gradient around each wire, principally
because of the operation of the inverse square law from
every element of every source. It is essential that the
sources are not so widely separated that, if the dose is
prescribed to an isodose that envelops all the wires, the
inevitable high dose region around each source is large
enough to cause necrosis. The guidelines for maximum
source separations used in the Paris System may be taken
as a useful indicator. It is also essential that the
brachytherapist makes a carefully considered choice of
prescription isodose. An isodose which is at a large dis-
tance from the sources may appear to be a good choice
in that it covers the required treatment volume, but if the
dose is prescribed at a large distance from the sources,
necrosis may occur in the vicinity of the sources. Again,
the Paris System guidelines may be used to determine the
maximum treatment thickness permissible with any par-
ticular source separation.
The dose delivered by brachytherapy sources falls off
toward the physical end of the source and for that reason
the sources must always extend beyond the end of the
target volume or, alternatively, the quantity of source
activity at the boundary of the target volume must be
increased by 'crossing the ends' as per the Manchester
System. Once again, even if the brachytherapist is not
Non-gynecological treatment systems 43
adhering strictly to a system, the Manchester or Paris
rules on source length will provide satisfactory guide-
lines.
It is worth noting that there is a small amount of dis-
agreement between the Paris and Manchester systems
about the distance beyond the target volume which the
sources should extend. The Paris System recommends
that the source length is 40% greater than the target vol-
ume length, whereas the Manchester System recom-
mends the source lengths are increased an additional
10% of the volume length for each uncrossed end, i.e.,
20% of the target volume length if the sources are
implanted in one direction only.
Consideration of the above leads to the conclusion
that it is impossible to carry out any sort of brachyther-
apy work without following some basic guidelines or
rules for source distribution and choice of prescription
isodose, even if these are not quite so formally set out as
for the systems described above. It is appropriate to
emphasize at this point that systems should not be
mixed. For example, one should never distribute the
source activity in accordance with the Paris or Quimby
systems and then use the Manchester System tables to
determine the treatment time. If one chooses to use a
particular system, then the rules for that particular sys-
tem should be scrupulously followed. If the brachyther-
apist chooses not to use a system, then particular
attention must be paid to the choice of source separa-
tion, prescription isodose, and length of treatment
sources with respect to the treatment volume.
DOSE-VOLUME HISTOGRAMS
Dose-volume histograms are, strictly speaking, not a
dosimetric system, but a method of examining and ana-
lyzing the implant. The analysis may be used to change
the treatment prescription and for that reason dose-
volume histograms are discussed in this chapter.
The simplest form of dose-volume histogram is
obtained by calculating the dose at every point on a
matrix which covers the dose volume and sorting the
points into dose bins. Each point represents the dose in a
volume element of the matrix and thus counting the
points which fall into each dose band allows the volume
receiving a minimum of any particular dose to be calcu-
lated. This will allow the volume receiving a high dose,
for example twice the prescribed dose, to be calculated
and may give some information about possible dangers
of necrosis. There is little useful information to be
obtained about uniformity of the implant.
An alternative approach, known as 'natural' volume-
dose histograms, was developed by Anderson [18] in
1986. The basic aim of their work was to remove one
large source of dose variation within the implant, the
inverse square law, from the dose-volume histogram in
order that the effect of other contributors to non-
uniformity to the implant, i.e., poor source positions,
44 Systems of dosimetry
could be more clearly seen. They showed that for a sin-
gle source plotting the volume in dose bins which varied
with dose rate to the power 3/2 would result in every
bin containing the same number of dose points or vol-
ume elements. However, for multisource implants, a
peak in the graph is obtained at a dose rate approxi-
mately equal to the average value at points midway
between adjacent sources. A typical multisource implant
graph is shown in Figure 4.7. The more uniform the
dose rate within the implant, the higher and sharper the
peak will be. Anderson suggests that the dose rate at
which the prescribed dose is delivered should be close to
the dose rate at which the histogram peak occurs. If the
treatment dose rate is substantially lower than the peak
dose rate, undesirably large doses may be given within
the implant, with the accompanying risk of necrosis,
whereas if the treatment dose rate is significantly higher
than the peak dose rate, a large volume outside the tar-
get region may be receiving a dose close to the treat-
ment dose.
In practice, it has been found that, for implants car-
ried out following the Paris System rules, the peak of the
volume-dose histogram corresponds closely to the aver-
age basal dose rate [19]. Thus, the position of the peak
on the natural dose-volume histogram could be used as
a guide to the value of the basal dose rate. For implants
which follow the Manchester System, the treatment dose
rate has been found to be approximately 60-90% of the
peak dose rate. Because the Manchester System is based
on delivering an average dose to a particular treatment
plane, it is not surprising that the peak of the histogram
does not reliably indicate the Manchester treatment dose
rate.
The position of the peak in the natural dose-volume
histogram may be helpful in choosing a treatment iso-
dose, particularly for those implants that were based on
the Paris System, even if the final source distribution
does not comply strictly with the Paris rules. The
brachytherapist should be wary of routinely prescribing
to 85% of the peak dose rate without first checking that
this will not lead to a significant overdose in any part of
the implant.
Arbitrary units on scale of (dose rate) -3/2
Figure 4.7 'Natural' dose-volume histogram for seven evenly
spaced wires.
43 INTRACAVITARY THERAPY FOR
GYNECOLOGICAL CANCER
4.3.1 Cervical cancer
THE MANCHESTER SYSTEM
This system was initially developed for radium tubes, but
was easily adapted to different afterloading systems. The
Manchester System [20] specifies the spatial distribution
of sources in specially designed applicators and their rel-
ative activity and defines reference points at which the
dose is calculated. The applicators consist of a central
tube inserted into the uterus and locating on the cervix
by means of a flange, and a pair of ovoids, which nor-
mally sit in the vaginal fornices. To cope with individual
variations in patient anatomy, different combinations of
central tube length and ovoid size are used and the sepa-
ration between the ovoids can also be adjusted. In the
extreme case of the narrow vagina, it may be necessary to
insert the ovoids in tandem along the vagina.
In the Manchester System, the dose is specified at
point A, which is defined as 2 cm superior to the mucous
membrane of the lateral fornix (which, for practical pur-
poses, is level with the external os) in the plane of the
uterine tube and 2 cm lateral to the center of the uterine
canal, as shown in Figure 4.8. The dose at point A is rep-
resentative of the dose throughout much of the malig-
nant tissue. In addition, point B is defined 5 cm laterally
to midline at the same level as the A points and repre-
sents the dose to the pelvic wall. The dose at point B is
approximately 20-25% of the dose at point A and is of
importance when calculating the total dose when
brachytherapy is combined with external-beam irradia-
tion.
There were two reasons for the choice of point A as the
dose specification point: treatment was thought to be
limited by the tissue tolerance of the paracervical trian-
gle, and the dose rate at this point is not too sensitive to
small variations in applicator position. When loaded
according to the rules shown in Figure 4.9, the different
combinations of central tube and ovoid deliver approxi-
mately the same dose rate to the A points (as shown in
Table 4.12), and ensure a suitable ratio between the vagi-
nal and intrauterine contributions to the dose at point A,
with the ovoids contributing no more than one-third of
the dose. Although point A was thought to be anatomi-
cally comparable between patients, it is in fact a point
which is related to the geometry of the sources and not
to patient anatomy. Consequently, for a non-ideal inser-
tion in which the uterine canal is rotated, the A points
also rotate as shown in Figure 4.10. A typical isodose dis-
tribution is shown in Figure 4.11.
Applicators that reproduce the traditional Manchester
geometry are available for manual and low and high dose
rate remote afterloading systems. In order to minimize
the risk of sources sticking in the afterloading
 Intracavitary therapy for gynecological cancer 45

Figure 4.8 Position of A and B points for an ideal insertion, (a) Lateral view, (b) anterior-oblique view.

Figure 4.9 Manchester System: loading patterns for uterine tubes and avoids.
46 Systems of dosimetry

Figure 4.10 Position of A and B points for a non-ideal

insertion.

applicators, they usually have a less flexible central tube
and the geometry of the applicators is often more rigid.
Some configurations, e.g., ovoids in tandem, which were
possible with the traditional Manchester applicators may
not be possible with all afterloading systems, although
alternative applicators may be supplied.
In the traditional system, for treatment using
brachytherapy alone the dose prescribed to point A at
conventional low dose rates is 74 Gy in 140 h split into
two fractions with approximately 1 week between frac-
tions. (Please refer to Chapter 25 for further details of
cervix treatment.) Manchester applicators do not incor-
porate rectal shielding. The dose to this critical structure
is minimized by careful positioning of the applicators
and by careful packing of at least 1.5 cm of gauze behind
Figure 4.11 A typical isodose distribution for treatment of
carcinoma of the cervix according to the Manchester System.
the ovoids. The packing also eliminates movement of the
applicators during treatment.
Strict adherence to the Manchester System means that
the dose rate and hence the insertion time are taken from
the standard tables for an ideal insertion. Many oncolo-
gists, however, prefer to calculate the dose rate, and
hence the insertion time, at point A by computer. The
use of computer planning and afterloading systems
allows standard dose distributions to be modified if
required by adjusting the source arrangement or dwell
times of individual source trains. Caution must be

Table 4.12 Dose rates at point A for standard Manchester loadings

6-cm uterine tube 6, 4, 4 units 34.4

4-cm uterine tube 6,4 units 34.2
2-cm uterine tube 8 units 27.3
Large ovoids 9 units 1 -cm spacer 18.3
Medium ovoids 8 units 1 -cm spacer 18.8
Small ovoids 7 units 1 -cm spacer 18.9
Large ovoids 9 units Washer 18.9
Medium ovoids 8 units Washer 19.0
Small ovoids 7 units Washer 19.0
Large ovoids 9 units In tandem 14.6
Medium ovoids 8 units In tandem 14.9
Small ovoids 7 units In tandem 14.8

The unit of source activity is 18 u.Gy h-1 (2.5 mg radium equivalent).


exercised when departing from the standard conditions.
In particular, the radiobiological effect of different dose
rates must be taken into account.
Isodose distributions produced by computer can be
used to establish afterloading source distributions which
give rise to dose distributions comparable to those pro-
duced by conventional radium systems. A remote after-
loading implementation of the Manchester System has
been described by Wilkinson et al. [21].
OTHER DOSIMETRY SYSTEMS FOR CERVICAL
CANCER
The use of Fletcher-type applicators (where shielding is
used in the colpostats to reduce the bladder and rectal
dose) with afterloading systems has been considered by
Marbach et al. [22]. Fletcher applicators require the
placement of two sources in the vagina in a manner sim-
ilar to that of the Manchester System, but the source
applicators are of a different shape from Manchester
ovoids. Shielding is placed in the upper and lower poles
of the vaginal applicators to provide rectal and bladder
shielding. The original system did not permit afterload-
ing but there are now modified designs available for
afterloading machines.
Isodose distributions can also be used to design load-
ing patterns for different types of applicator and tech-
nique, effectively tailoring the treatment volume as
defined in the ICRU Report 38 [23] to the requirements
of the brachytherapist. Excellent descriptions of the
Gustave-Roussy technique and the Creteil System are
given by Pierquin et al. [7].
The majority of techniques for brachytherapy of the
cervix give rise to a pear-shaped irradiation volume.
Some systems, e.g., the Newcastle System [24], are
designed to give a more cylindrical distribution which
can be matched more easily to external-beam irradiation.
This is achieved by replacing the two ovoids with a single,
cylindrical, vaginal applicator. It is possible to incorpo-
rate rectal shielding into the cylindrical applicator. The
Newcastle System continues to use the Manchester defin-
ition of points A and B for dose specification.
4.3.2 Carcinoma of the body of the uterus
THE MANCHESTER SYSTEM
Traditionally, a 1 cm diameter uterine tube was used in
conjunction with ovoids positioned in the vaginal for-
nices, the applicators again being loaded with radium. In
the absence of a special-purpose afterloading applicator,
a Manchester-type cervical applicator set can be used
provided that it is possible to obtain the length (up to 12
cm in extreme cases) of uterine tube required. The load-
ing patterns of the uterine tube and the ovoids differ
from treatment of the cervix, with a higher proportion of
the dose being delivered by the uterine source train.
References 47
THE STOCKHOLM SYSTEM
The traditional technique involved packing the uterus
with capsules containing radium sources known as
Heyman capsules. The uterus was stretched as these were
inserted until it was full. At the end of treatment, the
carefully numbered sources had to be removed in reverse
order from that in which they had been inserted. The
dose specification point is 15 mm from the surface of the
most lateral applicator. Lundberg et al. [25] describe an
adaptation of this technique for remote afterloading.
433 Vaginal irradiation
Vaginal applicators include cylinders of different diame-
ters, ovoids, and custom-made moulages, which may be
used to deliver a surface dose (typically 60 Gy) for treat-
ment given by brachytherapy alone.
4.4 PRACTICAL CONSIDERATIONS
The different dosimetry systems all have slightly differ-
ent philosophies and it is important not to attempt to
change from one system to another without giving due
consideration to the consequences to the patient in such
an event.
The Manchester mould and interstitial system
achieves a high degree of uniformity to a particular
treatment plane if the rules are carefully followed, but
the required source positions may sometimes be difficult
to achieve in an afterloading system. The source posi-
tioning is simpler for the Paris and Quimby systems, but
the dose specification is different.
Whichever system is used, it is essential for accurate
dosimetry that the source positions of any implant are
known precisely. They can be obtained from orthogonal
or isocentric radiographs, direct measurement from the
patient or a template, shift films or possibly computed
tomography. Poor reconstruction of source positions
will inevitably lead to poor accuracy of dosimetry.
REFERENCES
1. Coliez, R. (1923) Les bases physiques de I'irradiation du
cancer de col uterin par la CurietherapieJ. Radio!., 7,
201.
2. Patterson, R. and Parker, H.M. (1934) A dosage system for
gamma ray therapy. Br.J. Radiol., 7, 592.
3. Quimby, E. (1944) Dosage tables for linear radium
sources. Radiology, 43, 572-7.
4. Quimby, E. and Castro, V. (1953) Calculation of dosage in
interstitial radium therapy. Am. J. Roentgenol., 70(5),
739-9.
5. Pierquin, B. and Dutreix, A. (1966) Pour une nouvelle
48 Systems of dosimetry
methodologie en curitherapie; le Systeme de Paris. Endo
et plesio-radiotherapie avec preparation curietherapie
non-radioactive. Ann. Radiol., 9,757.
6. Pierquin, B., Dutreix, A., Paine, C.H.et al. (1978) The Paris
system in interstitial radiation therapy. Acta Radiol.
Oncol.,17,33.
7. Pierquin, B., Wilson, J. F. and Chassagne, D. (1987) Modern
Brachytherapy, New York, Masson.
8. Aird, E.G.A., Jones, C.H.Joslin, CAR et al. (1993)
Recommendations for Brachytherapy Dosimetry. London,
British Institute of Radiology.
9. Meredith, W.J. (ed.) (1949) Radium Dosage, The Manchester
System. Baltimore, Williams and Wi I kins.
10. Gibbs, R.and MasseyJ.B. (1980) Radium dosage: SI units
and the Manchester system. Br.J. Radiol., 53,1100-1.
11. MasseyJ.B., Pointon, R.C.S. and Wilkinson,]. (1985)The
Manchester system and the BCRU recommendations for
brachytherapy source specifications. Br. J. Radiol., 58,
911-12.
12. Quimby, E. (1932) Grouping of radium tubes in packs or
plaques to produce the desired distribution of radiation.
Am.J. Roentgenol., 27(1), 18-39.
13. Godden, T. J. (1988) Physical Aspects of Brachytherapy.
Bristol and Philadephia, Adam Hilger.
14. Anderson, LL, Kuan, H.M. and Ding, I. (1981) Clinical
dosimetry with 125I. In Modern Interstitial and
Intracavitary Radiation Cancer Management, 3rd edn., ed.
F.W. George. New York, Masson, 9-16.
15. Krishnaswamy, V. (1978) Dose distribution around an
1-125 seed source in tissue. Radiology, 126(2), 489-91.
16. Nath, R., Anderson, LL, Luxton, d.et al. (1995) Dosimetry
of interstitial brachytherapy sources: recommendations
of the AAPM Radiation Therapy Committee Task Group
No. 43. Med. Phys., 22(2), 209-34.
17. Yang, G., Reinstein, L.E., Pai, S. and Zhigang, X. (1998) A
new genetic algorithm technique in optimisation of
permanent 125 prostate implants. Med. Phys., 25(12),
2308-15.
18. Anderson, L. (1986) A natural volume-dose histogram for
brachytherapy. Med. Phys. 13(1), 898-903.
19. Langmack, K.A. and Thomas, S.J. (1995), The application
of dose-volume histograms to the Paris and Manchester
Systems of brachytherapy dosimetry. Br.J. Radiol., 68,
42-8.
20. Tod, M. and Meredith, W.J. (1953) Treatment of Cancer of
the Cervix Uteri - a Revised 'Manchester Method'. Br. J.
Radiol., 26,252.
21. Wilkinson, J.M., Moore, C.J., Notley, H.M. and Hunter, R.D.
(1983) The use of Selectron afterloading equipment to
simulate and extend the Manchester System for
intracavitary therapy of the cervix uteri. Br.J. Radiol., 56,
409-14.
22. Marbach, J.R., Stafford, P.M., Delclos, L. and Almond, P.R.
(1984) A dosimetric comparison of the manually loaded
and Selectron remotely loaded Fletcher-Suit-Delclos utero-
vaginalapplicators. In Brachytherapy 1984, Proceedings
of the 3rd International Selectron Users Meeting 1984,
ed. R.F. Mould. Veenendaal, Netherlands, Nucletron BV,
255-65.
23. International Commission on Radiological Units and
Measurements (1985) Doseand Volume Specification for
Reporting Intra-cavitary Therapy in Gynaecology, ICRU
Report 38. Bethesda, MD, ICRU.
24. Dawes, P.J.D.K., Roberts, J.T., Dean, E.M., Lambert, G.D.
and Locks, S. (1988) The treatment of cancer of the uterine
cervix using the Newcastle Afterloading System. In
Brachytherapy 2, Proceedings of the 5th International
Selectron Users Meeting 1988, ed. R.F. Mould. Veenendaal,
Netherlands, Nucletron BV, 235-9.
25. Lundberg, L.M., Mattsson, 0. and Ragnhult, I. (1988)
Remote afterloading of the uterine cavity using a
microSelectron LDRunit. In Brachytherapy2, Proceedings
of the 5th International Selectron Users Meeting 1988,
ed. R.F. Mould. Veenendaal, Netherlands, Nucletron BV,
223.
 5
Computers in brachytherapy dosimetry

ROBERT VAN DERLAARSE AND ROBERT W. LUTHMANN

5.1 INTRODUCTION utilizing computerized tomography (CT) and magnetic

resonance imaging (MRI) images, (iv) optimization of
dose distribution to the target volume, (v) evaluation of
Historically, brachytherapy treatment planning involved dose distribution using dose-volume histograms, and
the use of systems and lookup tables that allowed an (vi) combination of external-beam and brachytherapy
empirical approach toward source placement and dose distributions.
calculations [1-4]. With the introduction of treatment
planning computers came the ability to display isodose
distributions around an implant and to analyze an 5.2 FORMALISMS FOR DOSE CALCULATION
implant not only by visual evaluation of two- AROUND A SOURCE
dimensional and three-dimensional dose distributions,
but also by dose-volume histograms.
Computer-assisted dose calculations around a
Compared to a conventional low dose-rate (LDR)
brachytherapy implant are currently based upon two
treatment, high dose-rate (HDR) brachytherapy offers
formalisms: the traditional formalism [5,6] and the
two additional degrees of freedom once the catheters or
American Association of Physicists in Medicine (AAPM)
applicator have been placed: source position and dwell
Task Group 43 (TG43) formalism [7]. Both formalisms
time. By manipulating these two parameters, one can,
determine the dose to a point in medium from a single
either interactively or by computer methods, optimize
source. Basically, the AAPM Task Group 43 formalism
the dose distribution around the implant.
combines several traditional dose calculation quantities
Computerized optimization algorithms have been
into new ones, as discussed below.
developed that explicitly define the desired target dose
Using the traditional formalism, the dose rate at a
distribution and then calculate the 'optimal' dwell times
point with coordinates (r,q), Dr(r,q), can be expressed as:
and source positions required to obtain this distribution.
Optimized HDR brachytherapy is a highly conformal D,(r,Q) =Aa (U/^/pr* [G(r,e)/G(r0,00)] T(r)F(r,Q) (5.1)
type of cancer therapy.
where:
Current developments in the use of computers as
applied to brachytherapy include (i) methods for dose Aa = apparent activity in mCi.
calculation around sources, (ii) methods for source (r,)x, = exposure rate constant [R h-1mCi-1cm2]:
localization, (iii) three-dimensional visualization of for medium and low energy isotopes like
target volume, organs at risk, and dose distribution iridium-192, the value of (Gd)x depends on
50 Computers in brachytherapy dosimetry
the spectral distribution of the attenuation
of radiation filtered through the
encapsulation of the source.
/ = exposure to air kerma conversion factor
[cGy R-1] (0.8764 cGy/R-1 in air).
(m/p)tissue/air = ratio of the mass energy absorption
coefficient of tissue to that of air, where
(m/p)tissue/air=/(m/P)air,
G(r,q) = a geometry factor for the dose in point (r,q)
accounting for the distribution of the
radioactive material. For a point source,
G(r,q) = 1/r2. For a line source with active
length I, G(r,q) = b/(L r sin q) with b the
angle subtended by the active length L at
point (r,9) (Figure 5.1).
(r0,q0) = the reference point that lies on the
transverse axis of the source (q0 = 90) at
1 cm distance from the source. Thus, for a
point source, G(r0,q0) = 1 and, for a line
source, G(r0,q0) = b/I.
T(r) = tissue attenuation function (e.g., the
Meisberger function [8]). This function
accounts for absorption and scatter in
tissue along the transverse axis. For
medium or low energy isotopes, T(r) also
depends on the filtering of the radiation
through the source encapsulation.
F(r,q) = the angular anisotropy function that
accounts for the absorption and scattering
in the medium and the source
encapsulation. The function value on the
transverse axis, F(r,90), is defined as 1 for
all r values.
Figure 5.1 Illustration of the geometry used in the dose
calculation around a line source. L = active length of line source;
P( r o>q 0 ) - reference point on the transverse axis of the source;
P(r,q) = point to calculate the dose at; (3 = angle subtended by
the active length L.
For the source strength specification of sources, the ref-
erence air kerma rate (Kk) or the reference exposure rate
(Xk) is usually given:
Kk = reference air kerma rate (cGy h-1 m2), the kerma
rate in air at 1 m, disregarding air attenuation
and room scatter.
Xk = reference exposure rate (R h-1 m 2 ), the exposure
rate in air at 1 m, disregarding air attenuation
and room scatter.
In the case of a point source:
The factor 104 accounts for K k and Xk being defined at
1 m and (Fg)x at 1 cm.
The AAPM Task Group 43 [7] focuses on the dosime-
try of iridium-192, iodine-125, and palladium-103
seeds. However, the TG43 formalism is also applied to
HDR and pulsed dose-rate (PDR) stepping sources. It
recommends obtaining the dose rate in a point with
coordinates (r,q) as follows:
Where:
Sk = air kerma strength (cGy h-1 cm2): the air kerma
rate on the transversal axis at 1 cm distance
from the source, based on a measurement at a
large distance and converted to 1 cm distance by
considering the source as a point source. Thus,
this quantity is related to the reference air kerma
rate Kk(cGy h-1 m2) by the inverse square law:
S k =10 4 K k .
A = specific dose rate constant: the dose rate in
tissue per unit air kerma strength at 1 cm
distance from the source. This constant is not
based upon an idealized point source, but,
instead, is dependent upon the physical
configuration of the source.
g(r) = radial dose function: this function accounts for
absorption and scatter along the transverse axis.
Note that g(r) = 1 for r = r0 (= 1 cm).
For a point source, equation (5.3) can be obtained from
equation (5.1) by combining several traditional dose cal-
culation quantities into new ones:
Note that Sk is the air kerma rate at 1 cm on the trans-
verse axis of the source as if the source is a point source.
SkA is the real dose rate in tissue at 1 cm on the trans-
verse axis of the source. From this follows that A is also a
function of the active length of the source.

53 CALCULATING OF DOSE BY COMPUTER
To calculate dose to points around an HDR source,
either equation (5.1) or (5.3), or a mixture of both, can
be used by computer algorithms. The orientation of the
source in free space must be known in order to apply the
geometry factor G(r,q) and the anisotropy factor F(r,q).
Localization techniques that supply this information are
an essential part of any brachytherapy treatment plan-
ning system and are discussed in section 5.4.
In this section, the different dose calculation parame-
ters are discussed, with emphasis on sources used in
afterloading.
53.1 Source strength
Typically, the source strength is derived from the mea-
sured air kerma rate at 1 m, a distance much larger than
1 cm, at which distance a source is practically a point
source. The reference air kerma rate kk, defined at 1 m, is
obtained directly from this measurement. The air kerma
strength Sk is derived from Kk using Sk = 104 Kk for both a
point source and a line source. Thus, Sk is the air kerma
rate at 1 cm on the transverse axis of the source, as if the
source is a point source. The apparent activity (Aa) fol-
lows from Kk using equation (5.2), Aa = 104 Kk/[(Gd)xf].
For iridium-192 sources, Kk or Sk values should be
entered into the planning program instead of the derived
Aa values, as there are different values published for (Gd)x.
If a planning system requires the entry of apparent activ-
ity, then the same (Gd)x must be used when converting
measured air kerma rate to apparent activity as when cal-
culating dose values. Otherwise, a serious error in the
dose given to the patient may occur.
53.2 Specific dose-rate constant (A)
The specific dose-rate constant (A) is defined as the dose
rate in tissue per unit air kerma strength at 1 cm from the
source center along the transversal axis of the source. It
depends upon the physical configuration of the source,
i.e., its active length, and upon the radiation spectrum.
The latter influence is due to the tissue scattering and
absorption factor at 1 cm, T(r0), which depends on the
radiation spectrum. Thus, there will be different dose
rate constants for identical isotopes in sources with dif-
ferent physical configurations.
533 Geometry factor, 6(r,q)
Depending on the active length of a source, either a
point source or a line source should be assumed. For a
point source, G(r,q) = 1/r2 and for a line source with
active length I, G(r,q) = b(I r sin 0) with (3 the angle
Calculating of dose by computer 51
subtended by the active length L at point (r,q). The mod-
eling as a line source is of importance when calculating
dose rates at distances shorter than 2 L. If HDR stepping
sources with an active length of 3 mm or more are not
modelled as a line source, doses calculated at distances
shorter than 6 mm are less accurate [9-11].
53.4 Dose anisotropy function, F(r,q)
The dose anisotropy function, F(r,q), accounts for the
anisotropic behavior of the dose distribution around the
source, due to the self-absorption in the active material
and the attenuation in the encapsulation of the source.
The value of the anisotropy function at the distance r
from the source along the transversal axis, F(r, 90), is
defined as 1.0. The anisotropy correction can be handled
in several ways, depending upon the radiation spectrum
of the isotope and the physical form and encapsulation
of the source. Measured F(r,q) values, stored in tables,
are often fitted to functions that are used in computer
algorithms.
For sources emitting high energy radiation, such as a
cesium-137 source, the anisotropy correction for a point
P(r,q) can be calculated by subdividing the active mate-
rial in the source in small volume elements Da. For each
element Da the path ra through the active material itself
and the path rw through the source wall are determined.
This gives a correction factor exp [-(ma ra + mw rw ], with ma
the linear attenuation coefficient for the active source
material and |iw the linear attenuation coefficient for the
encapsulation material. By summing over all active vol-
ume elements Da, the correction factor C(r,q) for point
P(r,q), is found. NowF(r,q) = C(r,q)/C(r,90).
In the traditional approach of dose calculation around
radium and cesium tubes, the interval method is used.
This method divides the source in a large number of
point sources and calculates the attenuation of the rays
from each point source by the source encapsulation
[12,13]. Thus, there is no strict separation between the
geometry factor and the anisotropy factor.
For sources with medium or low range energies, an
analytical correction is not possible due to the depen-
dence of the tissue scattering and absorption on the radi-
ation spectrum. For such a source, a table with measured
values of F(r,0) or a function fitted to these values is
used. The AAPM Task Group 43 report [7] gives tabu-
lated values of -F(r,q) and G(r,q) for iodine-125, iridium-
192, and iridium-103 seeds, currently in use. Some
authors present tables which are corrected for the inverse
square law only and normalized to 1 at 1 cm distance
from the source center on the transversal axis, thus rep-
resenting F(r,q) g(r) values. The multiplication factor to
the dose in the point (1 cm, 90) to obtain the dose in
point (r,0) then becomes F(r,q) g(r)/r2 [14].
For sources of medium range energies, such as
iridium-192, there is less variation in the values of the
52 Computers in brachytherapy dosimetry
anisotropy function with distance r from the source.
Therefore, the anisotropy function in some older plan-
ning systems is taken as F(q), with F(90) again defined
as 1. It is usually implemented as F(q)/r2, with F(q) a
table with values for 0 between 0 and 180 [15].
Accurate dose values around an HDR source with an
active length of 3.5 mm are obtained by using F(q)
G(r,q), with G(r,q) applied for a line source of 3.5 mm.
These dose values are even valid for short distances up to
1 mm to the source center [9].
If the orientation of an HDR stepping source in space
is not known, then only the inverse square law with a
fixed anisotropy factor, the anisotropy constant (jan, can
be applied. The value of (jan is less than 1.
53.5 Tissue attenuation factors, T(r)
andg(f)
The tissue attenuation function, T(r), and the radial dose
function, g(r), both account for the effects of absorption
and scatter in tissue along the transverse axis of the
source. In most computer algorithms, the tissue attenua-
tion function is applied to represent the dose fall-off
along the transverse axis, due to tissue absorption and
scattering. The function T(r) is normally expressed as a
polynomial in the form of:
The parameters a; most often used are those of
Meisberger et al. [8], which are valid for the range of 1
cm through 8 cm. At depths beyond 8 cm, the above
expression decreases sharply and, at those depths, T(r) is
usually approximated by exp(m t r).
A fit function with the least number of parameters is
the modified Van Kleffens and Star function [16]:
For indium-192 the parameter a equals 0 and equa-
tion 5.8 reduces to T(r) = d(l + b r2) with 8 = 1.008 and
b = 0.0012 cm-2. Equation 5.8 coincides with the
Meisberger relation within 0.5% for sources with
medium and high range energies, such as iridium-192,
cesium-137, and cobalt-60. At depths beyond 8 cm, equa-
tion 5.8 decreases gradually and a separate exponential
attenuation function is not needed when calculating clin-
ical dose distributions around implants or applications.
5.4 RECONSTRUCTION OF SOURCE
LOCALIZATION
In order to obtain the dose distribution around an
implant or application, the exact position of each source
or dwell position in space must be known. For the recon-
struction of the source localizations by a treatment plan-
ning program, different techniques are available.
5.4.1 Specification of coordinates
If the three-dimensional coordinates of the sources or
dwell positions are known, keyboard entry of these data
can be used. This, of course, is the most accurate descrip-
tion of the source positions.
5.4.2 Localization using film imaging
techniques
If the absolute coordinates are not known, imaging
localization techniques must be used. These imaging
techniques utilize either plane radiographs taken from
different directions, or computed tomography (CT)/
magnetic resonance imaging (MRI) images of the
implant. If an afterloading technique is used, it is neces-
sary to simulate the position of the sources or dwell posi-
tions utilizing localization markers. These X-ray markers
must be (i) easily discernible on the radiograph or
CT/MRI slice, (ii) accurately depicting the source or
dwell position, and (iii) coded such that the user can
determine which markers correspond to a given catheter
or applicator. They usually consist of a thin, braided,
metal wire with markers of high Z metal at every cen-
timeter. By counting from the catheter tip, correspond-
ing images of a given X-ray marker are easily found. The
images of these markers are called catheter describing
points as the corresponding images of two plane radio-
graphs are projections of the same point in a catheter.
In implants with many catheters close to one another,
it is sometimes difficult to follow these X-ray markers. In
this case high Z wires can be inserted in each catheter up
to the catheter tip. The images of these wires, starting at
the catheter tip, are digitized from two-plane radio-
graphs. The localization in space of each catheter can be
reconstructed from its images on the two radiographs by
dedicated software. This technique is called catheter
image tracking. The points describing the curvature of
an image are called catheter image points. Contrary to
the catheter describing points, there is no direct link
between the catheter image points on the two radio-
graphs.
ORTHOGONAL RECONSTRUCTION METHOD
The most widely used radiographic method for source
localization is the orthogonal reconstruction method
[17]. Two-plane radiographs of the implant are taken in
a lateral and antero-posterior (AP) orientation. Either a
radiotherapy simulator is used or a localization box with
cross-wires on the faces of the box is placed over the
patient (Figure 5.2). In the latter case, the beams are
aligned such that the X-ray images of opposing cross-
wires coincide. The advantage of this technique is that
AP and lateral radiographs are easily interpreted by the
physician. A disadvantage is, however, that sources or
X-ray markers in the lateral X-ray film are often difficult
 Reconstruction of source localization 53

Figure 5.2 Orthogonal reconstruction. The beam set-up is
obtained by calculation of the localization of the AP and lateral
X-ray foci from the cross-wire images on the radiographs. Instead
of a reconstruction jig to adjust the AP and lateral beams, a
radiotherapy simulator with gantry angles of 0 and 90 can be
used. I - isocenter; P = point to be reconstructed.
Figure 5.3 Semi-orthogonal reconstruction. The beam set-up is
obtained by calculation of the localization of the AP and the
lateral X-ray foci from the size and the displacement of both
cross-wire images on the radiographs. I = center of box; P - point
to be reconstructed.

ISOCENTRIC RECONSTRUCTION METHOD

to distinguish, particularly in the pelvic region, due to With an isocentric X-ray unit, such as a radiotherapy
the thickness of tissue and the overlying bony structures. simulator, two images of the X-ray markers in each
catheter can be obtained on a single, large-size radio-
SEMI-ORTHOGONAL RECONSTRUCTION METHOD graph [17] (Figure 5.4). The gantry angle of the first
Truly orthogonal orientations for the AP and lateral X-ray beam is -a and of the second beam is +a, with the
film are not easily obtainable with portable X-ray units.
In the semi-orthogonal reconstruction method, a local-
ization jig with AP and lateral cross-wires is placed over
the patient and two radiographs (a lateral and AP) are
taken [18] (Figure 5.3). It is not necessary for these to
be truly orthogonal, because the set-up information
will be determined by the computer from the size and
the relative distances of the cross-wire lead marker
images on each of the two films. This method, there-
fore, accepts X-ray beams whose central axes do not
intersect and are not perpendicular to one another. The
only requirement is that the projections of the cross-
wires on the two corresponding box faces are visible on
the radiographs.
The semi-orthogonal reconstruction method has
proven to be particularly advantageous in HDR endo-
bronchial applications. Directly after insertion of the Figure 5.4 Isocentric reconstruction, a - reconstruction angle;
catheters, a portable radiographic X-ray unit can be used FID -focus to isocenter distance; IFD = isocenter to film
with the localization box to obtain the radiographs for distance; I = isocenter; P=point to be reconstructed. This method
localization of the catheters. This will shorten the time requires an isocentric X-ray unit such as a treatment simulator. A
between the insertion of the catheters and the treatment large-size film is placed under the patient. The beam set-up is
of the patient considerably, because there is no localiza- obtained by rotating the gantry over an angle of +a and -a,
tion session on a radiotherapy simulator required. with a preferably in the range of 15-30.
54 Computers in brachytherapy dosimetry
total angle (2a) between the central axes of the project-
ing beams taken as large as possible. In order to visualize
both images on this radiograph, it is essential that the
isocenter is placed in the center of the implant and that
the X-ray field is defined such that the two images on the
radiograph do not overlap.
Due to the equal angles between the left and right cen-
tral axes with respect to the normal to the radiograph,
lines between corresponding points on the left and right
image all run parallel. This aids in the determination of
individual seed or dwell positions from one image to the
other. Usually, the gantry angle of each image with
respect to the normal of the radiograph is between 15
and 30, depending on the extension of the implant and
the distance between the isocenter and the X-ray film.
STEREO-SHIFT RECONSTRUCTION METHOD
The set-up is similar to that of the isocentric method,
but, instead of the X-ray tube rotating, it is moved later-
ally over a given distance [ 17]. This method is applicable,
for instance, with a ceiling-mounted X-ray unit where
such a lateral movement is available. Usually, the angle
between the two projecting beams is very small, typically
7, which makes this method very sensitive to even small
errors in the measuring of the source images or a small
movement of the patient between the taking of the radi-
ographs. If possible, this reconstruction method should
be avoided.
VARIABLE ANGLE RECONSTRUCTION METHOD
This method reconstructs the localization of the
catheters from two radiographs taken with a therapy
treatment simulator [19] (Figure 5.5). The only limita-
tion is that the central axes of the projecting beams are
not coinciding or opposing. The reconstruction algo-
rithm requires that the angle, focus-isocenter distance,
and isocenter-film distance of each radiograph are accu-
rately known. The advantage of this technique is that the
implant can be observed fluoroscopically at various
gantry angles to define the two gantry angles that display
the sources or localization dummies with the highest
clarity and least obstruction. It is preferred that the total
angle between the two projecting beams lies between 60
and 120. Of course, the greatest accuracy is obtained
when this total angle is 90. The orthogonal reconstruc-
tion method is a special case, e.g., with gantry angles 0
and 90.
RECONSTRUCTION METHODS USING
CORRESPONDENCE LINES
A digital image can be obtained by scanning a radi-
ographic film with a film scanner or, in real time, by a
portal imaging device mounted on the X-ray equipment.
These images are then displayed on the treatment plan-
ning computer which has options to enhance them to
Figure 5.5 Variable angle reconstruction. a=gantry angle
beam 1; b=gantry angle beam 2; FID 1 -focus to isocenter
distance beam 1; IFD 1 = isocenter to film distance beam 1; FID 2
=focus to isocenter distance beam 2; IFD 2 = isocenter to film
distance beam 2; I = isocenter. The two gantry angles a and b
are determined such that the catheters are clearly visible on the
image intensifier. The total angle a+b should preferably lie
between 60 and 120. The radiographs are made with the film
in the cassette holder on top of the image intensifier.
better delineate the source or X-ray marker positions, the
target volume, and the surrounding organs. A problem
exists with imaging equipment such as image intensifiers,
where the image may be distorted by the cushion effect
and the influence of the earth magnetic field, which will
change with the gantry angle. To minimize these effects,
the implant should be kept in the center of the image.
Of course, the reconstruction methods based on two
radiographs taken at different directions can still be used
by replacing the digitizer with the mouse. However, if
both digitized films can be displayed together on the
monitor, an extension of the variable angle reconstruc-
tion method becomes possible. By pointing with the
mouse to a point on one of the digitized films, the plan-
ning program can draw the ray from the corresponding
X-ray focus to that point. The other X-ray focus will pro-
ject that ray to the other film as a line over it. This line on
the second film is called the correspondence line to the
point on the first film (Figure 5.6). Thus, by moving the
mouse over one of the digitized films to the image of an
X-ray marker, the correspondence line moves over the
other film until it intersects the other image of this
marker. In this way the corresponding images in both
radiographs are easily found and reconstruction meth-
ods based on catheter describing points can be used.
5.43 Tracking of catheter images
Sometimes, visually matching of X-ray markers on the
two localization radiographs is not easily done, as in the

Figure 5.6 Reconstruction using correspondence lines. C1 and
C2 are images of the same X-ray marker in the catheter. [1] and
[2] are the films obtained by variable angle reconstruction. They
are digitized by a film scanner and displayed on the monitor.
After entering marker image C2 on film 2, the ray of focus 2 to C2
is projected to film [1] as the correspondence line of C2. The
intersection of this projection with the catheter image on film 7
gives the point C1. The intersection of the rays focus 2-C2 and
focus 1-C1 gives the reconstructed localization of the marker in
the catheter. Similarly, if C1 is entered, the corresponding image
C2 on film 2 can be found. With this method, corresponding
image points can be found without the use of an X-ray marker in
the catheter.
case of implants with many catheters. In a lateral radi-
ograph only a cloud of X-ray markers is visible, but not
the braided metal cables. In such an implant, continuous
radio-opaque wires should be used instead of the X-ray
markers.
As stated earlier, the isocentric reconstruction method
connects corresponding catheter describing points
between the two X-ray images with parallel lines. The
localization of a catheter in space from its two images on
the isocentric film is reconstructed as follows. First, the
two X-ray images of the catheter are described with
catheter image points. If on both X-ray images the
catheter tip is clearly visible, the line connecting these
tips is taken as the horizontal base line. This corrects for
any patient movement between the taking of the two
exposures. Otherwise, the line connecting the images of
the isocenter is taken as the horizontal base line.
With appropriate software, any set of variable angle
radiographs taken with the same focus isocenter distance
can be converted to a computer-generated isocentric
'radiograph' (Figure 5.7). Then each point with which a
catheter image is described can be connected by the
planning software to its corresponding point on the
other image by a line parallel to the one connecting
the images of the catheter tip.
This conversion of the variable angle reconstruction
to the isocentric one is not possible with the semi-
Reconstruction of source localization 55
orthogonal reconstruction method. In the case of after-
loaded sources or of stepping source dwell positions in a
catheter, image tracking reconstruction can still be used
[ 19]. Again, the tip of each catheter needs to be visible on
both images. Subsequent points on each image are
placed such that they describe the curvature of the
image. Each one of the two catheter images is then digi-
tized, starting with the tip, until a point beyond the last
source or dwell position is entered. The advantage of this
technique is that the points depicting the image on the
first radiograph are not corresponding to the ones on the
second radiographic image. Thus, any radio-opaque
marker (e.g., any flexible metal cable) can be used to
depict the catheter. This technique simplifies the data
entry into the planning system, but is less accurate in
handling any patient shift between the taking of the two
radiographs, as is discussed in the section on reconstruc-
tion accuracy below.
Digital images from CT or MRI scanners are also used
for treatment planning. Usually, a series of parallel,
transverse slices through the treatment volume and its
surroundings is obtained. The digital images are dis-
played on the monitor of the treatment planning com-
puter, which has options to enhance them to better
delineate the source or X-ray marker positions, the tar-
get volume, and surrounding organs. They are distin-
guished by their position along the caudal-cranial axis
along the CT table top. The coordinates of an image of
a source or X-ray marker can be obtained with a point-
ing device such as a mouse. Reconstruction of the
localization is straightforward; the x-coordinate and
y-coordinate are obtained directly from the mouse
coordinates and the 2-coordinate is given by the table
position of the slice.
5*4.4 Reconstruction accuracy
ACCURACY OF THE DIFFERENT RECONSTRUCTION
METHODS
The most accurate reconstructed catheter or source
coordinates are obtained when the central axes of the
two projecting beams are perpendicular to each other.
This is achieved by the orthogonal reconstruction
method or by the variable angle method when the gantry
angles differ by 90 (or 270). The accuracy remains high
if the angle between the two beams lies in the interval
(60-120). A reconstruction set-up which uses an angle
outside that interval, thus smaller than 60 or between
120 and 180, becomes sensitive to patient shifts
between the taking of the radiographs and to digitizing
errors. The stereo-shift reconstruction method is
extremely sensitive to digitizing errors, due to the small
angle between the two projecting beams, up to 10, and
should be used with great care [17]. The reconstruction
accuracy depends also on the use of X-ray markers.
56 Computers in brachytherapy dosimetry
RECONSTRUCTION USING a OR MRI SLICES
The main factor determining the accuracy of the recon-
structed localization is the slice spacing, the distance
between consecutive slices. A typical value of 4 mm
results in an accuracy of 2 mm in that direction. The
choice of the material for the catheters and the X-ray
markers is also essential because dense high Z material
will introduce artifacts in the scan.
RECONSTRUCTION USING CATHETER DESCRIBING
POINTS
The localization in space of a catheter describing point
from its two X-ray images is defined by constructing the
two rays projecting the catheter describing point to its
X-ray images. These two rays will not intersect because
there will always be some movement of the patient
between the taking of the two radiographs. The recon-
structed localization of the catheter describing point is
taken halfway on the line connecting the two rays along
their shortest distance (Figure 5.8). Thus, if the patient
Figure 5.7 Variable angle
reconstruction using isocentric
pseudo-film. The intersections
of the rays to the catheter
image points with a
computer-generated isocentric
plane are determined.
Corresponding images on the
pseudo-film are all connected
by parallel lines. This method
is suitable for reconstruction
of implants with flexible
catheters using a therapy
simulator. If the patient shifts
between the taking of the
radiographs, lines between
corresponding images are
parallel to the line connecting
the images of the catheter tip.
moved a certain distance between the taking of the two
radiographs, the resulting error in localization of the
catheter describing point is only half that distance.
RECONSTRUCTION USING CATHETER IMAGE
TRACKING
The accuracy of image tracking reconstruction depends
strongly on any movement of the patient between the
taking of the two films. Because the projections of the tip
of a catheter on both radiographs are usually visible, the
shift of this catheter due to a patient shift between the
taking of the two radiograph images can be determined.
One of the images can then be adjusted by the planning
system such that the rays from the X-ray foci to these
first image describing points intersect. However, a rota-
tion of the patient cannot be taken into account and will
result in an error in the reconstructed localization of the
source or wire. With catheter image tracking, the error in
catheter localization due to a given patient movement is
about twice the error obtained with catheter describing
points.

Figure 5.8 Correction for patient shift between thetakingof
radiographs 7 and 2. To find the localization of an X-ray marker,
the shortest distance between the rays to the corresponding
images of this marker is determined. The reconstructed
localization of this marker is placed midway on the line along
this shortest distance.
5*5 OPTIMIZATION TECHNIQUES IN
STEPPING SOURCE BRACHYTHERAPY
Once the catheters are placed in the patient, stepping
source brachytherapy offers two degrees of freedom: the
dwell position and the dwell time. Usually, the dwell
positions are placed in the sections of the catheters that
are inside the target volume. Then optimization of the
dose distribution is performed by manipulation of the
dwell times either by the user or by dedicated software.
Most optimization procedures do not determine the
absolute dwell times for each dwell position. Instead,
they result in a set of relative values for the dwell times in
the range 0.0-1.0 with a corresponding set of relative
dose values in the dose points. Another module of the
treatment planning program calculates the absolute
dwell times for the stated mean dose in these dose points.
There are several factors which influence a mathemat-
ically optimized dose distribution. For example, due to
the radial nature of radiation from a point source, it is
not possible to obtain along the axis of a catheter a pre-
scription isodose curve in the shape of a box. Also, if the
placement rules for the catheters of a given target vol-
ume are not adhered to, it is difficult, if not impossible,
to obtain a good dose distribution. Or, if an implant is
not covering the target volume geometrically, manual
changing of relative dwell times may be required to cover
the target volume with the prescription isodose surface.
Thus, a mathematically optimized dose distribution does
not always represent the best possible one in and around
an implant. Finally, different types of optimization algo-
Optimization techniques in stepping source brachytherapy 57
rithms with varying user-defined constraints may all
deliver different dose distributions. Therefore, clinical
experience will always be needed to judge the mathemat-
ically optimized dose distribution for actual patient
treatment. Based on that judgement, changes may be
made in the optimization constraints, resulting in a new
optimized dose distribution, before the final dose distri-
bution will be accepted for clinical use.
5.5.1 Distance and volume implants
In mathematical optimization, two types of implants are
distinguished: distance implants and volume implants.
In a distance implant, dose points are placed at a given
distance around the catheters. The mathematical opti-
mization aims at determining the dwell positions and
relative dwell times such that the prescription isodose
surface passes through these dose points [ 16,20,21]. This
is called 'optimization on distance.' Examples of distance
implants are single catheters, double catheters, and
single-plane implants. If digital imaging with transverse
slices is used, these so-called dose points can be placed
equidistantly on the target contours in the displayed
cross-sections of the patient. With reconstruction by
radiographic films, dose points can be placed only rela-
tive to the catheters.
A volume implant contains one or more planes of
catheters. Series of dose points are placed inside the tar-
get volume midway between the catheters and through-
out the implant. In a volume implant, the relative dwell
times are optimized to the same dose in these dose
points. This is called 'optimization on volume' [16,21].
The prescription dose is defined as a given percentage of
the mean dose in these dose points, with the prescription
isodose surface encompassing the target volume as
closely as possible. However, the above definition of opti-
mization of volume is a gross simplification. The place-
ment of dose points midway between the catheters alone
is not sufficient for optimization (Figure 5.9).
In cases in which dose point placement is complicated
due to irregularities in the distances between implanted
catheters, the dwell positions themselves can act as dose
points for optimization. This technique is called 'geo-
metric optimization' and can be performed either on
distance or on volume [16,23].
5.5.2 Rules of optimization
Once a stepping source implant is optimized, it can be
evaluated by the following rules.
Rule 1. The optimized isodose distribution should
match the requirements specified by the physician. In
the case of a distance implant, the prescription isodose
surface should pass as closely as possible through each
of the defined dose points. For a volume implant, the
58 Computers in brachytherapy dosimetry

Figure 5.9 Distance

optimization of a volume
implant. A two-plane implant
with five parallel catheters is
optimized to the same dose in
rows of dose points, placed
midway between the catheters. A
perfect fit is obtained by only
activating the central catheter. If
the sum of the squares of the
dwell times is minimized, the
central catheter is switched off.
Dwell positions 1-13 in each
catheter; step length 0.5 cm;
reference air kerma rate 4.0682
cGy h-1 m2, i.e., 10 Ci iridium-192.
: Active source dwell position;
O: Inactive source dwell
position; : Dose points, midway
between catheters along 6 cm
active length.

dose in the volumes midway between the catheters
should be as homogeneous as possible throughout the
implant.
Rule 2. The shape of the isodose surface close to the
applicator or catheters should be smooth and resemble
as closely as possible the shape of the isodose surfaces at
distances further from the catheter.
Rule 3. Active dwell positions should not extend
outside the target volume.
Rule 4. Optimization algorithms should be fast
enough to keep the time between the application and
treatment to a minimum.
The first rule of optimization addresses the optimiza-
tion goals of a distance and a volume implant. The sec-
ond rule aims at the minimization of hot or cold spots in
the implant, especially close to the active dwell positions.
The third rule requires the active dwell positions to
remain within the target volume, because extending
beyond this boundary would increase dose to healthy tis-
sue. To satisfy this rule, the most distal dwell positions
must be increasingly weighted to account for the lack of
contributions of dose from adjacent dwell positions. The
fourth rule minimizes the hardship to the patient by
keeping the time that the catheters or applicators remain
in the patient to a minimum.
5.53 Optimization of distance implants by
least square minimization
The aim in optimization of a distance implant is to have
the prescription isodose surface pass at a given distance
from the dwell positions along the catheter(s). To
accomplish this, dose points are placed at this distance
from the implant, relative to the successive dwell posi-
tions.
To obtain the best combination of dwell positions and
relative dwell times, a mathematical object function
must be minimized. This consists of the difference
between the actual dose calculated at each dose point
and the ideal dose requested. Usually, this optimization
problem is addressed by least squares minimization. In
that case, if there are N dose points, each receiving a dose
contribution from M sources (active dwell positions),
then the following least squares function is to be mini-
mized [16,21]:
where N is the number of dose points, Dpi is the pre-
scribed dose to point i, and Dci is the calculated dose to
point i. (See the equations representing the prescribed
doses, Dpi, in Figure 5.10.)

The dose Dci to a dose point i from each source j is cal-
culated by using equation 5.3 for a point source:
where
Sj is the source strength of source j: Sj = (Sk A)j
tj is the time that source j stays at distance ri,j
C( r i,qi,j) combines the radial dose function and the
anisotropy function:
Ai,j is the dose contribution in point i from dwell
position j for tj = 1.
In the case of a stepping source implant, the source
strength Sj for all j sources is the same. Thus, the only
variable that can be altered to minimize equation 5.9 is
the dwell time tj at each dwell position j.
x2 can be minimized by setting its derivative to each tj
toO:
In this way, M equations are obtained which are linear
in their M unknown tjs. There are a number of mathe-
matical procedures available to solve these equations.
This results in a set of values for the tp. A problem arises
when there are fewer dose points than dwell positions.
Then, the set of equations is underdetermined and many
mathematical solutions exist. To arrive at a unique solu-
tion, an additional criterion must be supplied.
Intuitively, a suitable criterion would be to minimize the
sum of the squares of the relative dwell times, thus
Optimization techniques in stepping source brachytherapy 59
Figure 5.10 Optimization on distance
of the dwell times in a straight catheter
to prescribed doses in dose points along
the catheter. Dpi=prescribed dose in
dose point i; Dcj = calculated dose in
dose point i; Au = dose in point if mm
dwell position] for tt = 1, see equation
5.10. The Chi-square function x2 is
minimized by setting the derivatives
8%V8f,for each dose point i to 0 and
solving the resulting set of equations.
suppressing wildly varying values. The method of singu-
lar value decomposition (SVD) contains this additional
criterion [24]. The SVD method minimizes the least
square differences between prescribed and calculated
dose in the dose points. If there are fewer dose points
than relative dwell times (i.e., fewer equations than vari-
ables), SVD also minimizes the sum of the squares of the
relative dwell times in order to arrive at a unique solu-
tion.
DWELL TIME GRADIENT
When a set of equations linear in tj is solved, negative rel-
ative dwell times may result. For example, in Figure
5.11 (a), an endobronchial application is simulated by a
single catheter with 25 dwell positions. It is optimized
using 25 corresponding dose points at a lateral distance
of 1 cm from each dwell position. The solution which
gives exactly the prescribed dose to the dose points
results in large positive and negative values for the rela-
tive dwell times in adjacent dwell positions. This is unac-
ceptable because large fluctuations will cause hot and
cold spots (a violation of the second rule of optimiza-
tion) and negative relative dwell times are a physical
impossibility. An unacceptable solution to this problem
is to set all negative relative dwell times to zero. In doing
so, the calculated dose in the dose points changes con-
siderably, which will offset the requirement of an equal
dose to each dose point.
A solution to prevent these negative and strongly fluc-
tuating relative dwell times was developed by Van der
Laarse et al. [16,19-21]. By gradually suppressing large
fluctuations of dwell times in adjacent dwell positions,
the negative relative dwell times must eventually all
become positive, because in the limit situation where all
dwell times are equal, they are positive (Figure 5.1 Ib). To
60 Computers in brachytherapy dosimetry
Figure 5.11 The influence of the dwell time gradient restriction
on the dwell times of a straight catheter implant optimized on
distance. By restricting the difference between the dwell times of
adjacent dwell positions, an optimized solution with positive or
zero dwell times is obtained, (a) Optimized relative dwell times
where there is no dwell time gradient restriction (DTGR) imposed
on dwell times of adjacent dwell positions. The maximum
difference of successive dwell times is nearly 2, the limit value.
(b) Optimized relative dwell times with a small DTGR of 0.01.
The maximum difference of successive dwell times is reduced to
1.2. (c) Optimized relative dwell times with a DTGR of 0.18. The
maximum difference of successive dwell times is 0.4. All dwell
times are positive or zero, so this represents the best possible fit
of an isodose line through the dose points.
implement this limitation of the variance of relative
dwell times between adjacent dwell positions, the so-
called dwell time gradient restriction was developed. The
dwell time gradient restriction is applied to equation 5.9
as follows:
where w is the weighting factor for the dwell time gradi-
ent restriction. This expression remains linear in tj so x2
can be minimized as given by equation 5.11.
By increasing the weighting factor, w, the dwell time
gradient in adjacent dwell positions is reduced. This, in
turn, reduces the likelihood and magnitude of negative
relative dwell times (Figure 5.lib). The minimum value
for the weighting factor is the one that makes all values
of the relative dwell times positive or zero. As previously
stated, the concept of the dwell time gradient is based on
the second rule of optimization, which requires that the
isodose surfaces remain as close in shape as possible as
they get closer to the catheters. Thus, by requiring a
smooth transition of relative dwell times along the
catheters, smooth isodose surfaces will be obtained with
a minimum of hot and cold spots close to the catheters.
POLYNOMIAL OPTIMIZATION
Optimization of a distance implant by setting the deriv-
atives of x2 to each tj to 0 results in M equations with M
unknown tp. Thus, in an M x M coefficient matrix, with
M being the number of active dwell positions, large
implants may exceed the available memory of the plan-
ning computer. For example, an implant with 500 active
dwell positions requires the planning computer to solve
500 equations with 500 unknown tjs. Also, the computa-
tion times may become unacceptably long.
The dwell time gradient also offers a solution to this
problem. Because the differences between successive rel-
ative dwell times are smoothed, the relative dwell times
in a given catheter can be approximated by a continuous
function t(x) with x the distance to the catheter tip [16].
Thus, the relative dwell time at dwell position j with a
distance xj from the tip, is given by tj = t(xj). For t(x), a set
of polynomial functions, Pm(x), to the order m can be
taken, similar to describing a continuous curve by a
Fourier series expansion to a given order. Thus:
where m is the index, indicating the order of the polyno-
mial Pm(x), am is the mth parameter, Pm(x) is the polyno-
mial of order m, and p is the number of parameters
required for an adequate approximation of tj by t(xj at all
dwell positions x}. By inserting equation 5.13 into equa-
tion 5.12, x2 is now expressed as a function of the p para-
meters am instead of the M relative dwell times tj.
Minimizing of x2 is again obtained by setting the deriva-
tives dx2 da m to 0. This leads to a p x p coefficient matrix
instead of the M x M one when the derivatives of x2 to tj
are taken.

Figure 5.12 Relative dwell times as in Figure 5.Tib, with just
sufficient dwell time gradient restriction but now parameterized
in terms of distance along the catheter. t(x) is approximated by
polynomials P(x) to the degree m with m<M.
Take as an example a catheter with 33 active dwell
positions (Figure 5.12). The value of p will be much
smaller than 25 because, due to the dwell time gradient,
the dwell times are interrelated. A suitable value of p is
given by p = 2 m - 1. Thus, the set of 25 tjs can be
described by nine parameters, am. This reduces the mem-
ory requirements by a factor of 8, from 25 x 25 to 9 x 9.
5.5.4 Optimization of distance implants by
linear programming
Linear programming, as applied to stepping source
brachytherapy, solves the problem of minimizing a func-
tion linear in the dwell times, subject to a finite number
of constraints. These constraints are again linear in the
dwell times. The problem is formulated mathematically
as follows [25]:
In the case of a distance implant, one can construct
circles with a given radius around each dwell position
which are perpendicular to the catheter. The radius of
the circles is the distance to the prescribed dose. Dose
points are placed on the circles at equal angle intervals,
e.g., every 15. The calculated dose, Dci, in each dose
point i is required to be at least equal to the stated pre-
scription dose Drep thus Dci > Dref. Using equation 5.10,
this translates in equation 5.14 to ay= C(r i,j qi,j)
and b = Dref, again M being the number of dwell positions
and N the number of dose points. If as object function
M
is minimized, taking cj = 1, the treatment is opti-
Optimization techniques in stepping source brachytherapy 61
mized to the shortest overall time possible, with positive
or zero dwell times and with the doses in the dose points
at least equal to the prescription dose [26].
A disadvantage of this technique is that the dose dis-
tribution is solely defined by these dose points, with no
regard to the dose distribution close to the catheters.
This may conflict with rule 2 of optimization, which
states that isodose surfaces near the catheters should be
smooth and resemble as closely as possible the shape of
the isodose surface through the dose points. Thus,
implants optimized by equation 5.14 often show the
occurrence of hot and cold spots at distances close to the
catheters. Of course, this is not a problem when opti-
mizing a vaginal cylinder application, where the dose
inhomogeneities are within the plastic of the applicator.
However, for an endobronchial implant, these volumes
with high and low doses are within the target volume.
Note. The concept of minimum dose points on circles
with a given radius around the dwell positions can also
be applied using least squares optimization. First, evenly
spaced dose points are constructed on the circle around
each dwell position, perpendicular to the catheter. The
radius of the circle is the distance to the prescribed dose.
Then, all relative dwell times of the active dwell positions
are set to unity and the doses in these dose points are cal-
culated. Finally, for each circle around an active dwell
position, the point with the minimum dose is found and
stored. These points with minimum dose will always lie
in the area of lowest dose, even after optimization. They
define the surface of the treatment volume. The points
with minimum dose are now taken as dose points for
the polynomial optimization technique, previously
described. This technique has the advantage of minimiz-
ing the effort of placing the dose points, like in the linear
programming approach, but overcomes the problem of
irregular isodose surfaces close to the catheter by apply-
ing the dwell time gradient restriction.
5.5.5 Optimization of distance implants by
simulated annealing
Another optimization technique suitable for brachyther-
apy treatment planning is simulated annealing. This
technique solves the optimization problem in a stochas-
tical way, using a directed random search for the dwell
times to seek the lowest value for an object function such
as defined in equation 5.14 [27]. Simulated annealing
proceeds iteratively as follows:
1. An initial solution (set of dwell times and/or source
positions) is chosen and evaluated using the
objective function.
2. A new solution is constructed from the current one
by varying the dwell times in a random direction
and by an amount which is initially large but
decreases sufficiently slowly so that a global
minimum can be found. If the new solution is
62 Computers in brachytherapy dosimetry
better, it replaces the current one. If it is worse, it is
accepted with a probability that depends on the
difference from the current one and on the size of
the change in dwell times.
3. The process iterates with the amount of change in
dwell times being reduced sufficiently slowly such
that the system can search out the region in solution
space containing the global optimum and converge
to it.
This method has been applied by Sloboda [28,29] for
planning low dose-rate treatments with trains of active
and non-active pellets in the catheters. In this case, a step
is performed by switching an active position to an inac-
tive one, or the reverse. An evaluation of different imple-
mentations of simulated annealing in brachytherapy is
given by Wehrmann et al. [30].
5.5.6 Optimization of volume implants
A volume implant is any implant with two or more
planes. Polynomial optimization of a volume implant
aims to make the dose in the volumes midway between
the catheters as homogeneous as possible. This opti-
mization cannot be based on dose points alone. If dose
points are placed only outside a volume implant, the
inner part of the target volume will be underdosed
because the outer dwell positions will be used mainly to
deliver the required dose to these dose points. This is due
to the inverse square dependency of the dose on the dis-
tance and to the minimization of the overall time by the
optimization procedure. It is explained in a similar way:
that the periphery will be underdosed if points were
placed midway between the catheters. Of course, it is
possible to place dose points inside the implant and
around it at a given distance. However, except for very
regular implants, it is not possible to determine the rela-
tion between the doses in the inner points and in the
outer ones. It is obvious, therefore, that in optimization
Figure 5.13 Geometric optimization (GO) of a two-plane American-type implant with six catheters. Separation between the sources in
the catheters is about equal to the distance between the catheters. Calculation is midway between the planes, (a) No optimization.
Note the hot spot where the catheters converge, (b) Geometric optimization.
of volume implants additional constraints are required.
These are provided by applying polynomial optimiza-
tion with constraints obtained by geometric optimiza-
tion.
GEOMETRIC OPTIMIZATION ON AMERICAN
VOLUME IMPLANTS
Geometric optimization is an alternative approach to
optimization on dose points. It is based solely on the
dwell positions on the assumption that they represent
the target volume. Originally, it was applied only to those
stepping source implants for which the spacing between
the dwell positions (the intracatheter spacing) is about
equal to the spacing between the catheters (the inter-
catheter spacing), typically 1-1.5 cm [16,23]. This type
of implant is performed mainly in the USA. It results in
an equidistant, three-dimensional grid of dwell positions
in the target volume (Figure 5.13).
The basic assumption underlying geometric opti-
mization is that the dwell time in a dwell position is
inversely related to the dose given in that position by the
other dwell positions [23]. Take, for example, a dwell
position at the border of the target volume. It requires a
larger dwell time than a dwell position in the center,
because it is further away from the other dwell positions
which all contribute according to the inverse square of
their distance (Figure 5.13).
Geometric optimization in treatment planning soft-
ware is based on the following two suppositions: (1) the
dwell time at a dwell position is inversely proportional
to the dose delivered by the other dwell positions; and
(2) the dose given by another dwell position is inversely
proportional to the square of its distance. So the influ-
ence of source geometry and tissue scatter is disre-
garded, i.e., the factor C(ri,j, qi,j) in equation 5.10 is
assumed to be constant. Thus, the dose in a given dwell
position i is inversely proportional to the sum of the
inverse square of the distances from that point to all

other dwell positions j. So the relative dwell time tt at
position i becomes
with ri,j the distance between dwell positions i and j, and
M the number of dwell positions.
Note the following:
1. Using the inverse square of distances as doses in
equation 5.15 is a simplification, but acceptable for
iridium-192 or cobalt-60 sources. Of course, the sum
of the actual dose contributions from the other
dwell positions can also be used.
2. The optimized dwell time in a given dwell position is
mainly determined by the dose contribution from its
nearest neighbors.
3. Only relative dwell times are determined and one or
more dose points are still required to define the
prescription dose.
An obvious advantage of this technique is its simplic-
ity. However, this algorithm relies on good geometry of
the implant itself and on the intracatheter spacing being
about equal to the intercatheter spacing. When catheters
converge, the algorithm tends to overcompensate by
reducing the dwell times too much. Therefore, the con-
tribution from any dwell position at a distance less than
a given threshold distance is ignored. On the other hand,
when the intercatheter distance is larger than the intra-
catheter one, the intracatheter distances dominate the
dwell time calculation and the separation between the
catheters is insufficiently taken into account.
GEOMETRIC OPTIMIZATION ON EUROPEAN
DISTANCE IMPLANTS
Interstitial brachytherapy in Europe is based on continu-
ous wires of iridium-192, usually with interwire spacing
of 1.5-2 cm [3,4]. In stepping source dosimetry, these
continuous wires are replaced by a source stepping in the
catheters with a step length of 2.5 mm or 5 mm. Thus, in
a European-type implant with intracatheter spacing of 5
mm, the intercatheter spacing is two to four times larger.
If geometric optimization is used as described above,
then the nearest dwell positions are always located in the
same catheter unless another catheter approaches within
the step length. Because the optimized dwell time in a
given dwell position is mainly determined by the dose
contributions from its nearest neighbors, this results in a
cylindrical dose distribution around each catheter, simi-
lar to the ones obtained with polynomial optimization
on distance with dose points placed laterally at 1 cm. So
the geometric optimization procedure as performed on a
USA volume implant results in optimizing on distance
on a European implant. When applied on European-type
implants, this technique is called geometric optimization
on distance (Figure 5.14).
Optimization techniques in stepping source brachytherapy 63
(I)
Figure 5.14 Geometric optimization on distance. The relative
dwell time = 1/dosefrom all other dwell positions. (1) High dose
contribution from both catheters. (2) High dose contribution,
mainly from both neighboring dwell positions. (3) Low dose
contribution, mainly from left neighbors. Thus, t1= t2 < t3.
Geometric optimization on volume. The relative dwell time =
1/dosefrom dwell positions in other catheters. Dose
contributions by other catheter (1) - high, (2) = medium, (3) -
low. Thus, t1< t2 < t3.
GEOMETRIC OPTIMIZATION ON EUROPEAN
VOLUME IMPLANTS
To optimize a European-type volume implant, a varia-
tion called geometric optimization on volume was devel-
oped [21]. This variation uses in equation 5.15 only the
distances between the dwell position i in the current
catheter k and all dwell positions j in the other catheters.
If a given dwell position in a catheter is at a large distance
from the ones in the other catheters, the dose contribu-
tion will be small, resulting in a large dwell time. This
will substantially increase the dose in the volume
between the dwell position and the other catheters
(Figure 5.14). The consequences of geometrical opti-
mization in pulsed dose-rate brachytherapy on
European volume and distance implants are discussed in
detail by Berns et al. [22]
Although geometric optimization on volume does not
require dose points, they are still required for the defini-
tion of the prescription dose. For a regular volume
implant, the best position for the dose points is in the
central transversal plane midway between the catheters.
The prescription dose is then based on a given percent-
age of the mean dose in these dose points. A percentage
of 90 is required for a distance of about 3 mm between
the outer catheters and the prescription isodose line in
the central transversal plane. A more detailed discussion
about the prescription dose of an optimized implant is
given in section 5.7.6.
Geometric optimization alone of a European volume
implant does not always suffice (Figure 5.15). It is not
strong enough to keep all dwell positions inside the tar-
get volume. At the outer ends of the catheters, active
dwell positions are needed on or even outside the target
surface. In the next section, a combination of geometric
and polynomial optimization is presented where all
active dwell positions are located inside the target
volume.
64 Computers in brachytherapy dosimetry

Figure 5.15 Intraluminal implant, optimized on distance, (a) Polynomial distance optimization on dose points placed at 1 cm
distance in region of minimum dose, away from the other catheter. Note that the WOO cGy prescription isodose runs through all dose
points, (b) Geometric optimization on distance of a European-type implant. The 1000 cGy prescription isodose is taken as the mean of
the dose values in the dose points. Note that the geometric optimization undercorrects when catheters coincide.

POLYNOMIAL OPTIMIZATION ON VOLUME target volume V = L x W x T a s a function of L, W, and

T, with L the length, Wthe width, and T the thickness of
As previously stated, European volume implants cannot
the target volume. The active lengths extend outside the
successfully be optimized based on dose points midway
target to correct for the bending of the prescription iso-
between the catheters alone. However, if an additional
dose surface in between the catheter ends. This is
constraint, supplied by geometric optimization on
because the Paris System applies wires of constant linear
European volume implants, is added to the least squares
activity and does not place a crossing catheter at the end
function x2 in equation 5.12, optimization on volume is
of the implant, as is done, for instance, in the Manchester
achieved [21]. This two-step process is called polynomial
System with a needle implant.
optimization on volume. In the first step, the geometric
As already described, the high dose-rate treatment of
optimization on volume is used to obtain the total rela-
volume implants is performed with a source stepping
tive dwell time for each catheter. The additional con-
through a set of catheters or needles. Thus, the Paris
straint now requires that the total relative dwell time for
Dosimetry System can easily be adapted to high dose rate
each catheter remains equal to the one obtained by geo-
by applying equidistant dwell positions with equal dwell
metric optimization. Thus, the total dwell time in each
times. If, however, the dwell times at the longitudinal
catheter, determined by geometric optimization, is redis-
ends of the catheters are increased by polynomial opti-
tributed by polynomial optimization in such a way that
mization on volume, the active dwell positions, even at
the dose points midway between the catheters all receive
the longitudinal ends, are kept inside the target volume.
the same dose.
This adaptation of the Paris System is called the Stepping
Polynomial optimization on volume is an essential
Source Dosimetry System (SSDS) [16,31].
part of the Stepping Source Dosimetry System, which is
The SSDS uses the same rules for implantation as the
presented in the next section.
Paris Dosimetry System, except that the active lengths in
the catheters remain within the target surface, even at the
longitudinal ends. Dose points are placed midway
5.6 THE STEPPING SOURCE DOSIMETRY
between the catheters over the whole length of the
SYSTEM
implant. When an implant is very regular, for example
when templates are used to maintain the prescribed dis-
Before the use of computers in brachytherapy, the Paris tances between the catheters, the first and the last dose
Dosimetry System was developed as a low dose-rate point of each row midway between the catheters should
dosimetry system using afterloading of iridium-192 be discarded. The SSDS applies polynomial optimization
wires with equal linear activity into thin flexible on volume to obtain the same dose in these dose points.
catheters or rigid needles [3,4]. For a given target vol- Originally, the SSDS defined the prescription dose as
ume, the Paris System gives rules on how to implant a 85% of the mean dose in these dose points [16,31]. As
 Dose-volume histograms 65

discussed in section 5.7.6, where non-optimized and
optimized implants are compared, the prescription dose
is best defined as 90% of the mean dose in the dose
points.
5.6.1 Summary of the Stepping Source
Dosimetry System
A comparison of an isodose distribution for a breast
implant using the Paris System and the SSDS is shown in
Figure 5.16. The optimized dose distribution shows a
more homogeneous dose distribution inside the target
volume and an appreciable dose reduction outside it. A
more graphical and quantitative approach for the evalu-
ation of a dose distribution is given by its differential or
natural volume dose histogram, presented next.

The following parameters are used in the SSDS:

L =
length of the target volume 5.7 DOSE-VOLUME HISTOGRAMS
T =
thickness of the target volume
S =
spacing between the catheters
Dose-volume histograms (DVHs) play an important
M =
the safety margin around an implant: it is the
role in evaluating the dose distribution in and around an
distance between the prescription isodose and
implant [32,35,36]. A DVH of a dose distribution is rep-
the active lengths in the outer catheters in the
resented as a graph with a series of dose intervals on its
central transversal plane
horizontal axis, and, on the vertical axis, for each dose
AL = active length in a catheter: it is the distance
interval, a volume related to that dose interval. Such a
between the first and the last active dwell
dose interval in a histogram is called a bin. For example,
position inside the target volume.
if 1000 bins are taken for a dose range of 500-2500 cGy,
The SSDS implantation rules are as follows. the first bin, DD1 will be 499-501 cGy, the second bin,
DD2, will be 501-503 cGy, etc., with the bin width AD
For a short target volume, L < 5 cm, the catheter
being 2 cGy.
spacing S varies between 8 mm and 15 mm; for a long
A differential DVH is a graph with dose intervals ADj
volume, L > 5 cm, S varies between 15 cm and 22 cm.
on the horizontal axis and on the vertical axis, for each
For a target thickness T < 12 mm, single-plane
dose interval DDi the ratio AV/AD with DVi the volume
implants are applied, with the catheter spacing
receiving a dose between Di - 0.5 AD and Di + 0.5 AD. In
S T/0.6, which gives M 0.35 S.
a clinically useful histogram, AD is much smaller than Di.
For a target thickness T > 12 mm, double-plane
Then the volume with a dose between Di and Dj is given
implants are used. A double-plane implant with a
by the area under the histogram between Di and Dj If a
catheter pattern in triangles must conform to
volume implant is optimized to the same dose midway
S 271.3. The safety margin Mbecomes M 0.2 S.
between the catheters, all the volumes midway between
For a double-plane implant with a catheter pattern in
the catheters will obtain that dose and the differential
squares, S 271.6 and M 0.3 S.
DVH will show a sharp peak for that dose. Based on this
The active dwell positions at the longitudinal ends of
behavior, a differential DVH can be used to assess the
the catheters are placed inside the target volume using
homogeneity of the dose distribution of a volume
the safety margin as given above, AL = L 2M.
implant.
The dwell position spacing is 5 mm.
A cumulative DVH has the same horizontal axis of
The dwell times are obtained by polynomial
dose intervals Di;, with bin width AD, as the differential
optimization on volume, using dose points midway
DVH. On the vertical axis, however, is given the volume
between the catheters along their whole active
receiving at least the dose Di - 0.5 AD for each DDi. In a
lengths. The first and the last dose point of each row
clinically useful histogram with AD much smaller than
midway between the catheters are usually discarded.
Di, the histogram presents for each Di the volume
The prescription dose is defined as 90% of the mean
encompassed by the isodose surface(s) of that dose.
dose in these dose points. As they are all optimized to
Thus, the cumulative DVH of the target volume can be
the same value, this definition is equivalent to 90% of
used to determine those parts of the target volume that
the mean basal dose points in the central transversal
are either underdosed or overdosed.
plane.
In a clinical case, the dose distribution around an
The above rules are guidelines on how to implant a implant is so complex that a DVH can only be deter-
given target volume. The resulting dose distribution must mined numerically, thus a discretization of the three-
be evaluated by assessing the isodose lines in several trans- dimensional dose distribution in and around the
versal and longitudinal planes. In order for the prescrip- implant must take place. It is common practice to con-
tion isodose surface to encompass the target volume as struct a grid of equidistant dose points inside a rectan-
closely as possible, dwell positions may have to be acti- gular box, placed around the implant with a given
vated or deactivated and dose points to be added or margin. A sufficient number of grid points is placed
removed, both near the longitudinal ends of the catheters. inside the box and the dose in each one of them is
66 Computers in brachytherapy dosimetry

Figure 5.16 Two-plane breast implant with seven catheters. The length of the target volume is 8 cm. The active length, i.e., distance
between first and last dwell position, is 10cm for Paris System implant, and 7 cm for SSDS implant. Step size is 5 mm. The 500 cGy lines
are the prescription isodose lines determined according to the rules of the Paris System and the SSDS System, respectively, (a) Dose
distribution in the central transversal plane. The solid HneZ=0 indicates the central longitudinal plane, midway between the two
planes, (b) Dose distribution in the central longitudinal plane. The solid line indicates the central transversal plane, (c) Comparison of
the dose distributions in three longitudinal planes of the Paris-type and the SSDS implant. PlaneZ=0is the central longitudinal plane;
plane Z=-8 is the plane through needles 4, 5, 6, and 7; plane Z=+8 is the plane through needles 1,2, and 3. The upper part of each
dose distribution is given by the SSDS implant, the lower part by the Paris implant.

Figure 5.16 cont.
calculated. Each grid point is the center of a cubical vol-
ume element, a voxel. The whole voxel is considered to
receive the same dose as the grid point. When a three-
dimensional equidistant grid with spacing s is applied,
the voxels are cubes with edge s, which are centered
around the grid points.
More explicitly, a differential DVH gives, for a given
dose interval (Di - 0.5DD,Di+ 0.5 DD), the correspond-
ing ratio DV/DD, with DVi the volume with a dose value
in that interval. DVi is obtained from the number of
Dose-volume histograms 67
voxels ni with a dose value between Di 0.5 AD and Di +
0.5 AD, multiplied by the voxel volume v; thus DVi = n- v.
A cumulative DVH gives for a given dose interval (Di
0.5 AD, Di + 0.5 AD) the corresponding volume Vi,
defined as the sum over all voxels with a dose equal to or
exceeding Di - 0.5 AD, thus Vi =
When a three-dimensional equidistant grid of points
over the implant is used, a large number of grid points,
between 50 000 and 200000, is needed for an accurate
DVH. This is due to the application of an equidistant
grid over the regular geometry of the implanted
catheters, which leads to a large redundancy of grid
points. It can be proven statistically that a more efficient
grid over a set of regularly implanted catheters is a grid
where the x, y and z coordinates of each point are deter-
mined randomly [16,33]. The voxel size is then equal to
the volume of the rectangular box around the implant,
divided by the number of grid points inside the box. The
number of randomly placed grid points needed for an
accurate DVH lies between 10 000 and 50 000.
The target volume is defined by the tumor and the
margin around it. The minimum peripheral dose
(MPD), is defined as the dose of the isodose surface that
just encompasses the target volume, thus the highest
dose still encompasses the target volume. The treatment
volume is defined by the prescription isodose surface
which is selected by the radiation oncologist when view-
ing the dose distribution. The prescription dose (PD) is
the dose prescribed to the prescription isodose surface. If
CT or MRI images with the contours of the target vol-
ume are not available, the target volume is considered to
coincide with the treatment volume and the MPD is
taken to be equal to the PD.
5.7.1 Differential dose-volume histogram
of a single point source
Understanding of the properties of a DVH of a single
point source is essential for the evaluation of implants
with more sources. If a point source is ideal, i.e., tissue
scatter and absorption can be ignored, then D = S/r 2 ,
with D the dose at distance r from the source. The values
of the differential DVH for an ideal point source can be
calculated directly [16], because the isodose surfaces are
spheres with the source as center, of which the volumes
are easily calculated by V= (4/3) p r3. For an ideal point
source with D = S/r2, Vcan be written as a function of D:
The numerical and analytical value of (DV/DD) for D =
1000 cGy will be calculated for an ideal point source with
S = 1000 cGy cm2. The numerical calculation requires the
distance r at which D = 1000 cGy: r = s/D = 1 cm. The
value of (AWAD) for D = 1000 cGy is found by calculat-
ing D and V for r equal to 0.99 cm and 1.01 cm. For
68 Computers in brachytherapy dosimetry

r = 0.99 cm, D099 = 1000/0.992 = 1020 cGy and V099 = (4/3)
n 0.993 = (4/3) p 0.997 cm3. For r = 1.01 cm, D101 =
1000/1.012 = 980 cGy and V,01 = (4/3) p 1.013 = (4/3) p
1.03 cm3. Thus, DD = D1.01 - D099 = -40.0 cGy and DV =
Voi -V0.99= 0.08 p cm3 This results in (DV/DD) = -0.002
p = -0.0063 cm3 cGy-1 for D = 1000 cGy.
Analytically, the differential DVH for an ideal point
source with D = S/r2 is given by, using equation 5.16:
For S = 1000 cGy cm2 and D = 1000 cGy, dWdD = -2p
10003/2 1000'5/2 = -0.0063 cm3 cGy-1. See reference 16 for
more details.
A differential DVH of an iridium-192 point source is
given in Figure 5.17. As in the above example, the dose at
1 cm given by this source is 1000 cGy. At such a short dis-
tance, the tissue scatter and absorption factor is near
unity. From the dependence of dWdD on 1/D5/2, it is
clear that, as the dose decreases, dV/dD increases more
than quadratically.
5.7.2 Differential dose-volume histogram
of multiple point sources
A differential DVH of a volume implant behaves as a sin-
gle point source for very low doses and for very high
doses. This is illustrated in the case of an implant consist-
ing of N identical point sources each with strength S
(Figure 5.18). Points far away from the implant receive
very low doses from the sources, and essentially respond
to all sources as a single source with strength N S.
Correspondingly, for these distant points the histogram is
dWdD = -2 7p(NSY3/2 D 5/2 . For points of very high doses,
thus very near to a source, only the dose contribution of
that source will be seen, due to the inverse square depen-
dence of the dose on distance. Now the histogram shows
the behavior of N times that of a single source: dV/dD =
- 2 p N S3/2 D-5/2, which equals, of course, the DVH of a
single point source with strength N2/3 S. For a large
number of sources, this strength is much smaller than
that at a large distance from the implant (Figure 5.18).
Consequently, the influence on the dose distribution of
the catheter placement and the dwell time optimization is
reflected most strongly in the middle section of the dif-
ferential DVH, which lies between about 75% and 200%
of the PD which encompasses the target volume. Visual
evaluation of this influence is difficult because of the
underlying inverse square law influence. In Figures 5.18
and 5.19, the differential DVH of a point source located
in the center of the implant is also given. The difference
between the point source curve and the implant curve
indicates how much better the implant is compared with
a single source. The strength of this point source is
defined such that the dose value of the spherical isodose
surface that just fits inside the rectangular grid box equals
that of the similarly fitting isodose surface given by the
implant. The margin of the grid box around the implant
is 1 cm. To determine the dose value of that spherical
isodose surface, the maximum dose occurring on the

Figure 5.17 Differential dose-volume histogram of an iridium-192 point source which delivers WOO cGy at 7 cm in tissue. The
influence of tissue scattering and absorption is hardly visible, as is indicated by the histogram value for D = 300 cGy and the theoretical
value, using dV/dD = -2p S3/2 D- 5/2 for an ideal point source. A shaded area between two dose values represents the volume between the
corresponding three-dimensional isodose surfaces. For a discussion of the three shaded areas of equal size, representing three equal
volumes, see 'Natural dose-volume histogram,' p.69.

rectangular box surface must be found. From that maxi-
mum dose value on the box surface, the source strength of
the point source in the center of the box is calculated. This
explains why both curves in Figures 5.18 and in 5.19 start
with the same dV/dD value for the minimum dose of 40.0
cGy. Figures 5.18 and 5.19 present various dose values
around the peak dose D100 to judge the implant. D100 is
defined as the largest difference between the dose his-
togram of the implant and that of the ideal point source.
So D100 is the dose under the peak after correction for the
slope by the ideal point source. D85, D95, D105, and D115 are
dose values of 85%, 95%, 105%, and 115% of D100. Note
that D100 is located in the center of the implant and that
the dose range where the implant differs from the point
source extends only about 15% from the peak dose D100.
D85 is usually taken as the PD for an implant which is not
optimized. Figure 5.19 indicates that, for an optimized
implant, the implant histogram value for DS5 already
approaches the point source histogram. As discussed in
section 5.7.6, the PD for an optimized implant should be
taken as 90% of the peak dose D100.
It is possible to evaluate an implant by its differential
DVH. In addition, figures of merit based upon DVHs
Dose-volume histograms 69
Figure 5.18 Differential dose-
volume histogram of the two-
plane breast implant of Figure
5.16, according to the Paris
Dosimetry System. The lower
peak is related to the volumes
between the outer catheters, the
higher peak to the volumes
between the inner catheters. The
underlying curve is the
histogram of the point source in
the center of the rectangular box
around the implant. The
strength of the point source is
such that the same maximum
dose on the grid surface is
obtained as given by the
implant. Note that the peak of
this histogram is not well defined
and the location of the 85% peak
dose value D85 is not at the base
of the peak.
have been developed [39]. However, to evaluate an
implant implies evaluating the differences between the
histogram of the implant and that of the corresponding
point source in its center (see Figures 5.18 and 5.19). To
address this problem, Anderson [34] in 1986 developed
the concept of the natural DVH and derived the
Uniformity Index (UI) as a figure of merit of the
implant. Based on the natural DVH, a new figure of
merit was defined, the Quality Index (QI) [22,35,36].
5*73 Natural dose-volume histogram
Because the inverse square law has such a detrimental
effect on interpretations of the differential DVH,
Anderson [34] introduced a new dose unit, u, for the
horizontal axis: u(D) = D-3/2. Now, for an ideal point
source, using equation 5.17 and dV/dw = (dV/dD)/
(dD/dw), it follows:
which is independent of dose D, thus the natural his-
togram of a point source is a horizontal line (see Figure
70 Computers in brachytherapy dosimetry

Figure 5.19 Differential dose-

volume histogram of the two-
plane breast implant of Figure
5.16, optimized according to
SSDS. The single high peak is
caused by the optimization to
the same dose of all volumes
midway between the catheters.
The underlying curve is again
the histogram of the point
source in the center of the
rectangular box around the
implant (see Figure 5.18). Note
that the 85% peak dose value
D85 is not located at the base of
the peak and therefore is
unsuitable as prescription dose.

5.20). Note that the horizontal axis is linear in u, thus

linear in D-3/2. Also, that for increasing dose, u decreases.
Thus, when expressed in dose D, the low dose section of
this axis is expanded and the high dose section is com-
pressed. The area under the curve between Dl and D2 is
proportional to the volume between the Dl isodose sur-
face and the D2 isodose surface. Note the difference in
appearance of three equally sized volumes in the differ-
ential DVH of Figure 5.17 and the natural DVH of
Figure 5.20.
The natural DVHs of the unoptimized and optimized
two-plane breast implants discussed in section 5.6 are
given in Figures 5.21 and 5.22. The peak of the histogram
represents the volumes, midway between the catheters,
that receive an approximately uniform dose. The nar-
rower the peak, the more uniform the doses in the vol-
umes between the catheters. The narrowest peak is Figure 5.20 Natural dose-volume histogram of an iridium-192
obtained by an equidistant three-dimensional grid of source which delivers 1000 cGy at 1 cm in tissue. The - sign of
dwell positions over the target volume with the dwell dV/du is disregarded. indicates the actual histogram.
times optimized to the same dose in dose points between indicates the theoretical value of 132.5 using equation
the dwell positions. The broader the peak, the less desir- 5.19. The three equal volumes of Figure 5.17 now show up as
able the implant, until finally a horizontal line remains areas with equal base, indicating the compression of the dose axis
which represents a single point source in the center of for high dose values and the expansion for low dose values.
 Dose-volume histograms 71

Figure 5.21 Natural dose-volume histogram of the two-plane breast implant of Figure 5.16, according to the Paris Dosimetry System.
(See legend of Figure 5.18 for explanation of the occurrence of two peaks.) Line (3) represents the theoretical limit, (4/3) p (nS)3/2 of
dV/du at a large distance from the implant, with n the number of dwell positions and S = D(r) r2 the source strength of the ideal point
source. Line (2) lies midway between lines (1) and (3) and defines the so-called 'low dose.' Line (5) represents the theoretical limit (4/3) p
p S3/2 of dV/du for very high dose values. Line (4) lies midway between line (1) and (5) and defines the so-called 'high dose.' The
prescription dose (PD) is defined as 85% of the mean dose in the basal dose points. See p. 72 for explanation of the Uniformity Index
and the Quality Index.

Figure 5.22 Natural dose-volume histogram of the two-plane breast implant of Figure 5.16, optimized according to the SSDS System.
The prescription dose (PD) is defined as 90% of the mean dose in the basal dose points, i.e., 90% of the peak dose value. Note the
relatively small change in the Uniformity Index compared to the unoptimized case (Paris System) in Figure 5.21 (2.26 versus 1.98). The
horizontal tails at the left side (very low dose values) and the right side (very high dose values) are explained on p. 71. The prescription
dose coincides with the natural prescription dose (NPD), which lies at the base of the peak at the LD side (see p. 74).

the target volume. It should be noted that only volume doses as if a single point source exists, and the natural
implants will show a peak in their natural histogram. DVH will thus display a horizontal line for these values.
As discussed in the section 'Differential DVHs of mul- Also, for very high doses, the histogram behaves as if a
tiple point sources', the histogram behaves for very low point source, although with much less strength, exists
72 Computers in brachytherapy dosimetry
(Figure 5.22). Because of the strong contraction of the
w-axis for high doses, the horizontal line at the high dose
end is sometimes hardly visible and appears as if it runs
straight down to this high dose limit value of dV/du
(Figure 5.21).
Anderson derived the Uniformity Index by taking the
ratio of the volume under the peak, normalized to the
w-scale, and the volume encompassed by the isodose sur-
face of the target dose, again normalized to the w-scale. A
related Figure of Merit is the Quality Index, which is
independent of the target dose [22,35,36]. The quantities
PD, LD, and HD are used in these indices. PD refers to
the target dose prescribed by the radiation oncologist.
Usually, it belongs to the isodose surface which encom-
passes the target volume with a margin of about
3-5 mm. LD refers to the dose value at the half height of
the peak in the low dose region. This half height is mea-
sured from the limit value of the histogram for dose val-
ues approaching 0. HD refers to the dose value at the half
height of the peak in the high dose region. This half
height is measured from the limit value of the his-
tograms for doses approaching infinity.
UNIFORMITY INDEX
The Uniformity Index is a quantitative index to assess
how well the dose distribution covers the target volume.
It is defined as the volume between the dose values of PD
and HD, normalized to the w-interval between PD and
HD, divided by the volume encompassed by PD, nor-
malized to the w-interval between PD and infinity dose.
Thus, the Uniformity Index is:
with V(PD) the volume encompassed by the prescrip-
tion isodose surface, V(HD) the volume encompassed by
the high dose isodose surface, w(PD) the w-value corre-
sponding to the prescription dose, and w(HD) the
w-value corresponding to the HD value.
By substituting u = D-3/2 and using u( ) = 0, we get
The first term of the UI is the volume under the peak
extended to the target dose, divided by the width of the
peak extended to the target dose. The narrower the peak,
the larger the first term will be. The effect of the second
term is the opposite. For a single point source, there is no
peak and the UI = 1.
As already mentioned, the UI is dependent upon the
PD chosen by the radiation oncologist. It is a measure of
the quality of the dose distribution within the selected
target dose. If a perfectly regular implant is not covering
the target volume completely and therefore a lower PD
must be selected, this is reflected by a lower value of the
UI.
QUALITY INDEX
To compare different geometries of implantation and
different dwell time optimization schemes, another
Figure of Merit is needed, which is independent of the
PD. For this purpose, the Quality Index is introduced
[ 16,39]. In the Quality Index, LD is substituted for PD in
equation 5.20. Thus:
A detailed study of the differences between UI and QI
in geometrically optimized breast implants is given in
reference 22.
5.7.4 Cumulative dose-volume histogram
The cumulative dose-volume histogram (CDVH) pre-
sents for each dose value the volume encompassed by the
isodose surface(s) of that dose [51,52]. It is widely used
to determine if a part of the target volume is underdosed
or if an organ at risk is overdosed. The CDVH of the tar-
get volume shows a distinct behavior (Figure 5.23). For
dose values lower than the minimum peripheral dose,
the complete target volume is covered and the CDVH
runs horizontal. When the dose value exceeds the mini-
mum peripheral dose, part of the target volume is not
included by the isodose surface with that dose value, so
the CDVH runs steeply downward with increasing dose.
For high dose values, only the small volumes directly
around the sources inside the target contribute and the
CDVH value decreases slowly.
5.7.5 Evaluation of dose distributions with
dose-volume histograms
DVHs play an important role in evaluating the following
aspects of dose distributions in brachytherapy [32].
How homogeneous is the dose distribution of a volume
implant? This can be assessed independently of the
actual PD, either by visual inspection or by the QI of
the natural DVH. Note that it is not possible to
evaluate the homogeneity of a distance implant,
because of the steep gradients around the catheters.
The differential and natural DVHs assess the
regularity of the catheters and the optimization of the
dwell times, irrespective of the coverage of the target
volume by the implant.
How well is the dose distribution covering the target
volume? This depends on the PD selected. It can be
assessed again by visual inspection. It is obtained from
the CDVH of the target volume by looking at the
amount of the target volume which is underdosed by
a dose less than the PD. The cumulative DVH is also
used to determine the amount of volume being
overdosed by, for example, a dose greater than 2 x PD.
 Dose-volume histograms 73

Figure 5.23 Cumulative dose-volume histogram of the target volume of a non-optimized prostate implant. On the horizontal axis is
given the dose relative to the prescription dose (PD). On the vertical axis is given the encompassed volume for each dose value, relative
to the target volume V. The minimum peripheral dose (MPD) is the highest dose still encompassing the target volume. If the PD was
taken to be equal to the natural prescription dose (NPD), it is evident that the implant is not covering 10% of the target volume.
Additional dwell positions must be activated in the missed volume (see p. 74). The dose/non-uniformity ratio for a non-optimized
implant, defined as DNR(D) = V(1.5 D)N(D), will show a minimum for the PD in this histogram as the curve slope is the steepest in the
dose range PD-1.5 PD (see p. 74).

The UI of the natural DVH, which is based on the PD,
scores the combination of aspects (1) and (2) only if
the PD equals the minimum peripheral dose of the
target. Thus, much more detailed information is
obtained when the dose homogeneity is evaluated
with the QI of the natural DVH and the coverage of
the target volume with the CDVH.
How much volume outside the target volume receives a
high dose? If CT or MRI images of an organ at risk are
available, the volume which receives a dose exceeding
the maximum dose allowed in that organ can be
determined. Then, a grid of dose points must be
placed over the organ at risk and the CDVH of that
organ be determined. Similarly, the difference
between the treatment volume and the target volume
can be assessed by the CDVH of the treatment
volume.
The last two aspects are strongly related to the value of
the PD. In a volume implant with an optimized dose dis-
tribution, dwell time has been moved from the center of
the implant to its periphery. This results in a steeper dose
gradient around an optimized implant, which influences
the definition of the PD and the treated margin around
the outer dwell positions.
5.7.6 Definition of the prescription dose in
non-optimized and optimized volume
implants
A non-optimized Paris-type dose distribution displays a
low dose gradient which starts from the center of the
implant. The 85% of the mean basal dose in the central
transversal plane coincides more or less with the mini-
mum peripheral isodose, i.e., the isodose surface with
the highest value, which still encompasses the complete
implant. In the natural DVH of the unoptimized breast
implant in Figure 5.21, the prescription dose PD lies
about halfway on the left side of the peak.
An SSDS implant shows a much more homogeneous
dose distribution inside the implant, which corresponds
to the pronounced peak in the natural DVH of Figure
5.22, and a steep inverse-square-law dose gradient
around it, which corresponds to the horizontal his-
togram curves away from the peak (see, again, Figure
5.22). The mean basal dose is practically equal to the
mean dose in all dose points midway between the
catheters, because these points are all optimized to
the same value. Figure 5.24 shows that the isodose sur-
face with a dose value of 90% of the mean basal dose
coincides with the highest dose value still lying in the
steep dose gradient area around the outer needles of an
implant, and maintains a margin of a few millimeters
around the implant. Therefore, the PD of an SSDS
implant is taken as 90% of the mean basal dose. This PD
isodose surface shows a smaller margin around the outer
dwell positions, due to the steeper dose gradient around
an optimized implant and the higher percentage of the
basal dose (see Figure 5.24). This margin is about 3 mm,
whereas the treated margin around a non-optimized
implant is about 5 mm. This definition defines a PD
which for an optimized implant lies at the base of the
peak of the natural DVH, at the LD side.
To define the PD as the dose value at the base of the
74 Computers in brachytherapy dosimetry
Figu re 5.24 The definition of the prescription dose for an
implant, according to the Stepping Source Dosimetry System.
The 90% value of the mean basal dose (BD) in the central
transversal plane is the highest percentage still lying in the steep
dose gradient area around the implant, thus just at the base of
the peak in Figure 5.22. The treated margin around the outer
sources is about 3 mm. Note that the 95% isodose line shows
deep bends between the catheter intersections.
peak of the natural DVH is generally valid for all volume
implants. It is the value of the isodose surface inside
which the optimized dose distribution lies and outside
which the inverse square law predominates. This defini-
tion of PD is called the natural prescription dose (NPD).
Note that this PD is defined on the dose distribution
only. The PD that covers the target volume is the mini-
mum peripheral dose (MPD). If the NPD is equal to the
MPD, the implant is well placed over the target volume
and the PD can be taken as equal to the MPD. The UI
now correctly scores both aspects of the dose distribu-
tion, the dose homogeneity and the target coverage.
If, in the natural DVH in Figure 5.22, the PD is taken
with a value lower than 90% of the mean basal dose, the
PD will shift more to the left on the horizontal tail for
low dose values. This implies that the PD is taken at a
distance so far away from the implant that the inverse
square law dominates. The UI will decrease correspond-
ingly.
Thus, according to the dose distribution, the PD
should coincide with the NPD at the base of the peak in
the natural DVH (Figure 5.22). According to the target
volume, the PD should coincide with the MPD, the high-
est dose value still encompassing the target volume. If
the PD does not match these two requirements, the dose
distribution does not cover the target volume adequately.
This matching is evaluated by the natural dose ratio
(NDR), which is defined as the ratio of the NPD and the
PD:
In clinical practice, the PD is often taken as equal to
the MPD. If the target volume is suitably covered by the
implant, the NDR has a value nearly equal to one. If the
target volume is not suitably covered by the implant,
cold spots in the target volume will arise, around which
the MPD runs. Or, stated differently, the volume encom-
passed by the NPD covers the target volume only partly.
Thus, an ill-covered target volume prescribed to the
same MPD as a well-covered target volume will receive
an overall much higher dose. This translates into values
of NDR greater than one. NDR equal to 1.4 means that
the base of the peak of the natural DVH starts at 1.4 PD
and the whole target will receive a 40% higher dose than
when treated to the same PD but with an NDR equal to
1.0.
The use of NPD, MPD, and NDR is of utmost impor-
tance for implants of the prostate [61]. If the NDR is
larger than 1 or, stated differently, if the required pre-
scription dose does not lie at the base of the peak of the
natural DVH, a part of the target volume is not covered
by dwell positions (or by seeds, in the case of permanent
implants). All transverse slices should then be inspected
visually for target areas with a dose lower than the NPD,
and dwell positions in these areas should be activated (or
seeds be placed).
5.7.7 Other methods for evaluation of
dose distributions
Another assessment of implant quality, utilizing only the
CDVH, is given by the dose-non-uniformity ratio
(DNR) [53,54] for the homogeneity of the dose distrib-
ution and the coverage index (CI) for the target coverage
[38]. The DNR ratio is a graph for each dose value of the
ratio of the volume receiving a dose larger by a given
fraction, say 50%, to the volume enclosed by that given
dose value. Thus, for a given dose value, D:
The behavior of the DNR versus dose plot can be
correlated with implant quality in the target volume.
For non-optimized implants, the fraction is usually
taken as 50%. In Figure 5.23, it is indicated that the
minimum value for DNR(D) is defined by the 50%
dose range where the volume curve has the steepest
slope and thus the difference between V(D) and V(1.5
D) is maximal. The steeper the CDVH curve between
D and 1.5 D, the better the dose distribution and the
smaller DNR(D) will be. However, the relation between
the minimum value of DNR and the MPD is defined
by the shape of the CDVH, and there is also no direct
relation with the NPD, as the latter is based on the
implant dose distribution and not on the target vol-
ume. DNR(PD) is also known as the Dose
Homogeneity Index (DHI) [37].

For optimized implants, it is better to take the fraction
as 25% [55]. This is explained as follows. The differential
histogram in Figure 5.19 shows that the dose range
where the optimized implant differs from a single point
source in the center of the target is only 15% of the
peak dose. As discussed in section 5.7.6, the PD of an
optimized implant is 90% of the peak dose; thus, the
dose range PD-1.25 PD just covers the volume under the
peak. From this follows that the DNR value will be
smaller for dose values other than 90% of the peak dose,
and the plot of DNR(D) versus D will show a minimum
at D equal to 90% of the peak dose. (For more details, see
reference 55.) When adapting the fraction to the amount
of optimization performed, the minimum value of
DNR(D) will not distinguish for different types of
optimization.
Depending on the regularity of the implant and the
type of optimization performed, the differential (and
natural) DVH will show different peak widths and, as a
result, different fractions are required in relation (22),
ranging from 25% for a regular, fully optimized implant
to 50% for a non-optimized implant. A detailed discus-
sion is given by Low and Williamson [55], in whose arti-
cle different optimization schemes were applied to
different implant types but a fixed fraction of 25% was
taken.
The Coverage Index (CI) scores the coverage of the
target volume by the PD. It is defined as:
In the CVDH of the target volume, V(target) is equal to
V(MPD). If PD is based on the minimum value of the
DNR(D) plot, then CI will be less than 1, about 0.9 for a
non-optimized implant [55] (see Figure 5.23). Thus, also
the combination of the DNR for the dose distribution
inside the target volume and the CI for the target cover-
age are not suitable, easy to apply, evaluation tools for
HDR implants.
Another index, based on the CDVHs of the target and
critical structures, is the Conformal Index (COIN),
which scores the target coverage together with the
unwanted irradiation of normal tissues and parts or all
of critical structures. (See reference 38 for an extensive
discussion.)
5.8 THREE-DIMENSIONAL IMAGING
TECHNIQUES
CT-based brachymerapy treatment planning is based on
the visualization of the tumor, the target volume, the
catheters, and the surrounding anatomical structures in
a series of two-dimensional CT slices or in three-dimen-
sional views reconstructed from these CT slices
Three-dimensional imaging techniques 75
[40-3,51]. Unfortunately, compared to catheter and
anatomical point reconstruction from two radiographs,
the localization of catheters or individual source posi-
tions using their intersections with CT slices is more
difficult.
The entry of anatomical structures into the planning
system is achieved either by digitizing these structures
from a hard copy of the CT slices on a digitizer tablet or
by delineating these structures by mouse on the com-
puter display. Usually, only the target and critical struc-
tures are entered, because the other internal structures
are of no clinical significance and are not taken into
account by the dose calculation routines in brachy-
merapy.
Reconstruction of source locations from CT images
poses several problems, especially if the spacing
between the slices is large. When an X-ray ruler is used
to reconstruct a catheter, markers may fall between the
slices and a high resolution scout view is then required
to indicate which marker is visible in a given slice. For
that reason, X-ray rulers are often used which consist
only of a single radio-opaque wire. If the tip of such a
marker wire falls between two slices, the intersections
of the marker wire in the first two CT slices must be
used to extrapolate the marker wire over the distance
between the first slice and the tip of the marker wire.
The reconstruction of a looping catheter requires the
differentiation in several slices between the images of
the two sections of the loop. In general, in order to get
the best reconstruction of a looping catheter, a small
interslice distance is required, resulting in the necessity
of handling a large number of CT slices. Dwell posi-
tions in these needles are calculated by the planning
system, using the distance of the first dwell position
from the tip and the dwell step.
If the patient can be reproducibly positioned on the
treatment table of both a CT scanner and a treatment
simulator, the localization of the target volume and crit-
ical organs can be obtained from the CT scans and the
localization of the catheters from two radiographs. The
intersection of the catheters reconstructed from radi-
ographs can be displayed in the CT slices. In this way, any
change in the patient localization between the CT ses-
sion and the simulator session can be visually detected
and corrected interactively. This method is of interest for
HDR implants of the prostate.
Ultrasound imaging and three-dimensional treatment
planning tools have been used for evaluation of HDR
prostate implants [51]. The dosimetric quality indicators
are the CI, the MPD, and the HI, which is the fraction of
the target volume receiving doses in the range of 1.0-1.5
times the PD.
The combination of different imaging modalities in
the treatment of prostate carcinoma with HDR iridium-
192 afterloading is becoming common practice [46]. The
flexible HDR catheters are inserted under guidance of
ultrasound imaging, but the treatment planning is per-
76 Computers in brachytherapy dosimetry
formed on the postneedle-placement CT images. The
target MPD is optimized to conform to the prostate's
peripheral shape as it changes from base to apex. The
urethra's dose is limited to 120% of the MPD.
MRI has excellent soft tissue imaging capabilities, but
the alinearities in the image prohibit direct utilization in
brachytherapy treatment planning. To get around this
problem, the reconstruction of prostate implant
catheters can be performed with radiography and the
imaging of the prostate and the implant can be done
with MRI [43]. In this paper, permanent seeds are
implanted, but the technique is equally valid for HDR
implants with catheters with X-ray rulers inserted for
radiography and MR rulers for MRI. With radiography,
the seed coordinates are reconstructed in the conven-
tional manner from a pair of isocentric radiographs. The
reconstructed seed distributions are verified on the AP
and lateral radiographs. With MR scanning, a flat table
top is used to allow reproducible patient positioning
between MR scanning and radiography. After scaling of
the MR dataset to the real-size seed distribution, corre-
sponding seeds in the data set of reconstructed seed
positions and signal voids in the MR images are interac-
tively identified. These corresponding seeds are distrib-
uted over a cranial, central, and caudal transverse slice
through the prostate. A total of about ten corresponding
seeds is then used for matching with the corresponding
signal voids in the MR images. The resulting rotation
and translation to the MR images is then applied to all
reconstructed seeds. Similarly, instead of radiography,
CT imaging can be used for seed reconstruction, and
image fusion is used for matching the MR images with
the CT ones [44].
Summarizing, three-dimensional imaging of a
brachytherapy implant is a valuable tool for reconstruc-
tion of target and organs, and for assessment of the
resulting dose distribution with the differential or nat-
ural DVH. The CDVHs of the target and of the critical
organs show quantitatively the part of the target volume
which is underdosed, and the amount of the critical
organ volumes which are overdosed. CT imaging can
also be used to reconstruct the localization of the
catheters or even sources, but only if proper software is
available. Finally, the dose distribution in transaxial
planes and even arbitrary user-defined planes can be dis-
played together with the patient structures, interpolated
between the CT slices.
5.9 THREE-DIMENSIONAL DOSE
CALCULATION ALGORITHMS
Three-dimensional dose algorithms which incorporate
the influence of tissue inhomogeneities and metal
shields on the dose distribution around brachytherapy
sources are just emerging. Promising approaches are the
Monte Carlo simulation of the radiation transport equa-
tion [47-50] and the convolution algorithms which are
based on a scatter dose kernel calculated by Monte Carlo
simulation [59]. An analytical approach is given by
Daskalov et al [60].
The Monte Carlo aided three-dimensional dose calcu-
lations have become so accurate that they function as the
standard against which other algorithms are compared.
For example, recent data for the dose calculation around
high dose-rate and pulsed dose-rate sources according to
the AAPM TG43 formalism are based on Monte Carlo
calculations [9,10,11]. The convolution algorithms are
suitable for dose computations in heterogeneous geome-
tries. They are similar in approach to the pencil beam
modeling of external beams, but are much more com-
plex. Current treatment planning computers are not yet
fast enough to use these algorithms for clinical treatment
planning. An overview of these algorithms is given by
Williamson [59].
5.10 DOSE SUMMATION OF
BRACHYTHERAPY AND EXTERNAL-BEAM
DOSE DISTRIBUTIONS
In order for doses from brachytherapy and external-
beam treatments to be combined, both dose distribu-
tions must be based on the same patient localization in
space. If the external beam and the brachytherapy treat-
ment planning are both based on the same set of CT
slices, the overlaying is straightforward. If this is not the
case, common reference points in space must be defined
for both modalities, or the brachytherapy patient orien-
tation must be matched interactively to the external
beam one. Once the matching is obtained, the proper
spatial transformations can be performed and the sum-
mation of the doses simply becomes an additive process.
Weighting factors based upon the biological effective-
ness of each treatment modality must be applied. These
weighting factors may be based upon radiobiological
models, such as the linear-quadratic (LQ) model [56].
This model can be used for high dose-rate, low dose-
rate, and pulsed dose-rate treatments [57,58].
The resulting dose distributions can be evaluated with
the viewing techniques available with current treatment
planning systems. Three-dimensional isodose surfaces
can be viewed together with the target and critical
anatomic structures [34]. For ease of viewing, the degree
of transparency and color of each of these isodose sur-
faces can be adjusted.
5.11 RECENT DEVELOPMENTS IN
BRACHYTHERAPY
With all the computing power, display techniques, and
optimization methods currently available, the degree to

which a brachytherapy implant will be effective is deter-
mined not by how well the implant is optimized, but by
how well the physician has physically placed the
catheters or applicators. Simply stated, optimization
software cannot provide a good dose distribution
around a badly placed implant. Therefore, to assist in the
correct implantation of the catheters or applicator, visu-
alization of the target volume, the critical structures, and
the catheters themselves is often essential.
When a CT scanner with a gantry tilt option is avail-
able, a regular volume implant, such as a brain implant
using a template and needles, can be performed interac-
tively, with each row of needles fully displayed in a CT
plane.
Filmless planning is the integration of the X-ray or
ultrasound imaging and the treatment planning
process. In such an integrated brachytherapy unit, an
isocentric radiographic localizer (such as a treatment
simulator) with digital imaging capabilities is directly
interfaced with the treatment planning computer. In
the surgical theater, the localizer transfers on-line the
image information to the treatment planning computer
for reconstruction, optimization, and display of the
dose distribution. However, if these digital images are
obtained from an image intensifier, they must be
corrected for the image distortion due to the curved
surface of the image intensifier screen, the influence of
the earth magnetic field, and any imperfections of the
electro-optical system. As the required accuracy in
reconstructing the catheters or sources is in the range
of 0.5 mm, the distortion of a digital image must be
corrected to the same extent. Such an integrated
brachytherapy system, which corrects these image dis-
tortions to the required accuracy, is currently already
available [45]. This allows an interactive assessment of
a needle position during implantation, especially if, in
the future, the localizer is also provided with a CT
option for visualization of the target volume and the
surrounding structures.
Three-dimensional ultrasound-guided perineal im-
plantation of the prostate, combined with real-time
treatment planning using ultrasound images, is also
becoming available [51]. Catheters, guided by a perineal
template, are inserted into the prostate and connected to
an HDR afterloader. The three-dimensional ultrasound
unit provides real-time transverse and longitudinal slices
through the prostate and its immediate surroundings. A
longitudinal plane through the prostate and its sur-
roundings can be oriented such that a catheter being
inserted can be imaged real-time in that ultrasound
plane.
The ultrasound images with the catheters depicted
are directly available to the planning computer, which is
an integral part of the implantation system. The treat-
ment planning process consists of three distinct stages,
the preplanning, the live planning and the postplan-
ning. In the preplanning stage, transverse ultrasound
Recent developments in brachytherapy 77
images are used to determine the catheters to be placed
through the template. Longitudinal ultrasound images
are used to determine the depth of insertion. After the
virtual catheters have been placed, the virtual dwell
positions inside the target volume are activated by the
planning system. Geometric optimization on volume is
currently available to obtain a real-time optimized dose
distribution. Dwell positions and dwell weights can be
modified interactively to obtain the required dose spar-
ing of the urethra, e.g., to 120% of the MPD. In the live
planning stage, the virtual catheters are replaced one by
one by the real inserted catheter. The real dwell posi-
tions are activated by the planning system and the dose
distribution from the catheters already placed, and the
virtual catheter left is displayed real time. In this way,
deviations of the catheters from the planned position
and the corresponding deviation from the planned dose
distribution can be corrected with the catheters still to
be placed. Finally, when all catheters have been placed
and the dose distribution has been decided upon, the
actual treatment can start. Postplanning is done one or
more days after the actual treatment has started, to
check the stability of the catheter positions in the target
volume.
A full, real-time optimization method for volume
implants is still to be developed. Such a method should
combine the ease of the geometrical method (no dose
points to be placed midway between the catheters) with
the full optimization quality of the SSDS and should
allow one or more critical volumes inside and outside
the target organ to be treated to a predefined value of
the PD. This is important for the HDR treatment of
the prostate, where the urethra is to be treated to a
given fraction of the PD and where the rectal wall
adjacent to the prostate is to be spared. Only when
such a fast volume optimization is available, will real-
time full optimization of HDR volume implants
become possible.
Considerable research is still to be conducted to
develop a bioeffect dose model that can be applied
clinically. Computer software to implement such a
model in a computer planning system is readily
available and will allow the display of radiobiological
isoeffect distributions instead of physical isodose
distributions.
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60. Daskalov, G.M., Kirov, A.S. and Williamson, J.F. (1998) Wijrdeman, H.K., Battermann, J.J. (2000) The combined
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Dose specification and reporting:the ICRU
recommendations
ANDRE WAMBERSIE AND JAN J.BATTERMANN
6.1 INTRODUCTION
This chapter addresses the problem of dose specification
for reporting in brachytherapy. It is based on the recom-
mendations of the International Commission on
Radiation Units and Measurements (ICRU), mainly
ICRU Report 38, 'Dose and volume specification for
reporting intracavitary therapy in gynecology' (1985)
[ 1 ]1,and ICRU Report 58, 'Dose and volume specifica-
tion for reporting interstitial therapy' (1997) [2] 2 .
Exchange of clinical information between radiation
oncology centers requires uniformity and agreement on
the methods used to specify the doses and the volumes
to which these doses are delivered. To avoid confusion,
an agreement has also to be reached on definitions of
the terms and concepts necessary for reporting treat-
ments.
Due to the limitations of the irradiation techniques,
the doses delivered to the target volumes are in general
not homogeneous. In external-beam therapy with pho-
1. The Reporting Committee for ICRU Report 38 was the following: D
Chassagne and A Dutreix (Co-Chairmen), P Almond, JMV
Burgers, M Busch, and CA Joslin (Members), M Cohen and T
Landberg (Consultants).
2. The Reporting Committee for ICRU Report 58 was the following: D
Chassagne and A Dutreix (Co-Chairmen), D Ash, WF Hanson, AG
Visser and JF Wilson (Members).
6
tons and electrons, the differences between the maxi-
mum and the minimum doses in the target volume often
reach 10%, 15%, and even 20%. Therefore, one can
introduce large discrepancies, and thus confusion,
depending on the criteria (or the dose levels) used for
prescribing, recording, and reporting the treatment, e.g.,
maximum, minimum, or any mean dose or 'weighted'
mean dose. Such discrepancies are in general much
larger than the current dosimetric uncertainties. On the
other hand, a difference in dose of 5% can be detected
clinically for some radical treatments [3,4].
The ICRU recognized the importance of the problem
many years ago and, in 1978, published Report 29, 'Dose
specification for reporting external beam therapy with
photons and electrons' [5]. This report was superseded,
in 1993, by ICRU Report 50, 'Prescribing, recording and
reporting photon beam therapy' [6]. A 'Supplement to
ICRU Report 50' appeared recently [7].
In brachytherapy, the situation is even more difficult
because very high doses are always obtained close to the
sources, and there are actually no large volumes for
which the dose is nearly homogeneous (reaches a kind of
plateau), as in external-beam therapy. The problem is
addressed in ICRU Reports 38 and 58. In order to retain
as much consistency as possible, it is desirable to use,
wherever possible, in the same terms and
concepts and the same approach as in external-beam
therapy. In particular, the definitions of the volumes are
therefore the same for the two techniques. It is, however,
82 Dose specification and reporting: the ICRU recommendations
recognized that brachytherapy raises some specific prob-
lems which have to be taken into account.
Other ICRU reports dealing with dose specification
for reporting special techniques, such as electron, pro-
ton, and neutron beam therapy, are in preparation.
For reporting in external-beam therapy, the dose is
specified first at the ICRU reference point, which is
located (always) in the central part of the clinical target
volume, and (when possible) at, or near, the intersection
of the beam axes. The maximum and the minimum
doses to the planning target volume (or their best esti-
mation) should also be reported. In brachytherapy, there
are high dose gradients within the clinical target volume
and the use of a single reference point is not, therefore,
sufficient. It is, however, appropriate to consider the dose
at points where plateaus of dose occur in the central part
of the clinical target volume and where the bulk of the
malignant cell population is generally located. This leads
to the concept of the mean central dose.
In addition, the whole of the clinical target volume
must receive a certain minimum dose in order to achieve
the desired clinical effect. It is therefore also important to
record the minimum dose at the periphery of the clini-
cal target volume, i.e., the minimum target dose.
Several systems of brachytherapy have developed his-
torically. Best known and most widely used (with or
without modification) are the Manchester, Quimby and
Paris systems [8-14].
The term 'system' denotes a set of rules which takes
into account the source types and strengths, geometry
and method of application to obtain suitable dose distri-
butions over the volume(s) to be treated. The system also
provides a means of calculating and specifying dose. It is
important to remember that, whereas an implant may
follow the source distribution rules of a system, it does
not comply with the system unless the method of dose
prescription and specification are also followed. In addi-
tion, if the implant rules are modified, the dose unifor-
mity intended by the system may be compromised.
The situation is more difficult in intracavitary therapy
due to the steep dose gradient in the vicinity of the
sources, i.e., throughout the target volume. Therefore,
the specification of the target absorbed dose in terms of
the absorbed dose at specific point(s), in the vicinity of
the sources, becomes less meaningful and a different
approach is required. Instead of a target-dose specifica-
tion, a volume specification is an alternative and, in that
respect, specification of an intracavitary application in
terms of the 'reference volume' enclosed by a reference
isodose surface of 60 Gy has been proposed in ICRU
Report 38.
The problems of interstitial therapy (and of
brachytherapy in general) are discussed first. The specific
problems encountered in intracavitary therapy, and
especially in gynecology, are dealt with in section 6.6.
Over the last two decades, technological developments
in brachytherapy have seen the introduction of minia-
turized and highly flexible sources which can be used in
afterloading devices with radionuclides of different
activities that can produce a wide range of dose rates. At
the same time, sophisticated three-dimensional source
localization methods have been developed and can be
linked to computerized methods of dose calculation and
representation of dose distribution. These developments
have led many clinicians to depart from the long-
established implant systems and it is for this reason that
a common language is valuable to provide a method of
dose specification for reporting which can be used and
be common for all types of brachytherapy applications.
It should be stressed from the beginning that it has not
been the intention or the role of the ICRU to encourage
users to depart from their current practice of brachyther-
apy and from their method of dose prescription. The aim
of the ICRU recommendations is to develop a common
language for reporting a treatment, based on existing
concepts. The description of the treatment and the
method of dose specification for reporting should be
presented in a way that can be easily understood and
closely related to the treatment outcome.
6.2 DEFINITION OF VOLUMES
The definition of volumes is of utmost importance, both
in external-beam planning and in brachytherapy plan-
ning. The process of determining volumes for the treat-
ment of a malignant disease consists of several distinct
steps, during which different volumes may be defined.
6.2.1 Gross tumor volume
The gross tumor volume (GTV) is the gross palpable or
visible/demonstrable extent and location of the malig-
nant growth.
The GTV may consist of the primary tumor ('GTV
primary'), metastatic lymphadenopathy(ies) ('GTV
nodal'), or other metastases. The GTV almost always
corresponds to those parts of the malignant growth
where the tumor density is largest. Due to the high den-
sity of the cancer cells in the GTV, an adequate dose must
be delivered to the whole GTV in order to achieve the
aim of therapy in radical treatments.
According to the above definition, there is no GTV
after complete 'gross' surgical resection. There is no GTV
when there are only a few individual cells or 'subclinical'
involvement (even histologically proven). From the ori-
gin of medical terminology, the latin word tumor was
used to designate a swelling, which could be of various
types.
The shape, size, and location of the GTV may be
determined by means of different diagnostic methods
such as clinical examination (e.g., inspection, palpation,
endoscopy), and various imaging techniques (e.g., X-ray,

computerized tomography (CT), digital radiography,
ultrasonography, magnetic resonance imaging (MRI),
and radionuclide methods). The methods used to deter-
mine the GTV should meet the requirements for scoring
the tumor according to the TNM [15,16] and American
Joint Committee on Cancer (AJCCS) [17] systems, and
the definition of the GTV is then in full agreement with
the criteria used for the TNM classification.
The GTV (primary tumor, metastatic lymphadenopa-
thy, other metastases) may appear to be different in size
and shape, sometimes significantly, depending on what
examination technique is used for evaluation (e.g., pal-
pation versus mammography for breast tumors, CT ver-
sus MRI for some brain tumors). Therefore, the
radiation oncologist should, in each case, indicate which
method has been used for the evaluation and delineation
of the GTV.
A GTV may be confined to only part of an organ (e.g.,
a Tl breast cancer), or involve a whole organ (e.g., mul-
tiple metastases of the brain). The GTV may or may not
extend outside the normal borders of the organ tissue
involved.
For reporting, the GTV should be described in stan-
dard topographical or anatomical terms, e.g. '18 x 12 x
20 mm3 tumor in the left lobe of the prostate adjacent
but not reaching the capsule.' In many situations, a ver-
bal description might be too cumbersome and, there-
fore, for the purpose of data recording and analysis, a
classification system is needed. Several systems are pro-
posed for coding the anatomical description, some of
them are mentioned in ICRU Report 50 [6].
There are at least three reasons for identifying the
GTV. First, accurate description of the GTV is needed for
staging (e.g., TNM). Second, identification of the GTV is
necessary to allow for recording of tumor response in
relation to the dose and other relevant factors. It can be
used (carefully) as a prognostic factor. Third, an ade-
quate dose must be delivered to all parts of the GTV in
order to obtain local tumor control in radical treat-
ments.
6.2*2 Clinical target volume
Clinical experience indicates that around a GTV there is
generally subclinical involvement, i.e., individual malig-
nant cells, small cell clusters, or microextensions, which
cannot be detected by the staging procedures. The GTV,
together with this safety margin consisting of tissues
with presumed or proved subclinical involvement, is
defined as the clinical target volume (CTV). The tissues
immediately surrounding the GTV usually have a high
malignant cell density close to the edge of the GTV; the
cell density decreases toward the periphery of the CTV
(often a safety margin of about 1 cm thick is taken). This
CTV is usually denoted CTV-T.
If the GTV has been removed by radical surgery, but it
Definition of volumes 83
is still thought that radiotherapy is needed for the tissues
that remain close to the site of the removed GTV, this
volume is also usually designated as CTV-T (e.g., in
breast-saving procedures).
Additional volumes with presumed subclinical spread
(e.g., regional lymph nodes) may also be considered for
therapy. They are also defined as CTVs and may topo-
graphically be designated CTV-N1, CTV-N2, etc.
The CTV is a tissue volume that contains a gross
tumor volume and/or subclinical microscopic malignant
disease. This volume has to be treated at an adequate
dose level (and time-dose pattern) in order to achieve
the aim of therapy - cure or palliation.
Delineation of a CTV will require consideration of
factors such as the local invasive capacity of the tumor
and its potential to spread to, for example, regional
lymph nodes.
The CTV, like the GTV, is a purely clinical-anatomical
concept. It must always be described, independently of
the dose distribution, in terms of the patient's anatomy
and the tumor volume. As a minimum recommenda-
tion, the physical dimensions of the clinical target vol-
ume are described in terms of its maximum diameters
(cm) in three orthogonal directions. For reporting, the
CTV must be defined in plain topographic terms and/or
according to a corresponding code in conformity with
the recommendations for the GTV.
If different dose levels are prescribed, different CTVs
have to be defined. This is the case, for example, in
'boost' therapy where the 'high-dose' volume (often con-
taining the GTV) is located inside the 'low-dose' volume.
It must be stressed that the descriptions of the GTV(s)
and CTV(s) are based only on general oncological prin-
ciples, and are independent of any therapeutic approach.
In particular, they are not specific to the field of radia-
tion therapy. For example, in surgery, a safety margin is
taken around the GTV according to clinical judgement,
and this implies the use of the same CTV concept as in
radiation therapy. In brachytherapy, as in external-beam
therapy, volumes to be irradiated are defined, and thus
the same concept of CTV is applied. Furthermore, the
CTV concept can be applied to other modalities, e.g.,
regional chemotherapy, hyperthermia, and photocoagu-
lation.
The definitions of GTV and CTV in brachytherapy are
thus identical to the definitions given for external-beam
radiotherapy in ICRU Report 50 [6] and Supplement to
Report 50, ICRU Report 62 [7].
6.2.3 Planning target volume
In external-beam therapy, to ensure that all tissues
included in the CTV receive the prescribed dose, one has,
in principle, to plan to irradiate a volume geometrically
larger than the CTV. This is the planning target volume
(PTV).
84 Dose specification and reporting: the ICRU recommendations
The additional safety margin included in the PTV
results from a number of factors:
expected physiological movements (e.g., with respira-
tion) and variations in size, shape, and position (e.g.,
stomach, bladder, rectum) of the CTV;
all variations and uncertainties in beam geometry and
patient-beam positioning.
The PTV is a geometrical concept, used for treatment
planning, and it is defined to enable selection of appro-
priate beam sizes and beam arrangements, taking into
consideration the net effect of all the possible geometri-
cal variations, in order to ensure that the prescribed dose
is actually absorbed in the CTV.
The dose distribution to the PTV has to be considered
to be representative of the dose distribution to the CTV.
As indicated in ICRU Report 50 for external-beam
therapy, when delineating the PTV, consideration may
also be given to the presence of any radiosensitive nor-
mal tissue (organs at risk) as well as to other factors such
as the general condition of the patient. Delineation of
the PTV is a matter of compromise, implying the judge-
ment and thus the responsibility of the radiation oncol-
ogist.
In brachytherapy, the PTV is in general identical to the
CTV. There are only very few exceptions. For instance,
with some techniques in which there are uncertainties of
consistency of source position (high dose rate, moving
sources, fractionated techniques) or alteration of
source position (intracavitary applications, permanent
implants) during the application, the PTV may be larger
than the CTV to take these factors into account.
In this chapter, as in ICRU Report 58 [2], the term
clinical target volume is used rather than planning target
volume.
In external therapy, the two steps localization of CTV
and treatment planning can always be dissociated and
therefore checked separately. However, in interstitial
therapy, the CTV is finally decided upon by the clinician
at the time of implantation on the assumption that it is
contained within the minimum target isodose surface
(see section 6.4.4).
This procedure cannot be recommended, and the
CTV should be clearly described in the patient chart
before the implant is planned.
6.2*4 Treated volume
The treated volume is that volume of tissue, based upon
the implant as actually achieved, which will receive at
least a dose selected and specified by the radiation oncol-
ogist as being appropriate to achieve the purpose of
treatment (e.g., tumor eradication or palliation).
The treated volume is thus encompassed by an isodose
surface corresponding to that dose level, which is the
minimum target dose (see section 6.4.4). This isodose
surface should, ideally, entirely encompass the CTV.
6.3 TECHNIQUES OF BRACHYTHERAPY:
CLASSICAL SYSTEMS
The Paterson-Parker or Manchester System was devel-
oped to deliver a reasonable dose uniformity (10%)
throughout a region implanted with radium needles
[10].
The system specifies rules for the geometrical arrange-
ment of the sources, and for the linear activity required
in order to cover a PTV with a sufficiently homogeneous
dose (Figure 6.1). The system includes tables of
milligram-hour needed to deliver specified doses for dif-
ferent sizes of implants or moulds. The proportion of
activity on the periphery is specified according to the size
of the implant; it is larger for smaller implants. The
system is still used for single-plane and double-plane
implants in many centers.
The Quimby System is characterized by uniform
source spacing and uniform source activity [11].
Consequently, this arrangement of sources resulted in a
non-uniform dose distribution, higher in the central
region of the implant (as in the Paris System; see Figure
6.2). This system was particularly used in the US
centers.
The Paris System of implant planning has been devel-
oped mainly with iridium-192 wire sources [13,18]. The
sources are of equal linear activity, parallel, placed at
equal distances, and arranged in such a way that their
centers are in the same plane perpendicular to the direc-
tion of the lines (Figure 6.2a and b). This plane, called
the central plane, is the midplane of the application
(Figure 6.3a, b, and c). If the volume to be treated is
large, more than one plane containing wires is used.
Again, equidistance of the radioactive lines is required.
This means that their intersections with the central plane
are arranged according to the apices of equilateral trian-
gles or squares (Figure 6.3b and 6.4a and b). This regu-
lar distribution of the wires results in a slight overdose at
the center of the target volume. The dose rate at a point
in the middle of a group of sources is called the basal
dose rate (BD). This BD is always calculated from the
position of the sources in the central plane and is the
minimum dose rate between a pair or group of sources.
The values of the isodose curves are expressed as a per-
centage of the BD.
The reference dose rate is derived from the BD and is
equal to 85% of the BD. It is used for calculating the total
treatment time of the implant.
Because the ends of the active wires are not crossed, as
in the Manchester System, the active sources should be
20-30% longer than the target volume at both ends. The
minimum thickness of a treated volume is 50-60% of
source separation for single planes and 130-150% for
two planes.
Dosimetry according to the Paris System has many
advantages. The use of equal linear activity, equal dis-
tance between the sources, and the fact that no cross

needles are used make the application itself relatively
easy. The relationship between the geometry of the
implant, and the dimensions of the target volume can
easily be determined. The dose rate can be quickly con-
trolled with a planning computer, even in complicated
implantations. Nowadays, most of the implant tech-
niques are based on the original Paris System.
For rapid planning, in some institutes, normograms
have proven useful as approximate planning guides. Both
for removable iridium implants and for permanent
iodine implants, normograms were developed at the
Memorial Sloan Kettering Institute [19]. However, indi-
vidualized computer planning, in general is superior to
Techniques of brachytherapy: classical systems 85
Figure 6.1 Manchester System for application of radioactive
sources with different loading. As an example, (a) is the
localization film for a bladder implant with radium needles of
different activity. Although the Manchester System was designed
for radium sources, it can be used with other radionuclides as
well, such as cesium-137 needles or iridium-192 wires.
As an example of the application of the Manchester System
with radioactive sources other than radium, (b) and (c) give the
distribution of dose rates for a single-pi one implant with
iridium wires of unequal linear activity in order to ensure dose
uniformity throughout the implanted region. Wires 1, 4, 5, and
6 (peripheral) contain a linear activity of 60 MBq (1.6 md) per
cm; wires 2 and 3 contain a linear activity of 37 MBq (1 md)
per cm. Wires 1, 2, 3, and 4 are 6 cm long; wires 5 and 6 are 3.5
cm long, (b) The dose rates in the plane containing the wires;
(c) the dose rates in a perpendicular plane.
the above-described techniques, because the isodose
lines generated by the computer allow a far more com-
plete evaluation of the treatment plan. Both orthogonal
and isocentric techniques are used to reconstruct the
source coordinates. The isocentric reconstruction
method is a variation of the stereo-shift method. With
isocentric equipment, like a treatment simulator, the
angle between the central axes of the projecting beams
can be enlarged up to 60, still obtaining two projections
of the sources (carriers) on the same radiograph (Figure
6.5 a, b, and c). With the simulator, variable angles can
also be chosen, such that sources are not obscuring one
another.
86 Dose specification and reporting: the ICRU recommendations

Figure 6.2 lridium-192 wire implant according to the Paris System (single-plane implant). The wires are of equal linear activity,
parallel, and arranged in such a way that their centers are in the same plane perpendicular to the direction of the wires (i.e., the
central plane, see Figure 6.3).

Figure 6.3 Central plane. In an

implant where the source lines
are rectilinear, parallel, and of
equal length, the central plane
is perpendicular to the direction
of the source lines and passes
throughout their centers. The
mean central dose (DJ is the
arithmetic mean of the local
minimum doses D, (i = A, B ...)
in the plateau region, (a) A
single-plane implant; (b) a two-
plane implant; (c) an actual
single-plane implant where
sources are not rectilinear: the
central plane can be defined as
in (a). (From ICRU Report 58
[21)

6,4 DESCRIPTION OF DOSE DISTRIBUTION regions of high dose surrounding each source. However,
IN INTERSTITIAL THERAPY within the volume of the implant there are regions where
the dose gradient approximates a plateau (Figure 6.6).
6.4.1 General concepts 1. In an interstitial implant, the regions of plateau dose
are equidistant between adjacent neighboring
In interstitial therapy, the dose distribution is non- sources, for sources of identical activity. They are
homogeneous and includes steep dose gradients and regions of local minimum doses.
 Description of dose distribution in interstitial therapy 87

Figure 6.4 Dose planning for implants with iridium-192 wires contained in two parallel planes, following the Paris System. Examples
of a breast implant in two planes, (a) The seven wires are equidistant and arranged in triangles (length of the wires 7 cm for the
upper row and 8 cm for the lower row), linear activity 52 MBq cnr1 (1.4 md cnr1), application time 43.32 h for a reference dose of
20 Gy. (b) The six wires are equidistant and arranged in squares (length of the wires 6 cm for the upper row and 7 cm for the lower
row), linear activity 52 MBq Cm-1 (1.4 mCi cm-1), application time 42.91 h for a reference does of 20 Gy.

2. Variations between these local minimum doses can
be used to describe the dose uniformity of an
implant.
3. A region of plateau dose is the place where the dose
can be calculated most reproducibly and compared
easily by different departments.
Although in modern computer systems the three-
dimensional dose distribution can be computed and pre-
sented as isodose surfaces, these facilities are not yet
available in all departments.
In order to provide the minimum of information
needed about the dose or dose rate distribution, the cal-
culation of isodose curves in at least one chosen plane is
necessary. If only one plane is chosen for isodose calcu-
lation, the central plane of the implant (as defined in sec-
tion 6.4.2) should be chosen for this purpose. In order to
assess the dose distribution in other areas of the implant,
multiple planes for isodose calculation can be chosen,
either parallel or perpendicular to the central plane.
6.4.2 The central plane
In source patterns in which the source lines are straight,
parallel, of equal length and with the centers which lie in
a plane perpendicular to the direction of the source lines,
this plane is the central plane (see Figure 6.3a and b).
In an actual implant, all source lines may not neces-
sarily be straight, parallel, and of equal length. In such
cases, the central plane should be chosen perpendicular
to the main direction of the source lines and passing
through the estimated center of the implant (see Figure
6.3c).
For more complex implants, it may be necessary to
subdivide the target volume into two or more subvol-
umes for dose evaluation. In this event, a central plane
may be defined for each of these subvolumes (Figure
6.7).
The calculation of dose distributions in multiple
planes throughout the target volume shows that a varia-
tion of a few millimetres in the position of the central
plane is not critical.
6.43 Mean central dose
In interstitial therapy, the mean central dose is taken to
be the arithmetic mean of the local minimum doses
between sources in the central plane (or in the central
planes if there are more than one).
In the case of a single-plane implant, the mean central
dose is, in the central plane, the arithmetic mean of the
doses at mid-distance between each pair of adjacent
source lines, taking into account the dose contribution at
88 Dose specification and reporting: the ICRU recommendations

Figure 6.5 Orthogonal AP (a), lateral (b) and isocentric (c)

radiographs of Fletcher-Suit rigid applicator. Note lead wire in
vaginal packing, contrast medium in balloon of Foley catheter,
and air in distal rectum.

that point from all sources in the pattern (see Figure

6.3a).
In the case of an implant with line sources in more than
one plane, the mean central dose is the arithmetic mean of
the local minimum doses between each set of three adja-
cent source lines within the source pattern (see Figure
6.3b). As seen in Figure 6.4a, the minimum dose lies at the
intersection of perpendicular bisectors of the sides of the
triangles (geometric center) formed by these source lines.
This point is equidistant from all three source lines.
In some complex implants, a single central plane may
not bisect or even include all the sources. In these cases,
a mean central dose based on one plane can be mislead-
ing and it is advisable to subdivide the volume and to
choose a separate central plane for each sub volume (see
Figure 6.7).
Figure 6.6 Plateau dose region between radioactive sources. In
Three practical methods are acceptable for determin-
a plane perpendicular to linear and parallel sources, the dose
ing the mean central dose:
distribution shows a plateau region of low dose gradient. In this
1. If parallel lines are used, one can identify triangles example of three sources, 6 cm long and with 1.5 cm spacing,
consisting of three adjacent source lines for all the the dose varies by less than 2% in the gray region between the
sources, so that the triangles formed constitute as sources. (From Dutreix et a I. [18].)
 Description of dose distribution in interstitial therapy 89

Figure 6.7 Central planes in a complex implant. It is

sometimes necessary to plan the treatment in terms of two or
more subvolumes. In the example shown, where all source lines
are not of equal length, two central planes are identified: (a) for
the longest source lines and (b) for the shortest ones. Two mean
central doses are determined in the two subvolumes Dma and
Dmb, respectively. Open circles are the intersections of the sources
with the central planes, and closed circles are the points where
the local minimum doses are calculated. (From ICRU Report 58
[2].)

many acute triangles as possible. The intersection

points of the perpendicular bisectors of each triangle
are determined and the local minimum doses are
calculated at each of these points. The mean of these
local minimum doses is the mean central dose. This
method is the most precise one when parallel lines
are used.
2. Evaluation of dose profiles: the dose profiles are
calculated for one or more axes through the center
of the implant expected to pass through as many
local minima as possible. The local minimum doses
are determined by inspection. The mean of these
local minimum dose values is the mean central dose
(Figure 6.8). In a single surface implant performed
following a curved surface, a profile may lead to an
underestimation of the mean central dose. In a
complex implant, it may be difficult to find axes Figure 6.8 Evaluation of dose profiles. Three profiles (b) are
passing through the minima and profiles may lead to drawn along two orthogonal directions through a two-plane
an overestimation of the mean central dose. implant (a) with eight parallel line sources, 10 cm long, 1.8 cm
However, experience shows that the error lies within spacing. The profiles are calculated in percentage of the
acceptable limits. This method is sometimes minimum target dose (thick line) along axes XX, YY and YY in
preferred for seed implants. In a seed implant, such the central plane. The profile along the axis YY is the most
as the one presented in Figure 6.9, the dose should representative to estimate the mean central dose. The mean of
be calculated along several random profiles passing the local minimum doses is the mean central dose. The mean
through the implant. central dose is equal to 7 78% of the peripheral dose. (From
3. Inspection of dose distribution: the dose ICRU Report 58 [2].)
90 Dose specification and reporting: the ICRU recommendations
Figure 6.9 Seed implant with 68 iodine-125 seeds of 19.2 MBq
(0.52 md), total activity 1310 MBq (35.4 md). (a) Radiograph of
implant, (b) Dose distribution in the central plane.
distribution is plotted in the central plane. With
isodose lines varying by 5% (at most 10%) of the
local dose in the central region, the local minima can
be determined by inspection. The mean of these
local minima is the mean central dose (Figure 6.10).
This method is often preferred for complex implants
with line sources.
6*4.4 Minimum target dose
The minimum target dose is the minimum dose at the
periphery of the CTV. It should be equal to the mini-
mum dose decided upon by the clinician as adequate to
treat the CTV.
The minimum target isodose surface is the isodose
surface corresponding to the minimum target dose. As
indicated above, it defines the treated volume and should
entirely encompass the CTV (see section 6.2.2). The
minimum target dose corresponds to the prescribed
dose in many instances.
Figure 6.10 Determination of mean central dose from
inspection of dose distribution. Dose distribution in the central
plane of an implant with six parallel iridium-192 line sources,
6 cm long, 1.5 cm spacing, reference air kerma rate 14.5 mGyh-1
at 1 m. The dose varies by 5% between plotted isodose lines in
the region of interest. The idodose values are 16, 19, 22, 24, 26,
28, 30, 31.5, 33, 35, 40, and 45 cGy h-1 The local minima, A, B,
C, and D, can be easily estimated by inspection. DA and DD
approximate 31 cGy h-1 and D6 and Dc approximate 34 cGy h-1
The estimated mean central dose is Dm - 32.5 cGy h-1 (From
ICRU Report 58 [2].)
The minimum target dose is known in some
American centers as the 'minimum peripheral dose' [20].
It is known as the 'reference dose' in the Paris System,
and is equal to about 90% of the prescribed dose in the
Manchester System for interstitial therapy.
6.4.5 High-dose regions
In order to correlate radiation dose with late damage, the
high-dose regions around sources should be assessed
(Figures 6.4 and 6.11).
There will inevitably be a high-dose zone around each
source. Although this zone is often small and well toler-
ated, the exact tolerance dose and volume for interstitial
therapy are not known. However, it is necessary, for
intercomparison purposes, to agree on a way to describe
the high-dose volumes. It has been suggested that a dose
of approximately 100 Gy is likely to be significant in
determining late effects. In those patients who receive
50-60 Gy as peripheral minimum dose or 60-70 Gy as
mean central dose, 100 Gy corresponds approximately to
150% of the mean central dose. It is therefore recom-
mended in ICRU Report 58 [2] to report the size of the
region receiving more than 150% of the mean central
dose.
The high-dose regions should be defined as the

regions encompassed by the isodose corresponding to
150% of the mean central dose around the sources in any
plane parallel to the central plane where a high-dose
region is suspected. The maximum dimensions of all
regions in all planes calculated should be reported.
6.4.6 Low dose regions
A low dose region should be defined as a region within
the CTV, encompassed by an isodose corresponding to
90% of the prescribed dose. The maximum dimension of
the low dose region in any plane calculated should be
reported.
In implants for which the CTV is included within the
minimum target dose isodose, the occurrence of a low
dose region is exceptional. If the clinical target volume is
not covered by the minimum target dose isodose, there
will be low dose regions due to geographical miss.
Low dose regions should be reported in order to cor-
relate the local recurrence rate with the dose distribu-
tion.
6*4.7 Dose uniformity parameters
Several indices quantifying the homogeneity of the dose
distribution have been proposed (see, for example, refer-
ences 21-23).
Description of dose distribution in interstitial therapy 91
Figure 6.11 Tongue implant, using five loops of 8 cm indium
wires with activity of 68 MBq cm'1 (1.8 md cm-1).
(a) Radiographs of the implant, (b) Dose distribution in the
central plane of the implant.
Two parameters describing dose uniformity for inter-
stitial implants are recommended in ICRU Report 58
[2]. They can be derived directly from the concepts of
minimum target dose and mean central dose:
1. the spread in the individual minimum doses used to
calculate the mean central dose in the central plane
expressed as a percentage of the mean central dose;
2. the dose homogeneity index, denned as the ratio of
minimum target dose to the mean central dose.
6*4*8 Additional representations of the
dose distribution
In order to obtain a full perception of the dose dis-
tribution of an implant, the use of volume-dose calcula-
tions has been advocated (see, for example, references
24-26).
For this purpose, the CTV (or a larger volume includ-
ing an additional margin) is subdivided in subvolumes
(e.g., voxels) and the dose rate is calculated at the center
of each subvolume. The volume receiving at least a spec-
ified dose is then defined as the sum of all subvolumes
where at the center at least that dose is received.
Examples of results are shown in Figure 6.12. Because of
high dose gradients, significant differences in calculated
volumes can be observed, depending upon the size of the
elementary subvolumes. The size of the grid and of the
92 Dose specification and reporting: the ICRU recommendations
Figure 6.12 Volume-dose curves. Volume (sum of subvolumes
receiving at least a certain dose) versus dose, for two different
patterns of parallel source lines: a two-plane implant with six
sources 5 cm long (upper curve), and a cylindrical implant with
seven sources 4 cm long (lower curve). The dose is expressed as
percentage of the minimum target dose. The size of the voxel
used for calculation is 1 mm3. For the upper curve, linear
sources are simulated by point sources (seeds) arranged in a
linear fashion. (Bridier et al. [25])
elementary subvolumes used in dose and volume calcu-
lations should be clearly stated.
Volume-dose data can also be represented by means
of histograms showing the distribution of fractions of
the CTV receiving doses within chosen intervals, espe-
cially the natural volume-dose histogram (NVDH) as
published by Anderson [27]. With this model, even small
differences between implants can be revealed. The main
characteristic of the NVDH is the peak that occurs with
regular implant of several sources (see, for example,
Figure 6.13). In fact, the peak dose reflects the basal dose
of the Paris System. If the implant is less uniform, the
peak is wider. So, the NVDH can be used for intercom-
parison between planned and realized source arrange-
ments [28,29].
The value of these alternative representations of the
dose distribution as a possible prognostic factor for
treatment outcome has still to be established in clinical
research.
6.5 RECORDING AND REPORTING
INTERSTITIAL THERAPY
Adequate information must be recorded in order to give
a consistent description of any implant. The guidelines
for reporting doses will make it possible to compare
results of future brachytherapy practice and to better
relate outcome to treatment. In order to report an
implant, at least the following should be recorded [2].
Figure 6.13 Natural volume-
dose histogram of the tongue
implant in Figure 6.11.
Treatment dose rate of 1 Gy h-1
was chosen to deliver 60 Gy in
60 h. (From Anderson [27].)

6.5.1 Description of volumes
The description of volumes should include as a mini-
mum the GTV, the CTV, and the treated volume.
6.5.2 Description of sources
The description of the sources employed should include
details of:
Radionudide used including nitration, if relevant.
Type of source used, i.e., wire, seed, seed ribbon,
hairpin, needle, etc.
Length of each source line used.
Reference air kerma rate of each source (or source line):
the reference air kerma rate of a brachytherapy source
is the kerma rate to air, in air, at a reference distance of
1 m, corrected for air attenuation and scattering. The
quantity reference air kerma rate is expressed in Gy s-1
at 1 m, or a multiple of this unit (in a convenient way,
for low dose-rate brachytherapy, in microgray per
hour, )m,Gy Ir1, at 1 m).
The problem of specification of sources used in
brachytherapy has been discussed by several authors,
and the quantity reference air kerma rate has been
increasingly adopted by different organizations or
commissions [1,2,30-39].
The distribution of the strength within the source
should be described (uniform or differential loading,
etc.) [40,41].
6.5.3 Description of technique and
source pattern
If the source distribution rules of a standard system have
been followed, this must be specified. If it is not the case,
the source pattern should be described completely and
unambiguously.
In addition, the following data should be recorded:
number of sources or source lines,
separation between source lines and between planes,
geometrical pattern formed by the sources with the
central plane of implant (e.g., triangles, squares),
where relevant,
the surfaces in which the implant lies, i.e., planes or
curved surfaces,
whether crossing sources are placed at one or more
ends of a group of linear sources,
the material of the inactive vector used to carry the
radioactive sources, if any (e.g., flexible or rigid);
whether rigid templates are used at one or both ends,
type of remote afterloading, if used.
Recording and reporting interstitial therapy 93
6.5.4 Description of time-dose pattern
The description of the time-dose pattern should include
the type of irradiation with the necessary data on treat-
ment and irradiation time, as described below. The infor-
mation on dose and time should provide the necessary
data to calculate instantaneous and average dose rates.
Continuous irradiation: the overall treatment time
should be recorded.
Non-continuous irradiation: both the overall
treatment time and the total irradiation time should
be recorded.
Fractionated, hyperfractionated, and pulsed
irradiation: the irradiation time of each fraction, the
interval between fractions, and the overall treatment
time should be recorded.
When the irradiation times of the different sources
are not identical, they should be recorded.
Moving sources:
Stepping sources: step size and dwell time should be
recorded if constant. Variation of the dwell times of a
stepping source can be used for manipulating the dose
distribution. If such a dose optimization is applied,
this should be specified (e.g., optimization on dose
points defined in the implant or geometrical
optimization [42].
Oscillating sources: speed in different sections of the
vectors should be recorded.
6.5.5 Total reference air kerma (IRAK)
The total reference air kerma is the sum of the products
of the reference air kerma rate and the irradiation time
for each source.
The TRAK is an important quantity which should be
reported for all brachytherapy applications. It is a quan-
tity that is simple to calculate and on which there can be
no ambiguity. It is analogous to the milligrairrhour
(mg.h) of radium. The conversion of the quantity mg.h
to the TRAK is easy and straightforward (1 mg.h radium
equivalent corresponds to 7.2 mGy h-1, at 1 m).
In addition, the TRAK is proportional to the integral
dose to the patient, and can also serve as a useful index
for radiation protection of personnel. However, the sim-
ple determination of the TRAK does not allow one to
derive, even approximately, the absorbed dose in the
immediate vicinity of the sources (i.e., in the tumor or
target volume).
6.5.6 Description of dose distribution
The following doses should be recorded.
Prescribed dose: if the dose is not prescribed at the
level of either the minimum target dose or the mean
central dose, the method of dose prescription should
94 Dose specification and reporting: the ICRU recommendations
be recorded. If, for clinical or technical reasons, the
dose received differs from the prescribed dose, it
should be noted.
Minimum target dose.
Mean central dose.
The following additional information, when available,
should be recorded:
Dimension of high dose region(s).
Dimension of any low dose region.
Any dose uniformity data.
Additional representation of dose distribution, if any.
The above guidelines are based on the recommenda-
tions contained in ICRU Report 58 [2]. It should be
stressed again that it is not the intention, or the role, of
the ICRU to encourage radiation oncologists to depart
from their current practice of dose prescription or tech-
nique of application.
The ICRU reports aim to help radiation oncologists to
report a given application in the same way, using the
same definitions and concepts. One should avoid a situ-
ation in which the same application would be described
differently in different centers or, conversely, in which
the same reported dose would correspond to completely
different actual dose distributions.
For the purposes of this chapter, the prescribed dose is
defined as the dose which the physician intends to give
and which is entered in the patient's treatment chart.
Depending on the system used, the approach for dose
prescription in interstitial therapy may be different from
center to center.
6.6 SPECIFIC PROBLEMS FOR
INTRACAVITARY THERAPY IN GYNECOLOGY
6.6.1 Introduction
As the absorbed dose in soft tissues from intracavitary
applications is so highly non-uniform throughout the
target volume, the concepts of maximum, mean,
median, and modal target absorbed dose, as defined in
ICRU Report 50 [2], are not relevant. The minimum tar-
get absorbed dose is the only useful concept and is, by
definition, equal to the treatment absorbed dose level.
For external-beam therapy, it has been recommended
that the target absorbed dose be defined as the absorbed
dose at one or more specification points which are rep-
resentative of the dose distribution throughout the tar-
get volume. These specification points could be
established with respect to the target volume (center or
central part) or to the beam axes, or both.
In contrast, in intracavitary therapy, due to the steep
dose gradient in the vicinity of the sources, i.e., through-
out the target volume, the specification of the target
absorbed dose in terms of the absorbed dose at specific
point(s), in the vicinity of the sources, is not at all mean-
ingful and a different approach is required. Instead of a
target-dose specification, a volume specification is rec-
ommended in ICRU Report 38 [1].
Specification of an intracavitary application in terms
of the 'reference volume' enclosed by the reference iso-
dose surface of 60 Gy is proposed. However, as the dif-
ferent isodose surfaces are close to each other, the
indication of the reference volume must be supple-
mented, for safety reasons, by the indication of the
TRAK. In addition, recording the absorbed dose at refer-
ence points related to organs at risk or to fixed bony
structures is recommended.
As for interstitial therapy, the ICRU recommendations
contained in Report 38 [1] do not imply a modification
of the method used for the calculation of the treatment
duration, but they require the calculation of specific
quantities for reporting.
The recommendations presented in ICRU Report 38
[1] must be considered a minimum requirement for
reporting. On the other hand, the reported parameters
will be meaningful only to the extent that the technique
of the particular intracavitary application has been com-
pletely described.
ICRU Report 38 [1] deals mainly with the treatment
of cervix carcinoma, for which the anatomical region of
interest is similar for every patient and the possible vari-
ation in the position of the radioactive sources is limited.
However, for other gynecological intracavitary applica-
tions, the same philosophy can be adopted, but some of
the numerical values and definitions may need to be
modified according to the type of application.
6.6.2 Description of the technique
It is recommended that the technique be described on
the basis of the guidance given below.
THE SOURCES
1. Radionuclide
2. Reference air kerma rates
3. Shape, filtration, etc.
SIMULATION OF LINEAR SOURCES
When a linear source is simulated by a set of point
sources, the activity of these point sources and their sep-
aration^) must be indicated [25,43].
When moving sources are used to simulate a set of dif-
ferent sources in fixed position, in order to produce an
appropriate dose distribution, the following indications
are required [44-47]:
1. type of movement (continuous or stepwise, step
distance),
2. unidirectional or oscillating movement,
3. range of movement or oscillation,

4. speed in different sections of the applicator, or dwell
times of the source at different positions.
THE APPLICATOR
Reference to the applicator is sufficient when a complete
description has already been published, provided that there
is no significant difference between the applicator used and
the one described in the literature. To avoid confusion, it is
recommended that the applicator be described, including
the name of the manufacturer. The description should
include information on the following points:
1. rigid (or not), consequently with fixed known
geometry (or not) of the complete applicator,
2. rigid uterine source with fixed curvature (or not),
3. connection between vaginal and uterine applicators,
i.e., fixed, loose (semi-fixed), free,
4. type of vaginal sources, number and orientation of
line sources, special sources (box, ring, etc.),
5. high atomic number shielding materials in vaginal
applicator (or not).
6.63 Recommendations for reporting
Three sets of quantities are recommended in ICRU
Report 38 [1] to specify intracavitary application for
cervix carcinoma; they complement each other and
should be combined.
TOTAL REFERENCE AIR KERMA (TRAK)
The TRACK will always be reported (see section 6.5.5).
DESCRIPTION OF THE REFERENCE VOLUME
The description of the reference volume, i.e., the tissue
volume encompassed by a reference isodose surface, has
been proposed for specification in reporting. The rea-
sons for this approach are described in section 6.6.1.
Dose level
An absorbed dose level of 60 Gy is widely accepted as the
appropriate reference level for conventional low dose-
rate therapy. When two or more intracavitary applica-
tions are performed, the absorbed dose to consider is
that resulting from all applications. The time-dose
pattern should be clearly stated.
When intracavitary therapy is combined with
external-beam therapy, the isodose level to be considered
is the difference between 60 Gy and the dose delivered at
the same location by external-beam therapy. For exam-
ple, if a dose of 20 Gy were delivered to the whole pelvis
by external-beam therapy, the isodose level to be consid-
ered would be 60 20 Gy = 40 Gy. Nevertheless, it is rec-
ognized that the combined dose does not necessarily
produce the same effect as a similar dose from intracav-
itary therapy alone.
For intracavitary therapy at medium or high dose
Specific problems for intracavitary therapy in gynecology 95
rates, the radiation oncologist has to indicate the dose
level which he or she believes to be equivalent to 60 Gy
delivered at the conventional low dose rate, and this
should be clearly stated [48-50].
Reference volume: description of the pear-shaped
volume
When the uterine source(s) is combined with vaginal
sources, or when the uterine source is more heavily
loaded at the lower end, the tissue volume to be
described presents a pear shape, with its longest axis
coincident with the intrauterine source (Figure 6.14).
This reference volume is defined by means of three
dimensions (Figure 6.15):
1. the height (dh)is the maximum dimension along the
intrauterine source and is measured in the oblique
frontal plane containing the intrauterine source;
2. the width (dw) is the maximum dimension
perpendicular to the intrauterine source and is
measured in the same oblique frontal plane;
3. the thickness (dt) is the maximum dimension
perpendicular to the intrauterine source and is
measured in the oblique sagittal plane containing the
intrauterine source.
The definitions of dh, dw and dt are proposed in order to
minimize the number of calculations. These dimensions
are usually expressed in centimeters. The volume esti-
mated from the intersections of the surface of a pear-
shaped volume on two conventional planes does not
necessarily represent the size of the true reference vol-
ume. However, for most applications they do not differ
from the maximum dimensions of the reference volume
by more than 1 or 2 mm.
ABSORBED DOSE AT REFERENCE POINTS
Several reference points are in current use. Some are rel-
atively close to the sources and related either to the
sources or to organs at risk; others are relatively far from
the sources and are related to bony structures. The fol-
lowing definitions apply to the case where the doses are
calculated from two perpendicular radiographs, anterio-
posterior (AP) and lateral. When other methods are
used, such as stereographic X-ray films, oblique perpen-
dicular radiographs or transverse sections (CT scans),
the calculations need to be modified.
Reference points close to the sources and related to
the sources
As such points are located in a region where the dose
gradients are high, any inaccuracy in the determination
of distance results in large uncertainties in the absorbed
doses evaluated at these points. Such calculated absorbed
doses do not, therefore, seem an appropriate means of
characterizing an intracavitary application and/or of
reporting the target absorbed dose, particularly if rigid
source combinations are not used. Such points are not
recommended in ICRU Report 38 [ 1 ].
96 Dose specification and reporting: the ICRU recommendations
Reference points relatively close to the sources but
related to organs at risk
The determination and specification of the absorbed
dose to organs at risk (bladder, rectum, etc.) are obvi-
ously useful with respect to normal tissue tolerance lim-
its. However, such information will be meaningful only
to the extent that it is obtained and expressed in precise
and well-codified ways.
Calculated values: reference points for the expression
of the absorbed dose to the bladder and the absorbed
dose to the rectum (see Figure 6.16) have been
proposed by Chassagne and Horiot [51].
The bladder reference point is obtained as follows. A
Foley catheter is used. The balloon must be filled with
7 cm3 of radio-opaque fluid. The catheter is pulled
Figure 6.14 Dose distribution
of Fletcher-Suit rigid
applicator, as in Figure 6.5,
using total activity of 606 MBq
(16.4 md) cesium-137 and
showing the pear-shaped tissue
volume, (a) Plane
perpendicular to Z-axis. (b)
Plane perpendicular to X-axis.
downwards to bring the balloon against the urethra.
On the lateral radiograph, the reference point is
obtained on an AP line drawn through the center of
the balloon. The reference point is taken on this line at
the posterior surface of the balloon. On the frontal
radiograph, the reference point is taken at the center
of the balloon.
The point of reference for the rectal dose is obtained
as follows. On the lateral radiograph, an AP line is
drawn from the lower end of the intrauterine source
(or from the middle of the intravaginal sources). The
point is located on this line 5 mm behind the
posterior vaginal wall. The posterior vaginal wall is
visualized, depending upon the technique, by means
of an intravaginal mould or by an opacification of the
vaginal cavity with a radio-opaque gauze used for the

Figure 6.15 Geometry for measurement of the size of the pear-
shaped 60 Gy isodose surface (broken line) in a typical treatment
of cervix carcinoma using one rod-shaped uterine applicator
and two vaginal applicators. Plane a is the 'oblique'frontal
plane that contains the intrauterine device. The oblique frontal
plane is obtained by rotation of the frontal plane around a
transverse axis. Plane b is the 'oblique' sagittal plane that
contains the intrauterine device. The oblique sagittal plane is
obtained by rotation of the sagittal plane around the AP axis.
The height (d J and the width (d J of the reference volume are
measured in plane a as the maximal sizes parallel and
perpendicular to the uterine applicator respectively. The
thickness (dt) of the reference volume is measured in plane b as
the maximal size perpendicular to the uterine applicator. (From
ICRU Report 38 [1].)
packing. On the AP radiograph, this reference point is
at the lower end of the intrauterine source or at the
middle of the intravaginal source(s).
Monitoring of the absorbed dose rate to the rectum: in
addition to calculating the rectal dose, the dose, or
dose rate, can be measured at different points along
the anterior rectal wall to ensure that no area of the
rectal mucosa receives a dose above the tolerance
level. This type of measurement requires special care
in positioning the measuring probe. An example is
given in Figure 6.17.
Specific problems for intracavitary therapy in gynecology 97
Figure 6.16 Determination of the reference points for bladder
and rectum as proposed by Chassagne and Horiot [51].)
Reference points related to bony structures
The lymphatic trapezoid is obtained as follows (Figure
6.18). A line is drawn from the junction of S1-S2 to
the top of the symphysis. Then a line is drawn from
the middle of that line to the middle of the anterior
aspect of L4. A trapezoid is constructed in a plane
passing through the transverse line in the pelvic brim
plane and the midpoint of the anterior aspect of the
body of L4 (from Fletcher [52]).
A point 6 cm lateral to the midline at the inferior
end of this figure is used to give an estimate of the
dose rate to mid-external iliac lymph nodes.
At the top of the trapezoid, points 2 cm lateral to
the midline at the level of L4 are used to estimate the
dose to the low para-aortic area.
The midpoint of a line connecting these two points
is used to estimate the dose to the low common iliac
lymph nodes.
The pelvic-wall reference point [51] can be visualized
on an AP and a lateral radiograph and related to fixed
bony structures. This point is intended to be
representative of the absorbed dose at the distal part
of the parametrium and at the obturator lymph nodes
(Figure 6.19). On an AP radiograph, the pelvic-wall
reference point is intersected by the following two
lines: a horizontal line tangential to the highest point
of the acetabulum, and a vertical line tangential to the
inner aspect of the acetabulum. On a lateral
radiograph, the highest points of the right and left
acetabulum, in the cranio-caudal direction, are joined
and the lateral projection of the pelvic-wall reference
point is located at the mid-distance of these points.
Evaluation of the absorbed dose at reference points,
related to well-defined bony structures and lymph node
areas, is particularly useful when intracavitary therapy is
combined with external-beam therapy. It is also useful in
98 Dose specification and reporting: the ICRU recommendations

Figure 6.17 Measurement of the rectal dose rate. The rectal dose
is measured following the insertion of the source applicators,
either preloaded (low-activity treatment) or manually loaded with
low-activity sources identical in design to those used during high-
activity afterloaded treatment. Method A: the measuring probe is
moved relative to a rigid guide tube inserted into the rectum and
held in position. The point of maximum rectal dose rate is noted
and the distance d, in cm, from the anal verge deduced. Method
B: the measuring probe is moved so that the tip of the probe is
moved along the midline of the recto-vaginal septum until the
point of maximum dose rate is reached. Distance is taken as a
direct reading on the central tube and at the anal verge. The dose
rate and distance are recorded.
The major disadvantage of Method A is that the probe tip
cannot follow the surface of the anterior rectal wall closely.
However, a IIowa nee for the distance of the probe sensor from the
vagi no-recta I septum needs to be taken into account. (From ICRU
Report 38 [1].)

Figure 6.18 Determination of

the lymphatic trapezoid. On the
left is an anteroposterior view
and on the right a lateral view
(see text). (From Fletcher [52].)

helping to avoid an overdose when intracavitary therapy
is to be followed by surgery.
CALCULATION OF DOSE DISTRIBUTION
The present recommendations, in particular the descrip-
tion of the reference volume encompassed by the 60-Gy
isodose surface, necessitate the computation of complete
dose distributions in several planes.
The respective planes for which the dose distribution
is to be computed will depend on the technique and the
particular clinical situation. However, as a minimum
requirement, it is recommended that the dose distribu-
tions be computed in two planes: the oblique frontal
plane and the oblique sagittal plane, both containing the
intrauterine source.
When practicable, it is recommended that dose distri-
butions be calculated in additional sets of planes and

that these dosimetric data be correlated with those
obtained from radiographs or CT sections, in order to
determine the absorbed dose at any relevant anatomical
point.
While this additional information will be of value in
assessing effects in any individual patient, it will also
provide:
1. the possibility of comparing the methods of
specification used in different centers and of
evaluating their respective merits;
2. the possibility of comparing the methods of
specification used in historical series (mgh, points
'A' and 'B') with the methods recommended in ICRU
Report 38 [1];
3. the possibility of deriving new clinical and
radiobiological data and correlations which could
improve treatment techniques and develop further
the method of specification.
6.6*4 Definition of the 60-Gy reference
volume in special situations
One linear source only. In some situations, only one
linear source is present:
in the case of a narrow vagina with a uterine source
protruding into the vaginal cavity,
in the case of vaginal irradiation with a central source
from a cylindrical applicator.
In estimating the volume in this simple case, the
width is equal to the thickness, as the dose
distribution is symmetrical about the source axis.
Vaginal sources only. When only vaginal sources are
present, width is the largest dimension from right to
left in an oblique frontal plane through the main axis
of the vagina.
Thickness is the largest dimension in a direction
perpendicular to the above oblique plane. Height is
measured along the vaginal axis, and is commonly
shorter than the other two dimensions.
Rigid applicator. Provided that there is a fixed
connection between vaginal and uterine sources, pre-
Concluding remarks 99
Figure 6.19 Determination of
the right (RPW) and left (LPW)
pelvic wall reference points (see
text). (From Chassagne and Horiot
[57].;
calculated isodose surfaces can be obtained for given
loadings of the applicator. Therefore, pre-calculated
dimensions of height, width, and thickness can be
given [53].
Uterine packing in endometrial carcinoma. In
connection with uterine packing, the same definitions
of height, width and thickness given in section 6.6.3
can be used. However, two facts need to be noted:
width and thickness are usually located at the level of
uterine fundus (the pear-shaped volume is
reversed),
height should be determined in the oblique frontal
plane, which gives the maximum dimension.
6.7 CONCLUDING REMARKS
At the end of this chapter, it should be stressed again that
the aim of the ICRU Reports 38 and 58 [1,2] is not to
encourage the users to depart from their current practice
in brachytherapy. Treatment prescription is the respon-
sibility of the radiation oncologist (or team) in charge of
the patient; it is based on the radiation oncologist's
judgement and experience and implies his or her respon-
sibility.
Reporting a treatment is another issue. The aim of the
ICRU efforts is to recommend a common language for
reporting a treatment in such a way that the clinical
information can be exchanged in a relevant way, avoid-
ing misinterpretation and confusion between radiation
oncologists and departments.
However, the use of the same sets of definitions, con-
cepts, and approaches for prescribing, recording, and
reporting a treatment has obvious advantages in simpli-
fying the issues and avoiding confusion. It could be a
long term beneficial consequence of the ICRU efforts.
ICRU Report 58 [2] on interstitial brachytherapy was
published at the end of 1997, but Report 38 [ 1 ] was pub-
lished in 1985. Significant changes took place during the
14 years in the field of brachytherapy, especially the
development and dissemination of high dose-rate, and
pulse dose-rate applications.
100 Dose specification and reporting: the ICRU recommendations
Revision of ICRU Report 38 [1] becomes necessary
and is welcomed by the radiation oncology community,
as indicated by a recent inquiry [54,55]. The ICRU initi-
ated a revision of Report 38, in 1998, on the basis of the
answers to a questionnaire sent to the ESTRO members
and a large survey of the recent literature. The following
topics are considered: HDR, MDR, PDR, exploitation of
the patient data provided by the modern imaging tech-
niques, localization of the different Volumes', and identi-
fication of the organs at risk, specification of dose,
combination of external and intracavitary therapy,
three-dimensional treatment planning, and radiobiolog-
ical issues raised by the different dose rates which can
now be applied.
The use of the TRAK should be encouraged. The fact
that several companies use this quantity to specify the
sources they are manufacturing will certainly facilitate its
general use (e.g., Amersham,1 CIS Bioindustries,2
Mallinckrodt Medical3).
Finally, as in externa-beam therapy (see ICRU Report
50 [6]), several levels of complexity could be proposed
for reporting the treatments in brachytherapy (see, for
example, reference 56):
Level 1: basic techniques-minimum requirements. A
standard applicator is used, with a fixed geometry.
Unambiguous and simple definitions of reference
points are required. Radiographs are taken to check
the position of the applicator.
Level 2: advanced techniques-modern radiotherapy
standards. An individual assessment of absorbed
doses at reference points, in different volumes (GTV,
CTV, PTV), organs at risk, and normal anatomy is
needed, based on radiographs taken in well-defined
geometry or CT sections. Computer-assisted dose
calculations are performed in three planes at different
levels/sections, indicating accurately the doses at the
chosen reference points, reference volume(s), and
other volumes of interest, e.g., high dose volumes.
Level 3: developmental techniques-clinical research.
Planning and performance of brachytherapy
according to proposed level 3 imply individualized
three-dimensional, computer-assisted assessment of
the patient anatomy based on sectional imaging (e.g.,
with CT, MRI, ultrasound). The different volumes,
such as GTV, CTV, PTV, and organs at risk, can be
identified and localized. This makes possible accurate
three-dimensional dose computation at selected
reference points and in different volumes of interest.
Dose-volume histograms can also be computed.
1. Amersham International pic, Amersham Laboratories, White Lion
Road, Amersham, Buckinghamshire HP7 9LL, UK.
2. CIS Bioindustries (Compagnie ORIS Industrie S.A.), CEN Saclay,
91190 Gif-sur-Yvette, France.
3. Mallinckrodt Medical B.V., Westduinweg 3, NL-1755 LE Petten,
The Netherlands.
As in external-beam therapy, the limits between the
three levels proposed for reporting in brachytherapy are
not definitely fixed, but may vary, in time, with the devel-
opment of the imaging, computation, and dosimetry
techniques.
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47. von Essen, C.F. (1980) Clinical application of the
Brachytron: the San Diego technique for treatment of
cancer of the cervix. In High Dose-rate Afterloading in the
Treatment of Cancer of the Uterus, ed. T.D. Bates and R.J.
Berry. British Journal of Radiology Special Report 17,
p. 117.
48. Hall, E.J. (1994) Radiobiologyfor the Radiologist,
Philadelphia, J.B. Lippincott Company.
49. van Limbergen, E., Chassagne, D. Gerbaulet, A. and Haie,
C. (1985) Different dose rates in preoperative
endocavitary brachytherapy for cervical carcinoma./ Eur.
Radiother., 1,21-7.
50. Leborgne, F., Fowler, J.F., Leborgne, J.H., Zubizaretta, E.
and Chappell, R. (1997) Biologically effective doses in
medium dose rate brachytherapy of cancer of the cervix.
Radial Oncol. Invest., 5,289-99.
51. Chassagne, D. and Horiot, J.C. (1977) Propositions pour
une definition commune des points de reference en
curietherapiegynecologique.y. Radiol. Electrol., 58,371.
52. Fletcher, G.H. (1980) Squamous cell carcinoma of the
uterine cervix. In Textbook of Radiotherapy, ed. G.H.
Fletcher. Philadelphia, Lea & Febiger, 720-851.
53. International Atomic Energy Agency (1972) Atlas of
Radiation Dose Distributions, Vol. IV, Brachytherapy
Isodose Charts. Sealed Radium Sources, ed. M. Stovall, L.H.
Lanzl and W.S. Moos. Vienna, International Atomic Energy
Agency, Vienna.
54. Groupe Europeen de Curietherapie-European Society for
Therapeutic Radiology and Oncology (1998) Workshop
ICRU 38: The basis for a revision (Dir. R. Potter), Napoli,
11-13 May.
55. Potter, R., van Limbergen, E., Gerstner, N. and Wambersie,
A. (2000) Survey of the use of the ICRU 38 in recording and
reporting in brachytherapy of cervical cancer. Radiother.
Oncol.
56. Potter, R., Kovacs, G. and Haverkamp, U. (1995) 3D
Conformal Therapy in Brachytherapy, 8th International
Brachytherapy Conference, Nice (France), 25-28
November 1995, Nucletron-Oldelft, PO Box 930,3900 AX
Veenendaal, The Netherlands.

Afterloading systems
A. FLYNN
7,1 INTRODUCTION
The aim of this chapter is to examine the various after-
loading systems that are currently available and also some
that are perhaps not strictly currently available but have
been used in the recent past. It is not intended to be a com-
plete itemization of the subject, but rather an overview of
the main types of equipment and the uses to which they
are generally put. It is anticipated that this chapter will
help the newcomer to this field to see which systems are
particularly suited to each treatment site and method of
treatment. It is inevitable in an analysis of this nature that
there will be omissions, as it is impossible to cover every
aspect of each use of each piece of equipment or tech-
nique, and the writer apologizes in advance to any user of
this equipment if his or her particular technique has been
omitted. However, it is hoped that there is sufficient infor-
mation for a user or potential user to perceive the relative
clinical and technical advantages and disadvantages of
each method or equipment. No attempt has been made to
assess the relative costs of the equipment, as this will vary
from one country to another depending on the local sup-
ply situation and servicing and delivery costs. However, it
will become apparent that some types of equipment are
designed to be specific for a particular site in the body,
whereas others are more flexible in the way that they can
be adapted for use in several body sites, and the financial
considerations of whether a particular machine will be
more or less cost-effective will depend, in part, on the
anticipated number of applications and the case mix.
It is stated at the outset that, whilst various suppliers
of radioactive sources and manufacturers of brachyther-
7
apy equipment are mentioned, this should not be taken
to imply any specific recommendation of the products of
any individual company. The chapter does not make rec-
ommendations of the merits and demerits of similar
treatment machines made by the different manufactur-
ers. The reader will appreciate that machines which are
similar (but not identical) in their mode of operation are
available from different manufacturers and suppliers: an
example of such a pair of similar machines is the
microSelectron-HDR (supplied by Nucletron) and the
Varisource (supplied by Varian). It is the responsibility of
the prospective purchaser to decide which particular
machine of a certain type is best suited to his or her pur-
pose, bearing in mind the cost, safety aspects, supplier's
service record, and all other appropriate considerations.
The reader is referred to Chapter 1 for further details
of the radioactive sources associated with these after-
loading techniques, and to Chapters 8 and 9 for a full
discussion of commissioning and quality assurance
aspects of low, high, and pulsed dose-rate equipment. An
excellent review of remote afterloading technology may
be found in American Association of Physicists in
Medicine (AAPM) Report No. 41 [1], and internation-
ally agreed specifications for the safety requirements of
remotely controlled afterloading equipment may be
found in reference 2.
7.2 ADVANTAGES OF AFTERLOADING
The accelerated development of afterloading from the
1960s onwards was initially driven by the desire to
104 Afterloading systems
improve the radiation protection environment of the
staff involved in the provision of brachytherapy treat-
ments. Readers of older textbooks will find pictures of
implants using many radium needles, all of which were
inserted manually in the operating theatre, with the con-
sequent radiation exposure of the clinicians and other
staff, and there are both documented and anecdotal
reports of radiation injury to the fingers of radiothera-
pists.
The technique of afterloading involves the placing of
the non-radioactive needles, tubing, or applicators into
the patient without the presence of the radioactive
sources. Often, dosimetry radiography will be performed
at this stage using non-radioactive marker inserts in the
applicators. The radioactive material is inserted only
when all of the preliminary procedures have been carried
out and the operator is satisfied that the applicators are
placed correctly within the treatment site. In the case of
manual afterloading, the sources are introduced into the
carrier needles or tubing directly by the operator, using
forceps or other appropriate manipulation instruments.
This may be done in the operating theatre (for example,
in the case of iridium-192 hairpins) or perhaps on the
ward (as may be the case for cesium-137 gynecological
source trains or iridium-192 wires). In this way, the radi-
ation exposure to operating room and radiography staff
may be minimized. An important 'by-product' of the use
of non-radioactive materials at this stage is that the
radiotherapist is able to spend more time in the placing
of the applicators and can therefore obtain an improved
geometry within the implant site. Thus, afterloading
confers a benefit to the patient, even with this minimal
afterloading method.
However, it is apparent that with manual afterloading
the radiation protection advantage is gained only in the
initial phases of the treatment and that, eventually, the
sources themselves have to be inserted into the applica-
tors by the operator and the patient has to be cared for
by the nursing and clinical staff, with radioactive sources
in position, for the duration of the treatment. The use of
remote or machine afterloading extends the radiation
protection advantage to the whole of the brachytherapy
treatment in that not only are the sources placed initially
in the applicators by the machine, but they may also be
temporarily withdrawn from the patient into the
machine's protected safe for the duration of any nursing
procedures that the patient may require. In addition,.the
treatment machine timer(s) controls the duration of the
treatment to a high degree of accuracy.
Whereas considerations of radiation protection were
the main driving force for the development of afterload-
ing, more recently other advantages have become appar-
ent. For example, high dose-rate (HDR) and pulsed
dose-rate (PDR) brachytherapy would not be possible
(or would at least be highly inconvenient) without the
use of afterloading devices. Also, the modern develop-
ment of conformal brachytherapy using stepping or
oscillating source positions has been dependent on the
availability of computer-controlled, accurate source
positioning, which would not be possible without after-
loading.
73 DEFINITION OF LOW, MEDIUM, HIGH,
AND PULSED DOSE RATES
There is no general agreement in the literature regarding
the boundaries between low, medium, and high dose rate
or even where the relevant dose rates are defined. Both
the International Commission for Radiological Units
(ICRU) [3] and the AAPM [1] base their definitions on
the dose rate at the prescription point or prescription
isodose. ICRU 38 is a document concerned solely with
intracavitary therapy, so it may be reasonably assumed
that it refers to the dose rate at or near point A of the
Manchester System, but a similar inference cannot be
made for the AAPM categories. The ICRU recognizes
three categories:
Low dose rate (LDR): 0.4 Gy Ir1 to 2 Gy Ir1
Medium dose rate (MDR): 2 Gy Ir1 to 12 Gy Ir1
High dose rate (HDR): greater than 0.2 Gy mhr1
(i.e., 12Gyh-')
although it acknowledges that these definitions are
debatable.
On the other hand, the AAPM defines LDR in terms of
'... conventional doses of about 10 Gy are delivered daily
...,' which implies a prescription dose rate of about
0.5 Gy Ir1. An HDR category is defined as having a pre-
scription dose rate greater than 0.2 Gy min~', which is the
same as the ICRU definition of HDR. MDR is defined as
being 'between LDR and HDR,' but the boundary
between LDR and MDR is not defined. It is interesting
that the dose rate of about 1.5 Gy Ir1 that has been fre-
quently used for cervix treatment since afterloading was
introduced, and for which radiobiological considera-
tions require a dose rate correction factor to be used, is
actually less than the lower boundary for MDR as
defined by the ICRU, and is therefore regarded as LDR by
this authority, although it could be classed as MDR
according to the AAPM definitions. However, this dose
rate is often colloquially called MDR.
Another definition may arise from the standpoint of
radiation protection, where the interest is in the envi-
ronmental levels of radiation around equipment rather
than the clinical dose rates. For example, the Guidance
Notes for the United Kingdom's Ionising Radiation
Regulations [4] defines equipment giving a dose rate of
less than 10 m Gy h-1 at 1 m as LDR; radiation levels
greater than this are HDR. This boundary corresponds
approximately to a dose rate at point A of 0.4 Gy mur1,
which is not the same as the ICRU and AAPM boundary.
In practice, these differences are somewhat academic,
as HDR machines generally operate at dose rates well
 Manual afterloading systems 105

above these boundaries, typically at around 2 Gy mhr1, The implantation of the carrier tubing into the treat-
which is well within the HDR category as denned by all ment site may be performed either with flexible nylon
the aforementioned documents. The boundary between tubing or with rigid needles, depending upon the cir-
LDR and MDR is more questionable. In any event, the cumstances of the particular case. Surgical methods of
only safe practice when reporting radiotherapy is to state placing the tubing in the implant site have been
exactly the dose, dose rate, and fractionation used, as described by Pierquin et al. [9]. The encapsulated irid-
recommended in the ICRU Report 38 [3]. ium wires are held in place for the duration of the
The idea behind pulsed dose-rate (PDR) brachyther- implant by crimped lead discs separated from the
apy is to replace continuous low dose-rate brachytherapy patient's skin by nylon balls. These may be easily
(CLDR) by a series of 'pulses' of higher dose-rate treat- removed to allow removal of the wires from the patient
ment. Brenner and Hall [5] and Fowler and Mount [6] at the end of treatment. The main problem with the use
have published analyses of studies of the radiobiology of of these flexible tubes is that it is difficult to achieve good
these modalities, from which come recommendations implant geometry, as the tubes do not generally remain
that, to obtain equivalence to CLDR, the PDR should straight in the patient. The use of rigid needles (and,
give the same overall dose in the same overall time, pro- where possible, templates) permits improved implant
vided that the pulse interval is about 1 h, the length of geometry: this method is preferred where possible.
each pulse should be not less than 10 min, and each
pulse should give a dose of about 0.5 Gy, i.e., a dose rate
7.4.2 Iridium hairpins
of not more than about 3 Gy h-1 within the pulse. Some
early studies of the use of PDR have been reported [7,8].
These have a larger diameter than the wires and are
The main advantage of PDR is technical, in that it
therefore more rigid. The overall diameter is 0.6 mm,
enables the equivalent of CLDR to be given with a single
this being made up of a 0.4 mm diameter central 'core' of
stepping source, thereby increasing the range of active
iridium/platinum alloy, surrounded by a platinum
lengths and dose distributions that may be obtained.
sheath of thickness 0.1 mm. They are available in a pre-
formed 'hairpin' shape, as shown in Figure 7.1. The
length of each 'leg' of a hairpin is 60 mm, and this may
7A MANUAL AFTERLOADING SYSTEMS be cut down to the required length just prior to implan-
tation. Single pins may be available to special order.
Hairpins are implanted into the tissue with the aid of
7.4.1 Iridium wires
slotted hairpin guides. The guides are implanted and
their positions checked by radiography. If they appear
Iridium wire has an external diameter of 0.3 mm and is
satisfactory, the hairpins are inserted into the guides,
generally supplied as a loosely wound coil containing a
which are then removed, leaving the hairpins in the tis-
length of 500 mm, although other lengths may be avail-
sue. These are secured by a suture around the crosspiece
able to special order. In cross-section there is a central
of the hairpin.
'core' of iridium/platimim alloy of diameter 0.1 mm,
which is surrounded by a sheath of platinum of thick-
ness 0.1 mm, giving the overall diameter of 0.3 mm, as
stated above. It is available in a range of activities; for
further details, the reader is referred to Chapter 1.
In use, the wire is cut to the appropriate lengths
required for the particular application. Before being
afterloaded into the needles or 'outer' tubing implanted
in the patient, it is normal practice for the wire itself to
be encapsulated into the so-called 'inner' tubing. Once
the wire has been fed into its encapsulating tubing, the
latter is deformed slightly, either mechanically (for
example by the Amersham crimping tool or the
Amersham Iridium Wire Loader crimping tool) or by
heat (for example, by the now obsolete TEM Iridium
Wire Loader), to provide a seal in the tubing at each end
of the wire which fixes the wire into the tubing. Non-
active ends of empty tubing may be left at each end of
the wire and these may be used to control the position of
the active material within the 'outer' tubing or needles.
Equipment to facilitate the preparation of iridium wires Figure 7.1 Indium wire hairpin (courtesy Nycomed-Amersham
is commercially available. pk).
106 Afterloading systems
Hairpins are particularly useful in head and neck
implants where the implant site is often only accessible
from one end. The radioactive 'bridge' across the top of
the hairpin provides an effective 'crossing source,' which
allows the reference isodose to be brought up to the level
of the mucosa.
7*43 Iridium ribbons
In North America, iridium-192 is available in the form of
'ribbons.' A ribbon consists of 12 seeds loaded into a
nylon carrier, the seeds being placed at 10 mm intervals.
They are used in a similar way to iridium wires in that
the ribbon is afterloaded into previously positioned car-
rier tubing in the implant site. The ribbon may be short-
ened to the required active length by cutting between the
seeds. One advantage over conventional wire is that it
becomes unnecessary to cut through the active material
itself when preparing the sources. Otherwise, the
method of use is similar to that for the iridium wires
already described.
7.4*4 Iodine seeds
Iodine seeds are mainly used for non-afterloaded tech-
niques and are therefore beyond the scope of this chap-
ter. Examples of their use are for transperineal
implantation of the prostate, which has been described
by Blasko et al. [10], and for the manufacture of oph-
thalmic applicators. However, the treatment of brain
lesions using removable afterloaded high activity seeds
has also been described [11].
7*4*5 Tantalum wire
This material was similar in construction to iridium
wire, which has now superseded it, owing to the latter's
greater specific activity. It was used in the late 1940s and
early 1950s as a source for interstitial implants.
7*4*6 Fletcher-Suit applicators
These applicators for treatment of the uterine cervix
developed from a non-afterloading system designed by
Fletcher [12] and modified in the early 1960s by Suit
[13]. Suit's modification allowed the use of afterloaded
radium sources, now superseded by cesium-137 sources,
held in a hinged carrier, which could be inserted into the
tubes. The source arrangement has similarities to the tra-
ditional Manchester System (see Chapter 4) in that it
employs a line source in the uterine canal and two vagi-
nal sources, one placed in each lateral fornix. In the
Fletcher-Suit system, the vaginal sources are called 'col-
postats' rather than 'ovoids.' There are three sizes of col-
postat, 20 mm, 25 mm, and 30 mm diameter (similar to
the Manchester ovoids), but they are cylindrical in shape
and incorporate tungsten rectal and bladder shielding.
The colpostats are linked external to the patient and may
move with a 'scissor' action to allow the separation
between them to be varied.
A further modification was reported and evaluated in
1985 [ 14] to enable the applicator system to be used with
the Selectron-LDR afterloading unit.
7*4*7 Amersham Gynecological System
A manual afterloading system is supplied by Nycomed-
Amersham. The applicators are based on the Manchester
System and are designed to allow the ovoids to be sepa-
rated by a 'washer' or 'spacer' or be used 'in tandem.'
There is a choice of three sizes of applicators. The appli-
cators are made of semi-flexible plastic tubing and are
supplied pre-sterilized and are intended to be disposed of
after a single use. The uterine tube and ovoids are linked
together, but they can slide longitudinally with respect to
one another to accommodate differing anatomy. In con-
trast to the traditional Manchester System, the ovoids lie
with their axes parallel to the vaginal axis.
The source trains used with these applicators consist
of a flexible helical spring, which is loaded with an
arrangement of miniature cesium-137 sources and spac-
ers. A number of standard source train arrangements are
available and, if required, the supplier can make up
trains to the customer's requirements at the time of pur-
chase. Normally, therefore, a selection of trains would be
needed to cover the variations in source requirements
envisaged. The handle of each source train is marked
with a code to aid identification, as shown in Figure 1.2
in Chapter 1. Figure 7.2 shows a typical applicator set.
Other applicators are available based on the Fletcher and
the Henschke systems, but these use the standard
cesium-137 tubes. This system is described in more
detail in Chapter 1.
Figure 7.2 Amersham manual afterloading system for the
uterine cervix; plastic applicator set (courtesy Nycomed-
Amersham pic).

7.5 LOW DOSE-RATE REMOTE SYSTEMS
The reasons behind the introduction of remote after-
loading systems are considered in section 7.2. However,
it will also be apparent from the foregoing descriptions
of manual afterloading systems using pre-prepared
source trains that another significant disadvantage to
this method is the limited availability of source arrange-
ments. An institution would generally have only a small
number of source trains, which limits the number of
applicator combinations and dose distributions that may
be employed. Remote afterloaders were therefore
designed to attempt to overcome this restriction by
increasing the number of available source patterns. In
earlier machines, this was done by having a larger num-
ber of preloaded trains, whereas later machines allow the
user to compose source trains in the required pattern at
the time of use, or by using a single source whose move-
ment through the applicators can be controlled to give
the desired dose distribution.
This section reviews some of the LDR afterloaders and
their applications.
7.5.1 Curietron
The Curietron is one of the older type of afterloaders. It
was designed and manufactured in France and was used
during the 1960s and 1970s, though it is now largely
obsolete. The machine was used for the treatment of the
uterine cervix. It employed pre-loaded flexible source
trains, consisting of cesium-137 sources and spacers in
various combinations. The trains were mechanically
coupled to drive motors and up to three trains could be
transferred to the patient applicators. The treatment
exposure of each train could be independently timed
and the treatment could be readily interrupted to allow
for nursing care. The treatment unit contained a safe for
the source trains, to which they were withdrawn during
interruptions and at the end of the treatment.
The capacity of the main treatment unit was limited
to four source trains, so the Curietron also had a 'sec-
ondary' radiation sources safe, separate from the main
treatment unit, which housed extra source trains,
thereby increasing the range of treatment dose distribu-
tions that could be obtained. When the applicators and
treatment requirements for a particular application
were known, the appropriate source trains were trans-
ferred to the main treatment unit, from whence they
were subsequently driven into the applicators, as
described above.
The radioactive sources were cesium-137 pellets of
length 5.3 mm and diameter 1.8 mm. These were loaded
into source holders, with spacers, to give a variety of
active lengths. The use of this machine is described in
reference 15.
Lose dose-rate remote systems 107
7.5.2 Selectron-LDR/MDR
Whilst a number of types of afterloading machines pre-
date the Selectron-LDR (Nucletron), it could be argued
that this machine was the first LDR afterloading machine
to achieve worldwide acceptance. It was developed by
Nucletron during the late 1970s and has been in exten-
sive clinical use since around 1980. There are over 100
installations around the world and the reader will find
numerous references in the literature relating to its clin-
ical use. It was designed initially for the treatment of the
uterine cervix [16], but it has also been used for intra-
luminal and surface applicator treatments.
The Selectron-LDR was designed to circumvent the
aforementioned difficulty by allowing the user the flexi-
bility of being able to construct source trains as required
for a particular insertion. To this end, it contains up to 48
cesium-137 sources of external diameter 2.5 mm (see
Figure 1.3 in Chapter 1) and a large number of inactive
spacers, also of diameter 2.5 mm. The sources and spac-
ers are initially stored in their respective compartments of
the main safe. When a source train is programmed and
composed by the user, the machine selects sources and
spacers in the correct order, as required, and places them
in a vertical column in the so-called 'intermediate safe.'
Three-channel and six-channel versions of the machine
are available, so this process is repeated until all the
required channels have been prepared. When all channels
have been composed, they may be pneumatically driven
through flexible transfer tubes into the treatment appli-
cators. The trains may be withdrawn into the intermedi-
ate safe during planned treatment interruptions, under
alarm conditions, and finally at the end of the treatment.
Each channel may be independently timed.
Source activities between 20 mCi (740 MBq) and
40 mCi (1480 MBq) are available. Most users opt for the
higher activity sources, which typically give a dose rate to
the Manchester Point A of about 1.5-1.7 Gy tr1, putting
it in what might be called the MDR category.
The gynecological applicators are constructed of stain-
less steel, the tubing being 6 mm external diameter. They
are available in various configurations, including the
Manchester set, the Fletcher set (which incorporates
shielding in the ovoids), the Henschke set, and a ring appli-
cator set in which the vaginal component is in the form of
a ring of sources around the cervical os. There are also
applicators for vaginal and endometrial treatments. The
open ends of the applicators are mechanically coded to
ensure that they connect to the correct transfer tubes.
The Selectron-LDR has also been used for the treat-
ment of the oesophagus [17] and nasopharynx [18].
7.5.3 microSelectron-LDR
High dose-rate afterloaders have now mainly superseded
this machine. It is an LDR system that can position
108 Afterloading systems
radioactive sources into up to 18 treatment catheters
simultaneously, and has been typically used for LDR
implant therapy. The catheters have an external diameter
of 2 mm and may be either flexible tubes or rigid nee-
dles. Flexible transfer tubes connect the catheters to the
treatment unit. As with most other afterloaders, each
catheter may be timed independently.
A choice of source systems is available. Originally, the
microSelectron-LDR was used with iridium wires.
These were made from the standard coils of iridium
wire (as described in section 7.4.1) and had to be made
up to the required lengths and attached to the drive
cables, using a preparation station supplied with the
machine. A range of lengths would be made up to
ensure that wires suitable for any proposed treatments
were available. The treatment unit itself could store up
to 18 wires; any further lengths were stored in a sepa-
rate sources safe, from where they could be transferred
to the treatment unit when required, in a manner rem-
iniscent of the Curietron. The main disadvantage of
these was the short half-life of iridium-192, which
meant that new sources had to be prepared every few
weeks. Later, miniature cesium-137 source trains were
introduced, which overcame this disadvantage.
Reference 19 describes an example of the use of this
system.
7*5.4 Buchler System
This machine has been used in both low dose-rate and
high dose-rate versions, and in single-channel and three-
channel configurations, and is intended principally for
the treatment of the uterine cervix. It uses either cesium -
137 or iridium-192 sources. Each channel is treated by a
single source, rather than a train of sources as used in the
machines described above. All sources are mechanically
afterloaded, but the central source of a three-channel
unit (or the only source of a single-channel unit) is
mechanically coupled to a drive system which controls
the position of the source in an oscillating manner
within its catheter, the range and pattern of movement of
the source being used to provide the required dose dis-
tributions. An eccentric cam within the drive system, the
shape of which determines the position of the source at
any instant, controls the oscillating movement of this
source. The main advantage of this system is its repro-
ducibility, it being necessary only to select the appropri-
ate cam corresponding to the dose distribution required.
However, the cams have to be specially made for each
dose distribution, so it is inflexible in use, as changes in
dose distribution cannot be implemented at short
notice.
Typical source activities are 300 mCi (11.1 GBq) of
cesium-137 for low dose-rate use, but activities up to
4Ci (148 GBq) of cesium-137 or 20 Ci (740 GBq) of
iridium-192 were used in high dose-rate versions.
7.6 HIGH DOSE-RATE SYSTEMS
High dose-rate afterloading has become increasingly
popular in recent years. The main advantage is the
increased rate at which treatments can be carried out,
which is particularly important when a high patient
throughput is required. Treatment may be given in min-
utes instead of several hours or days, and may be given
on a day-case basis in many instances. The short treat-
ment times allow rigid rectal retractors to be used,
thereby reducing the rectal dose compared with LDR
systems. However, these advantages must be offset to
some extent by the fact that the treatment has to be frac-
tionated, so a patient may need several of these, albeit
shorter, treatments within a course of treatment. Also,
there may be a clinical disadvantage in that a patient may
need several anesthetic episodes during the course of
treatment, depending on the insertion procedure being
performed. Also, the treatment rooms required for HDR
equipment need to be more substantial than for LDR
equipment, due to the extra radiation protection
required, making HDR installations generally more
expensive.
Reference is made in the clinical sections of this book
to some of the treatment regimes used in HDR
brachytherapy; these, of course, are very different from
those used for the equivalent LDR therapy due to radio-
biological considerations. Now that much experience has
been gained in the clinical applications of HDR therapy,
most new installations of afterloading equipment are of
this type. The reader is referred to a recently published
report of the AAPM Task Group 59, which considered
the practice of HDR afterloading brachytherapy [20].
7.6.1 TEMCathetron
Although most of these machines have now been de-
commissioned, the Cathetron is discussed here as it was
the first HDR afterloader to be put into general use, par-
ticularly for the treatment of the uterine cervix, and con-
siderable valuable data regarding treatment schedules for
this condition were obtained using this machine. It was
introduced in 1966 and its early clinical use is described
by O'Connell et al. [21]. It consisted essentially of a
spherical lead safe in which there were channels for nine
source trains. The source trains were made up of cobalt-
60 pellets and inactive spacers; these were made up to the
user's specification at the time of purchase and were
therefore fixed for the useful life of the sources. The
sources and spacers were held in helical steel springs (the
source holders), which were welded on to the end of a
Bowden cable, at the distal end of which was an 'eye' con-
nector. When in the standby state, the sources rested
close to the center of the safe, each in its own channel,
with the end of the Bowden cable projecting from the
rear of the safe.

Outside the treatment room was the control and drive
system. This provided three drive cables, each powered
by its own electric motor and independently timed.
These drive cables entered the treatment room (through
a curved track or under the floor, to maintain radiation
protection) and could be connected to up to three (of
the nine) source trains required for use. At the front of
the safe, three hollow transfer tubes were connected to
the output ports of the appropriate source trains, and
these transfer tubes led to the stainless-steel applicators
in the patient. The three drive cables and the three trans-
fer tubes were color coded to enable them to be matched
throughout the system, and mechanical and electrical
interlocks ensured that everything had to be connected
correctly before a source transfer could be initiated.
The safe was designed for a maximum content of
50 Ci (1850 GBq) of cobalt-60. Source trains would usu-
ally be made up to provide for the various lengths of
intrauterine tube and ovoids sizes of the Manchester
(cervix) System. Some users also used this machine for
the HDR treatment of surface moulds and appropriate
source trains would then be included, for example per-
haps a single source pellet for use as the center spot of a
mould.
7.6.2 Selectron-HDR
The Selectron-HDR (Nucletron BV) operates in a similar
general manner to its stable-mate, the Selectron-LDR, in
that source trains consisting of 2.5 mm diameter sources
and spacers are composed at the time of use, and these are
then transferred pneumatically to and from the applica-
tors as required. However, there are differences in the
source type and safe design, to accommodate the HDR
requirements of this machine. In this case, the sources are
cobalt-60 (see Chapter 1), each has a nominal activity of
500 mCi (18.5 GBq), and the machine can contain up to
20 such sources. There are three output channels, as the
machine can only be used for one patient at a time. The
system is controlled from the operator's desk situated
outside the treatment room.
The machine is designed specifically for gynecological
treatments, and the treatment applicators are similar to
(in fact, mechanically interchangeable with) those for
the Selectron-LDR. However, for a busy center, much of
the time advantage of HDR is lost if pre-treatment
dosimetry has to be performed between performing the
insertion and starting the treatment, and many users
therefore use applicator systems whose geometry within
the patient is predictable, allowing the use of pre-calcu-
lated treatment plans and standard treatment times. The
Joslin-Flynn applicator (Figure 7.3) is an example of
such an applicator system; this allows the operator to
select one of two intrauterine tube lengths and one of
two ovoid positions, and it also gives rectal dose sparing
by means of a rigid retractor. Typically, dose rates of
High dose-rate systems 109
Figure 7.3 Joslin-Flynn afterloading applicator (HDR) for the
uterine cervix (courtesy Nucletron BV).
about 2 Gy min-1 at the Manchester Point A are obtained,
and the rectal dose may be kept to less than 60% of the
Point A dose.
7.63 Stepping source units
The availability of iridium-192 sources that are physi-
cally small but that contain typically an activity of
10-20 Ci (370-740 GBq) has led to the development of
this type of treatment machine, in which a single source
is sequentially stepped through a series of dwell posi-
tions in all the treatment applicators in turn, thereby
removing the need for several sources or source trains
to be present in the machine. There are several machines
of this type now available; examples are the
microSelectron-HDR (Nucletron), the Varisource
(Varian), and various versions of the Gammamed
(Isotopen-Technik Dr Sauerein). Whilst there are differ-
ences between the different system relating to source
design, maximum catheter number and dimensions,
number of dwell positions etc., they are sufficiently sim-
ilar to be dealt with generically for the purpose of this
present description.
Generally, an encapsulated iridium-192 source is
attached to the end of a drive cable. Usually, the machine
also contains a 'check cable,' which is essentially a dummy
source on its own drive cable. The purpose of the check
cable is to be driven out through the transfer tubes and
applicators before the source is transferred, in order to
check the correct connection of all the components and
also for obstructions or tight curves. The check cable may
also be used as a simulated source for radiography in
some systems. The source and check cable are driven out,
when appropriate, by stepper motors to a claimed posi-
tional accuracy of 1 mm. Each machine will treat a
number of channels, for example up to 18 for the
microSelectron-HDR and up to 24 for the Gammamed,
and each channel may be 'treated' by a number of dwell
positions, for example, up to 48 for the microSelectron-
HDR and up to 40 for the Gammamed. The interval
110 Afterloading systems
between the dwell positions depends on the type of
machine, but is typically 2.5 mm, 5 mm, or 10 mm.
The source diameter is small, typically about 1 mm, so
the catheters through which it travels can also be narrow;
an external diameter of 2 mm (6 French gauge) or less is
common. Also, the length of travel of the source (and
check cable) is long, from 1.5 to 2 m depending on the
machine. The combination of these two features makes
this type of machine very adaptable and it may be used
for intraluminal, interstitial, and intracavitary therapy.
Each of the individual dwell times in each of the
catheters may in general be different, and this gives the user
the opportunity to optimize dose distributions to suit the
target volume. Optimization is dealt with more fully in
Chapter 5. With older versions of these machines, data
from the treatment planning computer had to be manually
entered into the treatment unit; with multicatheter treat-
ments and many dwell positions per catheter, this required
a lot of data to be entered and was prone to errors. Later
machines used a program card system to transfer the data,
and the latest machines incorporate combined treatment
planning and machine control systems into one computer.
Iridium-192 has a half-life of 74 days, and source
exchanges are required at (usually) 3-month intervals.
Frequent source calibrations are therefore required - this
and other quality assurance aspects are fully dealt with in
Chapter 9. All the machines have various fail-safe sys-
tems built into them to reduce the possibility of errors
and accidents.
At the time of writing, machines of this type have been
used experimentally for the emerging technique of
intravascular brachytherapy. This is a developing field, so
it is inappropriate to go into detail here, but the reader is
referred to references 22 and 23 for further information.
7.7 PULSED DOSE-RATE SYSTEMS
The only commonly available PDR system is the
microSelectron-PDR (Nucletron), which is an adaptation
of the microSelectron-HDR machine. Its external appear-
ance, mode of operation, and safety systems are similar.
However, there are two major differences. First, the
iridium-192 source contains less radioactivity, typically
having an activity of 0.5 Ci (18.5GBq) to 1.0 Ci
(37 GBq). Consequently, it is also physically smaller, hav-
ing an active length of 0.5 mm and an overall length of
2.7 mm. Second, the operating software is different,
allowing the source movement to be programmed for the
pulsed nature of the treatment, as described in section 7.3.
REFERENCES
1. AAPM (1993) Remote Afterload ing Technology, AAPM
Report No. 41. New York, American Institute of Physics,
for The American Association of Physicists in Medicine.
2. BSI 5724 Section 2.17 (equivalent to IEC 602-1-17) (1990)
Specification for Remote-controlled Automatically-driven
Gamma-rayAfterloading Equipment. London, British
Standards Institute.
3. ICRU Report 38 (1985) Dose and Volume Specification for
Reporting Intracavitary Therapy in Gynecology. Bethesda,
MD, International Commission on Radiation Units and
Measurements.
4. N RPB (1988) Guidance Notes for the Protection of Persons
against Ionising Radiations arising from Medical and
Dental Use. Didcot, UK, National Radiological Protection
Board.
5. Brenner, D.J. and Hall, E.J. (1991) Conditions for the
equivalence of continuous to pulsed low dose rate
brachytherapy. Int.). Radial Oncol. Biol. Phys.,20,
181-90.
6. Fowler, J.F. and Mount, M. (1992) Pulsed brachytherapy:
the conditions for no significant loss of therapeutic ratio
compared with traditional low dose rate brachytherapy.
Int.J. Radial Oncol. Biol. Phys., 23,661-9.
7. Mazeron, J.S., Boisserie, G., Gokarn, N. and Baillet, F.
(1994) Pulsed LDR brachytherapy: current clinical status.
In Brachytherapy from Radium to Optimisation.
Veenendaal,The Netherlands, Nucletron BV.
8. Swift, P.S., Fu, K.K., Phillips, T.L, Roberts, LW. and
Weaver, K.A. (1994) Pulsed low dose rate interstitial and
intracavitary therapy. In Brachytherapy from Radium to
Optimisation. Veenendaal, The Netherlands, Nucletron,
BV.
9. Pierquin, B., Wilson, J.F. and Chassagne, D. (1987) Modern
Brachytherapy. New York, Masson.
10. Blasko, J.C., Ragde, H. and Schumacher, D. (1987)
Transperineal percutaneous iodine-125 implantation for
prostatic carcinoma using trans-rectal ultrasound and
template guidance. Endocuriether. Hypertherm. Oncol., 3,
131-9.
11. Liebel, S.A., Peschel, R.E., Hilaris, B.S., Gutin, P.M. and
Wara, W.M. (1990) Principles of Implantation for Brain
Tumours, Interstitial Collaborative Working Group. New
York, Raven Press.
12. Fletcher, G.H., Shalek, R.J. and Cole, A. (1953) Cervical
radium applicators with screening in the direction of
bladder and rectum. Radiology, 60,77.
13. Suit, H.D., Moore, E.B., Fletcher, G.H. and Worsnop, B.
(1963) Modification of Fletcher ovoid system for
afterloading using standard radium tubes. Radiology, 81,
126.
14. Marbach, J.R., Stafford, P.M., Delclos, L and Almond, PR.
(1985) A dosimetric comparison of the manually loaded
and Selectron remotely loaded Fletcher-Suit-Delclos
utero-vaginal applicators. In Brachytherapy 1984.
Veenendaal, The Netherlands, Nucletron BV.
15. Jackson, A.W. and Davies, M.L (1983) In Radiation
Treatment Planning, ed. N. Bleehan, E. Glatsein and J.
Haybittle, New York, Marcel Dekker.
16. Wilkinson, J.M., Moore, C.J., Notley, H.M. and Hunter, R.D.
(1983) The use of Selectron afterloading equipment to

simulate and extend the Manchester System for
intracavitary therapy of the cervix uteri. Br.J. Radial., 56,
404-14.
17. Rowland, C.G. (1985) Treatment of carcinoma of the
oesophagus with a new Selectron applicator. In
Brachytherapy 1984. Veenendaal, The Netherlands,
Nucletron BV.
18. Flores, A.D. (1989) Remote afterloading intracavitary
irradiation for cancer of the nasopharynx. In
Brachytherapy 2, Veenendaal, The Netherlands,
Nucletron BV.
19. de Ru, V.J., Hofman, P., Struikmans, H., Moerland, MA
Nuyten-van-Deursen, M.J.H.and BattermannJ.J. (1994)
Skin dose due to breast implantation for early breast
cancer. In Brachytherapy from Radium to Optimisation.
Veenendaal, The Netherlands, Nucletron BV.
20. Kubo, H.D., Glasgow, G.P., Pethel, T.D., Thomadsen, B.R.
References 111
and Williamson J.F. (1998) High dose-rate brachytherapy
treatment delivery: report of the AAPM Radiation
Therapy Committee Task Group No. 59. Med. Phys., 25(4),
375-403.
21. O'Connell, D., Joslin, C.A., Howard, N., Ramsay, N.W. and
Liversage, W.E. (1967) The treatment of uterine carcinoma
using the Cathetron. fir. J. Radiol., 40,882-9.
22. Schopohl, B., Liermann, D., Pohlit, LJ. etal. (1996) 192lr
endovascular brachytherapy for avoidance of intimal
hyperplasia after percutaneous translumenal angioplasty
and stent implantation in peripheral vessels: 6 years of
experience. Int.]. Radial Oncol. Biol. Phys, 36,835-40.
23. Nath, R.,Amols, H.,Coffey, C.etal. (1999) Intravascular
brachytherapy physics: report of the AAPM Radiation
Therapy Committee Task Group No. 60. Med. Phys., 26(2),
119-52.

Quality assurance in low dose-rate afterloading
ERICD.SLESSINGER
8.1 INTRODUCTION
The advent of remote afterloading brachytherapy
devices has required that the scope of quality assurance
in brachytherapy be broadened substantially. This is due
to the fact that these devices are designed to perform the
basic tasks that previously had been directly controlled
by staff: source selection, transport and positioning in
the treatment applicators, the monitoring of elapsed
treatment time, and treatment termination. These
remote functions should practically eliminate the radia-
tion exposure to anyone involved in the treatment and
care of brachytherapy patients. A comprehensive quality
assurance program is necessary to verify that these
devices perform in accordance with the manufacturers'
specifications to deliver treatment accurately and safely
[1].
This chapter describes the methodology for achieving
those ends. The process starts with planning for the
equipment and the treatment facility, the application for
authorization to use the equipment, the coordination of
the facility construction and the equipment installation.
The facility and equipment must be thoroughly tested,
new treatment procedures must be established, and per-
sonnel trained and an ongoing quality assurance and
equipment maintenance program must be developed. A
successful quality assurance program requires a team
approach, incorporating the radiation oncologist, med-
ical physicist, device manufacturer, brachytherapy tech-
nologist, nurse, dosimetrist, health physicist, and service
technician. The experience of this author in low dose-
rate (LDR) remote afterloading has been exclusively with
8
devices manufactured by the Nucletron Corporation BV,
specifically the Selectron-LDR and the microSelectron-
LDR. The principles of quality assurance that have been
applied for those devices serve as a basis for comparable
systems.
8.2 PREPARATION FOR A LOW DOSE-RATE
REMOTE AFTERLOADING PROGRAM
8.2.1 Equipment selection
The selection of appropriate equipment is one of the first
steps toward the establishment of a remote afterloading
program. The type of brachytherapy procedures to be
performed (intracavitary, interstitial, intraluminal etc.)
with remote afterloading should be determined and then
matched to the most suitable device. These devices offer
a variety of features for consideration, including source
types and activities, applicator systems, the number of
treatment channels, the means for programming treat-
ment times, and the ability to customize source configu-
rations. Other basic device design features include the
mechanism for source transport, the monitoring of cor-
rect source positioning, the safety interlocks and fail-safe
systems, and the shielded source storage containers. For
a more complete description of remote afterloading sys-
tems, see Chapter 7.
The review, selection, and specification of applicator
designs must be done carefully, consistent with the antic-
ipated treatments. This process will directly influence the
selection of the source activities and possibly the
 Preparation for a lose dose-rate remote afterloading program 113
selection of the treatment machine as well. If a radiation
oncology department is converting from manual after-
loading to remote afterloading, maintaining similar
applicator styles and source activities is important. For
example, if the Fletcher-Suit afterloading tandem and
ovoid system had been used, then a comparable applica-
tor set, compatible with the remote afterloading device,
should be requested. In addition, applicators for treating
the vagina, endometrium, oesophagus, bronchus, and
nasopharynx should also be considered.
With a remote afterloader like the Selectron-LDR, lin-
ear sources are replaced by uniform activity spherical
sources configured with inactive spherical spacers. These
spherical cesium-137 sources have an outer diameter of
2.5 mm and are available with a maximum activity of 40
mCi (1480 MBq or 115 U) per source. When specifying
the source inventory for this type of remote afterloader,
the following questions should be addressed:
What is the range of prescription dose rates for the
different clinical applications that are anticipated?
How many channels may be in use at one time?
How will the active and inactive source pellets be
configured to achieve suitable dose distributions?
What is the recommended maximum activity for the
main and intermediate source safes?
These questions should aid in deciding the total number
of sources and the activity of each source. Combinations
of eight sources and spacers can be used to compose 2-cm
long sequences that can replace 2-cm linear sources. The
medical physicist should determine the ideal source
strengths to deliver the prescribed dose rates for each clin-
ical application as specified by the radiation oncologist,
and a treatment planning computer should be used to
verify the design of the source-spacer configurations. At
the Mallinckrodt Institute of Radiology, St Louis,
Missouri, a six-channel device with a 36-source inventory
(36 U/source) has proven to be adequate for enabling two
simultaneous intracavitary treatments. Further discus-
sion of spherical source configurations is presented in the
clinical implementation section of this chapter.
The specification of sources for a remote afterloader
that uses drive motors to transport source-cable assem-
blies requires a different rationale, because the source
trains usually cannot be easily reconfigured, if at all. A
list of required source trains, their activities, and active
lengths must be established that will satisfy most clinical
situations. Certain applicators, such as the intrauterine
tandem, may require source trains composed with dif-
ferential linear activity. Their designs can be based on the
non-uniform linear activities that had been used for
the manually afterloaded treatments. The position of the
source in the applicator can also be specified by the user,
but the physical constraints of source rigidity and the
curvature of the source transport channels may not nec-
essarily allow ideal source alignment. In that case, dosi-
metric analysis should be used to evaluate the clinical
utility. Several papers [2-5] have reported on source
inventory specification, source assembly design, and
source-spacer configurations.
For interstitial work, the user can select rigid metal
needles or flexible plastic needles or catheters. The
availability of templates from the manufacturer should
be explored, as well as the compatibility of existing
templates with the remote afterloading device. For
interstitial applications, a permanent inventory of fixed
cesium seed source trains or an inventory of temporary
iridium wires or seed ribbons, or a combination of
both, may be used. The purchase of cesium seed source
trains is practical if one can anticipate an appropriate
source inventory. The cesium seed source trains are
expensive, but can be used over a long time period,
whereas the iridium, though requiring frequent pur-
chases, allows the user more options. A rationale for
choosing a specific cesium seed ribbon inventory has
been reported [6]. Whether cesium or iridium is used
for interstitial application, the positioning of the active
length within the needle or catheter must be well
understood, because these techniques can use varied
active and inactive source lengths as well as varied nee-
dle or catheter lengths. Special procedures must be
established for iridium source preparation and for veri-
fication of accurate interstitial source placement. These
procedures are reviewed in greater detail later in this
chapter.
8.2.2 Site preparation
LOCATION
Careful planning for a remote afterloading facility is
very important to achieve convenience and safety for
the patient and staff, and to avoid unnecessary costs.
Physicians, physicists, nursing personnel, and the manu-
facturer should all be involved in the planning.
Typically, LDR brachytherapy is given in a private
patient room on a surgical or cancer nursing division. It
is ideal if the brachytherapy room is near to the nurse
station and to the brachytherapy preparation labora-
tory, while being as far as possible from unrestricted
patient rooms. Multiple LDR treatment rooms should
be adjacent to each other. Figure 8.1 shows an example
of a floor plan of an extensive LDR remote afterloading
facility.
SHIELDING CONSIDERATIONS
The shielding design must be based on the anticipated
maximum source activity loadings and duration to
limit exposure rates and total exposure in unrestricted
areas to less than the maximum level allowed by the
user's regulatory agency. In the USA, for example, the
United States Nuclear Regulatory Commission
(USNRC) limits the radiation exposure to 2 mrem
114 Quality assurance in low dose-rate afterloading

Figure 8.1 Floor plan for a four-treatment device remote afterloading facility at Barnes-Jewish Hospital in St Louis, Missouri. The
equipment shown consists of two microSelectron-LDRsfor intracavitary applications, a six-channel Selectron-LDR for simultaneous
treatments in two adjacent rooms, and a microSelectron-LDRfor interstitial Indium located in the room opposite to the source
preparation laboratory where the two air compressors for the systems are housed.

(0.02 mSv) in an hour to any non-monitored person,
with an annual limit of 100 mrem (1 mSv) [7]. The
USNRC ALARA (as low as reasonably achievable) pro-
gram limits exposure in restricted areas to 500 mrem (5
mSv) per year. For LDR brachytherapy rooms that were
previously used for manual afterloading, it is possible to
use rolling bedside shields to protect unrestricted areas
on the same floor, but lead thicknesses in the range of
0.6-1.3 cm should be anticipated for the floors above
and below. New construction is best served with
shielded walls. The recommendations for room shield-
ing should be made after studying appropriate blue-
prints and considering the actual location of the
brachytherapy patient within the room, as well as the
weight limitations of the room [8]. Empirical radiation
survey testing of existing room shielding may also be
performed to determine if shielding deficiencies are
present before installing remote afterloading equipment
[9]. The National Council on Radiation Protection and
Measurements (NCRP) Report 49 [10] should be used
to guide the determination of the shielding specifica-
tions that will achieve the required exposure limits. For
more information on this subject, the reader should
refer to Chapter 10.
FACILITY DESIGN
Room design details for remote afterloading brachyther-
apy are summarized in Table 8.1. Electrical power to the
device should be provided from a dedicated circuit that
is also served by emergency power. If compressed air is
required, then the decision whether to use in-house or
free-standing compressors must be made. Although it
may seem simpler to use the hospital air, a dedicated
compressor specifically suited to the device can give
greater assurance as long as it can be situated far enough
from the patient so that its noise is not disturbing. It is
possible to install an air compressor in a small hallway
enclosure or in the source preparation laboratory, pro-
vided there is adequate space for inspection and servic-
ing.
An area radiation monitor with an independent
secure power supply should be installed adjacent to the
implant patient's bed for maximum sensitivity. A remote
 Preparation for a low dose-rate remote afterloading program 115
Table 8.1 Treatment room details for low dose-rate remote
afterloading brachytherapy
Area radiation monitor (with a dedicated check source and
battery pack) and remote display
Closed circuit TV (monitor at nurses' station)
Compressed air system
Electric power on emergency power circuit
Emergency container and equipment
Remote controls with treatment status displays in the hallway
and at the nurses' station
Treatment tubing support device
Door-mounted board for posted warnings and instructions
Door interlock system
Door lock
Intercom to hallway and nurses'station
Rolling bedside shields
Permanent shielding in floor and above
Wall pass-through for two simultaneous treatments from one
device
display for the area monitor is necessary, situated either
outside or just inside the doorway to alert anyone enter-
ing the room about exposed sources before approaching
the implant patient. The area monitor is intended to
indicate the safe status of the sources in the entered
room only. Therefore, it may be necessary to mount the
area monitor against a small lead shield on the wall so
that it is not sensitive to radiation from an adjoining
brachytherapy room.
The remote controls for the afterloaders are usually
installed in the corridor, adjacent to the patient's room
door. Typically, the treatment room door is closed dur-
ing treatment and a door interlock switch is installed to
automatically retract all sources into the intermediate
safe in the event that the treatment interrupt button is
not activated prior to entering the room. A window in
the door can provide only limited visual contact with the
patient. It is recommended to install a closed circuit tele-
vision camera for remote patient observation from the
nurse station. In addition to the normal intercom system
from the nurse station to the patient, a two-way hallway
intercom to the patient is also practical for limiting the
number of treatment interruptions. A remote treatment
status display at the nurse station is also recommended,
which can indicate whether treatment is progressing, is
interrupted, or if an alarm status exists. Display of the
remaining treatment time should also be available. If one
remote afterloading device is capable of treating two
patients simultaneously in adjacent rooms, then a wall
pass-through is needed for the source transport tubing.
The wall opening should be devoid of sharp edges that
could damage the tubing. Each treatment room should
have its own independent controls installed, when prac-
tical, so that one patient can be safely visited without dis-
turbing the treatment in the adjacent room. Door locks
should be installed to secure the treatment room when
not occupied by a patient, because the remote afterload-
ing device and its source inventory generally remain in
the room. 'Radioactive Material' and 'Radiation Area'
warning signs must be posted on the room door or at the
entrance to the brachytherapy ward. These warnings can
conveniently be embossed on a hanging door placard
designed also to display treatment forms, nurse instruc-
tions, and the room diagram.
AUTHORIZATION FOR REMOTE AFTERLOADING
In some countries, it is necessary to apply for authoriza-
tion to use an afterloader. Registration of the afterloader
may also be necessary depending upon the policies of the
agency that regulates its use. The regulatory agency
should specify what information must be submitted
before authorization and/or registration can be consid-
ered. If the agency is not very familiar with afterloading
technology, the device manufacturer should be able to
suggest which information is required to submit,
because the manufacturer will have also gone through a
similar submission of specifications and information in
order to obtain the approval to market the device. Table
8.2 lists the points that should be addressed when sub-
mitting a license amendment proposal to the USNRC.
Generally, one should not commit in the application to
any procedures that are not required by the licensing
agency [8]. However, the licensing agency will be seeking
assurance that the proposed treatment program will be
safe and has been well thought out.
INSTALLATION
The installation of remote afterloaders should be coordi-
nated by a physicist or biomedical engineer. The installa-
tion process will proceed smoothly as long as the needs
of the manufacturer's installation engineer, in-house
engineering, clinicians, nurses, and physicists are under-
stood. The process should begin with a pre-installation
meeting, at which time the responsibilities of the manu-
facturer and the hospital are defined and agreed upon. If
existing shielded brachytherapy rooms are to be con-
verted for remote afterloading, temporary relocation of
brachytherapy patients may be required during the
installation process. Appropriate shielding similar to that
in regular use should be provided for these temporary
areas. If no supplemental temporary shielding is used,
vacating adjacent areas will be necessary unless the expo-
sure rates are within the allowable limits. Therefore,
radiation surveys are necessary to verify acceptable expo-
sure levels in the unrestricted areas around the tempo-
rary brachytherapy rooms.
The manufacturer's engineer initially should review
and verify receipt of all equipment. The project coordi-
nator should oversee this process, maintain a file of all
116 Quality assurance in low dose-rate afterloading
Table 8.2 Information to submit to the licensing agency when
requesting authorization for remote afterloading
Remote afterloader model and manufacturer
Source description (radionuclide, size, the activity,
manufacturer, and physical construction)
Certification of federal registration of the device
The intended clinical applications
The intended users, their training, certification, and
experience
Radiation-detection instruments to be used
Facility floor plan and elevation
Calculations that demonstrate acceptable exposure levels in
unrestricted areas
Describe area security, including access to operating keys, door
interlocks, and radiation warning systems
Describe patient viewing and communication
Describe dosimetry equipment, calibration procedures and
frequency, leak test procedures and frequency, and the
qualifications of those performing the tests
Emergency procedures and frequency of mock emergency
drills
Personnel-monitoring program
Describe the titles and locations of procedure manuals
Procedures to prevent multiple treatment devices from
operating simultaneously
Quality assurance program
Training of the source exchangers
Training and frequency for operators
Disposal of decayed sources
Adapted from AAPM eport No. 41 [8].
equipment receipts, and verify that the complete order
has been received. The engineer should test the equip-
ment prior to installation, verifying such items as correct
battery function, electrical parameters, air pressure sen-
sors, and switches. The installation process includes
cable routing between the machine and the remote con-
trols outside the treatment room, wiring the door inter-
lock mechanism, and installation of the radiation
monitors. Additional cables are routed to the nurses' sta-
tion to connect to the remote treatment status display
and the closed circuit television monitor. If remotely
located air compressors are to be used, a pipefitter will
install the appropriate lines to a compressed air outlet
near to the treatment machine. The manufacturer's engi-
neer should verify that all cables are properly connected
and functioning correctly. If several rooms require
installation, it may be possible to schedule the work from
one room to the next, with the manufacturer's engineer
testing and verifying the installation as it proceeds. This
will also allow the physicist to begin the evaluation of the
installation, possibly prior to the completion of all the
rooms. The device manufacturer's equipment test proce-
dures and results should be carefully reviewed by the
responsible physicist to determine which tests should be
repeated and which additional tests need to be added to
the acceptance testing procedure.
83 ACCEPTANCE TESTING
8.3.1 Introduction
Acceptance testing for a new remote afterloading device
must be performed prior to clinical implementation in
order to certify that the device performs in accordance
with the manufacturer's specifications. If the treatment
facility is also new, then it must also be carefully evalu-
ated. This initial testing also establishes a starting point
for machine performance evaluation and provides the
basis for the development of an ongoing quality assur-
ance program. There have been several acceptance test
approaches reported in the literature [8,11-16]. AAPM
Report 41 divides the acceptance testing process into sev-
eral broad categories, including evaluations of the
radioactive sources, the mechanical and electrical opera-
tion of the remote afterloading device, the radiation
monitors and facility, the applicators, and the treatment
planning computer. The following sections of this chap-
ter address many of the issues that comprise a thorough
acceptance-testing program.
The testing sequence begins with new source evalua-
tions. Once the sources are loaded into the machine,
radiation surveys are performed. This is followed by the
evaluation of the safety features and interlocks, machine
performance and applicator function, and finally the
treatment planning system. Some of these tests will yield
quantitative results, however much of the testing
involves verification of correct function.
83.2 Brachytherapy source testing
Several excellent reviews of brachytherapy source testing
can be found in the literature [8,12,17]. The process
begins with a careful review of the new source certifi-
cates. The isotope, its activity or air kerma strength, the
uncertainty of the calibration, the active and physical
lengths, and source encapsulation must all be verified to
assure that the correct sources have been received. The
documentation of acceptable leak tests (<5nCi or 200
Bq removable activity) within the previous 6 months
should also be checked. The sources should be visually
examined through shielded glass, looking for any signs
of damage. Any engraved serial numbers or other identi-
fying details should be recorded. If there is any sugges-
tion of damage to any sources or if the sources have not
been leak tested within the previous 6 months, new leak
tests must be performed. After the sources have been
loaded into the remote afterloader, periodic leak testing

can be accomplished by wiping the inner surfaces of the
source transport tubes or, if accessible, the inner surface
of the storage container positions. The manufacturer
should provide detailed source diagrams indicating the
source construction, dimensions, and materials used.
These source documents are very important and should
be copied and filed so that working copies are available
for fast reference and the original documents are safely
stored with other source certificates. A bound logbook
should be obtained for each remote afterloader for
recording tests and measured results, and for documen-
tation of the routine quality assurance testing. The initial
entries into this logbook should pertain to source docu-
mentation, listing the source model numbers and serial
numbers, activities, active and physical lengths, encapsu-
lation material and thickness. Copies of the source cer-
tificates and diagrams should contain all of this
information. The assigned storage container position for
each source should also be recorded when relevant.
The new sources should be autoradiographed to eval-
uate the uniformity of the activity distribution and its
location within the physical length. The results are then
compared to the source diagrams. The autoradiographs
are obtained by placing the sources in uniform close
contact with film that is wrapped in light-tight paper.
The source position must be maintained for a brief time
period, usually 30 s or less, depending on the film sensi-
tivity and source strength. Kodak Ready-Pack localiza-
tion film is suitable for this purpose. Catheters or other
narrow source applicators can be used to maintain pre-
cise source positioning. Reference marks such as pin-
pricks are used to indicate the source location on the
developed film, and the area of relatively high optical
density can be evaluated in relation to those marks. Jones
[12] has described an autoradiograph technique that
uses moulded wax to position and support the sources or
applicators, with lead foil markers embedded between
the wax and the film to provide a radiographic image of
identification marks and scales for precise comparisons.
These films can be evaluated by visual inspection, using
a ruler to compare the stated active length against the
film image and the activity location relative to the phys-
ical ends of the source. When possible, radiographs of
the sources provide additional verification of source
construction details and, when combined with the
autoradiograph exposure, the image of the physical
structure superimposed over the autoradiograph image
provides the most complete evaluation. The use of a
scanning optical densitometer could provide additional
graphic information to identify accurately the center of
the source activity and to evaluate the activity unifor-
mity. Typically, the results of the source evaluations
should appear practically identical for all sources of the
same model. If any variants are discovered, those sources
should be isolated and the source manufacturer con-
tacted. The subject of brachytherapy source calibration
is covered in Chapter 3.
Acceptance testing 117
833 Radiation surveys
Once the documentation and testing of the new
brachytherapy sources have been satisfactorily com-
pleted, the source inventory is loaded into the main safe
of the remote after-loading device. Radiation surveys are
then performed to monitor the exposure rate on the sur-
face and at 1 m away from the main and intermediate
source safes. By wrapping the surface area around the
safes with a sensitive film wrapped in light, tight paper,
shielding defects can be detected and the areas where the
surface exposure is relatively high can be located.
Average and maximum exposure rates at the surface and
at 1 m should be documented and should be consistent
with the manufacturer's specifications and national
guidance. Radiation protection aspects are dealt with in
more detail in Chapter 10.
83.4 Safety features
The safety features of the remote afterloading device and
the facility must be thoroughly evaluated. Table 8.3 lists
Table 8.3 Safety features of a remote afterloading treatment
program that should be tested or established and available
Source leak testing
Radiation exposure rate surveys in compliance with the
regulations
Radiation warning lights inside and outside the treatment
room function properly
Independent radiation monitor in the room and its remote
display function properly using a check source with normal
and with back-up battery power and during treatment
Closed circuit TV system and intercom systems
Door interlock causes source retraction and cannot resume
treatment until the on/off switch is activated and sources
cannot be driven out of the safe with the door open
Treatment controls
Treatment status indicators, outside of treatment room and at
the nurses'station
Back-up storage batteries used during power failure
Disconnected applicator interlock
Compressed air lines maintain adequate pressure under load
and for treatment duration
Back-up compressed air reservoir for source retraction when
normal air compression fails
Emergency-off switches and equipment for source removal,
handling, and storage
Treatment bed and bedside shields arranged to optimize
protection
Hand-held radiation exposure survey meter
Radiation warning signs and posted instructions
Room and afterloader secured when not in use
118 Quality assurance in low dose-rate afterloading
the safety features to be tested, equipment that should be
available, and procedures to be established. These
include the treatment controls, safety interlocks, and the
response to an electrical power disruption or an air com-
pression failure. The area radiation monitor should be
evaluated with its normal power supply and with its
back-up battery power. The sensitivity of the radiation
monitor to a minimal source loading should be verified
as well as its insensitivity to radiation from an adjacent
room. The operation of the closed circuit television cam-
era, monitor system, and intercom system should also be
checked.
83.5 Source transport and applicator tests
Applicator tests are performed to verify functionality
and to document source position within the applicator.
Applicators should be easily coupled to and decoupled
from the source transport tubing and should be
designed to detect when an applicator is not adequately
connected. The integrity of the source guide tubes
should also be evaluated. Cable-driven source assem-
blies should have source guide tubes of constant length
to assure 1 mm source position accuracy. For pneumatic
source transport, the transport tubing should be
inspected for leaks, constrictions, and other obstacles. If
specific transport tubes are designed to connect only to
specific applicators, this should be tested, as well as all
possible combinations of applicators and transport
tubes to detect faulty connectors. The applicators
should be visually inspected to evaluate the mechanical
integrity and radiographed with dummy sources in
place to clearly document source position with respect
to the applicator surfaces and to verify agreement with
the applicator design. For certain applicators, more than
one radiograph may be necessary to view the source
position along different applicator axes. The location
and size of internal applicator shields should also be
documented. To illustrate a potential problem, Figure
8.2 shows the dummy source position within the
microSelectron-LDR shielded ovoid. Due to the rigidity
of the source, it assumes the tipped alignment relative to
the ovoid axis. This was not considered to compromise
its clinical utility in this case. Autoradiographs with
sources loaded in the applicators demonstrate the relia-
bility of the radiographic markers to indicate actual
source positions. Dosimetry measurements should also
be made to evaluate the effects and adequacy of the
shields and to determine if any transmission corrections
are indicated.
The speed of source transport can be determined
indirectly by methods based on ionization measure-
ments or can be observed using video equipment. These
techniques have been described by Meigooni et al. [18].
The resultant velocity can be used to predict the transit
dose to tissues that are close to the source transport tub-
Figure 8.2 Radiographic evaluation of the source position in
the microSelectron-LDR shielded ovoid. The dummy source
shown here is constructed to appear identical to the actual
source. An autoradiograph (not shown) demonstrated agreement
between the applicator positioning of the dummy and actual
sources. Solder wire is used to delineate the surface of the
plastic caps that enlarge the surface diameter to 2.5 and 3.0 cm.
These plastic caps do not extend the anterior ovoid surface.
ing. Alternatively, direct measurement of the transit radi-
ation dose can be made using thermoluminescent
dosimetry. These measurements should be repeated at
least annually. The many treatment interruptions that
can occur during LDR remote afterloading treatments
should be considered in order to determine the total
dose that normal tissues may receive. However, the mag-
nitude of this transit dose should not be significant. To
illustrate this point, assume that transported sources
come into close proximity to a normal tissue point for
effectively 1 s in each transport direction. For a 40-h
treatment, the number of interruptions (2 s of close
exposure per interruption) to give 1% of the total treat-
ment dose to normal tissue would have to be close to 720
and, depending on how close this point is to the implant
site, this transit dose may be relatively low when com-
pared to the dose received from the sources while in the
treatment position.
If transparent applicators are available, the position of
simulated dummy sources and radioactive sources can
be observed via closed circuit television within an accu-
racy of 1 mm. Certain disposable applicators, such as the
Norman-Simon capsules, and flexible interstitial needles
require quality assurance testing to verify consistent
insertion depth. The Norman-Simon capsules should be
tested to verify source insertion capability and autoradi-

ographs obtained to demonstrate the actual source loca-
tion relative to the capsule tip. For interstitial applica-
tions, the appropriate gauge needle or catheter must be
established. A 20-cm long, 15-gauge, plastic flexiguide
needle has been used for perineal applications using the
microSelectron-LDR. All new flexiguide needles should
be checked for length accuracy and trimmed if necessary.
A special needle obturator can be marked to indicate the
20-cm insertion depth and serve as a guide if trimming
is necessary. If new plastic materials are being used, the
effects of gas sterilization should be investigated.
Shrinkage of the plastic during sterilization can compro-
mise the source transport and reduce the insertion
depth.
83*6 Functional tests
Functional tests to be performed are listed in Table 8.4.
Additionally, a list of suitable tests can be found in refer-
ence 19. For afterloader systems that utilize air compres-
sion for source transport, simulated treatments should
be performed to evaluate the reliability of the air com-
pression supply under full demand and the minimum air
compression that the compressors will allow. Airflow
Table 8.4 Operations that should be verified by functional
testing of a remote afterloading device
Console functions: key switches, main power, battery power,
source on/off, door open/close
Programmability of treatment
Correct console displays and treatment data printout
Printer function
Timer accuracy and transit time measurements
Sources retract to safe at the end of a preset time, when
treatment is interrupted, when electrical power or air
compression is lost, when the room door is opened, or when
the emergency off button is activated
Treatment cannot proceed if applicators are not connected
correctly or are obstructed
Source selection or configuration (autoradiograph)
Source transport and positioning (autoradiograph)
Air compressors maintain adequate compressed air
Response to loss of air compression
Maintenance of remaining treatment time when treatment is
interrupted or after a power failure
Battery voltage under load is adequate and operating
functions are retained under battery power
Return of sources to intermediate safe and main safe
Accuracy of source decay computations
Proper operation of radiation detectors in the afterloader
Manual means for source retraction if the remote system fails
Acceptance testing 119
sensors in those systems are used to detect whether or
not a source loading has been completely transported
into the treatment applicator. A control pellet at the dis-
tal end of the source assembly or source train should seal
the inner tube of the source container, preventing airflow
into the source tube when the sources are completely
extended into treatment. If this does not occur within a
certain time period, the sources should be automatically
withdrawn into the intermediate safe, eliciting an alarm
condition.
Autoradiographs are very important for verification of
correct source selection, source configuration, and
source positioning. The applicator must be secured as
close as possible to the film. This technique is similar to
the one described earlier for initial source testing, but
now the intent is to determine exactly where the sources
are positioned within the treatment applicators during
treatment, and this should be verified on a regular basis.
The International Standard recommended by the
International Electronical Commission (IEC) specifies a
maximum variation in source position within an appli-
cator set to be 2 mm [20]. Williamson [17] has sug-
gested that geometric accuracy of 1 mm should be
achievable. Radiographs with dummy sources loaded
should clearly delineate source position in all applica-
tors. Comparisons between simulator radiographs with
dummy sources in place and autoradiographs with
applicator surfaces delineated provide the basis for
establishing source position. However, the distance
between the sources and the film can limit the measure-
ment precision of source position reproducibility,
because as the applicator diameter increases, the distance
to the film also increases, causing the image of the source
activity to be less discrete. Autoradiographs for each
applicator should be marked so that localization of
source position can be correlated to the dummy source
radiograph. If the remote afterloader and a radiographic
unit can be used together, combining the radiograph and
autoradiograph onto one image makes the evaluation of
actual source position within the applicator direct, sim-
ple and precise. The comparison of this film to the radi-
ograph of the dummy source marker position within
that applicator also provides very precise positioning
verification. The position of radiographic markers
should vary by less than +1 mm.
Prior to commencing a treatment, an autoradiograph
should be obtained to verify correct source selection and
the channel and applicator that will contain each source.
This autoradiograph is especially critical for interstitial
iridium seed ribbon assemblies, where the correct source
design for each channel must be verified. The most direct
autoradiograph process involves sources transported
into the same treatment applicators as those in the
patient. If a more general autoradiograph device is used,
the relation between source extension in an applicator
and its position in the autoradiograph device must be
established. This involves the use of dummy sources that
120 Quality assurance in low dose-rate afterloading

can either be visualized and measured directly when 83*7 Acceptance test report
inserted or radiographed to determine where the sources
extend relative to reference fiducial marks. For the inter- The results of all tests performed during the commis-
stitial sources, this enables not only verification of the sioning of a remote afterloading device and facility
number of seeds per channel but also documentation of should be summarized in a report, which should serve as
the inactive length. a benchmark from which the quality assurance program
Tests should be performed to verify that interlocks can continue. In addition to the test results, the report
operate effectively. These tests should include attempting should document operational procedures and describe
to treat without an applicator properly connected. If an the basic mechanics of the system. If the report is for a
applicator is designed to be connected only to a particu- new remote afterloading facility, treatment-related pro-
lar channel, that specificity should be tested. A dummy cedures and a quality assurance program should also be
source used with a device such as the microSelectron- specified in the report prior to clinical implementation.
LDR can be intentionally unsnapped from the drive Some of these clinical procedures are discussed in the
cable to test that the absence of the source will be following sections. Table 8.5 gives an example of the con-
detected upon source retraction. The door interlock tents of an acceptance test report.
must also be tested, by verifying that treatment is pre-
vented unless the door is completely closed, and by veri-
fying that treatment is interrupted should the door be
opened.
The treatment timing mechanisms must be tested Table 8.5 Example table of contents for a remote afterloading
for accuracy, and source transit time should be deter- device acceptance report
mined. These tests can be performed using a thimble
1. Institution and location
ionization chamber that is positioned in close proxim-
ity to sources in an applicator. Once the sources are 2. Facility name
transported into treatment, an integrated charge can be 3. Remote afterloading device
measured over a certain time period to determine the 4. Sources and applicators
static ionization current (coulombs/s). Additional mea- 5. Tests and results Source calibration
surements of charge for different programmed treat- Radiation safety
ment times are then used to determine the actual Mechanical
'measured' time by dividing the measured charge for Programming a treatment
the programmed treatment time by the static ioniza- 6. Procedures Machine start-up and daily
tion current [17]. A curve-fitting routine is then used quality assurance
to relate the time measured to the time set by the lin- procedures
ear relation: Nurse's instructions
Radiographic localization
Timemeas = (Timeset)(Timer accuracy slope) + Transit time Computed clinical dosimetry
Emergency procedures
Treatment completion
In general, the measured time should agree with the
procedures
machine-set time within 2%, but, as treatment time Patient instruction
decreases or the number of interruptions increases, the Room assignment
dose effects due to transit time error increase. Quality assurance program
Williamson has reported timer error to be of the order of Physician loading and
a few seconds, while absolute timer accuracy is usually unloading procedures
within 1%. The distance between the dosimeter and the 7. Summary and
sources should be kept constant and as small as possible, recommendations
because this parameter will affect the timer error deter- 8. Appendix Source data
mination. Radiation surveys
Another way to determine transit time is similar to the Applicator radiographs
method used for cobalt teletherapy units [21], where Source position
integrated charge is measured for one exposure period autoradiographs
and then compared to the same total exposure time Tim ing tests
administered over several on/off sequences. For both Special forms and techniques
methods described, the results will be clinically applica- License application
ble if the distances between the source and chamber are Manufacturer's field service
reports
similar to a typical treatment depth. Additional func-
Machine specification
tional tests are included in Table 8.4, many of which can
Error codes
be verified simply by observation.
 Quality assurance procedures and clinical implementation 121

8.4 QUALITY ASSURANCE PROCEDURES
AND CLINICAL IMPLEMENTATION
8.4.1 Conversion from manually loaded
tube sources to source-spacer pellet
configurations
A methodology for converting manually loaded, 2-cm
long sources to source-spacer configurations has been
described by Grigsby et al [3]. This approach replaces
the 2-cm long sources by groups of eight 2.5-mm
source-spacer pellets. To duplicate the inactive ends of
the tube source, the first and eighth positions are
reserved for spacer pellets. The remaining six positions
contain the active sources, distributing them as uni-
formly as possible. Isodose comparisons of linear
sources and active/inactive pellet configurations gener-
ated by the treatment planning system should be used to
match the two dose distributions. The Fletcher-Suit
ovoids designed for the Selectron have six active source
positions between the bladder and rectal shields. The
active sources are therefore arranged within those posi-
tions. Table 8.6 lists some of these source configura-
tions. The concept of using six source positions to
specify an active length close to 14 mm is also supported
by the analytic approach reported by Williamson [22],
which states that a linear array of n point sources,
spaced at center-to-center intervals S, approximates a
Table 8.6 Cesium source and spacer arrays developed by
Grigsby et al. [3] to replace the previously used 2-cm tube sources
144 U -2 - 4 5 - 7 - 72 U - 2- - 5-
72 U -2 7 _ 144 U 1 - 3 4 - 6
180 U 1 2 3 - 5 6
216 U 1 2 3 4 5 6
Each 2.5 mm source pellet is nominally 36 U (5 mg radium
equivalent).
line source of active length n x S, i.e., (6) x (2.5 mm) =
15 mm.
Others have also reported on source-spacer pellet
configuration schemes for the replacement of an intra-
cavitary Manchester radium source technique [4] and
for source optimization in vaginal cylinder applica-
tions using a simulated annealing algorithm [5]. The
limitations of point source algorithms to model
Selectron source configurations have also been
reported, and measured dose distributions have
demonstrated where the effects of attenuation by inac-
tive spacers, other sources, and applicators are the
greatest [23,24]. This is discussed further in the dose
computation section.
8.4.2 Conversion from manually loaded
tube sources to motor-driven source-cable
assemblies
The specification of source activities and active lengths
for motor-driven remote afterloaders is a relatively
straightforward process. Because the sources cannot be
reconfigured, one must list all the sources anticipated to
be needed. An example of an intracavitary cesium source
inventory for a 15-channel, cable-driven, remote after-
loader is shown in Table 8.7. Each source should have a
documented assigned location in the main storage con-
tainer so that prescribed sources can be easily identified.
The design of a remote afterloader will sometimes
limit how closely one can replicate manually loaded
brachytherapy technique. For example, if the path of the
source transport tube through an applicator such as a
Fletcher-Suit-style ovoid will not permit the use of a
2-cm long rigid source, then a shorter source length may
be necessary. This was the case when an 8.5-mm active
length source replaced a 14-mm active length cesium
tube source and, as a consequence, the dose rate on the
lateral surface of the ovoid increased by 6% to 15% as the
ovoid diameter decreased from a 3 cm to the 1.6 cm mini
ovoid [2].

Table 8.7 The intracavitary cesium source inventory for a microSelectron-LDR1

Norman-Simon Capsule 12 8.5 9.11 1-12 1-12

Mini ovoid 2 8.5 9.74 19,20 13,14
Shielded ovoid 2 8.5 18.93 21,22 13,14
Shielded ovoid 2 8.5 28.50 23,24 13,14
Tandem 1 40.0 19.12-9.54 38 15
Tandem 1 60.0 9.54-19.12-9.54 39 15
Tandem 1 60.0 19.12-9.54-9.54 40 15

a
Purchased by the Mallinckrodt Institute of Radiology for treatments given at Barnes-Jewish Hospital, St Louis, Missouri.
MLDR, microSelectron-LDR.
122 Quality assurance in low dose-rate afterloading
It is important to note a significant treatment limita-
tion with the fixed-style cable-source assembly. There is
no adjustment of the source position in the applicator.
With manual afterloading, sometimes a spacer of length
between 5 mm and 15 mm at the cephalad aspect of the
tandem is used to optimize the position of the most dis-
tal tandem source in relation to the ovoid sources.
Without that option, the flange of the tandem must be
set after evaluating the sounding of the uterine depth
and reviewing the source lengths that are available.
External markings on the tandem can indicate the distal
extent of the available source trains for the tandem and
the most appropriate source train can be selected.
8.4.3 Iridium seed ribbon preparation
Conventional iridium seed ribbons reinforced with
internal plastic filaments can be configured for remote
afterloading as long as they have not been previously
used for manual afterloading. The depth of the inner
lumen of the implanted catheters or needles must be
known in order to accurately position the active length at
the prescribed treatment area. The depth information is
determined either by pre-cutting the catheters for a con-
stant inner depth or by measuring the insertion depth of
each catheter with a special 'measuring dummy' or com-
parable commercial measuring device.
A special ribbon preparation station is necessary to
prepare the source assembly safely and accurately [25].
The process begins with trimming away any active por-
tion of the ribbon not to be used. This trimming involves
cutting the interseed plastic filament leaving a small (2-3
mm) inactive tip that is heated with a special element to
achieve a bullet-shaped tip for smooth transport. The
inactive proximal end is then cut to the length that will
position the active length to span the prescribed treat-
ment length. Accurate ribbon preparation must also
account for the ribbon length that inserts into the con-
trol pellet and any gap between the control ball and the
opening of the needle or catheter. The total source length
should be prepared so that at least 2 mm of gap is main-
tained between the ribbon tip and the inner depth limit.
This gap is necessary to ensure that the control pellet
seats completely, enabling treatment to proceed. Clinical
experience can help to determine the optimal gap. The
control pellet also serves as the connection for the source
ribbon and the drive cable. The drive-cable length con-
trols the positioning of the source assembly within the
shielded area when situated in the intermediate safe.
Therefore, the drive-cable length must be determined
based on the sum of the active and inactive lengths of
each source ribbon. Finally, the completed source assem-
bly is transferred from the preparation station to the
source storage container, from where it is subsequently
transferred to a channel of the intermediate safe and
from there to the treatment catheter. An autoradiograph
must be obtained to verify the details of the source con-
struction as well as to ensure that each source resides in
the correct machine channel. A current source inventory
list must also be maintained as new sources are created
and old ones disposed of.
Because of the many steps involved in iridium source
preparation, a source preparation form is very practical
to ensure that all source details are incorporated. It is
important for a user to experiment and establish a sys-
tem that prepares an iridium ribbon so that, when it is
finally configured, it delivers the correct active length to
the prescribed treatment length of the catheter or needle.
The process of ribbon preparation can be simplified if
certain source dimensions can be kept constant, but in
many clinical situations that is not possible. Another
approach for interstitial source preparation is to main-
tain a stock of fixed-length sources and vary the length of
the catheter or needle. However, this will cause the trans-
fer tubes to have varying radii of curvature, increasing
the likelihood of source transfer difficulties [26].
Although interstitial applications can be performed for
almost any body site, LDR remote afterloading may be
better suited for perineal and breast applications,
whereas head and neck applications are generally more
difficult. Special attention also needs to be paid to assur-
ing that templates designed to hold the implanted
catheters securely are also fixed securely to the patient
and, finally, never allow flexible catheters to be cut after
the measurements for source preparation have been
obtained.
8*4*4 Treatment planning
LOCALIZATION RADIOGRAPHS
The localization radiographs for the evaluation of appli-
cator placement, the determination of applicator source
loadings, and the computation of dose distributions are
obtained in a way similar to that used for manual after-
loading. The radiographic source markers should be
inserted in the operating room once the applicators have
been secured, and the patient has arrived for simulation
ready for filming. A quick inspection of the applicators is
advised to verify that the radiographic markers are still
completely inserted. The configuration of dummy mark-
ers should be documented for general reference. The
physicians, simulator technologists, and dosimetrists
should all be familiar with the dummy source configura-
tions so that, while reviewing the radiographs, errors are
not made due to misunderstanding which markings rep-
resent the actual source positions. Documentation of the
position of the dummy sources and/or actual sources
within applicators is also useful for reference, especially
for ovoids, because those dummy source markers will
not always be distinct on lateral localization radiographs.
Figure 8.3 shows the dummy source positions in the
Selectron-LDR Fletcher-Suit-style ovoids and demon-

strates that source positions 1-6 are situated between the
bladder and rectal shields. Standard active source posi-
tions can therefore be established, because the positions
relative to the shielding are fixed. The plastic caps that
enlarge the ovoid diameter should be evaluated to docu-
ment the distance from the sources to the vaginal
mucosa and to the applicator surfaces adjacent to the
rectum and bladder (which are not necessarily equal).
For interstitial applications, verification measurements
of catheter insertion depth should be made while the
patient is in the operating room. If catheters can be pre-
measured and cut to known lengths or marked in a way
that can guide precise cutting, that is a simpler process
than measuring catheters of varying lengths. Catheters
should extend at least 5 cm from the patient's surface to
allow connection to the transfer tubes.
DOSE COMPUTATIONS
Low dose-rate remote afterloading does not require spe-
cial treatment planning equipment. The radiographs
used for source reconstruction should be obtained fol-
lowing whichever techniques are convenient and com-
patible with the user's planning system. However, if a
new planning system is obtained specifically for a remote
afterloading system, acceptance testing of the treatment
planning computer must be performed before any
brachytherapy dose calculations are obtained for patient
treatments. Evaluations of treatment planning algo-
rithms for remote afterloading have been reported with
reference to source reconstruction methods [27] and
dose calculation [23,24,28,29]. Results from one report
are shown in Figure 8.4. There are several methods for
source reconstruction. The accuracy of each technique
Quality assurance procedures and clinical implementation 123
Figure 83 Radiograph of the
shielded Fletcher-Suit-style
ovoid for the Selection
demonstrating the available
source positions. Positions 1-6,
indicated by the square and
round radiographic markers, are
shielded in the directions toward
the bladder and the rectum.
This radiograph can serve as a
reference for determining source
positions for dose distribution
computations because the
source positions are usually not
distinct on the lateral source
localization film.
must be evaluated before it is used clinically. Source
positional accuracy should be within 2 mm. Details of
source calculation algorithms can be found in Chapter 5.
The clinical evaluation of computed isodose distribu-
tions is no different for manual or remote afterloading.
However, once the dose distributions for remote after-
loading have been reviewed and the final decisions on
source configuration and treatment duration have been
documented, it may be necessary to reprogram the treat-
ment times or possibly modify a source configuration.
However, unlike manual afterloading, there is no
attempt to calculate the precise time of day the implant
will be completed, because treatment interruptions
occur during the implant course for various reasons,
such as patient care and visitors. It has been reported
that on average 14% more time is required to complete
the treatment, with 4% due to mechanical failures and
the other 10% to patient care [2].
TREATMENT PRESCRIPTION
Treatment prescriptions for remote afterloading differ
from those for manual afterloading only with respect to
the source types and the specification of the treatment
machine. This assumes that the source activities available
are similar to the manual sources that were used previ-
ously. To prescribe a Selectron treatment, a diagram of
the 48 available source positions for each of the three
channels is helpful. The physician can darken the pre-
scribed active sources with ink, and the number of hours
for each channel can be documented adjacent to the
source column of each channel. Figure 8.5 shows a pre-
scription form that was designed for both remote and
manual afterloading.
124 Quality assurance in low dose-rate afterloading

Image Not Available

Figure 8.4 Dose profiles for a single source in a Selectron applicator (profiles 1, 2, and 3) and for three sources in the applicator
(profile 4) for geometries shown in the right-hand inset. The solid profiles labeled 'a' are measured below the applicator; the dashed
profiles labeled 'b' are calculated. Profile 4b is the sum of profiles Ib, 2b, and 3b and is valid for the geometry of profile 4a except
that the attenuation effects of the stopping screw and spacers are ignored. The left-hand inset shows a correction factor to the
calculated dose for the four dose profiles. (Reprinted with permission from Conrado Pla, PhD (1987) in the International Journal of
Radiation Oncology, Biology and Physics, 13, 1761-6.)

8.5 THE ONGOING QUALITY ASSURANCE
PROGRAM
8.5.1 Treatment verification
Treatment verification procedures must be performed
for all remote afterloading treatments. The prescribed
treatment is programmed by a brachytherapy technolo-
gist, who refers to a copy of the physician's written direc-
tive. A physician should check the treatment data before
treatment begins. The treatment verification process
includes reviewing the machine console displays and
printout tape, indicating source selection or configura-
tion, channel selection, and treatment duration. When
applicable, the source storage container positions from
which sources were drawn for the prescribed channels
should also be checked. An autoradiograph should be
obtained for each treatment so that source configuration
or source selection can be verified for each treatment
channel and applicator. It should be noted that source
storage containers might allow manual manipulation of
the source locations, which can allow accidental source
relocation to a new container position. This could only
be detected by means of the autoradiograph. Devices for
autoradiography may be commercially available, but a
simple device that secures the applicators in close con-
tact to a Ready-Pack film can be easily designed and con-
structed. It is also possible inadvertently to connect a
treatment tube to the wrong channel connector.
Verification that source transfer tubes are connected to
the corresponding treatment channels is therefore neces-
sary on some afterloaders. Connections should be veri-
fied during patient connection by tracing each transfer
tube back to the channel locking mechanism. Therefore,
the ideal autoradiograph device should be capable of
detecting not only source relocations in the storage con-
tainer, but also errors in transfer tube connections. In
comparison, autoradiographs of the Selectron are less
likely to reveal source configuration errors that could not
have been detected from the machine displays or print-
out tape, but rather, they serve primarily to document
correct source and spacer configuration. Autoradio-
graphs should be reviewed by a physicist on the same day

that the treatment is started and filed as a source verifi-
cation document. Figures 8.6 and 8.7 show two excellent
autoradiograph devices that were developed by Dr Ali
Meigooni and Dr Jeffrey Williamson.
Sometimes, it is necessary to reprogram selected chan-
nels that require longer total time. If the reprogramming
is done during the nighttime, it may be difficult to have
it double-checked. As soon as possible, the reprogram-
ming should be verified by reviewing the treatment his-
tory printout. When possible, reprogramming should be
scheduled to occur at a time when immediate verifica-
tion is possible.
Procedures should also be established to verify the
dose calculations on which the treatment prescription is
based. Ideally, a qualified person who has not made the
initial calculation performs this check. Items to check
The ongoing quality assurance program 125
Figure 8.5 This intracavitary
prescription form was developed
at the Mallinckrodt Institute of
Radiology, St Louis, Missouri, for
remote afterloading and manual
afterloading.
include: a review of the written directive, recalculation of
any arithmetic, data transfer from tables and graphs, and
correct use of data. Computer-generated dose calcula-
tions should be verified by confirming correct source
and geometric input parameters [16]. An alternative
method compares the manual calculation of a point dose
to the computed dose at that same point.
8.5.2 Shield placement and surveys
Prior to initiating treatment, portable bedside lead
shields should be positioned, when necessary, as indi-
cated on the established floor markings or room dia-
gram. Radiation surveys in restricted and unrestricted
areas contiguous to the treatment room must be
126 Quality assurance in low dose-rate afterloading

Figure 8.6 Verification of correct source selection and position for the microSelectron-LDR channels designated for the tandem and
avoids is accomplished with a special autoradiograph device (a). The three applicators can only be coupled to designated transfer
tubes and the same is true for the patient's applicators. The resultant autoradiograph (b) can be overlaid directly onto the dummy
marker film template by aligning the fiducial pinholes. The development of this device was necessary due to the possibility of
changing source positions in the storage containers which could result in an incorrect source loading. (Courtesy of Ali Meigooni and
Jeffrey Williamson.)

Figure 8.7 A special autoradiograph device (a) was

developed for the Selectron-LDR to facilitate quality
assurance testing and to verify the prescribed treatment
configuration of active cesium pellets and spacers. The 48
available source positions are indicated by the
radiographic markers and the three fiducial pinholes
enable a resultant autoradiograph (b) to overlay the
device radiograph and easily check the positions where
active sources have been sequenced. (Courtesy of Ali
Meigooni and Jeffrey Williamson.)

performed immediately after the treatment has begun to
verify compliance with the regulations of the governing
radiological health agency. The survey results must be
documented, including the model and serial number of
the survey instrument used and the initials of the person
performing the survey.
8.5,3 Machine-testing Schedules
The AAPM [8] recommends that the quality assurance
testing schedule be designed by the physicist in charge in
accordance with the established regulations and recom-
mendations, and advises that the schedule of testing be

frequent enough to guarantee that the equipment will
work properly during a therapy session. Prior to starting
a treatment, the brachytherapy technologist or physicist
should perform tests to verify normal operations of crit-
ical components and, once all tasks have been per-
formed, the treatment can be programmed and
independently verified by the physician. A listing of daily
quality assurance tests is included in Table 8.8. It is use-
ful to establish a form that lists the daily test items and
allows for the entering of the treatment date, the test
results, and the initials of the individual performing the
tests. These daily test results should be maintained in a
special quality assurance binder and reviewed regularly.
Daily air compressor testing includes checking the oil
level, bleeding off moisture build-up, and venting the
Table 8.8 Quality assurance review schedules for low dose-rate remote afterloaders
(Technologist) (Physicist)
Air compressors General
Area radiation monitor Key switch
Paper-tape supply Channel connectors
Treatment indicator lights Coupling mechanisms
Door interlock Audio/visual communications
Treatment interrupt switch Air compressors
Intercom system Room condition
CCTV system Safety
Coupling cleanliness Operating instructions
Treatment tubing integrity Emergency instructions
Bedside shields positioned Radiation warning sign
Operating instructions Regulatory agency notices
Emergency instructions
Treatment autoradiograph
Functional tests
Door interlock
Dooroperability
Indicator lights
Audible signals
Bed location
Daily quality assurance log
Functional
Air loss test
Power I oss test
Alarm indicators
Timer versus stopwatch
Transit time
Time/date printout
Source inventory printout
Autoradiograph
Correct storage locations
Correct source sequencing
(Maintenance technician)
Maintenance review
Complete treatment cycle
Interlock operations
Power supply voltage
Air pressure levels
Air compressor operation
The ongoing quality assurance program 127
system. The pressure levels that activate and terminate
the compressor cycle should be recorded. The area radi-
ation monitor and its back-up battery power are checked
using a low-activity source (20-40 KBq), with the nor-
mal electrical power disconnected. The source transfer
tubing should be inspected for defects and cleanliness
and the applicator-transfer tube coupling mechanism
should operate smoothly and easily. During treatment,
loose protective tubing or plastic wrapping should be
used to help protect the transfer tubing from becoming
soiled. The applicator connectors should be cleaned
promptly after each treatment. While verifying the func-
tion of the door interlock, other machine functions are
also tested, including programmability of a treatment,
correct response of the air compression sensors and
(Physicist)
Source
Leak test (semi-annual)
Calibration
Treatment-planning parameters
Facility
Radiation survey
Area radiation detectors
CCTV system
Air compressors
Treatment device
Main safe radiation survey
Intermediate safe radiation survey
Area radiation monitor
Autoradiograph
Source selection
Position in applicator
Complete treatment cycle
Safety
Interlock systems
Power loss back-up system
Timer linearity
Air loss back-up system
Applicator tests
Air leaks
Ease and specificity of coupling to transfer tube
Total source inventory
Source and dummy positioning agreement
Internal shield position and dosimetry effects
Temporal
Timer accuracy
Transit time
Dose computations
Source para meters
Point dose comparisons
128 Quality assurance in low dose-rate afterloading
valves, and treatment status indicators. Other items to
check include the paper tape printer, the intercom,
closed circuit television system, and the accessibility of
the operating instructions and emergency instructions.
If the outcome of any of the daily tests is not satisfactory,
the physicist should be notified to determine whether a
repair is required or if the treatment must be cancelled.
For example, if the door interlock is disabled, the remote
afterloader should not be used.
Finally, just prior to treatment, the autoradiograph of
the programmed sources is obtained, the bedside shields
are properly positioned, and the physician reviews the
programmed treatment parameters and initials the
paper tape printout if everything is correct. Instructions
should be reviewed with the patient regarding the lim-
ited range of motion due to the connection to the
machine, as well as the importance of minimizing treat-
ment interruptions. With only the patient remaining in
the room, the door is then closed and the treatment
switch activated, sending the sources into treatment. The
radiation exposure in the adjacent unrestricted areas is
then measured and recorded. If excessive exposure is
measured, the shield position or patient position should
be rechecked and, if necessary, the adjacent areas
vacated, posted, and secured.
Testing by a physicist should be done on a monthly or
quarterly schedule. The frequency of the physicist
reviews should be based on machine reliability. Initially,
a monthly schedule is appropriate, but, if the machine
performance proves to be stable and reliable, a quarterly
schedule is justified as long as the equipment perfor-
mance does not diminish. The items included in the
physics reviews are listed in Table 8.8. Although some of
the tests overlap those included in the daily testing pro-
tocol, additional tests are performed to monitor machine
performance more extensively. Functional tests of the
device, such as response to the loss of air compression
and electric power, are checked. These tests should be
performed in a manner that ensures that any personnel
radiation exposure is kept as low as possible. With the
physicist remaining in the treatment room, a spacer train
or a minimal number of sources is transferred into treat-
ment. The physicist then disconnects the air supply to
the machine and verifies that the back-up compressed
air reservoir is activated and retracts the source train
immediately and completely. The compressed air line is
then reconnected and the back-up power system is
checked in a similar way, by disconnecting the power
cable from the wall outlet and verifying that the back-up
battery system executes the source retraction and also
retains the treatment history. Once power has been
restored, the treatment should be ready to resume with-
out the necessity of reprogramming. During these tests,
the display of the appropriate error codes and alarm
conditions should also be verified.
Techniques for testing the timer system accuracy and
determining source transit time are described above, in
the acceptance testing section. Simpler tests can be per-
formed on a quarterly or monthly basis. Integrating ion-
ization charge over three different time settings and
normalizing the charges to one time setting can check
timer linearity. The relative charges and time settings are
then compared. The agreement should be within 2%.
Stopwatch measurements should be compared to the
machine timer and the machine calendar should also be
checked by inspecting the date and time listed on the
treatment printout tape.
An autoradiograph should be obtained documenting
the accountability of the complete source inventory and
that each source is located in its assigned container posi-
tion. For devices that can sequence sources and spacers,
the autoradiograph can also confirm correct source-
spacer sequencing.
A quarterly maintenance review by a qualified service
engineer is another important component of the quality
assurance program. However, it is very important to dis-
tinguish between different types of machine mainte-
nance, and who is authorized to perform those services.
For example, the USNRC states that authorized person-
nel are required for installation, replacement, relocation,
or removal of sealed sources. In addition, any adjust-
ment to any mechanism on the afterloading device,
treatment console, or interlocks that could expose the
source, reduce shielding around the source, or affect the
source drive controls can only be performed by autho-
rized personnel [16]. Therefore, it is necessary to clarify
with the appropriate regulatory agency the maintenance
tasks that can only be performed by an authorized ser-
vice engineer. The maintenance and repair history for
each remote afterloader should be well documented.
Table 8.8 also includes the items to be reviewed on the
quarterly maintenance schedule. The results of the
physics and maintenance reviews should be documented
on suitable forms that are filed in the logbook designated
for each afterloader.
On an annual basis, an in-depth physics review
includes source calibrations, radiation surveys, applica-
tor tests, radiographic dummy marker evaluations, and
treatment dose computations (see Table 8.8). It should
also report on the source leak test results that are done at
the prescribed intervals. A report is then generated based
on the annual review and the treatment history for the
year. In addition to this extensive quality assurance test-
ing schedule, the physicist must also determine the
appropriate tests to perform following the repair of an
afterloader before the device can resume clinical opera-
tion.
The schedule of routine quality assurance and mainte-
nance testing should be based on the ongoing perfor-
mance history of the device, and the tests to be performed
should also be evaluated. The pre-treatment tests may
reveal the most obvious machine problems, but more
subtle problems may go undetected. The more extensive
quarterly tests should expose those problems. The con-

tent of the quarterly review should be based on the fre-
quency of device mishaps. Williamson [17] has reported
that quality assurance testing rarely reveals problems
involving accuracy of source position or treatment tim-
ing, although he does acknowledge that interstitial tech-
niques are much more complex and require more effort
to verify correct source positioning. However, he has
found that the quality assurance testing can reveal system
failures involving interlocks, source transport, source or
channel recognition, and back-up battery power. He has
proposed a quarterly schedule for physics testing and a
quarterly schedule for maintenance review.
8*5*4 Documentation
Treatment documentation can be quite extensive for
remote afterloading. The treatment autoradiograph and
the treatment printout tape should be maintained for
that purpose. The treatment tape lists the entire treat-
ment history, complete with the initial programming,
treatment start time, treatment interruptions, error
codes, and treatment completion time. The rest of the
treatment documentation is applicable to all brachyther-
apy and includes the prescription/treatment form, com-
puted isodose distributions, point dose computations,
and a dose summary report. The physician should date
and sign the written record before the treatment has
begun. The record should list the radioisotope, treat-
ment site, total source strength, and exposure time or
total dose [16]. A quality assurance checklist from start
to finish can also serve as a valuable document. One crit-
ical item on that checklist should document that a sur-
vey was performed to verify that all sources were
transported to the storage safe of the remote afterloader
after the completion of treatment. The exposure rate
measured at the surface of the patient's implanted area
should be recorded. It is convenient to file copies of some
of the treatment documents in a special 'Quality
Management' binder, which can be used to facilitate
internal auditing that may reveal weaknesses in the qual-
ity management program and thereby continually
improve treatment quality.
8*5*5 Training personnel for remote
afterloading
Initially, the manufacturers of a new remote afterloading
device normally provide training for the users, opera-
tors, and supervisors of the equipment, as part of the
installation contract. The training should include appli-
cator description, the function and operation of the
devices under normal and emergency conditions, all
safety features, radiation protection procedures, sug-
gested quality assurance procedures and, when applic-
able, a review of the computerized treatment planning
system [8].
The ongoing quality assurance program 129
A continual program of ongoing training for the staff
is also very important. The device manufacturer should
provide annual refresher training, but this should be
supplemented with intramural reviews. The training of
all involved personnel must include the requirement for
implementing the instructions of the authorized users,
consistent with the quality management program and
government regulations. The training should be specific
to the device model and include radiation protection
principles and practice, operating and emergency proce-
dures, and system design. In addition to the formal train-
ing in the use of brachymerapy sources that attending
physicians and residents have been given, they must also
understand how the afterloaders function so that their
involvement in treatment verification, programming,
and treatment termination procedures is performed cor-
rectly. Physics procedures should also be reviewed regu-
larly.
The nursing staff need training in the operation of the
treatment controls as well as in interpretation of the
treatment status displays and the area radiation monitor.
They need to know who to contact in the event of a treat-
ment problem as well as emergency procedures. They
must also understand the need to control the number
and duration of treatment interruptions. A videotape is
a convenient way for nurses to review these procedures.
Table 8.9 gives a complete listing of the items to be
covered in an in-service training program for nurses.
Emergency procedures should be established that
ensure that the medical physicist or radiation safety offi-
cer be notified immediately if sources fail to retract com-
pletely. The names of emergency personnel and the
means for contacting them while on duty or off duty
should be posted at the operating console. The location
of emergency equipment should be specified. Emergency
equipment should include a portable radiation monitor,
shielded storage containers, and long source-handling
tools. Supplies for removing applicators should be
Table 8.9 Nurse in-service topics for remote afterloaders
Remote control button operation
Hallway intercom operation
Utilize closed circuit TV system
Procedures for patient control
Procedures to control treatment interruptions by coordinating
with housekeeping and dietary personnel and limiting
interruptions due to visitors, clergy, and medical staff
Notify physics staff if machine error occurs (give telephone
and beeper numbers)
How to recognize a source
How to interpret the area radiation monitor
How to handle a dislodged source
How to use a survey instrument
Radiation warnings and information posted on the room door
130 Quality assurance in low dose-rate afterloading
readily available. In an emergency situation, the area
should be posted with radiation warning signs to prevent
accidental exposures. Procedures should be carefully
designed to minimize personnel radiation exposure,
tested regularly, and be clearly displayed at the control
console and the room entrance.
Certain practical details should also be reviewed dur-
ing personnel training. These include scheduling proce-
dures. If more than one type of remote after-loader is
available, the scheduling should ensure that the appropri-
ate machine is available for each patient. As usual, good
communication between the radiation oncologist, the
referring physicians, and the brachytherapy technologist
is very important. Another practical point to review is
that flexible interstitial catheters should never be short-
ened after measuring to determine the necessary active
and inactive source lengths has been done. An undetected
shortened catheter will result in either a source position-
ing error or a source transfer alarm condition. One final
practical point is that applicator openings should always
be capped to prevent fluid or dirt from getting inside. The
applicators should only be uncapped when inserting or
removing dummy sources and when connecting to the
transfer tubes for treatment. Foreign material, if carried
by the source or source assembly into the afterloader inte-
rior, can damage optical sensors and cause premature
mechanical deterioration.
It is the responsibility of the physicists and
brachytherapy technologists to schedule and provide the
ongoing training. The reviews must be given to all
involved personnel at least once per year and promptly
for new staff. A reference binder containing descriptions
of established procedures and instructions for all
involved personnel should be readily available at the
afterloader treatment areas (Table 8.10).
8*5.6 Practical operational considerations
The introduction of new brachytherapy technology not
only demands that new treatment procedures be estab-
lished, but sometimes also requires modification of cer-
tain design features of a new device in order to achieve
smooth operation in the field. Some of these issues can
be resolved by further product development by the
Table 8.10 Contents of a procedures manual available at the
nurses'station
Procedures for machine programming and initiating
treatment
Procedures for uncoupling and terminating treatment
Procedures for cleaning treatment tubing and connectors
Emergency procedures
Error codes, their interpretation, and corrective actions to be
taken
manufacturer. A close and cooperative relationship
between the user and the manufacturer can facilitate
these improvements. This type of experience has been
reported with regard to the microSelectron-LDR [2]. A
brief review of some of those experiences is presented in
the following paragraph so that additional insight into
the mechanics of remote afterloading can be gained.
If difficulties in source assembly transport into treat-
ment are encountered, the first thing to check is the cur-
vature of the transfer tubing and flexible applicators,
especially at the applicator-transfer tube interface.
Irregularly shaped source tips have also been determined
to cause source transport problems, especially when the
source encounters a curvature just before it traverses the
transfer tube-applicator interface. This is why iridium
ribbon preparation includes the use of the special heat-
ing element to achieve a smooth, bullet-shaped, plastic
tip-
Other difficulties have been associated with flexible
catheters used for perineal implant sites. Flexing or con-
stricting of the catheters will result when the patient
shifts position in the bed or sits up. This may cause
source assemblies and drive cables to uncouple during
source retraction, leaving the sources in the catheters. An
alarm condition will occur. By inspecting the machine
console display, the errant channels can be identified.
The patient's position should be adjusted to relieve the
pressure exerted on the catheters so that source recovery
can be undertaken. The transfer tube should be uncou-
pled at its connection to the intermediate safe and a
source recovery tool passed down the transfer tube to
retrieve the source assembly and return it to the source
storage container. This problem can be minimized if the
patient's position is kept at a low angle in the bed. The
patient can be instructed via the intercom to assume this
position just before source retraction is activated. The
use of rigid implant needles should also reduce the fre-
quency of this problem. These corrective actions can also
be used to facilitate source transport into treatment.
Obviously, the audible alarm system is very important in
afterloaders.
Strengthening the connection of the drive cable to the
source assembly has also been attempted to prevent
uncoupling. This may be a reasonable solution if the
same source assemblies are used routinely, but requires
that those sources be stored indefinitely in the interme-
diate safe. However, this approach exposed a malfunc-
tion that otherwise might have never been detected. On
occasion, sources in the intermediate safe that were not
programmed for treatment would actually be trans-
ferred into treatment along with the programmed
sources, even without an applicator or transfer tube in
place. The discovery of that malfunction forced those
treatment machines to be removed from clinical service
until the problem was corrected.
Another potential problem involves perineal applica-
tions. When the patient adjusts his or her position in the

bed, the applicator system can become dislodged. This is
caused by the patient moving away from the transfer
tubing without the tubing being free to follow, as in the
situation in which the patient inadvertently places one
foot over the tubing while adjusting position. It is essen-
tial that the applicator systems be adequately secured to
the implant site, and the patients also need to be
reminded that they are tethered to the treatment
machine and care must be taken to avoid applying forces
that can disengage the implant systems. The nurses and
physicians should regularly check the source transport
tubing to prevent tangles and to verify that the applica-
tor system has not become dislodged.
Although not all remote afterloaders are plagued with
all the problems described above, a functional problem is
always possible due to the number of treatment inter-
ruptions over the long duration of the treatments.
Certain personnel, generally physicists, must be assigned
to respond to a machine failure at any time so that these
treatment-related problems can be resolved quickly and
safely. The nursing staff cannot be expected to be
responsible for this, although sometimes only a tele-
phone call to the physicist on call is necessary to resolve
a relatively simple problem.
The adjustments that one must make for remote after-
loading are related to the new source types, the changes
in the control of source placement and treatment timing,
the fact that the patient is tethered to a machine, and the
uncertainty of not knowing exactly when the treatment
will be completed. One must realize that reliance on a
machine to control a treatment requires a comprehen-
sive quality assurance program and ongoing training
and, despite it all, there will inevitably still be machine
failures at some time.
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Endocuriether./Hypertherm. Oncol., 9,46.
19. Thomadsen, B.R. (2000) Quality management for low and
medium dose rate afterloaders. In Achieving Quality in
Brachytherapy. Bristol, IOP Publishing.
132 Quality assurance in low dose-rate afterloading
20. International Electrotechnical Commission (1989)
International Standard IEC 601-2-17 Medical Electrical
Equipment Part2. Geneva, Bureau Central de la
Commission Electrotechnique International.
21. Orton, C.G. and Siebert, J. (1972) Instrument non-linearities
and therapy unit timer error. Phys. Med. Biol., 17,198-205.
22. Williamson, J.F. (1986) The accuracy of the line and point
source approximations in 192lr dosimetry. Int.J. Radial
Oncol. Biol. Phys., 12(3), 409-14.
23. Siwek, R.A., O'Brien, P.F. and Leung, P.M.K. (1991)
Shielding effects of Selectron applicator and pellets on
isodose distributions. Radiother. Oncol., 20(2), 132-8.
24. Pla, C, Evans, M.D.C. and Podgorsak, E.B. (1987) Dose
distributions around Selectron applicators. Int.J. Radial
Oncol. Biol. Phys., 13(11), 1761-6.
25. Slessinger, E.D. (1995) Commissioning of non-stepping
source remote afterloaders. In Brachytherapy Physics, ed.
J.F. Williamson, B.R. Thomadsen and R. Nath, Medical
Physics Publishing, Madison, Wl, 503-22.
26. Slessinger, E.D. (1995) Clinical implementation of LDR
remote afterloading. In Brachytherapy Physics, ed. J.F.
Williamson, B.R. Thomadsen and R. Nath, 521^0.
27. Slessinger, E.D. and Grigsby, P.W. (1989) Verification
studies of 3D brachytherapy reconstruction techniques,
in Brachytherapy 2, ed R.F. Mould. Leersum, The
Netherlands, Nudetron Trading BV, 130-5.
28. Meertens, H. and van der Laarse, R. (1985) Screens in
ovoids of a Selectron cervix applicator. Radiother. Oncol.,
3(1), 69-80.
29. Steggarda, M.J., Moonen, L.M., Damen, E.M. and
Lebesque, J.V. (1997) An analysis of the effect of ovoid
shields in a Selectron-LDR cervical applicator on dose
distributions in rectum and bladder. Int.J. Radial Oncol.
Biol. Phys., 39,237-45.

Quality assurance in high dose-rate afterloading
COLIN H.JONES
9.1 INTRODUCTION
A quality assurance program should give assurance to
the user that predetermined specific objectives are being
met. There are two fundamental requirements in
brachytherapy and these are: first, to deliver a prescribed
radiation dose within acceptable limits of accuracy; and,
second, to ensure that, in so doing, patient, staff, and
public are not irradiated unnecessarily. The uncertainty
in dose specification can be subdivided into that due to
clinical procedures, such as the uncertainty in the indi-
cation of the target volume on a localizing radiograph,
and that due to physical procedures. The latter is princi-
pally the uncertainty in dose determination due to cali-
bration of the source and dosimetric calculations. The
Netherlands Commission on Radiation Dosimetry
(1991) recommended that the uncertainty in the dose
specification due to these physical procedures (defined
as one relative standard deviation) should be less than
5%. This is consistent with the recommendations of the
International Commission on Radiological Protection
(ICRP) [1] and the World Health Organisation [2]. In
the USA, the Nuclear Regulatory Commission (NRC)
define a misadministration as a dose differential of 20%
between the prescribed and administered doses; a dose
delivered to the wrong treatment site is also considered
to be a misadministration. In order to achieve a high
level of accuracy and to minimize radiation exposure
beyond the treatment volume, it follows that a quality
assurance system must cover every aspect impinging
upon the treatment of the patient and that each part of
the treatment process should be evaluated critically. The
9
subject has been considered by several groups [3-5].
Chapter 8 describes the quality assurance measures
required in low dose-rate (LDR) afterloading. Many of
these measures apply equally well to high dose-rate
(HDR) procedures, and the contents of both chapters
may be considered to be complementary to each other.
There are four important elements which are com-
mon to quality assurance programs:
1. The appointment of a person experienced in
radiation physics to be responsible for drawing up
the quality assurance program, for training staff, and
for ensuring compliance with the program.
2. The program should be documented in detail,
including the procedures which must be followed,
the tests which must be carried out, and the
frequency of these tests. The results of these tests in
terms of compliance or non-compliance should be
recorded.
3. Radioactive sources should only be used in
compliance with local, or national and/or
international recommendations.
4. Incidents which have, or might have, affected the
precision of treatment or the safe use of sources
should be noted: the program can then be modified
in the light of experience. The overall program
should be reviewed periodically.
Quality assurance for remote afterloading devices
with HDR sources are considered here under the follow-
ing headings:
1. Regulatory requirements
2. Facility design
134 Quality assurance in high dose-rate afterloading
3. Machine function tests
4. Tests relating to treatment precisions
5. Quality assurance documentation.
9.2 REGULATORY REQUIREMENTS
Remote-controlled, automatically driven, gamma ray
afterloading equipment is made and finished with a
degree of uniformity and manufacturers are required to
comply with generally accepted principles of sound and
safe practice. This applies to the radiation source and to
all components of the equipment, including, for exam-
ple, any programmable electronic system used as a con-
trolling timer, or any interlocks that are used in the
equipment. Consequently, the machine features
designed by different manufacturers are often similar
and quality assurance procedures required for different
types of remote afterloading equipment are correspond-
ingly of a common nature. The fabrication of the
radioactive source and its containing capsule must con-
form with BS 5288 in the UK and the source housing
within the equipment must conform to regulatory
requirements. The International Standard IEC
601-2-17 [6] specifies the requirements with regard to
the design, function, testing, and use of remote after-
loading equipment. This standard specifies requirements
for equipment which gives air kerma rates up to
500 mGy rr1 at 1 m from the radioactive source or
sources in use. For equipment operating outside this
range, special precautions may be necessary. In the UK,
the use of such equipment is also covered by the Ionising
Radiation Regulations [7]. In the USA, the NRC specifies
a number of requirements with regard to the design,
function, testing, and use of such equipment.
The IEC Standard 601-2-17 [6] specifies require-
ments for equipment intended to be: used under the
supervision of qualified persons, maintained at predeter-
mined intervals, and subjected to regular checks by the
user. The requirements of the standard are based on the
assumptions that an irradiation treatment prescription
is available which prescribes appropriate values of the
treatment parameters and the air kerma rate at 1 m from
the radioactive source(s) in the equipment is known.
These requirements are intended to ensure that the pre-
scribed values of the treatment parameters can be
achieved by the equipment, in particular that the
selected radioactive source (or sources) is positioned or
moved within the source applicator in the selected con-
figuration relative to the source applicator. The indica-
tion that the position of any source or source train
within an applicator supplied with the equipment is to
be as selected will not be given unless such positions are
within 2 mm of those programmed, in any direction. It
is a requirement of the standard that the equipment is
provided with a controlling timer for each channel or
each group of channels where channels are grouped to
operate together. Furthermore, controlling timers must
have a mean percentage average error not exceeding 1. In
order to comply with these requirements, it is necessary
to undertake appropriate tests and these must form part
of a quality assurance program.
International regulatory requirements are designed to
ensure that, when equipment is used in compliance with
these standard recommendations, radiation hazards are
minimized and treatment delivery can be achieved safely.
Clearly, good radiation protection practice consistent
with regulatory requirements should be part of the
quality program.
93 FACILITY DESIGN
High dose-rate brachytherapy covers a wide range of dif-
ferent kinds of treatment, including the use of surface
moulds, intracavitary and interstitial techniques using
HDR treatments and pulse dose-rate (PDR) treatments.
The duration of a treatment might range from a few
minutes, as in the case of conventional HDR treatments,
to a few days for PDR treatments. Although it is possible
to install an HDR machine in a modified radiotherapy
treatment room, it is better to install such equipment in
a room designed specifically for the treatment tech-
niques envisaged.
The details of the design brief for such a room will
depend upon the type of brachytherapy being planned.
There are, however, various considerations that are com-
mon to most requirements:
The treatment room should be constructed to allow
safe implementation of the prescribed treatment.
The room should have sufficient shielding or be so
isolated that healthcare personnel, patients, and
members of the public will not receive incidental
radiation exposure in excess of recognized specified
limits. The radiation levels in and around the room
should be measured or calculated and staff working in
the area should be monitored. Areas where the dose
rate is more than 7.5 uvSv h'1 should be designated as
controlled areas: a supervised area where the dose rate
is less than 7.5 (iSv h-1 but more than 2.5 |lSv h-1 might
in some circumstances also be identified. Radiation
warning notices should be posted identifying the
controlled area.
The layout of the room should allow patients to be
nursed safely, efficiently, and with as little
inconvenience and discomfort to the patient and staff
as possible and also allow all the procedures
associated with the medical care of the patient to be
accomplished.
The room should be equipped so that any necessary
medical emergency procedures can be implemented
speedily and effectively.

Particular attention should be paid to the need for
coping with radiation emergencies that might occur
during the course of treatment.
It is important that the radiation protection adviser
and/or experienced radiation physicist should be
involved in the room design concept at an early stage in
the planning process. HDR sources are principally either
cobalt-60 or iridium-192. In both cases, the high dose
rates associated with the high-activity sources necessitate
a room design which has either some form of maze
entrance or a very heavy lead door. HDR treatment
rooms require walls of thickness 40-60 cm of concrete,
depending upon the size of the room and the energy and
activity of the sources that are being used. Table 9.1 lists
the physical characteristics of cobalt-60 and iridium-
192. In practice, a room with a maze-type entrance
requires more floor space, but allows economies to be
made in terms of cost and convenience. If adequate space
is available, it is also advantageous to include some form
of X-ray facility within the room so that applicator posi-
tions can be checked prior to treatment without the need
for moving the patient. Protective lead doors and also
any barrier to the maze entrance must be interlocked
with the treatment unit.
A comprehensive radiation protection survey should
be made prior to using the facility and this should be kept
for reference purposes: if alterations are made subse-
quently to the room structure or layout, these should be
recorded and the survey repeated. The air kerma rate
around the source storage container should also be sur-
veyed. At any position 50 mm from the surface of the
storage container or any other surface permanently fixed
to it, the air kerma rate mSv should not exceed
0.01 |0,Svh-1.The air kerma rate at any position 1 m from
the surface of the storage container should not exceed
1 (iiSv h-'. It is a requirement of the IEC standard that
these measurements should be made with the combina-
tion of radioactive sources that is possible within the
specifications given by the manufacturers and is the least
favorable with regard to the magnitude of the dose rates.
For measurements at 50 mm, the air kerma rate should be
averaged over an area up to but not exceeding 10 cm2; for
measurements at 1 m, the air kerma rate should be aver-
aged over an area up to but not exceeding 100 cm2. The
room containing the source safe should be lockable so
that access is restricted when the machine is not in use.
Table 9.1 Properties of principal brachytherapy nudities
"Co 5.27 years 1.17,1.33 309
92
lr 74 days 0.3-0.6 113
HVT = half value thickness; TVT = tenth value thickness.
Facility design 135
The room should be equipped with the following:
Closed circuit television (CCTV) cameras with
monitors at the control console: it is preferable that
one of these systems should be in color so that the
patient's clinical appearance can be viewed
satisfactorily.
Two-way patient intercommunication.
Radiation warning lights: these should be fitted inside
the treatment room, at the door entrance, and at the
control console, and should be activated when the
radiation source is exposed. Controlled area signs
should be posted to indicate areas where the dose rate
is greater than 7.5 (J,Sv h-1; these signs should
preferably be linked to the machine so that they will
be illuminated when the radiation sources are
exposed.
It is advisable to use an audible time delay interlock so
that the machine can only be switched on within a
predetermined time after the time delay has been
activated: the time setting should be adjusted so that
this is optimal, giving just sufficient time for
personnel to leave the treatment room and initiate
treatment.
There should be an independent audible radiation
alarm inside the treatment room.
Near the treatment console, there should be a hand-
held dose-rate meter and a personal integrating dose
meter for use in emergencies.
Within the treatment room, there should be a
shielded safe, which should be available for storing the
radioactive source(s) in the event of an emergency or
when the machine is being serviced.
There should be a clearly labelled 'emergency stop'
adjacent to the console.
If a diagnostic X-ray unit is available within the
treatment room for localizing radiographs, warning
lights should indicate when this machine is being
used and there should be adequate radiation
protection for the operator.
Many of these items will require checking at regular
intervals as part of a quality assurance program.
HDR equipment should not be used as mobile equip-
ment. In the USA, the NRC requires licensees to comply
with the above requirements, and relocation of the remote
afterloading device to another area is prohibited without
12 40 206
4.5 15 113
136 Quality assurance in high dose-rate afterloading
prior NRC approval. The dedicated treatment room must
be equipped with continuous viewing and intercom sys-
tems to allow for patient observation during treatment
and, if the systems do not have a back-up system to be
used if the primary system fails, the licensee must commit
to suspending treatments until the primary system is
repaired. In common with the IEC requirements, the
NRC specifies that areas or rooms used to store remote
afterloading devices or source containers housing a
source must be secured; dedicated treatment rooms must
have an electrical interlock system and restricted area con-
trols. If there are other radiation-producing devices
located in the treatment room, the licensee must institute
mechanisms to ensure that only one device can be placed
in operation at any one time.
9.4 MACHINE FUNCTION TESTS
The function of the remote afterloading device should
be evaluated before the radioactive source is installed.
When possible, a number of tests should be performed
with a dummy source substituted for the actual source to
test the source drive mechanism and safety interlocks.
These tests should include the following:
All door and safety interlocks.
Emergency return mechanisms.
Controlling timers.
The security of couplings and connections.
Catheters and any other accessories that are going to
be used during treatment should be checked to ensure
that all have closed ends so that the radioactive source
cannot be lost within a patient should source
encapsulation fail.
The limitations of channels and source applicators must
be tested and documented: in practice, acute directional
changes of source transfer tubes should be avoided to
prevent 'sticking' of the source in transit, and it is useful
to carry out such tests using a dummy source.
The operation of the door warning lights, CCTV
systems, intercoms, and the audible time delay
interlock should be checked for function and also
adjusted to work optimally.
The console display should be checked: test all button
functions by programming and carrying out a
simulated treatment; verify that all displays are
correct; verify that the data on any printout agree with
the programmed data; and, when appropriate, check
program card data input function.
Once the radioactive source has been installed into the
treatment device, the above tests should be repeated in
addition to the following tests:
With the source in its safe position, a survey should be
made with a portable radiation dose-rate meter
around the remote afterloading device to ensure that
the shielding of the source safe complies with
regulatory requirements.
With the source exposed, exposure rates in accessible
areas outside the treatment room should be
measured. The maneuverability of the unit should be
taken into account: in small treatment rooms it might
be possible for the machine to be near to the
treatment room door, which could result in high dose
rates outside the room. On the basis of the predicted
workload, it will be necessary to calculate the monthly
radiation exposures to staff operating the machine to
ensure that the dose levels are acceptable.
The user is required to estimate the dose delivered to
the patient during transit of the radioactive sources
into the treatment position. Transit doses are partly
determined by the time taken by the transit
movements, but they are also determined by the
strength of the radioactive sources selected by the user
and by the number of interruptions during treatment.
To calculate the total transit dose, it is necessary that
the user has information from which the transit doses
may be estimated and takes appropriate account of
them. The IEC standard relates to measurements or
calculations for two conditions for each channel: the
air kerma at a position 20 mm from the axial center of
the source applicator, and the air kerma at a position
1 m from the axial center of the channel. For each
condition, the air kerma should be measured or
calculated for one specified radioactive source and
should be at the positions that are least favorable with
regard to this requirement. For measurements at
20 mm the air kerma should be averaged over an area
of up to but not exceeding 2 cm2, and for
measurements at 1 m the air kerma should be
averaged over an area up to but not exceeding
100 cm2.
In the event of an emergency, it might be necessary for
a user to enter the treatment room with the source in
the exposed position. It is useful to have knowledge of
the radiation distribution inside the treatment room
so that the line of entry can be optimized to reduce
personnel exposure.
The radiation monitor used to check dose rates
outside the treatment room and also inside the room
and around the machine should be tested over the
entire range of radiation levels that might be present.
Some monitors will saturate and fail if directly
exposed to high dose rates, so it is appropriate to use a
survey instrument with a wide range from 1 mSv tr1
to at least 1000 mSvh-1.
Although remote afterloading devices make use of
radioactive sources in a sealed system, users are
obligated to check for leakage and/or contamination
of the source. It is not possible to check for
contamination directly and it is therefore appropriate
periodically to check the catheters through which the
radioactive sources pass. Sometimes, in the

preparation of encapsulating the source, radioactive
contamination adheres to the source capsule and it is
appropriate to check for this free radioactivity by
passing the source through a catheter several times
and then checking for any radioactivity with a
sensitive radiation detector capable of detecting less
than 200 Bq.
The radioactive source should be calibrated and the
strength of the source (or sources) should (when
appropriate) be entered into the treatment machine.
The output from the printer should be checked to
ensure that the correct source activity is displayed
and, if the machine corrects automatically for source
decay, it will be necessary to check that this
calculation is within acceptable limits.
9,5 TESTS RELATING TO TREATMENT
PRECISION
Accurate delivery of doses using HDR systems depends
on knowing the strength of the radioactive sources at the
time of treatment (see Chapter 3), the precision and con-
sistency of the timer, and the ability of the treatment
machine to position the source at the proper location
along the catheter or treatment applicator.
Reference has already been made to the requirement
that the equipment should provide a controlling timer
for each channel which should have a mean percentage
average error not exceeding 1. Timers should be checked
by selecting five pre-set times (not smaller than 1% of
the maximum pre-setable time) to cover the range pos-
sible with the treatment device - taking the mean per-
cent average error at the five pre-set times. In practice,
some equipment manufacturers arrange for these tests to
be carried out as part of a routine maintenance contract.
Even so, it is important for the user to recognize that
such tests have to be made. Timer errors can occur [8].
Likewise, machines that use a single source which can be
programmed into a number of dwell positions should be
checked to ensure that the programmed dwell times are
within the required precision.
Before describing specific quality assurance tests, it is
appropriate to mention that there are three principal cat-
egories of HDR equipment. These are:
Table 9.2 Details of sources used in remote afterloading equipment
192
HDR lr 400 1 Cylinder
192
PDR lr 20-40 1 Cylinder
HDR 60Co
4-20 20 variable
HDR = high dose rate; PDR = pulsed dose rate.
Tests relating to treatment precision 137
1. single HDR iridium-192 source machines
2. PDR single HDR iridium-192 source machines
3. machines that have multiple HDR cobalt-60 sources.
Details of these machines are shown in Table 9.2.
Whereas the majority of quality assurance checks are
common to all systems, some of the design features are
different and allowance has to be made for such varia-
tions in the quality assurance program that is adopted.
These may be summarized as follows:
In the case of single HDR iridium-192 source
machines, the high-activity source is physically very
small and attached to a cable which is driven by a
stepping motor so that the required radiation
distribution can be achieved. The half-life of iridium
is relatively short, so the source has to be changed at
approximately 3-monthly intervals. The physical
characteristics of the radioactive source are such that
very fine catheters can be used, with the result that
very high local doses are given to tissues surrounding
the catheters. Precise control of the stepping motion is
necessary if reliable radiation distributions are to be
achieved. The length of the cable to which the source
is attached must be constant and when sources are
replaced it is necessary to check that this length has
not altered. Providing the stepping function of the
machine works satisfactorily, then reliably high
precision radiation treatments can be achieved. The
versatility of the machine allows a wide range of
different types of treatments to be achieved, including
those using applicators, needles, and catheters. The
position of the source within these treatment devices
must be checked before clinical use. When the source
is changed, different tests must be carried out to
ensure that the catheter length has not been altered in
any way.
Several different commercial HDR iridium-192
source machines are commercially available and
such equipment has largely replaced multiple-source
HDR devices.
PDR single HDR iridium-192 source machines also
use a stepping source, but are designed specifically to
use a lower activity source and to deliver the radiation
dose over a much longer period of time. For example,
a treatment might consist of 30-40 fractions over a
1.1 Cable
1.1 Cable
Pellet 2.5 Pneumatic; cable
138 Quality assurance in high dose-rate afterloading

period of 3-5 days or maybe the dose will be delivered

with a series of fractions given each hour throughout
the day. The technique that is used might vary from
one center to another and, in some situations, it is
possible to disconnect the treatment machine from
the patient to allow the patient greater comfort during
the period when radiation is not being given. The use
of multiple fractions over a longer period of time can,
in some circumstances, be logistically difficult and it is
important to ensure that appropriate quality
assurance measures are adopted to prevent
applicators within the patient being displaced. This is
especially so when patients are disconnected from the
machine and then recoupled to the machine many
times over the treatment period. One very important
consideration of PDR brachytherapy is the safety Figure 9.1 Part of a radiographic marker (magnified) for HDR
aspect. Based purely on health and safety (MDR) Nudetron Selectron showing 'stacking' of dummy source
considerations directly related to the instantaneous pellets in photograph (a) in comparison with photograph (b).
exposure rate from PDR machines, it is necessary to
ensure the continuous availability of a trained person
during the delivery of the radiation dose. Should the each day of use and that the precision of reproducibility
device fail with or without alarm generation, due should be within 1 mm.
either to mechanical failure or facility power failure, The techniques can be used separately or conjointly to
the dose delivered to the patient could be considerable provide information about the distribution of radioac-
unless immediate removal of the source by manual tive material within the source container and positional
means by an experienced member of staff can be information about individual sealed sources in treat-
achieved. Other quality assurance measures are similar ment trains.
to those for a conventional HDR treatment machine. The autoradiography technique is simplified by hav-
HDR machines using multiple sources of cobalt-60 ing a PMMA or wax support which has a recess with the
are similar in design to LDR or medium dose-rate same dimensions as the source (Figure 9.2). Auto-
multiple source cesium-137 machines and the quality radiographs are useful for checking the uniformity of
assurance measures are similar to those described in radioactivity and are also a useful means of checking
Chapter 8. The source catheter is made up of active the relative strength of individual sources in a source
sources and inactive spacers and the size of each of train. Visual inspection of the autoradiograph might
these is greater than that of the cable-driven source. indicate lack of uniformity at the 10% level, but for more
The sources and spacers are spherical and driven reliable assessment, densitometric scanning is to be pre-
pneumatically from a treatment safe into a specially ferred.
designed treatment catheter. Stacking of sources In the case of positional studies, it is useful to incor-
occurs in a similar way to that shown in the porate lead markers into the wax support: secondary
radiograph of the dummy source train in Figure 9.1.
The fact that there are multiple sources means that
there is a range of source activity and there is no
control over which source is used for a particular
treatment. The consequence is that the precision with
which radiation doses can be delivered using such a
system is less than that for a single high-activity
stepping source.

9.5*1 Positional reproducibility

Sources used inside applicators, catheters, and needles

should be autoradiographed and radiographed. This is
to establish the precise location of the source with
respect to the end of the applicator and to check the
machine functions. The NRC requires that the repro-
ducibility of the source positioning should be checked Figure 9.2 Wax disc for applicator and source autoradiographs.
 Tests relating to treatment precision 139

electron emission from the lead results in an autoradio-

graph of the markers and provides the required posi-
tional data. This is particularly useful for checking the
position of sources loaded into applicators or catheters,
for which it is sometimes difficult to identify the precise
end or tip. The method allows precise comparison to be
made with different applicators and provides a record of
the location of the radioactive sources inside loaded
applicators (Figure 9.3). Envelope-wrapped Kodak
X-Omat Verification film is suitable for these studies.
Uniform pressure should be maintained over the film
and source to keep both in close contact.
For high-activity sources such as those used in HDR
equipment, film exposure is only a fraction of a second
and is suboptimal because the transit time is of compara-
ble magnitude. Gafchromic film is a useful alternative.
This is a thin radiation film which is colorless, grainless,
and offers high spatial resolution (1200 line pairs mm'1).
When exposed to high doses of radiation, typically
200 Gy, a dye in the film turns blue - the density of which
depends upon the absorbed dose. This means that expo- Figure 9.3 HDR microSelectron source autoradiograph showing
sures of about 20 s are required for autoradiography, position of source in relation to top of applicator.
which results in better control of the image quality. The
film is not light sensitive and produces high-quality
images. Figure 9.4 illustrates the response of Gafchromic
film to iridium-192 radiation, and Figure 9.5 illustrates a
multiple exposure of an HDR iridium-192 source in a test
jig designed for the measurement of source position [5].
Detex paper is a cheaper alternative to Gafchromic.
This paper is used in the printing industry and changes
color when exposed to high radiation doses. Before
exposure, the paper is yellow, but under irradiation,
hydrochloric acid is released from the ink and the yellow
azo dye turns red. The shade of red does not indicate the
dose, but rather that a certain level of dose has been
achieved. Detex labels, for example, are used to indicate
whether a product has received a sterilizing dose of radi- Figure 9.4 Density-dose response curve for Gafchromic exposed
ation. Detex paper can be used in situations in which the to iridium-192 source, using light of wavelength 600 nm.
dose falls within 1-100 kGy.

Figure 9.5 (a) Photograph of

test jig. (b) Autoradiographs of
HDR iridium-192 source in test
jig-
140 Quality assurance in high dose-rate afterloading
In summary, autoradiography forms an important
part of commissioning and quality assurance and may be
used to:
examine the distribution of radioactivity in the source
capsule or the distribution of activity amongst
sources
record the position of the source with respect to the
end of the transfer cable
record the relative position of each individual source
in a source train
check the reproducibility of source positions when
inserted into catheters, needles, or applicators. It is
important that every such device which is used
clinically should first be tested and the
autoradiographic test data should be used as a
baseline for subsequent quality assurance
investigations.
There is also a place for X-ray radiography in quality
assurance. For example, it is necessary to check the spa-
tial distribution of sources in the patient for dosimetry
purposes and this might require the use of radiographic
markers. These markers are inserted into empty applica-
tors prior to loading the radioactive sources into the
patient so that the geometrical position of the applica-
tors can be located accurately. In the course of commis-
sioning new equipment, radiographic checks should be
made to ensure that these markers are reproducible and
that their position within a set of applicators is clearly
defined in relation to the radioactive sources. The repro-
ducibility of a set of markers should be within 1 mm
(Figure 9.6).
The precision of the method used to localize the
inserted sources should be checked for each type of tech-
nique to be used. The accuracy of the reconstruction
Figure 9.6 Radiographs of markers in HDR (MDR) Nudetron
Selectron applicators showing relative positions of sources.
program used to determine the geometrical configura-
tion of the sources should also be checked.
In estimating the overall accuracy of a particular tech-
nique, some estimations should be made of the likeli-
hood of source displacement which might occur during
the course of treatment.
In the case of HDR machines with a single source, the
location of the source can be determined by alternative
methods. The simplest of methods is to use a video cam-
era system, a transparent plastic applicator, and a linear
scale.
On a daily basis, a check ruler (such as that available
for the HDR microSelectron) may be used to check the
accuracy of source positioning. The ruler is attached to
the treatment unit through a treatment transfer tube. It
consists of a scale and a marker rod, which is moved by
the source cable as it moves along the ruler. One can
evaluate the motion of the source by checking the posi-
tion of the rod against the programmed position of the
source. However, the technique only indicates the
motion of the end of the marker rod.
Speiser and Hicks [9] have modified a check ruler to
incorporate a diode radiation detector which indicates
source position (Figure 9.7). The diode is a 1 mm2 pho-
todiode placed within a few millimeters of the source
path. Its position corresponds to a fixed distance from
the treatment head. The diode is connected via coaxial
cables to an electrometer. As the source gets near the
diode, the reading on the diode increases. The electro-
meter readings can be correlated to source position with
an accuracy of 0.1 mm. The authors found this accuracy
sufficient to detect differences in length of transfer tubes,
as well as the variation of path lengths with relaxation or
change of curvature of the transfer tube.
As part of the basic equipment package, some manu-
facturers include a 'QA Physics Package.' This comprises
a well chamber and an electrometer for calibrating the
radioactive source, a camera and scale assembly, which
enables the source wire to be imaged against a scale at
specified distances of source travel. One such system is
the VariSource (manufactured by Varian Oncology
Systems) remote afterloading machine. A frame-grabber
captures the images of the calibration device and dis-
plays the position of the source wire on the VariSource
computer monitor (Figure 9.8). The system is conve-
nient to use and takes only 3 min to check and, if neces-
sary, recalibrate the drive positioning system and to
obtain an automatic printout for quality assurance
records; consequently, this can be done prior to each use
of the machine.
A well-type ionization chamber can also be used for
checking the source position at the end of a transfer
cable. By means of a specially designed quality assurance
insert which fits into the well of the ionization chamber,
it is possible to test not only source positioning but also
the timer and its consistency. Quality assurance inserts
for use with the Standard Imaging well chamber have

Figure 9.7 Top and side views of modified check ruler as described by Speiser and Hicks [9].
been described by Jones [10] and De Werd et al. [11].
One of these inserts for use with an HDR microSelectron
is shown in Figure 9.9. The insert consists of a lead cylin-
der 30 mm in diameter, 115 mm long, housed in a 2-mm
thick brass shield with a 100-mm deep central cavity of
2-mm diameter, which takes a bronchus source catheter.
The insert has a brass flange through which it is fixed by
a screw to the top face of the ion chamber. Four 2-mm
diameter holes pass radially through the 15-mm thick
lead cylinder: the apertures are in a plane at 72 mm from
the base of the insert and intersect centrally at right
angles to each other. The collimator insert modifies the
response of the chamber as the radiation source is
moved along its longitudinal axis. With the collimator in
place, the response of the chamber increases as the
Figure 9.8 Frame-grabber image of VariSource source wire
against a scale at 130 cm travel. (Courtesy of Varian Oncology
Systems.)
Tests relating to treatment precision 141
source comes in line with the four radial apertures. The
variation in response over the first 20 mm from the bot-
tom of the catheter cavity of the insert (positions 1 to 6)
is within 0.4% and one of these positions may be used
for source calibration measurements. When the source is
at position 1, the source center is 6.5 mm from the tip of
the catheter: each dwell position corresponds to an
increment of 2.5 mm. The position of the source can be
programmed to be in the plane of the apertures and the
resultant data may then be used as reference information
against which subsequent measurements of source posi-
tion can be checked.
This is achieved by a combination of altering the
length of the source cable and/or entering the dwell posi-
tion of the source. The cable length can be altered in
1 mm increments and the source positions can be
changed in steps of either 2.5 mm or 5 mm: by combin-
ing both of these, it is possible to alter the source posi-
tion in increments of 0.5 mm. This procedure may be
used to move the source step by step across the plane of
the aperture. The resultant profile enables the position of
the aperture to be determined in relation to the pro-
grammed position of the source. The method is useful
for measuring any changes that might occur when
source cables are replaced. Typical profiles are shown in
Figure 9.10: in practice, it is not necessary to record a
complete profile because the location of the maximum
chamber response can be determined satisfactorily by
means of four or five measurements made at 0.5 mm
intervals around the region of the aperture. The method
is very convenient and more precise than autoradiogra-
phy unless densitometric measurements are used: the
method is able to determine a source positional change
of less than 0.5 mm. Comparative measurements using
autoradiography and the well-type chamber insert have
shown good correlation.
142 Quality assurance in high dose-rate afterloading
Figure 9.9 shows a PMMA extension scale fixed to the
collimator insert. This is designed to facilitate with-
drawal of the source catheter by a measured distance so
that alternative source positions can be programmed
and checked. For example, if the aperture position is
found to be at a programmed distance of 54 mm corre-
sponding to a source position of 18 and a cable length of
919 mm, then by withdrawing the catheter 15 mm the
new aperture position should be at a source position of
12 for the same cable length.
De Werd et al. [11] have described an alternative qual-
ity assurance insert which is made of lead and has two
acrylic spacers, one of which is 4 mm thick and the other
1 mm thick. The device has been used for checking posi-
tional accuracy and also for checking dwell times and
source activity. As the source is moved across the 1 mm
spacer, the response of the ionization chamber results in
a profile similar to that shown in Figure 9.10, with a full
width at half maximum of 13 mm 0.5 mm, with the
peak also falling within 0.5 mm of the same location.
The authors conclude that the device is very easy to use
and gives more accurate results than conventional radi-
ographic film, and the measurement of dwell times is
more precise than measurements made using a stop-
watch. The positional accuracy was found to be 1 mm
;
igure 9.9 (a) The Standard
waging HDR 1000 re-entrant
?A7 chamber with collimator
nsert. (b) The collimator insert
hawing one of the four
'pertures.
and the relative dwell time accuracy was 5% for a 10 s
dwell time.
9.5.2 Positional reproducibility in
interstitial brachytherapy
Interstitial and intraluminal brachytherapy with HDR
iridium-192 and PDR iridium-192 afterloading
machines raise special problems in quality assurance.
Each catheter or needle implanted in the patient is
attached to the treatment machines via a transfer tube.
The precise position of the radioactive source is deter-
mined by the programmed length and the dwell position
selected for a particular treatment. The source position
within the needle or catheter is dependent upon the pre-
cise length of the needle and also upon the length of the
transfer tube. In practice, the lengths of individual nee-
dles vary, as also do the lengths of individual transfer
tubes. Tube-to-tube variation in length should be no
more than 0.5 mm and similar variations can occur in
the length of individual needles. Various methods of
checking the length of the needle and tube have been
described. Williamson [12] has dealt comprehensively
with some of these issues and has described three
 Quality assurance documentation 143

Figure 9.10 Typical

profiles obtained by moving
the HDR microSelectmn
source along the chamber
axis in front of the insert
apertures. Top profile:
345 GBq source; lower
profile: 145 GBq source.

methods for correlating treatment lengths and dwell measuring the distance from the applicator orifice to
position number. These are: the 995 mm seed center of a calibrated radiographic
marker (using graph paper and a transparent
1. The use of a source-like cable with tungsten seed
applicator), the actual transfer tube length may be
markers spaced at 1 mm intervals which is inserted
calculated. Tube-to-tube variations in length should
into the treatment tube applicator and then
be no larger than 0.5 mm.
radiographed. The marker centers function as
3. The applicator tip localization method: this method
individual catheter rulers with 1 cm gradations,
uses the closed end of each applicator to localize the
from which the programmed treatment length can
dummy marker relative to the index frame of
be read. This method has the advantage of
reference in combination with the radiographic
convenience of use, but multiple markers are
marker sounding of each transfer tube applicator
required so that individual markers can be inserted
combination. Simulation markers are fully inserted
into each of the implanted needles (or catheters).
into each implanted catheter and radiographs are
The basic check consists of comparing the marker
obtained: the appropriate transfer tubes are attached
positions of a fully inserted simulation marker with
to the applicators and each transfer-tube-applicator
the position of the actual radioactive source when
assembly is 'sounded' using a calibrated marker to
programmed to dwell at positions corresponding to
obtain the offset variation for each assembly.
the marker seeds. In practice, one marker is used as a
calibration standard against which other markers are In summary, the objectives of any quality assurance
measured: this may be achieved by inserting markers program are to ensure that the length of individual nee-
sequentially into a transparent catheter tube and dles or catheters that are used and also the length of indi-
marking the seed positions on graph paper. The vidual transfer tubes are known. Williamson [12] found,
calibration of the marker consists of superimposing over a 12-month period, the PDR flexible-catheter treat-
a transmission radiograph of the marker upon the ment tube length to be constant within 0.5 mm on
autoradiograph of a source itself. average. Over a 3-year period, semi-flexible HDR trans-
2. The applicator orifice method: this method is based fer tubes maintained their length within 1 mm, with
on the use of the insertion of a dummy marker tube-to-tube length variations within the 0.5 mm range.
relative to the applicator orifice which is constrained
by a small cap on the end of its proximal end. The
simulation marker acts as a 'sound' which is used to
measure the inner length of the needle or catheter,
9.6 QUALITY ASSURANCE DOCUMENTATION
from which the dwell position of the source can be
calculated. The method assumes that all transfer
tubes have the same length and that their average In practice, each user will develop his or her own quality
length is consistent with the cap to distal-node seed assurance program, but certain minimum requirements
position of the marker set. By independently are common to all.
144 Quality assurance in high dose-rate afterloading
The calibration procedure should include details of
the method used to determine the air kerma strength of
the source. It is required that calibrations be performed
following installation of a new source before patient
treatment is resumed and they are recommended at
monthly intervals thereafter.
The following list of quality control checks based on
NRC recommendations might be considered to be a
minimum requirement:
The afterloading device should be tested to determine
the accuracy of source positioning. Source
positioning within the catheter guide tube should be
accurate to within 1 mm of the programmed
position. A record of the test should be maintained
and should include the date of the test, the
programmed position, the actual position of the
source following activation of the device, and the
initials of the individual who performed the test.
Ideally, the record should include the radiograph or
autoradiograph used to determine the source
position.
Timer accuracy and linearity.
For devices that use a cable and/or wire to transport
the source, measurement of the source guide tube to
confirm the length to 1 mm of accuracy.
The back-up battery for the remote afterloading
device should be tested, in accordance with the
manufacturer's instruction, to verify emergency
source retraction capability upon power failure. The
minimum requirement for this test should consist of a
function test with the mains power disconnected.
A record of these tests should be maintained for a
period of at least 3 years and should include the date
of the check, the results of the check, and the initials
of the individual who performed the check.
In practice, it is useful to document quality assurance
information in the form of a monthly quality assurance
chart (Figure 9.11).
The NRC also recommends that at the beginning of
each day of use the following checks should be performed
in accordance with the manufacturers' instructions:
The permanent radiation monitor fitted within the
treatment room should be checked for proper
operation.
The television monitor and intercom should be
checked to verify proper operation.
The treatment console operational functions should
be checked, testing all indicator lamps, other status
and operational displays and, if appropriate, check the
printer and data which it displays.
Source status indicators ('safe' or 'unsafe'), including
those which are integral to the afterloading device as
well as any additional indicators installed at the
treatment console or room entrance, should be
checked.
Electrical interlocks installed at the room entrance
should be tested for proper operation. Records of
these tests should be maintained for a period of 3
years.
The mechanical integrity of all applicators, source
guide tubes, and connectors to be used should be
determined by visual inspection and/or radiographs.
The presence and correct placement of any internal
shields and other essential internal components
should be determined.
The records of all the checks specified above should be
maintained for a period of 3 years and should include
the date of the check, the results of the check, and the
initials of the individual who has performed the check.
One important aspect of documentation relating to
the use of HDR equipment is that related to the emer-
gency procedures that need to be implemented should
the source fail to return to its safe position. At a mini-
mum, these procedures should address the following:
The procedures should specify the circumstances in
which they are to be implemented, such as any
circumstances under which the source cannot be
retracted to a fully shielded position in the
afterloading device.
The action specified for emergency source removal
should give primary consideration to minimizing
radiation exposure to the patient and healthcare
personnel while maximizing safety to the patient.
The procedures should specify step-by-step actions
for equipment failure and specify the individual(s)
responsible for implementing the actions. The
procedure should clearly specify which steps are to be
taken in different scenarios (for example, source
decoupling versus a jammed source). The procedure
should specify situations in which surgical
intervention maybe necessary and the steps which
must be taken in the event that surgical intervention is
required.
In the event of an emergency, the procedures should
specify the names of authorized personnel who
should be informed, including the Radiation Safety
Officer and/or the Radiation Protection Adviser.
There should be requirements to restrict and 'post' the
treatment area with appropriate signs to minimize the
risk of inadvertent exposure of personnel not directly
involved in the emergency source recovery.
It is a requirement that the location of emergency
source recovery equipment should be specified and
the equipment that might be necessary for various
equipment failures should be readily available, and
their use described in the emergency procedure. At a
minimum, emergency equipment should include
shielded storage containers, remote handling tools,
and, if appropriate, supplies necessary to remove
applicators or sources from the patient, including
scissors and cable cutters.

REFERENCES
1. ICRP Publication 44 (1985). Protection of the patient in
radiation therapy. Ann. ICRP, 15,2.
2. Quality Assurance in Radiotherapy (1988) Institute of
Radiation Hygiene and World Health Organisation.
Geneva, WHO.
3. AAPM Report No. 13 (1984) Physical Aspects of Quality
Assurance in Radiation Therapy. American Institute of
Physics for the AAPM. Chapter 6.
4. Ezzel,G.A. (1991) Acceptance testing and quality
assurance for high dose rate afterloading systems.
Activity, 5(4), 2-6. Veenendaal, The Netherlands,
Nucletron BV.
References 145
Figure 9.11 A monthly quality
assurance HDR iridium-192 chart, Royal
Marsden NHS Trust, London, UK. The
Gafchromic autoradiograph is
photocopied onto the chart as a record of
positional accuracy of the source.
Jones, C.H. (1991) Quality assurance using the Selectron-
LDR/MDRand microSelectron-HDR./4rf/V/Yy, 5(4), 12-16.
Veenendaal, The Netherlands, Nucletron BV.
6. I EC 601 -2-17,1989 (1990) Specifications for Remote-
controlled Automatically Driven Gamma-ray Afterloading
Equipment. London, British Standards Institute.
7. The Ionising Radiation Regulations (1999) London,
HMSO.
8. Chenery, S.G.A., Pla, M. and Podgorsak, E.B. (1985)
Physical characteristics of the Selectron high dose rate
intracavitary afterloader. Br.J. Radiol., 58,735-740.
9. Speiser, B.L. and Hicks, J.A. (1994) Safety programmes for
remote afterloading brachytherapy: high dose rate and
pulsed low dose rate. In Brachytherapy: from Radium to
Optimisation, ed. R.F. Mould, J.J. Batterman,
146 Quality assurance in high dose-rate afterloading
A.A. Martinez and B.L. Speiser. Veenendaal.The
Netherlands, Nucletron International B.V., 270-84.
10. Jones, C.H. (1995) HDR microSelectron quality-assurance
studies using a well-type ion chamber. Phys. Med. Biol.,
40,95-101.
11. De Werd, LA, Jursimic, P., Kitchen, R. and Thomadson,
B.R. (1995) Quality assurance tool for high dose rate
brachytherapy. Med. Phys., 22(4), 435-40.
12. Williamson, J.F. (1995) Simulation and source localisation
procedures for pulsed and high dose rate brachytherapy.
Activity Report, 7,57-65. Veenendaal, The Netherlands,
Nucletron-Oldelft.

Radiation protection in brachytherapy
A.M.BIDMEAD
10.1 INTRODUCTION
A fundamental requirement of radiation protection
when brachytherapy is given is that the patient receiving
treatment, the hospital staff, and the general public are
not irradiated unnecessarily as a result of the brachyther-
apy. Protective measures should therefore be used to keep
the dose levels as low as reasonably achievable (ALARA).
Dose limits and recommendations are detailed in the
Recommendations of the International Commission on
Radiological Protection (ICRP), 1977 and 1978, and
the International Commission on Radiation Units
and Measurements (ICRU) and Institute of Physical
Scientists in Medicine (IPSM) [1-5]. An extract from
these recommendations, indicating the current and the
previous dose limits (Table 10.1) is shown in reference 6.
Each hospital in which brachytherapy is carried out is
required to have a comprehensive radiation protection
Table 10.1 Dose limits
Effective dose 20 mSv per year averaged
over defined periods of
5 years3
Annual equivalent 150mSv
dose in the lens of
the eye
a
With the further provision that the effective dose should not exceed 50 mSv in any single year.
b
In special circumstances, a higher value of effective dose could be allowed in a single year, provided that the average over 5 years does not exceed
1 mSv per year.
10
policy, based on the appropriate national or state regula-
tions. In the UK, these are the Ionising Radiations
Regulations (IRR) 1999 [7]. These regulations were
issued early in 2000 and some aspects of their detailed
implementation still need clarification, particularly
those aspects relating to the protection of the patient.
The previous regulations were IRR 1985 [8], together
with the POPUMET Regulations [9], Guidance Notes
[10] and approved codes of practice [11,12]. IRR 1985
dealt mainly with the safety of employees and the public
at large, whereas the new regulations include issues relat-
ing to the protection of patients, previously included in
POPUMET. The hospital policy should describe the
responsibilities of the hospital, departmental heads,
radiation protection adviser and supervisors, occupa-
tional employment medical advisers, and other staff
involved with the use of ionizing radiation.
The regulations require all staff concerned with the use
of radiation to have adequate training. Radiotherapists
1 mSv in a yearb 50 mSv 5 mSv
15mSv 150mSv 15 mSv
148 Radiation protection in brachytherapy
must have an Administration of Radioactive Substances
Advisory Committee (ARSAC) license to practice
brachytherapy, as described in the MARS regulations
[ 13]. Previously, outside employees - that is, employees of
another organization or company temporarily working
in the hospital (e.g., service engineers etc.) -were covered
by the Ionising Radiation (Outside Workers) Regulations
1993 [ 14], but this aspect is now included in the new reg-
ulations. The issues relating to pregnant staff are also cov-
ered in the new regulations. One new aspect in IRR 1999
is the specific requirement for formal risk assessments to
be performed and documented. Although this was prob-
ably done previously in a less formal manner, it is now
specifically required.
There are two main protection issues to address:
The design of protected rooms, for the protection of
the patient and staff during treatment and for the
protection of staff preparing and handling sources.
The tracking and recording of the whole treatment
process, starting with the progress of the source from
its protected environment, through to the treatment
delivery, continuing until the source is returned for
storage or disposal. This ensures a source can be
traced at every stage [15,16].
Radiation protection surveys of the designated rooms
and preparation areas, and monitoring of staff radiation
doses provide data on the effectiveness of the radiation
protection.
Protection of the patient includes the prevention of
gross treatment delivery errors, whether they are as a
result of device malfunction or of human error in the
design, evaluation, and execution of the brachytherapy
procedure. The development and maintenance of a good
quality assurance program (preferably to a recognized,
auditable standard) are a major factor in effective radia-
tion protection in brachytherapy.
10.2 QUALITY ASSURANCE ISSUES IN
BRACHYTHERAPY PROTECTION
10.2.1 Source identification and
description
Sources should be kept safely, with manufacturers' data
sheets or test reports appended to local documentation,
so that in the event of loss or damage as much informa-
tion as possible, relevant to each particular source, is
available [ 17]. The physical and chemical composition of
the radioactive source should be noted, including the
presence of any radioactive impurities.
Encapsulated sources with a long half-life should be
clearly identifiable and distinguishable from each other.
A closed circuit television (CCTV) camera with a close-
up lens is useful for this purpose.
The following information should be recorded:
1. the radionuclide, energy, emissions due to decay
2. the source encapsulation
3. the activity on a given date
4. the serial number or other distinguishing mark
5. the date of receipt
6. the normal location of the source
7. the recommended working life of the source (when
appropriate)
8. the date and manner of disposal (when appropriate).
Some sources (e.g., iridium-192) require a storage
period after initial production to allow the decay of
short-lived impurities: the user should ensure that such
procedures are followed. Sources (such as cesium needles
and tubes) should be assessed to determine whether they
are safe to use or should be replaced.
10.2.2 Source integrity checks: leakage
and contamination tests
Before sources are used clinically, and subsequently at
regular intervals, checks should be made to ensure that
they are not leaking and that the distribution of radioac-
tivity within the source is as expected and acceptable for
clinical use, and that this distribution does not change
with the course of time.
Long-lived brachytherapy sources are doubly encap-
sulated for mechanical strength and to prevent leakage of
radioactive material in the event of source damage.
Sources obtained from manufacturers are issued with
leakage test certificates, which describe the tests that have
been carried out: these include immersion tests at differ-
ent temperatures and wipe tests [18]. For cesium sources
manufactured in the UK, the safety level is taken to be
200 Bq (5 nCi). It should not be assumed that new
sources are necessarily free from surface contamination.
Long-lived sources in clinical use should be leak tested at
least every 2 years; annual tests should be made on
sources that have been in use for several years.
New, encapsulated sources should be wiped with a
swab or tissue moistened with water or ethanol and mea-
sured using a Geiger-Muller or scintillation counter
capable of detecting 200 Bq (5 nCi). The method used
should keep radiation exposure to a minimum and it
should swab the outside of the source without causing
abrasions to the source capsule.
When using iridium (iridium-192) and gold (gold-
198) wires and seeds, the principal hazards are those
caused by scoring of the surface and particulate frag-
mentation when the wire is manipulated or cut without
appropriate equipment. Handling tools and cutting
equipment should be monitored and decontaminated
regularly and cutting should only take place under con-
trolled conditions in protected areas.
In the case of beta-ray sources such as strontium-90/

yttrium-90 ophthalmic applicators, special care must
be taken because the surface of the applicator is particu-
larly delicate. Leak tests must be performed at least
annually.
10*23 Source strength measurements
Before being used clinically, sources should be calibrated
by the user. A useful measurement device is a re-entrant
ionization chamber (i.e., an isotope calibrator). In the
case of high-activity sources, accurate calibration can
also be achieved with an ion chamber. The calibration of
both these instruments should be traceable to a national
standards laboratory.
To achieve the required accuracy in the prescribed
dose, source calibration accuracy should be better than
5% of the true strength. Most manufacturers are
unable to provide calibrations of this accuracy and the
user must carry out independent measurements, but ref-
erence should always be made to the manufacturer's cal-
ibration certificate (agreement within 10%).
10*2.4 Autoradiography and radiography
These techniques can be used together or separately to
provide information about the distribution of radioac-
tive material within the container and positional infor-
mation about individual sealed sources in radioactive
source trains.
Autoradiography is useful for checking the uniformity
of wire sources and ribbons or radioactive seeds and pel-
lets. When radioactive wires are cut, it provides a means
of recording particulate contamination. Needle sources
might have two or more cells: the source activity and dis-
tribution in each cell can be checked with this method.
Autoradiography and radiography should be used to
check the configuration of single and multiple sources in
preloaded source trains. In the case of afterloading
machines whose source configuration can be pro-
grammed, autoradiographic checks should be carried
out at commissioning and after machine service or
source or catheter replacement to ascertain the precise
location of each source and the integrity of software and
machine function.
Applicators into which sources are loaded, either by
hand or automatically by machine, should be checked by
autoradiography before being put into clinical use, and
thereafter annually. Moulded wax is useful for position-
ing and supporting the applicators. Lead-foil markers
embedded into the surface of the wax can be used to pro-
vide identification marks and scales which are imaged on
film by electron emission. The method allows precise
comparisons to be made of different applicators and
provides a radiographic record of the location of the
radioactive sources inside loaded applicators. Radio-
graphy of the same applicators containing dummy
Source handling and associated protection issues 149
pellets (which are used to identify active source positions
for treatment planning) provides information to cross-
reference active sources and dummy source positions.
103 SOURCE HANDLING AND ASSOCIATED
PROTECTION ISSUES
The steps required for the safe use of radioactive sources
from storage, preparation, transportation, insertion,
removal, and cleaning are discussed in the following
paragraphs
103*1 Storage of sealed sources
Clean sources should be kept in a locked, radiation-
shielded safe designed to allow the safe visualization of
sources and identification marks: the safe should be
compartmentalized to permit easy and fast access for
removing individual sources and for carrying out stock
checks. The safe should be situated close to the source
preparation bench for easy access. The storage safe or
container should be swab tested annually and any
radioactive contamination found should be removed
and its source of origin identified.
A detailed inventory of the number, type, and activity
of sources in the store must be kept in addition to details
of sources being used in patients. When there is a large
number of long-lived sources, it is helpful to use a dis-
play board or computer spreadsheet to track and record
the whereabouts of each individual source.
An audit should be carried out at regular intervals for
every source in storage or in use. In the UK, an indepen-
dent audit should be made annually by a senior person
nominated by the employer.
Lead carrying pots should be monitored after transfer
of sources to ensure that all sources have been removed.
To reduce the chances of source loss, it is useful to have
gamma-ray alarms at the exits to areas where sealed
sources are routinely used.
103.2 Preparation of sources and
applicators for clinical use
Radioactive sources should not be issued or used clini-
cally without a written request from an authorized per-
son: transfer of the source(s) should be recorded, and
responsibility for the source taken by different signato-
ries during each stage of the source transfer, implant, and
source return.
Manipulation of sources should be with long, low-
pressure forceps to avoid mechanical damage; the for-
ceps should be monitored and cleaned after use. Wire
sources should be cut only with an appropriately
designed cutter. Wire sources with cut ends should be
150 Radiation protection in brachytherapy

sealed in plastic tubing before being inserted into body

tissues. The tools used to prepare wire sources (cutters
etc.) should be labelled and used only for this purpose,
checked for contamination at least twice a year, and kept
sharp. All handling must be carried out behind protec-
tive barriers which reduce the radiation to the abdomen
and chest. A protected observation screen is also useful
to reduce the dose to the head and eyes. The speed and
skill of the operator are also important. It is good prac-
tice to limit the number of sources out of the protected
storage area at any one time.
When necessary, sources should be sterilized before
clinical use. The efficacy of the process must be checked.
The source manufacturer should be consulted about the
effect of sterilization on source integrity: the sterilization
process must not be detrimental to the containment of
the radioactive source. Sources such as cesium needles
and tubes should not be exposed to temperatures above
180C. Iridium-192 is baked 'dry' at 150C for 1 hour.
Some brachytherapy techniques make use of empty
applicators, needles, or catheters into which the sources
are after-loaded. These devices should be checked before
and after use to ensure that they are mechanically sound
and free of contamination.
Figure 10.2 Long-handled carrying pot.

1033 Transportation of sources

Sources are carried from the preparation bench to the
patient in a specially designed lead pot. For iridium-192
wire, preloaded in plastic tubes, the pot is designed to be
sufficiently protective whilst not being too heavy to carry
(Figure 10.1). Alternatively, iridium hairpins and cesium
sources can be transported in a long-handled, lead-lined
pot which uses the principles of distance in addition to
protective material to provide a reduction in radiation
dose (Figure 10.2). Associated documentation accompa-
nies the sources.
10.3.4 Insertion of sources into patients
Mobile protective lead shielding barriers are used wher-
ever practicable around the patient's bed. Optimal thick-
ness is 2-2.5 cm lead, which reduces the dose recorded
on film monitors worn at waist level to 50% of the dose
recorded when worn on the chest. Faulkner et al. [19]
recommend wearing monitors at chest level when lead
shields are used, but at abdominal level when remote
after-loading systems are universally used. Using long-

Figure 10.1 Iridium wire-carrying pot.


handled forceps, the physicist and radiotherapist load
the active sources into the patient as quickly as possible,
fixing each source in place as it is positioned. The func-
tion of the radiation detector in the treatment room is
checked and warning notices posted outside the pro-
tected room for the duration of treatment (in addition to
illuminated signs warning of radiation dose in con-
trolled areas). A lead pot and long-handled forceps are
left in the room with the patient in case of emergencies.
If the patient is moved at any time from the protected
room (such as for X-ray), a radiation warning notice
should be prominently displayed on the trolley or chair
in which they are transported.
The use of small sealed sources, such as iodine-125
seeds, has great protection advantages (provided that the
sources are not lost), as shown by Hilaris et al. [20,21].
Exposures of the order of 2 |LlSv h"1 per 37 MBq at 0.75 m
from a patient with a prostate implant have been mea-
sured by Liu and Edwards [22]. The greater protection
hazard occurs if all sources cannot be accounted for. It is
good policy to X-ray patients as soon as possible after
implantation and to keep good account of the total
number of sources used.
103.5 Treatment delivery
The time that the sources were inserted into the patient
and the proposed removal time (dependent on dosime-
try calculations)) are recorded. The nurse in charge of
the patient accepts responsibility for the custody of the
radioactive sources whilst they are in the patient and
ward by signing the appropriate paperwork. The time
that the nurse may spend with the patient (daily nursing
time) is calculated from Table 10.2 (used for iridium
implants) and is dependent on the total activity
implanted. Permissible times, indicated by radiation
warning notices, are intended as a guide to nursing staff.
Nursing procedures can safely be carried out, but unnec-
essary time must not be spent close to the patient while
the warning notice is displayed.
The times given in Table 10.2 are such that a nurse
remaining at a distance of 50 cm from the patient for the
Table 10.2 Times for different total activities of iridium
administered
0.3-0.6 GBq (300-600 MBq) 1h
0.6-1.3 GBq (600-1300 MBq) 30min
1.3-2.5 GBq (1300-2500 MBq) 15min
2.5-3.8 GBq 10min
3.8-6.5 GBq 5min
6.5-13 GBq 3 min
13-20 GBq 1 min
In these cases the time to be indicated remains the same for each day
the radioactive sources are in position.
Source handling and associated protection issues 151
time indicated each day would, after 5 consecutive days,
have received a dose equal to his or her average weekly
dose limit.
The nurse in charge of the ward is responsible for
ensuring that the time on the warning notice is set cor-
rectly each day in accordance with Table 10.2 and for
removing the notice on the day indicated.
While the brachytherapy treatment is taking place, the
protected room becomes a controlled area and staff enter
under local rules only. Emergency procedures (e.g.,
unplanned removal of source, patient bleed) are docu-
mented in the local rules and are dependent on the site
and activity of implant. Visitors are discouraged, but if
absolutely necessary are allowed to spend no more than
the daily 'nursing time' with the patient.
103*6 Removal of sources from patients
When sources have to be removed from a patient, either
at the end of treatment or, occasionally, if a source has
been inadvertently displaced, they should be removed
carefully to avoid patient trauma and source damage.
Sources should be placed in a lockable, shielded con-
tainer lined with a plastic pot containing bactericidal
fluid. When removing iridium wire sources contained in
plastic tubes, great care must be taken not to cut the wire
when removing the sources. The patient must be
checked with a Geiger-Miiller monitor after removal of
sources from the treatment room to confirm that all
radioactivity has been removed from the patient.
The sources should be returned to the laboratory/
store as soon as possible after removal from the patient,
where they should be counted, checked for damage, and
stock records completed. Responsibility for the sources is
transferred from the ward nurse to the person who
transfers the sources and then to the source curator. Only
after all sources have been accounted for should the
patient be allowed to leave hospital.
103*7 Source and applicator cleaning
It is necessary to clean sources that have come into con-
tact with body tissues before they can be stored and/or
re-used. Immersion in bactericidal fluid on removal
from the patient prevents biologically active material
reaching the laboratory store. Source manufacturers
should advise about cleaning procedures: damage to
source capsules can occur as a result of chemical attack if
inappropriate cleaning agents are used.
Wire sources that are to be re-used should be
inspected for damage and re-measured prior to use.
After removal from the patient, applicators (catheters
etc.) should be immersed in bactericidal fluid, cleaned,
and inspected for damage.
Radioactive sources are often inserted into patients in
sealed plastic tubing, plastic applicators or stainless-steel
152 Radiation protection in brachytherapy

tubes. It is good practice to check these source-carrying that treatment times can be reduced (low-medium dose
devices for radioactivity with a Geiger-Miiller monitor rate treatments). Patients can be treated as out-patients
after each use. for fractionated high dose rate treatments (with cesium-
137 and iridium-192).

10.4 AFTERLOADING 10*4.2 Manual afterloading

Radiation exposure can occur during:

10.4.1 General
Afterloading in brachytherapy has achieved the biggest
improvement in radiation protection of staff and,
indeed, also of patients. It has minimized the exposure to
the technical staff involved in the preparation and trans-
portation of sources and it has reduced the dose to med-
ical staff. Staff on the wards who nurse patients have
their doses reduced by the use of automatic afterloading.
During afterloading techniques, applicators or
catheters are inserted into a patient and subsequently
loaded with radioactive sources. This method allows
optimal positioning of the applicators (or catheters)
without any radiation exposure to the clinician or sup-
port staff. Afterloading of the radioactive sources can
either be achieved by hand or remotely with specially
designed equipment that drives one or more of the
sources into the patient. In both situations, afterloading
occurs after the patient has had localizing radiographs
and, in the case of conventional brachytherapy, has
returned to the ward or room where treatment is to be
delivered. Although manual afterloading largely elimi-
nates exposure of the clinician, some staff have still to
work in significant radiation fields in the course of nurs-
ing the patient.
The evolution of afterloading has been linked closely
with the improved availability of flexible wire sources
and cobalt-60, cesium-137, and iridium-192 sources
designed specifically for use in remote afterloading
equipment. Remote afterloading systems have their own
in-built storage safes, the design of which ensures that
the maximum exposure rate on the surface of the safe is
less than 25 |lSv h~'. Table 10.3 summarizes the source
types that are currently available. Remote afterloading
permits the use of sources of higher air kerma rate so
transfer of source from storage and preparation for
use
transfer from preparation bench to patient
irradiation of patient
removal of sources from patient and transfer to
storage
removal from applicators, cleaning, returning to
storage.
10.4.3 Remote afterloading
Radiation exposure can occur when:
machine/door interlocks do not function
sources are changed
sources stick.
Regular quality assurance of the remote afterloading
machine helps to prevent machine malfunction and
unnecessary radiation exposure.
10.5 DESIGN ASPECTS OF BRACHYTHERAPY
TREATMENT ROOMS
10.5.1 Types of treatment room
Brachytherapy covers a range of different forms of treat-
ment and includes surface moulds as well as intracavitary
and interstitial techniques. The duration of treatment can
range from several days as in low dose-rate (LDR) intersti-
tial implants, or to 1-2 h per day (pulse dose rate, PDR) or
to a few minutes as in high dose-rate (HDR) brachyther-
apy. The treatment may be continuous or fractionated. A

Table 10.3 Properties of principal brachytherapy nudities

'"Co 5.27 years 1.17,1.33 309 12 40 206

125,
60 days 0.035 33 0.03 0.1 -
137
Cs 30 years 0.66 78 6.5 21 157
192
lr 74 days 0.3-0.6 113 4-5 15 113
198
Au 2.7 days 0.41 55.5 3 11 135

HVT = half value thickness; TVT = tenth value thickness.


large number of different nuclides are available for clinical
use, some of which have short half-lives and can be
implanted permanently; nuclides may be of low energy
and require little shielding, or of high energy requiring
specially designed rooms with thick concrete walls. The
wide range of techniques used and the large selection of
available nuclides necessarily influence the design of a par-
ticular treatment facility.
In the past, patients have been treated in open wards,
but this should be avoided whenever possible. A specially
designed and protected single room is optimal, but a sin-
gle room with appropriate shielding added or a shared
room with mobile shielding and/or inter-bed shielding
can be used. For HDR treatments where source activities
are 37-370 GBq, the room might be specially designed or
a modified shared radiotherapy treatment room.
Experience has shown that it is advantageous to have
a physics room (it need not be large) nearby with facili-
ties for storage and cleaning of sources, applicators, and
accessories. Ideally, the brachytherapy facility should be
designed according to the types of treatment envisaged.
This section describes factors that affect such a design.
Table 10.3 summarizes the properties of the nuclides fre-
quently used.
10.5*2 The design brief
The details of this brief will depend upon the type of
brachytherapy room being planned. There are various
considerations that are common to most brachytherapy
requirements:
The treatment room should be constructed to allow
implementation of the prescribed treatment with
precision and safety.
The room should have sufficient shielding or be so
isolated that hospital personnel, other patients, and
members of the general public will not receive
incidental radiation exposure in excess of specified
limits. Radiation levels in and around the room
should be measured and calculated and staff working
in the area should be monitored.
The layout of the room should allow patients to be
nursed safely, efficiently, and with as little
inconvenience and discomfort to the patient and staff
as possible, and to allow all the procedures associated
with the medical care of the patient, including any
necessary emergency procedures, to be accomplished.
Particular attention should be paid to the facilities for
removing sources and storing them until they can be
removed to a more permanent store.
The room should be constructed and equipped so
that it can be used for nursing non-brachytherapy
patients.
It is important that the radiation protection adviser or
an experienced radiation physicist is involved in the
Design aspects of brachytherapy treatment rooms 153
design concept at an early stage in the planning process.
It is usual for hospital planning (or estate management)
to be the interface between the consultant architect and
other interested professional groups within the hospital.
The physicist must ensure that the planning team under-
stands the need for a room with adequate radiation pro-
tection and should ensure throughout the planning,
building, installation, and commissioning periods that
the room is constructed and equipped accordingly.
At the design stage, consideration should be given to
the following.
THE INTENDED USE OF THE ROOM
This will be influenced by the current techniques in use,
the number of patients to be treated simultaneously, and
whether or not the facility will also be used by non-
radioactive patients who might have special require-
ments. The total amount of radioactivity and the energy
of photon emissions will determine the radiation shield-
ing requirements. The long-term use of the room should
be considered, especially in relation to techniques that
might require additional shielding. The storage of radio-
active sources, prior to or immediately after removal,
should be considered.
THE LOCATION OF THE ROOM
The room should be reasonably accessible from facilities
such as the operating theatre, X-ray, and computed
tomography (CT). If the room is to be used for inserting
radioactive sources by hand, it should ideally be located
within reach of the source preparation laboratory. The
location of the room must also be considered in relation
to surrounding areas, public corridors, and waiting
areas. Areas immediately adjacent and areas above and
below the proposed site must be surveyed early on in the
planning process to ensure that adequate shielding can
be incorporated.
THE SIZE AND LAYOUT OF THE ROOM
The size of the room will be determined by the available
space, and whether or not en-suite facilities are to be
provided. The detailed requirements will also depend
upon the type of treatments given. In general terms, it
will be necessary to ensure adequate access for patients
on beds and/or trolleys, to provide enough space for
local shielding, such as bed shields, and for inserting and
removing radioactive sources into patients from behind
protective shields. En-suite facilities may be provided so
that patients with implants can be confined to a clearly
defined 'controlled area.' Thought should be given to the
arrangements to be made for contingencies such as med-
ical emergencies that might require the rapid removal of
radiation sources.
154 Radiation protection in brachytherapy

10.53 Radiation protection requirements
It will be necessary to estimate the likely radiation levels
and the associated hazards to occupationally exposed
staff and also members of the general public. ICRP 60
(1990) [23] specifies that the dose limits should be:
occupationally exposed staff: 20 mSv per year
general public: 1 mSv per year
and the dose limits in the UK regulations (IRR 1999) are
based on these.
In situations that require an estimate of the dose likely
to be received or where room, wall, or door protection
calculations are undertaken, occupancy factors can be
used for various areas in the vicinity of the brachyther-
apy room. Occupancy factors indicated in NCRP Report
49 [24] are as follows:
T= 1 work areas such as laboratories and occupied
space in adjacent buildings
T = 1/4 doors, staff rooms, lifts, parking areas
T= 1/16 waiting rooms, toilets, staircases.
It is sometimes policy to work to lower levels than
those specified and, apart from local reasons, considera-
tion should always be given to the possibilities that:
be attenuated by the patient's body, but, except for low-
energy emitting sources such as iodine-125, this attenu-
ation is only 10-20%. Table 10.4 shows the thickness of
concrete required to reduce the dose rate to 7.5 (iSv Ir1
and 2.5 jiSv h'1 at 3 m from various activity sources
allowing for 10% absorption in the patient.
Room doors need to be lead lined, with a maximum
thickness of lead of about 6 mm (any more is too heavy).
The position of the patient's bed should not be in a
direct line with the door, so that door protection can be
kept within acceptable limits, as can the exposure of
nursing staff as they approach the patient.
Access to the room should be observable from the nurs-
ing station, and remote viewing of the patient by CCTV is
useful. The use of a two-way intercom also helps to reduce
the time spent by the nurse in the radiation environment.
If more than one protected room is required, rooms can
be built adjacent to each other so that the total shielding
requirements can be optimized. This arrangement, how-
ever, is not always advantageous when nursing expertise
for certain types of patients (gynecological, head and
neck) is highly specialized and focused on specific wards.
10.5.4 Additional requirements

current radiation exposure limits will be reduced;
brachytherapy techniques and technology might
change;
the use of rooms above and below and adjacent to the
facility might change.
It is therefore appropriate, whenever possible, to reduce
the dose rate outside the room to 2.5 (iSv h~' (the maxi-
mum dose rate allowable for the general public). Within
the room, the dose rates will be such that 'it is necessary
for any person who enters or works in the area to follow
special procedures designed to restrict significant expo-
sure to ionising radiation' (IRR 1999 [7]), and therefore
the room will be designated as a 'controlled area' under
those regulations. Brachytherapy sources are not colli-
mated and shielding calculations should take into
account the primary photon energy of the emission.
Radiation emanating from sources within a patient will
There are certain requirements that are common to all
brachytherapy patient facilities. These are:
A definitive area around the patient (where special
procedures are required under IRR 1999 [7]) must be
designated as a controlled area. A supervised area,
where dose rates need to be kept under review, might
in some circumstances be identified. Staff working
within the controlled area should be monitored.
Members of the general public who might wish to
visit a brachytherapy patient undergoing treatment
may do so provided they comply with the IRR 1999
regulations. Visiting in general is discouraged.
The dose rate in the area of the bedside should be
displayed visually. A beta/gamma mini-monitor type
of indicator is suitable for this purpose.
A portable dose rate Geiger-Muller monitor should
be available near to, but outside, the treatment area so

Table 10.4 Thickness of concrete (cm) required to reduce the dose rate to the specified values at 3m from various sources, assuming
10% attenuation in the patient

37
Implants Cs 1.85 50 8 19
37
Gynecological intracavitary Cs 7.4 200 19 28
37
MDRafterloading Cs 22.2 600 28 36
fl
HDRafterloading Co 185 5Ci 68 77
92
Implants lr 1.85 50 10 18
92
PDRafterloading Ir 37 1Ci 31 36
92
HDRafterloading Ir 370 10 Ci 44 51
 Design aspects of brachytherapy treatment rooms 155

that bed linen etc. can be checked for unsuspected
sources and also the patient can be checked to ensure
that all sources have been removed.
Radiation warning notices should be posted.
Suitable source container(s) and handling tools
should be available.
Preferably, there should be CCTV monitoring and a
two-way intercom to the patient.
out in Figure 10.4 shows that the afterloading machine is
housed in a separate, small, lockable room. The source
transfer tubes pass through the wall of each treatment
room into the treatment catheters. The air compressor is
located in a cupboard away from the patient area to min-
imize disturbance. The dose rates shown correspond to
15 GBq of cesium-137 in each patient. The concrete wall
thickness and lead door thicknesses are as shown.

10.5*5 Typical treatment rooms

A) FOR GYNECOLOGICAL INTRACAVITARY

TREATMENTS

Figure 10.3 shows a typical layout for a gynecological

intracavitary patient. The walls are 30 cm concrete,
which reduces the primary radiation from a cesium-137
source by the equivalent of two tenth value thicknesses.
Mobile lead bed shields are useful for reducing dose
rates. A typical shield might be of 2.5 cm thickness,
weigh 100-200 kg, and have a shielding area of 100 x 600
cm. Usually, shields are on lockable wheels. Inter-bed
shielding can be used to reduce the dose rate between
patients. This is usually 1 cm or 1.5 cm thick, but
requires steel frame supports. Under-bed shielding is
also feasible if the dose rate in the area immediately
below the patient is too high.

B) LOW DOSE-RATE/MEDIUM DOSE-RATE REMOTE

AFTERLOADING

In the case of remote afterloading, the treatment room

door can be interlocked with the machine. The room lay- Figure 10.4 Two-bed Selectmn-LDR suite.

l37 60
Cs Co Ratio
A 1. 9 5.6 2.9
B 2.7 7.8 2.8
C 1. 3 3.8 2.9
D 1. 3 1. 5 1. 5
E I.I 1. 7 1. 5
F 1. 4 2.2 1. 6
G I.O 2.0 2. 1
H 24.0 45.0 1. 8
I 1 9.0 33.0 1. 7
J 39.0 78.0 2.0
K 1 90.0 780.0 4.0

Figure 10.3 Dose rates at various positions around an afterloading room (in mv h-1 for cesium-137 and cobalt-60 sources of AKR
WOO uGy /?"' at 7 m).
156 Radiation protection in brachytherapy

Position

A 376 1 867 28! I

B 376 1 502 3004
C 94 5I5 3I76
D 94 494 1 502
E 32 75 1 70
F 19 36 79
G 9 19 36
H 2 - 8
I I - 2
J <0.5 <0.5 <0.5

Figure 10.5 Dose rates in u5v h ' at specific points for a 370 GBq iridium-192 source in a tissue-equivalent phantom placed in
positions 1, 2, and 3.

C) HIGH DOSE-RATE REMOTE AFTERLOADING Medical Examination or Treatment) Regulations 1988,

HDR treatment rooms require concrete walls of thick-
ness 50-80 cm, depending upon the size of the room and
the nuclide being used (see Table 10.4). Figure 10.5
shows a purpose-built radiotherapy theatre, indicating
dose rates in |J,Sv h'1 at specific points for a 370 GBq
iridium-192 source in a tissue equivalent phantom
placed at positions 1, 2, and 3.
Useful general references for brachytherapy protec-
tion are to be found in reference 25.
REFERENCES
1. ICRP (1977) Recommendations of the International
Commission on Radiological Protection. Ann. ICRP, 1(3).
2. ICRP (1978) Statement from the 1978 Stockholm meeting
of the International Commission on Radiological
Protection. Ann. ICRP, 2(1).
3. National Radiation Protection Board (1993) Radiation
Exposure of the UK Population -1993 Review. NRPB R263.
London, HMSO.
4. ICRU (1993) Quantities and Units in Radiation Protection
Dosimetry, ICRU Report 51. Bethesda, Maryland, ICRU
Publications Office.
5. IPSM (1986) Radiation Protection in Radiotherapy, IPSM
Report 46. York, IPSM Publications.
6. Council Directive 97/43/Euratom, 30 June 1997.
7. Ionising Radiations Regulations 1999 Statutory
Instrument 1999 No. 3232. London, HMSO.
8. Ionising Radiations Regulations 1985 Statutory
Instrument 1985 No. 1333. London, HMSO.
9. Ionising Radiations (Protection of Persons Undergoing
Statutory Instruments 1988 No. 778, London, HMSO.
10. N RPB, HSE DoH (1985) Guidance Notes for the Protection of
Persons Against Ionising Radiations arising from Medical
and Dental Use. London, HMSO.
11. Health and Safety Executive (1985) Approved Code of
Practice: The Protection of Persons against Ionising
Radiation arising from any Work Activity, The Ionising
Radiations Regulations 1985. London, HMSO.
12. Hea Ith a nd Safety Executive (1972) Code of Practice for
Protection of Persons against Ionising Radiation from
Medical and Dental Use. London, HMSO.
13. The Medicines (Administration of Radioactive Substances)
Regulations 1978, Statutory Instruments 1978 No. 1006.
London, HMSO.
14. Ionising Radiations (Outside Workers) Regulations 1993.
London, HMSO.
15. International Standards Organisation (1980) Sealed
Radioactive Sources-General, IS01677. Vienna, ISO
Publications.
16. The Radioactive Material (Road Transport) (Great Britain)
Regulations 1996, Statutory Instruments 1996, No. 1350.
London, HMSO.
17. International Standards Organisation (1980) Sealed
Radioactive Sources - Classification, ISO 2919-1980.
Vienna, ISO Publications.
18. International Standards Organisation (1979) Technical
Report, Sealed Radioactive Sources - Leak Test Methods,
ISO/TR4826-1979 (E). Vienna, ISO Publications.
19. Faulkner, K., James, H.V., Chappie, C.L and Rawlings, D.J.
(1996) Assessment of effective dose to staff in
brachytherapy. Health Phys., 71(5), 727-32.
20. Hilaris, B.S., Holt, J.G. and Germain, J. St (1975) The Use of
lodine-125 Interstitial Therapy. US Department of Health,

Education and Welfare Publication 76-8022, Rockville,
Maryland.
21. Germain,]. St (1975) Iodine seed brachytherapy. In
Handbook of Interstitial Brachytherapy, ed. B.S. Hilaris.
Acton, MA, Publishing Sciences Group, 117-28.
22. Liu, J. and Edwards, P.M. (1979) Radiation exposure to
medical personnel during iodine -125 seed implantation
of the prostate. Radiology, 132,748.
References 157
23. ICRP Publication 60 (1990) Recommendations of the
International Commission on Radiological Protection,
Ann. ICRP, 21(1-3), 11-201.
24. NCRP (1976) Structural Shielding Design and Evaluation for
Medical Use of X-rays and Gamma Rays of Energies up to
10 MeV. Report No. 49. NCRP Publications.
25. Godden, T.J. (1988) Physical Aspects of Radiotherapy,
Bristol, Adam Hilger.
This page intentionally left blank
 PART
II
Theradiobiologyof
brachytherapy

11 Theradiobiologyof low dose-rate and fractionated

irradiation 161
12 Dose-rate effects with human eel Is 180
13 Radiobiology of high dose-rate, low dose-rate, and
pulsed dose-rate brachytherapy 189
14 Predictive assays for radiation oncology 205
15 Principles of the dose-rate effect derived from
clinical data 215
This page intentionally left blank

The radiobiology of low dose-rate and
fractionated irradiation
JOELS. BEDFORD
11.1 INTRODUCTION
For exposure to sparsely ionizing radiations such as
X-rays or gamma-rays, the degree of a biological effect
produced can depend as much on the dose rate as on the
total dose received. The importance of dose rate and
dose fractionation effects has been recognized for more
than 70 years. Studies of Regaud and his collaborators
were perhaps the first to show the potential therapeutic
advantages of dose fractionation in the treatment of
patients with cancer by radiation [1,2]. Since that time,
the evolution of treatment regimes involving dose time
variations have increasingly improved cancer radiother-
apy and the evolution continues even today. Not only are
dose rate and dose fractionation important factors in
cancer radiotherapy, but also in connection with the
mutagenic and oncogenic hazards of radiation exposure
[3-5].
Generally, reducing the dose rate decreases the biolog-
ical effectiveness. Put in another way, decreasing the dose
rate generally increases the dose necessary to yield the
11
same level of effect. A number of factors can contribute
to the dose rate or dose fractionation effect, depending
on the conditions and cell or tissue system involved. For
example, in a tissue or tumor exposed over a period of
weeks or months, cells may migrate into or out of the
radiation field, or the oxygenation status may change to
alter the intrinsic ratiosensitivity of the cells during the
course of treatment. Such factors are not considered in
this chapter. Radiation responses in normal tissues and
tumors largely reflect the collective effect on individual
cells comprising them, and the discussion below focuses
on three major processes governing dose rate effects at
the cellular level: repair, cell-cycle-dependent radiosensi-
tivity, and perturbations in cell proliferation.
Repair is usually defined as a 'restoration to good,
sound, or healthy condition.' Various more or less strin-
gent definitions of the term have been used regarding
repair of radiation damage and it can apply to organs,
tissues, cells, subcellular structures, or molecules which
comprise them. It is useful to have at least an outline of
the broad perspective for a subject so important to
radiobiology as repair. It is among the most important of
162 The radiobiology of low dose-rate and fractionated irradiation

many contributions of radiation biology to biology in shoulder region of the curve (survivals below about
general, ranking with other contributions such as the 10%) would contain sublethal damage capable of inter-
first line of evidence that DNA and not protein is the acting with further damage to become lethal. They ques-
genetic material (based on absorption versus action tioned whether this sublethal damage might remain in
spectra), and the first demonstration of mutagenesis surviving cells, in which case their dose response at some
using X-rays and the utility of such mutants for genetics. later time would not be 'shouldered'. Alternatively, if the
sublethal damage were repaired, the cells would be
expected to respond as if they had never been irradiated,
11.2 THE GOOD OLD DAYS i.e., the surviving cells would display the same shoul-
dered survival curve for subsequent irradiation. The lat-
ter was found to be the case, as is illustrated in Figure
Repair of radiation damage, in the sense of 'restitution'
11.1 from their early work.
of chromosome breaks after exposure, was recognized
The curve indicated by filled circles in Figure 11.1
early in the history of radiation cytogenetics, perhaps
illustrates a dose-response curve for irradiations requir-
most notably by Sax [6]. Further, mathematical descrip-
ing only a few minutes each - high dose rate (HDR) or
tions of the dose rate effect in terms of the dependence
'acute' exposures - over a range of doses from 0 to about
of chromosomal aberration yields on the duration of
12.5 Gy. Curves starting at a dose of 5.05 Gy illustrate
exposure were presented by Lea and Catcheside [7], and
dose-response curves for cells surviving a first dose of
Marinelli and coworkers [8] and discussed in detail by
5.05 Gy followed by various additional doses given either
Lea in his classic book, Actions of Radiations on Living
immediately after the first dose (filled circles) or 18 h fol-
Cells [9]. As we shall see later, this is very pertinent to the
lowing the first dose (open circles). During the time
dose rate effect for cell killing that largely governs
interval between the first and second doses, the surviving
time-dose relationships in radiotherapy.
cells 'restored themselves to good (original) condition.'
The first observation of the enzymatic repair of radia-
They had repaired this so-called sublethal damage so
tion damage to DNA had its origins in the reports of
they again had to accumulate damage for cell killing.
photoreactivation of ultraviolet damage leading to
This sublethal damage repair (SLDR) is a repair
lethality in spores of the fungus Streptomyces griseus by
process operationally defined in terms of the observa-
Kelner in 1949 [ 10], and in the same year by Dulbecco in
the T group of coliphages [11]. About a decade later, this
was shown in Hemophilus influenzae and Saccharomyces
ceravisae to result from a light-mediated enzymatic
(photoreactivating enzyme or photolyase) splitting of
cyclobutane-type pyrimidine dimers in DNA induced by
the ultraviolet [12,13]. More relevant for mammalian
systems was the discovery of excision repair by Setlow
and Carrier in 1964 [14] and also in the same year by
Boyce and Flanders [15]. These and other repair
processes, involving (at first) ultraviolet damage in DNA,
preceded work with repair of ionizing radiation damage
in mammalian cells. Ionizing radiation produces negligi-
ble quantities of pyrimidine dimers, but does produce
other lesions such as base damage and DNA strand
breaks (which are discussed below).

113 SPLIT-DOSE RECOVERY FROM

SUBLETHAL DAMAGE IN MAMMALIAN CELLS

For ionizing radiation damage in mammalian cells, the

first direct demonstration of a cellular repair process
affecting cell killing that could explain dose rate and dose
fractionation effects seen in mammalian tissues or
tumors was provided by Elkind and Sutton [16]. They
reasoned that because the shouldered survival curves for
mammalian cells exposed to X-rays or gamma-rays indi-
cate the involvement of a damage accumulation process
in cell killing, then cells surviving a dose beyond the
Figure 11.1 Initial survival curve (closed circles) and
fractionation survival curve (open circles) for 'clone A' cultured
Chinese hamster cells. The fractionation survival curve was
determined 18.7 h after 5.05 Gy, and the curve is normalized to
the survival corresponding to 5.05 Gy. RE.- plating efficiency.
(Reproduced with permission from Elkind and Sutton [16].J

tions demonstrating the phenomenon, i.e., the increase
in the fraction of cells surviving. It says nothing about
what is being damaged and repaired. While survival
curve shapes were discussed at great length in terms of
target theory in the early literature, it was appreciated by
nearly everyone in the field some 30 years ago or more
that the simplifying assumptions necessary for target
theory to be useful were so overwhelmed by such com-
plexities as various repair processes and heterogeneity of
radiosensitivity within cell populations that we could
expect to learn very little about radiobiological mecha-
nisms by such analyses. This does not mean target theory
has not or cannot be useful or informative in certain
instances. What it does mean is that it is not very useful
for determining the nature, size, and number of critical
targets whose damage can kill cells after exposure to
sparsely ionizing radiations.
11.4 RECOVERY HAS ITS UPS AND DOWNS
One interesting aspect of the repair process, studied by
Elkind, was the reaction kinetics of sublethal damage
repair. By giving two 'acute' X-ray doses separated by
various periods of time, he and his colleagues, and later
others, found that the repair process was essentially com-
plete by about 2 h in randomly dividing log phase cul-
tures of V79 Chinese hamster cells. This is shown in
Figure 11.2. All the cultures received the same total dose,
Image Not Available
Figure 11.2 Survival curve (closed circles) and two-dose
fractionation curve (open squares) of 'clone A' cultured Chinese
hamster eel Is. The two-dose fractionation curve should be read
along the lower abscissa. P.E. = plating efficiency. (Reproduced
with permission from Elkind and Button [16].j
The cell-cycle complication: a heterogeneous population 163
given in two fractions of 5.05 Gy followed by 4.87 Gy,
but were separated in time by periods ranging from 0 up
to 30-40 h. What was immediately apparent from such
'split-dose recovery' curves was that repair was essen-
tially complete by 2-3 h. After this, however, survival
decreased during the next few hours, followed by another
increase. Aside from a few cells in mitosis or late G2 at
the time of the first dose, no appreciable cell division
occurred, at least during the early period from 0 to about
6 h after the 5.05 Gy first dose. Not until the cell cycle
dependence of radiosensitivity was discovered and stud-
ied did the explanation for this peculiar cyclic 'split-dose
recovery curve' become clear. Prior to this, survival stud-
ies in vitro all involved the use of randomly dividing cell
cultures where the population consisted of mixtures of
cells in all different phases of the cycle (M, Gl, S, and
G2).
11.5 THE CELL-CYCLE COMPLICATION: A
HETEROGENEOUS POPULATION
In the early 1960s, Terasima and Tolmach first showed
with synchronized cultures of HeLa cells that cellular
responses varied greatly throughout the cell cycle
[17,18]. This is illustrated in Figures 11.3 and 11.4, where
the experiments were carried out as follows. During
mitosis, cells become very loosely attached to the surface
of the culture vessel and these were collected by a 'shake-
off method, leaving the interphase cells behind in the
flask. Appropriate numbers of mitotic cell populations
were inoculated into dishes. After various periods of
incubation, different sets of the synchronously progress-
ing cells were irradiated when they were (for the most
part) at a particular stage of the cycle. When the dose was
the same for all cultures, but the time after mitotic
shake-off was varied, the proportion surviving to form
colonies varied as shown in Figure 11.3 in the upper
panel. Parallel cultures were flash labelled with tritiated
thymidine (3H TdR) to monitor the synchronous pro-
gression of cells into and out of S phase. For irradiation
of mitotic cells (Oh), survival was low, indicating a high
sensitivity for this cell cycle phase. As cells progressed
into mid-Gl (-2-6 h), the cells were more resistant. At
around the Gl/S border and in early S phase, cells were
again more sensitive, and as cells progressed toward late
S phase and early G2, the cells again became more resis-
tant. The changes were examined in more detail in other
experiments by determining complete dose-response
curves at different times after mitotic harvest, as shown
in Figure 11.4 where the '0-h' curve represents largely
mitotic cells, the 4-h curve Gl, the 13-h curve early-to-
mid S phase, and the 19-hour curve late S to G2. Because
there is some variation from one cell to the next in the
cell cycle transit times, particularly through Gl, there is
an increasing decay in synchrony and therefore the
164 The radiobiology of low dose-rate and fractionated irradiation

Image Not Available

Image Not Available

Figure 11.4 X-ray survival of HeLa S3-91V cells at four different

times during the division cycle measured from mitosis (0 h).
(Reproduced with permission from Terasima and Tolmach [18].J

starting population of mitotic cells through their first Gl

Figure 11.3 The upper curve shows the fraction of HeLa S3-91V and S phase, and because G2 transit times are relatively
cells surviving after 300 rod of X-rays administered at different short (about 1-2 h). A modification of the technique,
times in the division cycle. Mitosis is taken as 0 h. Each symbol
however, allows a much greater resolution for studying
represents data from a separate experiment, the time scales of
which have all been normalized to a minimum interdivisional
time of 18 h. The lower curve shows the fraction of cells in DNA
synthesis as found in three separate experiments with
synchronized cells. The fraction of labeled cells after 20 min in
medium containing H3-thymidine is plotted against time after
mitosis (normalized as in the upper curve). (Reproduced with
permission from Terasima and Tolmach [18].J

resolution of experimental data on cycle-dependent

radiosensitivity with time. Nevertheless, there is clearly a Image Not Available
large variation in the radiation response of cells through
the cell cycle.
Other cells have shown similar cell-cycle-dependent
variations in radiosensitivity (e.g., see references 19-26),
although the peak of resistance in Gl is not well resolved
experimentally in cells with very short Gl transit times.
An example of cell cycle variations in sensitivity for
Chinese hamster V79 cells, such as those used by Elkind
and his coworkers for the split-dose SLDR studies, is
Figure 11.5 Single-cell survival curves for Chinese hamster cells
shown in Figure 11.5 [20]. Special allowance was made
(V79 line) in different phases of the cell cycle, M, Gp early S (ES),
in the curves shown in this figure to eliminate the effect late S (LS), obtained by mitotic selection plus 3HTdR treatment to
of cross-contamination of resistant S-phase cells from kill contaminating S-phase cells, except where responses for
the more sensitive M, late G2, and Gl cells. The sensitiv- S-phase cells themselves were studied. A dose-modifying factor of
ity of cells in different parts of G2 is difficult to deter- 2.5, which might be expected fora noxic conditions, applied to
mine by the synchronization procedure described above mitotic cells is shown dotted. (Reproduced with permission from
because of synchrony decay during the passage of the Sinclair [20].)

G2 sensitivity. This is sometimes called 'retroactive syn-
chronization': cells are first irradiated and then, as a
function of time, cells arriving in mitosis are harvested
by mitotic shake-off and plated for survival. In this way,
Griffiths and Tolmach [24] showed for HeLa cells, and
Dewey and his colleagues [25,26] as well as
Schneiderman [26] for Chinese hamster CHO cells, that
early G2 cells are as radioresistant as late S cells, and late
G2 cells are nearly as sensitive as mitotic cells. A sharp
transition in radiosensitivity occurs around the so-called
X-ray transition point (now often called a 'check point')
for G2 cell cycle delay.
11,6 RADIATION AFFECTS CELL-CYCLE
PROGRESSION ITSELF
Radiation effects on cell cycle progression are yet
another factor that influences dose rate effects, and for
present purposes are the final area for discussion con-
cerning our present understanding and explanation of
observed variations in cellular effects related to dose
fractionation and dose rate.
That ionizing radiation reduces the mitotic index
within a short time after exposure (mitotic delay) has
been known for some time (e.g., see references 9,27).
This delay has been studied extensively in more recent
times, and the timing for the reduction in mitotic index
and subsequent recovery clearly indicates the delay is
reversible and occurs some time during G2 [28,29]. The
production of this effect is very radiosensitive.
Appreciable proportions of the cells are delayed by doses
of the order of tens of cGy [28-30]. The G2 delay
increases with dose and frequently corresponds to about
1-3 h Gy'1 depending on the particular cells and on the
stage in the cycle when the cells are irradiated.
Most of the extensive work on cell cycle progression
delays in cultured mammalian cells was carried out in
the 20-year period between about 1965 and 1985 using
'transformed' or tumorigenic cell lines. Delays in Gl or S
phase were relatively minor and, in many cases, unde-
tectable in the 0-5 Gy dose range. As it turned out, the
generalization or extrapolation of the results to normal
or untransformed cells was unwarranted. Some investi-
gators during this period, even as early as 1968 [31],
reported appreciable delays in the progression of 'non-
transformed' cells from Gl into S phase or in the transi-
tion from the non-cycling GO to the cycling state after
low dose or low dose-rate (LDR) irradiation [31-34].
More recently, the importance of p53 status in ionizing
radiation-induced Gl delay vis-a-vis transformed versus
non-transformed or tumor versus normal cells was dis-
covered by Kastan and his coworkers [3.5].
In any event, knowledge of the cell cycle dependence
of radiosensitivity with respect to cell killing as well as
the effects of radiation on cell cycle progression itself
The ups and downs are now explained 165
allowed the observations on the cellular basis of dose
fraction and dose rate effects to be largely understood.
11.7 THE UPS AND DOWNS ARE NOW
EXPLAINED
In a split-dose experiment, such as that discussed in con-
nection with Figure 11.2 using randomly dividing log
phase cells, the first dose kills a fraction of the cells, but
this fraction is not the same in all portions of the cell
cycle. Survival for cells in the most sensitive phases will
be much lower and, in resistant phases, much higher
than the average. Thus, after the first dose, the popula-
tion of cells surviving will not be distributed around the
cell cycle as it normally is, but will be highly enriched in
cells from more radioresistant phases. It is these surviv-
ing cells that determine the further reduction in survival
measured by the second dose. If the first dose is of suffi-
cient magnitude to bring the survival down to, say, 10%
or less, then these surviving cells will still contain sub-
lethal damage capable of interacting with an additional
dose. Thus, if the additional dose were given immedi-
ately after the first, the survival reduction would effec-
tively continue down along the single dose survival
curve. With a time delay, however, three things happen.
First, the sublethal damage begins to repair, and the half-
time for this process is relatively fast (by most cell cycle
transit time clocks) being 0.5-2 h depending on the sys-
tem. The effect of this repair process on the surviving
cells is to make them more resistant to a second dose, so
the proportion surviving will increase with an increasing
time interval between the first and second doses. This
process is 90% or more complete within about 2-4 h.
Second, the cells surviving the first dose which were
already in the more resistant phases of the cycle begin to
progress and, at least for the first few hours, this progres-
sion can only be toward a more sensitive state. For ini-
tially log phase populations, it is no longer surprising,
then, that with increasing time, between about 3 to 6 or
7 h after the first dose, the survival after the second dose
actually decreases. The first dose also produces a mitotic
and division delay, so the increase in number of surviv-
ing colonies with increasing time before the second dose
is not due to an actual increase in numbers of surviving
cells from cell division, at least for the first few hours. For
example, after a first dose of 5 Gy, there would be essen-
tially no cell division for some 5-10 h, depending on the
cells. Third, after the mitotic delay, cell division would
resume, so instead of having only one viable cell per sur-
viving colony, as would be the case immediately after the
first dose, some, and eventually all, would have two or
more viable cells, both of which would have to be killed
to prevent colony formation at that locus.
The influence of SLDR alone, without the complica-
tion of cell cycle effects, can best be seen by the simple
166 The radiobiology of low dose-rate and fractionated irradiation
expedient of using noncycling cells. One way is to reduce
the temperature between dose fractions to about
20-24C, where it has been shown that the rate of cell
cycle progression is greatly reduced while still allowing
the repair process to operate. This is shown in Figure
11.6, also from the work of Elkind and his colleagues
[36]. The reduction in survival between about 2 and 6 h,
followed by the subsequent rise from 6 to 10 h seen for
incubation at 37C are both eliminated for incubation at
24 C.
Especially appropriate for cell culture applications are
'normal' or 'nontransformed' cells, which form so-called
contact-inhibited monolayers. In such monolayers, the
cells enter a noncycling G0 state, where they are no longer
a heterogeneous population with respect to the
radiosensitivity of subpopulations and, of course, where
cell cycle progression and cell division during treatment
do not complicate the picture. One additional issue that
does arise with the use of contact-inhibited monolayer
systems as well as organized tissues in vivo is that
another, perhaps related, repair process known as 'poten-
tially lethal damage' repair (PLDR), also plays an impor-
tant role. This is very different from SLDR, at least in an
operational sense.
11.8 WHAT IS THIS THING CALLED
POTENTIALLY LETHAL DAMAGE?
When contact-inhibited monolayers of nontransformed
cells (or, for that matter, even plateau phase density-
inhibited cultures of transformed cells) are irradiated for
Image Not Available
Figure 11.6 Split-dose survivals for Chinese hamster cells
exposed to 2.5-MvX-rays and incubated at the temperatures
shown between doses. The split-dose survivals for 24 C were
adjusted to the same total dose as for 37 C. (Redrawn from
F/fom/etal.[36].;
a cell survival experiment, the flasks must, of course, be
subcultured and plated at a low enough density to allow
surviving cells to form colonies for the surviving fraction
to be assessed. As it turns out, the proportion of irradi-
ated cells surviving a single acute dose in such cultures
depends greatly on whether the cells are subcultured,
diluted, and plated for the colony forming assay immedi-
ately after irradiation, or the subculture is delayed for
some hours, in which case the survival is much higher.
This is illustrated in Figure 11.7 for human fibroblasts.
Image Not Available
Figu re 11.7 Survival response to various doses of X-rays
exhibited by density-inhibited normal (AG1522) and ataxia
(AT5BI) fibroblasts. Irradiated cultures were either subcultured
and plated for survival immediately (O, AG1522; A, AT5BI), or
aftera24hdelayat37C(O,AG1522; ,AT5BI). Thesurvival
data were fitted to an expression of the form $=read+bdal>wusing a
weighted least-squares method. Closed symbols represent survival
predicted on the basis of the mean number of metaphase
aberrations per cell for AG1522 (%) andforATSBI ( ). Bars
indicate 95% confidence limits for the sampling distribution of
mean survival estimates from up to four separate experiments.
The dashed line represents the predicted survival if cells
completely lacked the ability to rejoin any initially sustained
chromosome breaks as measured by premature chromosome
condensation (PCC) analysis and any excess fragment were lethal.
The D0 is approximately 0.17 Gy, suggesting that while A-Tcells
may be deficient in the amount of potentially lethal damage
(PLD) they can repair, they nevertheless must be capable of
repairing a large proportion of the chromosome breaks initially
produced. (Reproduced with permission from Cornforth and
Bedford [44].;

The interpretation of this phenomenon is that because
damage is lethal in some cells under one set of circum-
stances (e.g., immediate subculture) but is not under
another set (e.g., delayed subculture), such damage must
be considered not as 'inevitably lethal' but only 'poten-
tially lethal,' depending on the circumstances. Early work
in this area was summarized for density-inhibited or
plateau phase cultures by Little [37], but the general phe-
nomenon was first demonstrated by Tolmach and his
coworkers for cells whose cell cycle progression was
inhibited by drugs for various times after irradiation
[38]. It was also demonstrated at about the same time for
post-irradiation treatment in phosphate-buffered saline
[39] and later for post-irradiation treatment in aniso-
tonic salt solutions [40-42]. Even earlier than any of
these studies, a similar phenomenon known as liquid
holding recovery was described whereby the survival of
bacteria could be increased by post-irradiation incuba-
tion in nutrient-deficient phosphate-buffered saline [43].
Again, it is of interest to know about the kinetics or rate
of PLDR. This is shown in Figure 11.8, using the same
non-cycling contact-inhibited normal human fibroblasts
Image Not Available
Figure 11.8 Survival as a function of post-irradiation
incubation time before subculture}cor AG1'522 cells. Density-
inhibited cultures were given 6.0 Gy of X-rays, then incubated at
37 Cfor varying lengths of time before subculture and plating.
The solid line represents the increase in survival predicted on the
basis of the interphase chromosome (PCC) break induction and
rejoining kinetics. Bars are approximate 95% confidence limits
about the mean number of colonies scored per petri dish.
(Reproduced with permission from Cornforth and Bedford [44].)
What is this thing called potentially lethal damage? 167
as for the experiments illustrated in Figure 11.7 [44]. In
all samples for survival estimates shown in Figure 11.8,
contact-inhibited cultures receive a single dose of 6 Gy of
X-rays (0.55 Gy mhr1). Either immediately or at various
later times, cells were subcultured and plated at lower
densities for a survival assay by colony formation. The
increase for subculture from 0 up to 6 or more hours after
irradiation was from a survival of about 0.01-0.10 (i.e., a
factor of 10) and the rate of increase corresponded to a
repair half-time of about 1.7 h [44].
There has been some confusion about the apparent
similarity in the survival increases in split-dose SLDR
and delayed plating PLDR experiments and about the
processes underlying these phenomena. Even without a
knowledge of the mechanisms involved, however, a dif-
ference is clearly illustrated by split-dose experiments
carried out under conditions in which the full amount of
PLDR occurs in all samples but different amounts of
SLDR occur after the first dose, when the second dose is
given. Figure 11.9 illustrates this point. In this case,
Image Not Available
Figure 11.9 The increase in survival ofAG1522 cells as a
function of time between two 6-Gy doses. The solid circles are
observed survivals and represent the mean response of two
independent experiments carried out in parallel on the same day.
The open squares show the survivals predicted from the average
number of chromosome aberrations per cell measured for the 0-h
and 10-h split doses only. All monolayers were given a 24-h post-
irradiation incubation period prior to subculture for the
estimation of survival or aberration frequencies. The solid line
represents the predicted survival as a function of time, t (h),
between two equal split doses, where l is the rejoining rate
constant for X-ray-induced chromosome breaks. Dotted lines
indicate survival predicted within 2 SD of X. Bars represent
approximate 95% confidence limits associated with either the
mean aberration frequencies ( ) or the mean survival estimates
(). (Reproduced with permission from Bedford and Cornforth
[45].;
168 The radiobiology of low dose-rate and fractionated irradiation

non-cycling contact-inhibited cultures of normal

human fibroblasts were given two doses of 6 Gy, each
separated by times ranging from 0 to 10 h [45]. In each
case, the cultures were maintained in the contact-inhib-
ited state for 24 h after irradiation so that all of the PLDR
that could occur from each dose was allowed to occur
before subculture for the survival assay. Still, survival
increased from about 0.003 for a 0-h separation between
doses (the value expected from Figure 11.7 for a 12 Gy
dose with full PLDR) up to about 0.015 for a 10-h sepa-
ration between doses. The half-time for the SLDR
process is about 1.7 h. This is perhaps the best way an Image Not Available
experiment to distinguish SLDR from PLDR can be car-
ried out without seeing the varying contributions of
both PLDR and SLDR, and perhaps other processes,
together. If, for example, the cells were subcultured
immediately after the second dose, then the survival
would increase both because different amounts of PLDR
would occur from the damage inflicted by the first dose
and because different but increasing amounts of SLDR
would reduce the effectiveness of the second dose, for
which no extra time for PLDR would be allowed. Thus,
studying these processes in contact-inhibited systems
offers a way to isolate their individual contributions to Figure 11.10 Dose fractionation effects in plateau-phase
dose fractionation and dose rate effects. cultures of 7 OB cells. MuInfraction survival curves were
Another factor for the study of cellular radiation determined for doses per fraction ranging from 7.7 to 0.8 Gy
responses relevant to normal tissue effects is that virtu- delivered at 12-h intervals 7 days per week. The fractionated
ally no normal tissue contains cells existing in the abun- survival curves were compared in each case to a corresponding
dant nutrient conditions of in-vitro culture and which acute dose survival curve generated in that particular experiment.
Each point represents the mean of two independently determined
are proliferating with growth fractions near 1.0 and dou-
survival estimates. Whereas muInfraction survival curves should
bling times of 12-24 h. Perhaps intestinal crypt stem
ideally be exponential, one apparent discrepancy is that, at the
cells come as close to this unusual situation as any in larger doses per fraction, the survival curves for the slowly cycling
vivo. The non-cycling contact-inhibited state for normal untransformed cells were observed to bend toward lower
cells in culture may fail to simulate all conditions in vivo, survivals. (Reproduced with permission from Zeman and Bedford
but the conditions are perhaps a little closer in general to [34].;
those in most cell renewal tissues, and much closer with
respect to the cell cycling status.

main points to gain from the results shown in Figures

11.9 MORE AND MORE DOSE FRACTIONS
To this point, we have not dealt with multiple dose frac-
tionation or the case of continuous radiation exposures
at reduced intensities, i.e., with effects of reducing the
instantaneous dose rate. The latter situation represents
the limiting case of dose fractionation where the total
dose is spread over longer times with increasingly large
numbers of smaller and smaller doses per fraction.
The effect of multiple dose fractionation with differ-
ent doses per fraction and of continuous irradiation at
lower and lower dose rates is shown in Figures 11.10 and
11.11, respectively, for untransformed contact-inhibited
noncycling mouse C3H 10T1/2 cells where the effect of
repair alone can be assessed without the simultaneous
contribution of cell cycle redistribution and cell prolifer-
ation effects during treatments [33,34]. There are three
11.10 and 11.11. First, the dose fractionation or dose rate
effect is large, requiring nearly three times higher total
doses at the lowest dose rates or doses per fraction to
produce the same level of effect (for survivals < 10-3)
than that required for single acute doses delivered at the
highest dose rates. Second, the dose rate effect is most
pronounced (change in dose for a given level of effect
with change in dose rate) in the range just above and
below 2 Gy h'1 (3.3 cGy mhr1). Third, there is a limit
below which no further reduction in effect per unit dose
occurs with further reduction in dose per fraction or
dose rate. There is a residual nonrepairable component
of damage under these conditions. PLDR is not a factor
in any of these experiments because the contact-
inhibited cells were not subcultured for the survival
assays until at least 12 h after the total doses were
delivered and, therefore, full PLDR occurred in every
case. Further, it was also shown that the intrinsic

Image Not Available
radiosensitivity of the cultures was not changing during
the periods up to 4 weeks required to deliver the highest
doses at the lowest dose rate.
An example of the way cell cycling may influence the
dose rate effect is illustrated in Figure 11.12. In this case,
randomly dividing log phase cultures were irradiated at
Image Not Available
Figure 11.12 Survival curves for log-phase cultures of C3H 70Tj
cells exposed to cesium-137y-rays at dose rates of 55.6, 1.42, 0.49,
and 0.29 Gy /r'. Surviving fraction was determined by dividing
the number of viable cells present at the end of the exposure by
the number of viable cells at the beginning of the exposure.
(Reproduced with permission from Wells and Bedford [33].)
More and more dose fractions 169
Figure 11.11 Dose-rate
effects for density-inhibited
cultures of C3H WJ1/2 cells.
Subculture and plating for
colony formation were
delayed for 8-12 h at the
end of each exposure to
ensure that the same
opportunity for full
potentially lethal damage
repair would occur for all
dose increments during the
long or short exposures.
(Reproduced with
permission from Wells and
Bedford [33] J
different dose rates for different periods of time to cor-
respond to the various total doses, and the surviving
fractions were obtained by dividing the number of viable
cells present at the end of each exposure by the number
present initially [33]. When extensive cell proliferation
occurs during exposure, specification of the dose is a lit-
tle unclear because cells present at the end of an expo-
sure did not actually exist except as components of the
medium at the beginning of the exposure. Nevertheless,
we will specify dose as the average dose delivered to the
culture as a whole. There is a large dose rate effect due to
repair as the dose rate was reduced from 55.6 Gy h-1 to
1.4 Gy tr1, and relatively little proliferation or cell cycle
redistribution would have occurred because less than
one cell cycle would elapse during even the longest expo-
sure. For a further reduction in dose rate to 0.49 Gy tr1,
there appears to be little further reduction in effect per
unit dose. In fact, for the higher doses this dose rate is at
least as effective, and perhaps more so, as the higher dose
rate of 1.42 Gy h"1. There is a clear effect of cell cycling
and cell cycle redistribution here. Apparently only a few
cells were capable of dividing at this dose rate and were
blocked in a sensitive portion of the cell cycle. One com-
plete cell cycle would have elapsed after a dose of 12 Gy
at 0.49 Gy h-1, after which the remainder of the doses
would have been delivered to (mostly) G2 blocked cells.
When the dose rate was reduced even further to 0.29 Gy
tr1, the division of some viable cells actually allowed the
'apparent survival' to increase above 1.0 and even to
remain as high as 0.7-0.8 for doses up to 15 Gy, corre-
sponding to exposures lasting about 2 days. Then, as
proliferation ceased and a G2 block became effective, the
170 The radiobiology of low dose-rate and fractionated irradiation
reduction in survival with dose nearly paralleled the rate
of reduction for the higher dose rate of 0.49 Gy rr1.
That these principles are not a peculiarity of rodent
systems such as the mouse C3H 10T1/2 cells is shown in
Figures 11.13 and 11.14. Figure 11.13 illustrates an
experiment for multiple-dose fractionation using
contact-inhibited normal human fibroblasts [45]. Here,
the different total doses were given either as single acute
doses or as 4, 2, 1, or 0.5 Gy doses per fraction, with 6 h
allowed between fractions. Again, there is a large dose
fractionation effect, which corresponds to a factor of
nearly three in total dose to reach a given level of effect
(in the higher dose regions), and there appears to be a
limit or non-repairable component.
Figure 11.14 illustrates, for cycling 'transformed'
human tumor cells (HeLa), a very pronounced influence
of cell cycle redistribution and proliferation during
exposures at lower dose rates. In this study [30] as the
dose rate was decreased from the baseline high dose rate
of 143 cGy min~' (8580 cGy Ir1) down to 154 cGy Ir1,
(Figure 11.14, right panel), there was a sizeable reduction
in effectiveness per unit dose, but decreasing the dose
rate to 74 cGy h"1 did not further reduce the effective-
Image Not Available
Figure 11.13 Survival response of plateau-phase ACT522 cells to
X-mys delivered at 0.5 Gy'/fraction (H), 1 Gy/fraction (O),
2 Gy'/fraction (O), and 4 Gy/fraction (A,), as well as by a single
dose (O). As the dose per fraction decreases, survival approaches
that predicted by the a component (dashed line), which represents
the dose-rate-independent or dose-fractionation-independent
component of X-ray-induced cell killing. All cultures were allowed
24-h post-irradiation incubation at 37 C prior to plating for
survival. (Reproduced with permission from Bedford and
Cornforth [45].j
ness. Further reducing the dose rate to 55 cGy h' and
37 cGy h'1 actually increased the effectiveness. Extensive
experimentation with this HeLa human tumor cell sys-
tem [30,46] has shown that this reversal of the dose rate
effect, which more than counteracts the sparing from
repair, results from a block in a radiosensitive G2 +
M-like state. With reductions in the dose rate to
15 cGy h'1 and 10 cGy tr1, the G2+M block and subse-
quent redistribution are reduced or disappear and the
reduction in effectiveness per unit dose is then governed
principally by killing due to the dose-rate-independent,
nonrepairable component of damage, along with the
occurrence of cell proliferation or the division of viable
cells during exposure.
11,10 IS THIS CLINICALLY RELEVANT?
The possibility that these factors may have some impor-
tance for radiotherapy has been discussed on numerous
occasions. The question generally centers on the dose
rates or doses per fraction necessary to produce this G2
block during treatment, and the cell cycle transit times
and growth fractions in various tumors. The general
assumption is also made that proliferation and cell
cycle redistribution during low dose-rate irradiation are
not a factor for dose-limiting 'slow turnover' tissues
largely responsible for late-effects complications.
Although there is no universal agreement on this issue,
it is fair to say that, because of the enormous diversity
and variation among patients and tumors, the only
generalization that is likely to be correct is that any sin-
gle generalization about all tumors is almost certain to
be incorrect.
11.11 WHAT IS HAPPENING AT THE
SUBCELLULAR LEVEL?
With our current more detailed knowledge of the work-
ings of biological systems at the subcellular and molecu-
lar level, it is worth some discussion of what is a
reasonable hypothesis about the mechanism of the dose
rate and dose fractionation effect for mammalian cells.
Perhaps the most important progress in this area has
come from cytogenetics. Considerable evidence has
accumulated over the years indicating that gross chro-
mosomal aberrations leading to large genetic losses in
the progeny of irradiated cells are the principal cause of
cell reproductive death [44,45,47-55]. One of the most
convincing sets of experiments on this subject was car-
ried out by Revell and his colleagues [52,53], who
showed, for living normal diploid hamster cells, that vir-
tually every cell died where an acentric fragment yielding
a micronucleus was present in at least one daughter cell
after irradiation of a Gl cell in the previous cycle.
 The answer is: chromosome breaks! The question is: what is sublethal damage? 171

Image Not Available

Figure 11.14 Survival curves for log-phase S3 HeLa cells irradiated at different dose rates of j radiation. The right panel illustrates
survival curves for continuous irradiation where no cell division occurs during any of the exposures. The left panel illustrates survival
curves where in some cases (10 and 15 rod h~1) cell division was occurring during the irradiation. Vertical arrows on the curves indicate the
accumulated dose after a time equivalent to one generation time in unirradiated cultures. PE - plating efficiency. (Reproduced with
permission from Mitchell el al. [30]. j

Conversely, virtually every irradiated Gl cell that did
not yield a micronucleated daughter cell lived. If some
other independently produced but unseen lesion (rather
than the fragment-producing chromosomal aberration)
were actually responsible for cell killing, then some cells
with micronucleated daughter cells should have sur-
vived, and also some which did not yield micronuclei
should have died. This did not happen. Currently, there
is no evidence for any proposed killing process or mech-
anism for any other chemical or physical agent that
comes close to being as compelling as the one-to-one
correspondence demonstrated by this group for ionizing
radiation exposure of mammalian cells. Other experi-
ments Revell and his colleagues carried out on tetraploid
and aneuploid cells tended to show that in these cases
more than one fragment-producing aberration was nec-
essary to kill a cell [52,53]. Higher ploidy levels appar-
ently result in greater tolerance to chromosome
fragment loss, but the basic process or mechanism of
killing did not change.
Apoptosis is a process of 'programmed cell death.'
There is evidence that, for some cell types, particularly
those of lymphoblast origin, but for others as well, radi-
ation can trigger a signal transduction pathway leading
to apoptosis. In these instances, the contribution of
apoptosis to radiation-induced cell death adds appreci-
ably to that resulting from chromosomal aberrations.
(This is discussed in more detail below.)
11.12 THE ANSWER IS: CHROMOSOME
BREAKS! THE QUESTION IS: WHAT IS
SUBLETHAL DAMAGE?
If cells are killed by ionizing radiation mainly as a result
of acentric fragments generated from chromosomal
aberrations, it then requires only a few short steps to
explain the dose fractionation and dose rate effect along
with the shape of the survival curve for acute high dose-
rate exposures to sparsely ionizing radiations. Figure
11.15 shows a few examples of the kinds of chromoso-
mal aberrations produced by ionizing radiations. It is
worth noting that only very few agents, namely those
that produce prompt DNA double-strand breaks (dsbs),
give this kind of cell-cycle-related pattern of aberration
types at the first mitosis after treatment, i.e., chromo-
some types after GO or Gl treatment and chromatid
types after S or G2 treatment. Treatment with agents
that produce single-strand and base damage but not
DNA dsbs, such as ultraviolet light or alkylating agents,
172 The radiobiology of low dose-rate and fractionated irradiation

Image Not Available

Figure 11.15 Examples of the formation of some chromosome-type and chromatid-type aberrations appearing at the first mitotic
metaphase following exposure to ionizing radiation. Chromosome-type asymmetrical exchanges yield acentric fragments including both
chromatids of the chromosome or chromosomes. Examples shown in this diagram are the dicentric plus its acentric fragment
(asymmetrical interchange) and the interstital deletion (asymmetrical intra-arm intrachange) shown in the light chromosome along with
another unaffected (dark) chromosome. Interstitial deletions are mostly acentric rings, but are usually small so the 'hole' in the ring
cannot be seen. The other category of asymmetrical exchange is the centric ring plus its acentric fragment (asymmetrical inter-arm
intrachange), which is not shown in this diagram. It is seen at much lower frequencies than the aberrations shown. Only two
chromosomes (non-homologous) are shown per cell, because that is the minimum required for an interchange. (Reproduced with
permission from Bedford [55].)

yield chromatid types even when treatment is in GO or
Gl. Chromatid-type aberrations can also kill cells, but
more, on average, have to be produced in order that
both daughter cells experience the necessary genetic
loss. For the analysis below we will, therefore, confine
ourselves to the simpler basic case of diploid cells irra-
diated in GO or Gl, which would apply for most critical
normal cells governing normal tissue responses and
closely approximate that for most tumor cell popula-
tions.
Nearly all chromosome-type aberrations that gener-
ate acentric fragments are exchange types requiring at
least two breaks for their formation, either both in one
chromosome or one in each of two different chromo-
somes. Figure 11.16 shows dose-response curves for
the production of acentric-fragment-producing chro-
mosome-type aberrations in human fibroblasts irradi-
ated in a contact-inhibited GO state and then held for
full 'PLDR' before subculture and collection for scoring
at the first post-irradiation mitosis [44]. Together,
interstitial deletions and dicentrics with their associated
acentric fragments make up the great majority of total
aberrations, at least for higher doses, and the curve
relating their increase as a function of dose is not
linear.
If each requires the production of two chromosome
breaks by the passage of two independent electron
tracks, then their frequency would increase as the square
of the dose.1 This can be seen as follows. The actual num-
ber of total breaks within the cell nucleus (ND) increases
linearly with dose. In other words, the number of breaks
1
The formation of so-called 'complex' aberrations, which involve three
or more breaks in two or more chromosomes, was at one time thought
to occur with negligible frequencies even at relatively high single acute
(high dose-rate) doses of 5-10Gy. Recent studies indicate that the
fraction of complex aberrations begins to be appreciable for acute
X-ray or gamma-ray doses of 3-4 Gy and the relative frequency and
degree of complexity increase fairly rapidly with further increases in
acute dose. For densely ionizing radiations, the fraction that is complex
appears to be very high, even for lower doses. While there is little argu-
ment that the relationship between dose and the production of aberra-
tions yielding acentric fragments is well approximated by a
linear-quadratic function of dose for sparsely ionizing radiations,
there is ample and convincing evidence to argue against the simplified
notion that two breaks from two electron tracks account entirely for
the curvilinearity often referred to as the dose-squared or quadratic
component. Nevertheless, for acute dose fractions of 2 Gy or less and
for continuous low dose-rate exposures pertinent to brachytherapy, the
simplified picture is perfectly adequate to show the nature of the frac-
tionation and dose-rate effect.
 The answer is: chromosome breaks! The question is: what is sublethal damage? 173

Now, exchanges can also be produced as a result of two

breaks occurring close enough together along one electron
or other charged particle track and the number of these,
along with the proportion actually forming the exchanges
in question, would increase in direct proportion to the dose
giving a yield Y = gD. Also, breaks that do not rejoin at all
(usually a small fraction) produce terminal deletions,
adding to the acentric fragment category yield as Y = hD so
the total 'single track' production of acentric fragments,
Yp increases as Yl = gD + hD or if a = g+h, Yj - aD.
Image Not Available Thus, for both two-track and one-track modes of
acentric fragment production, the yield (Y) will be
Y= aD+f3D2. The total is shown in Figure 11.17 for the
sum of the curves (the same cells and conditions) shown
in Figure 11.16. In this case, the total yield of lethal
fragment-producing aberrations with dose is closely
fitted by a curve of the above form where a = 1.5 x
10-' Gy-1 and P = 2.5 x 10"2 Gy~2 [45]. The curve marked
'A-T fibroblasts' is for the very radiosensitive cells of
patients with ataxia telangiectasia. This genetic disease is

Figure 11.16 Chromosome-type aberrations per cell in the first

mitosis after irradiation of GO human fibroblasts, as a function of
dose. Bars around data points indicate 95% confidence limits.
(Reproduced with permission from Cornforth and Bedford [44].J

is directly proportional to the number of electron tracks,

and the latter is directly proportional to dose. To have an
exchange, a second break must occur within some max-
imum distance, say r, of any given break, i.e., it must
occur within the volume 47irY3, which itself occurs
within a cell nucleus of radius R. The number of these
additional or second breaks occurring within the inter-
action range would then be approximately Image Not Available
(47cr3/47cR3)(ND-l) = (r3.R3)(ND-l). The same considera-
tion must be given to each of the other NDl breaks and
all these N cases summed up to give the total pairs of
breaks, Yp, capable of interacting to form an exchange
which is (Nu) (A/D-1) (rVtf 3 ) or, if N is fairly large, this
will be approximately N^rV-R3). However, as we have
already said, the number of chromosome breaks, ND,
within the nucleus is directly proportional to dose, so
ND = bD and if the ratio rY3 = a then Y p =a(bD) 2 = jD2
where j=ab2. Because only some constant fraction, f, of
break pairs will interact to form an asymmetric
fragment-producing exchange (while the others will
either form a nonlethal symmetrical exchange or, by far
the majority, will restitute), then the yield of two-break Figure 11.17 Total chromosome-type aberrations per cell as a
asymmetrical exchanges produced by independent elec- function of X-ray dose for normal (ACT 522) and ataxia fibroblasts.
tron tracks Y2 will be fjD 2 or, if k = fj, Y2 = kD2. Density-inhibited cultures were irradiated and then subcultured
Of course, there is more than one kind of asymmetric 24 h later. Data from the normal cell strains were fitted by a
exchange and the value of k for each kind will differ, but weighted least-squares method to an equation of the form Y = C +
aD + pD2 (C = 0.070; a = 7.54 x 70-'; (3 = 2.52 x 70^, where D is
these constants will also sum, so:
the dose in gray. Bars indicate 95% confidence about means.
Y2 = k,D2+k2D2+ ... knD2=(k,+k2+ ... +kn)D2=$D2 (11.1) (Reproduced with permission from Cornforth and Bedford [44].,)
174 The radiobiology of low dose-rate and fractionated irradiation
the phenotype of individuals who are homozygous
recessive for the A-T gene. A number of other artifically
produced hypersensitive mutants are also now available
which should greatly help in the understanding of the
molecular mechanisms controlling radiosensitivity in
general and dose rate effects in particular [57-63].
From the above considerations, it is easy to see how a
repair process could operate to reduce the biological
effect with dose fractionation or a reduced dose rate.
Immediately after a given radiation dose there will be a
number of chromosome breaks located too far away from
any other break for an exchange to be possible, so the only
possibilities would be restitution (repair) or failure to
rejoin (lack of repair). Failure to rejoin is relatively infre-
quent, as seen from the curve for terminal deletions in
Figure 11.16. These open lesions or breaks too far from
another for rejoining can be considered as sublethal dam-
age and their rejoining or restitution as SLDR. If an addi-
tional dose is given immediately after the first, before the
isolated breaks have restituted, then they are available for
interaction with the additional breaks if such occur near
enough. If the additional dose is given at some later time,
after the isolated breaks from the previous dose have
rejoined, they will not be available and the effectiveness of
the additional dose will be lessened. For continuous LDR
irradiation, a similar consideration applies. If the dose
rate is high so the total dose is delivered in a time that is
short compared to the half-time for rejoining of breaks,
then the maximum number of break-pairs for potential
exchanges under these conditions will be produced. On
the other hand, if the dose rate is very low, a second break
will never be produced by an independent electron track
before the one produced by an earlier track has disap-
peared by restitution or rejoining. Thus, the '|3 term' in
the above equation will approach zero at low dose rates.
In this case, the only break-pairs for potential exchange
will be those produced simultaneously along the same
electron track. This 'a-term' or 'a-component' is dose
rate independent.
11.13 HOW DOES A LINEAR-QUADRATIC
INCREASE IN DAMAGE LEAD TO AN
EXPONENTIAL DECREASE IN SURVIVAL?
The damage killing the cells is being produced in a way
that increases both linearly with dose for one component
and as the square of the dose for the other component.
How does it happen, then, that the fraction of cells sur-
viving decreases as a complex exponential function of
dose? This follows because the damage which develops in
the form of lethal chromosome aberrations is distrib-
uted randomly and independently among cells (of uni-
form sensitivity) in a way that can be approximately
described by a Poisson distribution. The formula for the
total yield of the lethal aberrations per cell, Y, is
Y = aD + $D\ but Y is the average number per cell. Each
cell does not have exactly Y aberrations. Some have a few
more, some have a few less, and it is the ones that have
none that are of interest in this case of normal diploid
cells irradiated in GO or Gl because it is only these that
will survive. The Poisson distribution:
allows us to calculate the proportion of cells that have
exactly x events (aberrations) occurring in them when
the mean number is |i. Thus, the proportion with exactly
zero aberrations or the proportion surviving, S, will be:
In this case, the mean (m = Y, so the surviving fraction
is:
The way in which aberration yield and survival change
with dose fractionation and dose rate has been reported
and discussed on many occasions, both relatively early in
the history of the field by Lea [9] and Neary (64) and
also more recently [45,54,55]. For a damage-interaction
mechanism in general, by far the most comprehensive
treatment of this and other aspects has been given by
Kellerer and Rossi [65].
Figures 11.18 and 11.19 illustrate the way in which
chromosome aberration frequencies and the fraction of
cells surviving change when a total dose of 8 Gy is given
for all cells but the delivery is spread out in time by giv-
ing one acute dose of 8 Gy, two acute doses of 4 Gy, four
acute doses of 2 Gy, eight acute doses of 1 Gy, or 16 acute
doses of 0.5 Gy with a time between fractions of 6 h in
each case [45]. This illustrates the gradual and parallel
loss of the f3 component of aberration production and
cell killing.
11.14 DOES POTENTIALLY LETHAL DAMAGE
PLAY A ROLE?
Earlier another well-known cellular damage repair
process referred to as potentially lethal damage repair was
discussed. How does this relate to chromosomal aberra-
tions and the dose rate effect? Actually, it is connected in a
rather simple (but hypothetical) way under the current
framework or hypothesis of aberrations and cell death.
PLD can be considered as a break-pair with a certain
probability of break interaction to form a lethal aberra-
tion. If conditions change, such as post-irradiation hold-
ing in the contact-inhibited state versus subculture
stimulating cells into the cycle, or changing the osmolar-
ity of incubation medium from isotonic to hypertonic or
hypotonic, then the probability of break-pair interaction
may change. During incubation under one set of condi-

Image Not Available
Figure 11.18 Net frequency of different aberration types scored
in AG1522 cells as a function of the number of fractions used to
delivers Gy of X-rays. An additional 24-h incubation followed the
last fraction. Note that while the frequencies of rings plus
dicentrics and interstitial deletions decreased with increasing
fraction number, terminal deletions appeared to be independent
of dosefractionation. The dashed line traces the reduction in total
aberration frequency predicted from a chromosome break
rejoining half-time of 1.7 h. Solid lines were drawn by eye. Error
bars indicate 95% confidence limits about the mean number of
total aberrations per cell. (Reproduced with permission from
Bedford and Cornforth [45].;
tions, individual breaks comprising break-pairs (includ-
ing those produced by two breaks along single tracks,
known as the single-hit or a component) can rejoin, mis-
rejoin, or not rejoin at all in a way characteristic of this
incubation condition, but if the condition changes, the
relative frequencies or probabilities of these may change
so that survival is either higher or lower. It may even be
that certain conditions, such as those known to change
chromatin structure, could cause a change not in actual
number of total breaks at risk, but in the number of
breaks close enough to another, i.e., break-pairs, for an
exchange to occur. In any case, the issue of PLD versus
SLD is in no way a dilemma in regard to the dose rate
effect or cellular radiobiology in general.
11.15 CHANGES WITH LINEAR ENERGY
TRANSFER
Another issue worthy of comment is the question of
radiation quality and relative biological effectiveness
Changes with linear energy transfer 175
Image Not Available
Figure 11.19 Survival of plateau-phase AG1522 cells as a
function of the number of X-ray fractions used to deliver a fixed
dose of 8 Gy. Open circles (O) show measured survival as the
means of two separate experiments. Crosses (+) were derived from
the best-fit survival curves shown in Figure 11.13. Solid squares
(, 95% confidence about the means) show the survival
calculated from the expression S = e~Vi where Yt is the average
number of chromosome-type aberrations per cell from Figure
11.18. Cultures received a 6-h incubation at 37C between each
fraction, and a 24-h post-irradiation incubation following the
final fraction, before being subcultured and plated for survival or
chromosomal analysis. Survival expected after a large number of
very small doses is indicated following the break in the abscissa
and was derived from the best estimate of a for this experiment.
(Reproduced with permission from Bedford and Cornforth [45]J
(RBE) in the current context. The radiation dose deliv-
ered by an X-ray or gamma-ray exposure is delivered
almost exclusively by the production of ionizations
occurring along the tracks of electrons. The ionization
density or linear energy transfer (LET) is much lower for
such electrons than for heavier charged particles of mod-
est energy such as alpha particles or recoil protons aris-
ing from neutron irradiation. Obviously, if the spacing
of ionizations along a single electron track is close
enough together occasionally to form a break-pair for
potential exchange formation, then this should occur at
a correspondingly higher frequency if the spacing
between ionizations is even closer, as it is for higher LET
radiations. Accordingly, this should result in a greatly
increased contribution from a dose-rate-independent a
component of damage for high LET radiation. In fact,
this is the case and there is not only little or no dose rate
or dose fractionation effect for radiations such as a par-
ticles, but the a component of damage is so greatly
increased that the dose-response curve for exchange
aberrations is linear and completely overshadows any
intertrack P component. Likewise, the dose-survival
curve becomes dominated by the a component and is a
steeper simple exponential function of dose. It is of
interest that with respect to cell killing at high versus low
dose rates, certain X-ray-sensitive mutants behave for
176 The radiobiology of low dose-rate and fractionated irradiation
Image Not Available
Figure 11.20 The survival responses of plateau phase CHO 10B2
(open symbols) and irs-20 (dosed symbols) cells exposed at various
dose rates. Cells were incubated for 6-12 h before replating to
determine survival. O, , 0.75 Gym/Tr'/D, , 0.50 Gy/r'; A, A,
0.12 Gy h~1; 4, 0.06 Gy h~\ (Reproduced with permission from
Stackhouse and Bedford [56].,)
low LET radiation in a way that is similar to that for their
wild-type counterparts with high LET radiations. This is
illustrated in Figure 11.20, where a large gamma-ray
dose rate effect is seen for plateau phase CHO wild-type
cells but there is no dose rate effect for the CHO irs-20
mutant cells [57]. High LET data are not available for
CHO irs-20 cells.
11.16 MORE ON APOPTOSIS AND SIGNAL
TRANSDUCTION
While there are still many other issues and controversies
concerning the mechanisms of cell killing, and even
chromosomal aberration induction itself, the above
treatment is, to a first approximation, accurate enough to
account for most of the observations of importance for
dose rate and dose fractionation effects. As mentioned
earlier, one particularly interesting subject that has
recently moved into prominence for biology in general,
and naturally into radiation-induced cell killing, is the
process of apoptosis. This process of programmed cell
death appears to be induced to a greater or lesser degree
in some cells by the triggering of a signal transduction
pathway by ionizing radiation. Regarding radiotherapy,
cells of lymphocytic origin appear more radiosensitive to
this process of killing than the much reduced contribu-
tion to killing in other cells. Currently, however, the con-
tributions of apoptosis to radiation-induced cell killing
have not been carefully assessed in a quantitative way, as
has been done for aberration induction, but these may
not be altogether unrelated processes for some cells. For
example, apoptosis need not always occur before the first
post-irradiation mitosis. The fact that cells can be killed
by the loss of a large acentric chromosome fragment
after mitosis does not mean that the death such cells
eventually experience cannot be apoptotic. There are
several quantitative issues that need to be addressed and
resolved to assess the role of signal transduction and
apoptosis triggered by ionizing radiation, and its rele-
vance in regard to dose fractionation and brachytherapy.
One important question is whether radiation triggers
signal transduction in all cells but to a greater or lesser
degree depending on dose, or whether the fraction of
cells triggered or not triggered changes with dose in a
way that corresponds with the fraction killed or not
killed, respectively. Recently, the kinds of data necessary
are beginning to emerge. For example, R. Mikkelsen and
R. Schmidt-Ullrich and their colleagues are utilizing flu-
orescent reporter molecules to register the triggering of
signal transduction pathways in individual cells, and are
finding that in some cases the fraction of cells triggered
and not the degree of transduction increases with radia-
tion dose in the 0-10 Gy range [69]. Another important
question is the time course of damage development. Of
major concern for brachytherapy (or teletherapy) are the
late effects in dose-limiting normal tissues. In tissues that
turn over very slowly, late effects can be understood, at
least to some degree, if they result from a mitotic-linked
death from lethal chromosomal aberrations. Similar rec-
onciliation with long-delayed signal transduction path-
ways and apoptosis are needed to better assess their role
in the late tissue effects that essentially define the limits
of radiation treatment.
11.17 SELECTION OF MUTANTS BY LOW
DOSE RATE
Low dose-rate irradiation turns out to be a very effective
way to isolate repair-defective (or misrepair-proficient)
cells and also to map and isolate the gene(s) involved.
For example, irs-20 cells, a mutant CHO line, complete
only two or three divisions during irradiation at 6 cGy
h"1, a dose rate that has no effect on the growth of wild-
type CHO cells [56]. The defect in these mutant cells can
be corrected by fusion with a normal human cell and

repeated selection at LDR. This allows a FISH mapping
of the gene to human chromosome 8qll, which is the
location of the human homolog of the SCID gene [66].
The exact nature of the mutation, a substitution of
lysine for glutamic acid, has been determined [67,68].
Thus, LDR irradiation can be a powerful tool in gene
discovery.
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69. Mikkelsen, R.B. (2000) Personal communication.

Dose-rate effects with human cells
G. GORDON STEELANDJOHN H. PEACOCK
The term 'dose-rate effect' refers to the change in sensi-
tivity or tissue response when the dose rate of irradiation
is modified. Dose-rate effects are common in mam-
malian cell systems, including human tumors and nor-
mal tissues. The response of these tissues is complex,
depending in part on the radiosensitivity of the stem
cells (or 'clonogenic' cells) of the tissue, but also on the
modifying effects of cell proliferation and such physio-
logical parameters as oxygenation and growth factors.
Whereas in rodent cell systems it is possible to compare
effects seen in vivo with effects on cells brought into tis-
sue culture, such a comparison is difficult for human tis-
sues. There is a body of relevant clinical experience, but
this does not provide the necessary detail and precision
to allow theories to be tested in the way that can be done
in experimental laboratory systems. As a result, attention
12
is restricted in this chapter to dose-rate effects seen in
human cells studied in tissue culture. Although such cell
systems are necessarily artificial, it can be argued that
they do allow the major components of the dose-rate
effect to be demonstrated.
12.1 THE TIME-SCALE OF RADIATION ACTION
The time-scale of biological effects of ionizing radiation
is illustrated in Figure 12.1. It is the operation of some of
the processes represented in this chart that gives rise to
dose-rate effects. Immediately after exposure, free-radical
processes take place leading to damage to many con-
stituents of the cell. Because of its vital nature and the
Figure 12.1 Time-scale of
the effects of radiation
exposure on biological
systems. (From Steel [18].J

relative uniqueness of its genetic message, DNA is the
most important of these damaged molecules. Under
physiological conditions the rapid free-radical reactions
are complete within around 1 ms. During the subsequent
few minutes, enzymatic processes begin to operate on the
damaged molecules. Some of these act to repair the dam-
age; others leave the molecules in a changed but stable
form and we describe this as 'misrepair.' Within a few
hours, these enzymatic processes will be complete. Repair
of radiation damage to DNA is highly effective in most
cell types: a 1 Gy dose will induce upwards of 1000 DNA
strand breaks in every irradiated cell. Roughly half of the
cells will survive this dose, so strand-break rejoining must
be a remarkably error-free process. Most strand breaks
are to one strand only of the double helix, but a small pro-
portion can be recognized as affecting both DNA strands
(double-strand breaks, dsb). There is evidence that these
are much more serious for the viability of the cell. Even
so, the great majority of dsb are also successfully repaired.
Of particular importance are dsb that arise from clusters
of ionizations at the end of the tracks of secondary elec-
trons: these can involve severe damage to the DNA mole-
cule (so-called 'multiply damaged sites') and it may be
that these events have a relatively low probability of suc-
cessful repair and a correspondingly high likelihood of
leading to cell death or mutation.
At longer intervals after irradiation (Figure 12.1), cell
proliferation will take place within tissues, leading to the
replacement of radiation-damaged cells. In tumors this
may lead to recurrence or to a reduced likelihood of suc-
cess as a result of subsequent treatment. In normal tis-
sues, proliferation may prevent tissue breakdown and
the observed early effects of irradiation will then be min-
imal. However, if the level of cell killing is greater and of
such a severity that it cannot be counteracted by prolif-
eration, then serious tissue damage may appear. At even
longer time intervals after irradiation (months to years),
the very long-term effects will become apparent, includ-
ing tissue failure, formation of new tumors, and muta-
tional effects in germ cells.
Mechanisms of the dose-rate effect 181
12.2 MECHANISMS OF THE DOSE-RATE
EFFECT
Observed dose-rate effects derive from the operation of
the processes just described. Clinical external-beam
treatments are usually given within a few minutes. These
brief exposures are long enough for the initial chemical
effects of irradiation to be complete, but are too short for
the subsequent enzymatic and proliferation processes to
take place. As radiation dose rate is lowered, the irradia-
tion time for a given dose increases and it becomes pos-
sible for such processes to take place during radiation
exposure. These will modify the extent of damage and
thus lead to a dose-rate effect.
Four main processes lead in this way to the dose-rate
effect. They are the '4Rs of radiobiology': repair, redistri-
bution, repopulation, and reoxygenation. Among these,
repair is the fastest. As indicated below, the time required
to repair half the induced damage is often in the region
of 1 h. This means that as soon as the duration of expo-
sure becomes a significant fraction of an hour, some
repair will take place during irradiation. At the other
extreme, repopulation is a much slower process: repopu-
lation requires cell multiplication and human cells can-
not divide in less than about a day. Repopulation will
therefore only have a significant effect when the expo-
sure time is a day or more. Redistribution and reoxy-
genation probably have a speed that is intermediate
between these two processes.
Figure 12.2 illustrates the range of dose rates over
which each of these processes might be expected to influ-
ence radiation action. For dose rates in excess of a few
gray per minute, none of the processes will take place
significantly during irradiation and there will be no
dose-rate effect due to them. At much higher dose rates
than illustrated a further process, the consumption of
oxygen by radiochemical reactions leading to partial
hypoxia, may have an effect [1]. At dose rates around
1 Gy min-1, sometimes used for 'high dose rate' or 'acute'
irradiations, there may be a small amount of repair
Figure 12.2 The range of dose
rates over which repair,
reassortment, and repopulation
may influence radiation effects.
182 Dose-rate effects with human cells
during irradiation and (as illustrated in the figure) such
treatments will be slightly less effective than if given at a
higher dose rate. Even in this high dose-rate region there
may therefore be significant implications for practical
radiation therapy and care must be taken to make suit-
able corrections for a change in dose rate. Note that the
effect of repair increases smoothly over roughly two
decades of dose rate (from around 100 to 1 cGy min"1).
In the middle of this range the effect is changing most
rapidly with dose rate. This has important implications
for high dose-rate brachytherapy: when such dose rates
are used the biological effects may depend rather criti-
cally on the precise dose rate employed in a particular
study.
The lines drawn in Figure 12.2 to represent the effects
of repopulation or reassortment are diagrammatic.
Repopulation is a much slower process than repair and
only when the exposure time becomes a significant pro-
portion of a cell cycle time (perhaps 1-4 days in human
tumor and normal tissue cells) will it have a significant
effect during the period of irradiation. Reassortment
(otherwise known as redistribution) refers to effects that
derive from the movement of surviving cells through the
cell cycle after a first dose or dose increment of radiation.
These effects may modify the response of a tissue or cell
system to subsequent irradiation and occur over a dose-
rate range that is somewhere intermediate between those
of repair and repopulation.
The comparative effects of repair and repopulation are
further illustrated in Figure 12.3. This figure shows actual
calculations for a typical human cell line, based on a repair
half-time of 0.85 h and an oc/|3 ratio of 3.7 Gy. Curves are
drawn for four different cell population doubling times
and the calculations show the radiation doses (i.e., ED50
100
Figure 12.3 In human cell systems proliferation probably
affects radiation response for dose rates below about 1 Gy h'1 (or
a few cGy min'1). For a typical human tumor cell line the figure
shows isoeffect curves in the absence of proliferation or with
proliferation at a doubling time of 5, 10, 20, or 50 days. The
calculations are based on a simple model of exponential
growth, ignoring radiation effects on the rate of cell
proliferation.
values) for a survival of 0.01. For these parameter values
there is no effect of proliferation at dose rates above 1 cGy
min"1, but as dose rate is lowered to 0.01 cGy min'1 dra-
matic effects are predicted, depending on the cell popula-
tion doubling time. The implication for brachytherapy is
that above 1 cGy min'1 repopulation effects can be
ignored, but below this dose rate they can, under some
circumstances, predominate over effects due to incom-
plete repair. These calculations also show that in prolifer-
ating cell systems it is not possible to find a dose rate at
which repair is complete but no proliferation occurs:
there is significant overlap between these two processes.
123 DOSE-RATE EFFECTS IN HUMAN TUMOR
CELLS
Pioneering experimental studies of the dose-rate effect
were made in a number of publications by Hall, Bedford
and Mitchell (see reviews by Steel et al. [2,3]). The exper-
iments were performed on a variety of cell lines, mainly
derived from experimental animals but also including
the long-established HeLa cell line (derived from a
human cervix carcinoma). They showed that the dose-
rate effect mainly appeared over the range of dose rates
from 1 Gy min"1 down to 0.1 cGy min"1. There was con-
siderable variation in the magnitude of the dose-rate
effect (i.e., the relative radiosensitivities at high and low
dose rates). Steel et al. [2] analyzed these data and
showed that derived values for the half-time for repair of
radiation damage ranged widely: from below 0.1 h to
greater than 1 h.
Studies on human tumor cell lines taken from a vari-
ety of tumor types were reported by Steel et al. [4]. Most
of the cell lines were newly established. In some cases the
cells were taken directly from human tumors that had
first been grown as xenografts in immune-deficient
mice; other studies were made on cell lines established in
tissue culture. They were irradiated with cobalt-60
gamma-radiation at dose rates ranging from 1 to
150 cGy min"1 at body temperature and under condi-
tions of controlled oxygenation. Cell survival was mea-
sured using a colony assay, either in soft agar or in
monolayer, depending on the growth characteristics of
the cell line. Data on four cell lines are shown in Figure
12.4, covering the range of responses seen in a larger
group of human tumor cell lines. Figure 12.4a shows
results at high dose rate. The data are fitted by a linear-
quadratic equation; there is a well-defined initial slope to
the data, which are clearly consistent with a continuously
bending relationship. The range of sensitivities is consid-
erable. The doses required for a survival of 0.01 range
from 3.6 Gy in the HX142 neuroblastoma to 10.9 Gy in
the RT112 bladder carcinoma (i.e., by a factor of 3). In
the initial dose region the factor is greater. Figure 12.4b
shows the results for the same cell lines at the low dose

icr
Figure 12.4 Cell survival curves for four human tumor cell lines irradiated at (a) 150 cGy min-1 or (b) 7.6 cGy min~\ HX142,
neuroblastoma; HX58, pancreas carcinoma; HX156, cervix carcinoma; RT112, bladder carcinoma. (From Steel [18].j
rate of 1.6 cGy min '. The curves have fanned-out and
become straight or almost so on the semi-logarithmic
plot. It can be seen that at low dose rate the lines seem to
extrapolate the initial slopes of the high dose-rate curves.
The range of sensitivities among the cell lines is now
larger: by a factor of approximately 10.
The data shown in Figure 12.4 indicate the range of
sensitivities seen among tumors of different histological
types. Less information is available about the range of
sensitivities among tumors of the same type, from dif-
ferent patients. Kelland and Steel [5] studied five cell
lines newly established from human cervical carcinomas.
They found that at high dose rate the dose to produce a
surviving fraction of 0.01 ranged from 5 to 10.5 Gy. The
dose-rate sparing factors (the dose at 1.6 cGy min"1 com-
pared with the dose at 150 cGy min"1) ranged from 1.1 to
1.6. This showed that among tumors of the same type
there were considerable radiobiological differences that
could be clinically significant. There may be a number of
causes of failure in brachytherapy and these include the
inherent insensitivity of the tumor cells to radiation. A
so-far insufficiently explored aspect of brachytherapy is
the attempt to develop predictive tests of radiosensitivity
in order to identify patients most at risk of recurrence.
The data in Figure 12.4 clearly indicate that such tests
should be made at low dose rate, where the differences
Models of the dose-rate effect 183
among cell lines are greatest. Bjork-Eriksson et al. [6]
reported that dose-rate experiments were useful to dis-
criminate between radiosensitive and radioresistant
tumors. This confirmed the earlier work of Amdur and
Bedford [7].
12.4 MODELS OF THE DOSE-RATE EFFECT
Theoretical attempts to simulate the dose-rate effect were
made by Oliver [8], by Szechter and Schwartz [9], and by
Dale and Jones [10]. Thames [11] extended the work of
Oliver to the linear-quadratic model and developed what
he called the Incomplete Repair (IR) model. He formu-
lated this not only for the case of continuous low dose-
rate exposure but also for fractionated irradiation with
fractions too close together to allow full repair. The model
is empirical in the sense that it is not based on underlying
mechanistic assumptions. It has been very successful in
fitting a wide range of radiobiological data, both in exper-
imental and clinical studies. Curtis [12], based on earlier
work of Pohlit and coworkers, developed the
Lethal-Potentially Lethal damage (LPL) model. This is
conceptually different from the IR model. It is a mecha-
nistic model which assumes that radiation induces two
184 Dose-rate effects with human cells

types of intracellular lesion: lethal lesions (L) and poten-

tially lethal lesions (P). The L lesions are non-recoverable.
The P lesions may be repaired but they may also be 'fixed',
leading to cell death. The probability of fixation is
assumed to occur by binary interaction between P
lesions. At low dose rate the probability of such interac-
tions will be low (because the lesions are produced far
apart in time and will be repaired). This model thus pre-
dicts that the slope of the low dose-rate curves shown in
Figure 12.4B is due to the sensitivity of the cells to the
production of L-type lesions. This is a mechanistically
interesting hypothesis which is consistent with current
ideas about the production of 'clustered lesions' by low
linear energy transfer (LET) radiation (see reference 13).
Although the IR and LPL models have very different
starting points, they work equally well in most situations.
Thames [11] showed mathematically that they are equiv-
alent for cell survival down to about 0.01.
Data on human tumor cells are well fitted by both
these models [4]. Half-times for repair of radiation dam-
age were deduced to range from 0.4 to 2.3 h. An example
is shown in Figure 12.5. Human melanoma cells (HX34)
were irradiated at dose rates ranging from 1.6 to 150 cGy
min-1. Figure 12.5a shows the survival curves at the
extreme dose rates. These data, together with data at
intermediate dose rates, have been simultaneously fitted
by the IR model giving the following parameter values:
a - 0.27 Gy-1, P = 0.046 Gy2, half-time - 0.92 h. The
model allows an isoeffect curve to be drawn as a function
of dose rate (Figure 12.5b). This is a sigmoid curve of the
type that has been reproduced in Figures 12.2 and 12.3.
The steepest change of sensitivity with dose rate occurs
at around 10 cGy min'1 (if the half-time were longer, the
curve would lie to the left, and if it were shorter, the
curve would lie to the right of the present one).
Current models suggest that, in the absence of prolif-
eration, cellular radiosensitivity at low dose rate Figure 12.5 The dose-rate effect in a human melanoma cell
approaches a limiting value, indicated by the straight line line, HX34. (a) Cell survival curves at high dose rate (150 cGy
in Figure 12.5a. The steepness of this line is crucially min'1) and low dose rate (1 cGy min'1). (b) Isoeffect curve for a
important for the success of low dose-rate brachyther- survival of 0.01 as a function of dose rate. The full line is
apy. There is considerable research interest at the present calculated using the LPL model.
time in the determinants of low dose-rate radiosensitiv-
ity. According to the LPL model, this depends on the
probability of induction of non-repairable lesions in
12.5 EFFECT OF IRRADIATION ON CELL-CYCLE
cells. Such lesions could arise by a variety of processes,
PROGRESSION
including ion cluster effects, as mentioned above, or
recombinational effects during the processing of DNA
damage. Irradiation at high dose rate blocks cell entry into mito-
Values of radiosensitivity parameters for some human sis. The cell cycle may be interrupted at a number of so-
tumor cell lines are given in Table 12.1. These include the called 'check-points', and the biochemical processes
surviving fraction for 2 Gy given at high dose rate (SF2) involved in these arrests are the subject of intense labo-
and the sensitivity of the cells at a low dose rate of ratory research at the present time. At high dose rate
1-2 cGy min"1 (the slope of the linear survival curve is there are two reasons why proliferation effects during
given by the equivalent a value, Gy1). For tumor cell irradiation are unimportant: irradiation times are too
lines in which detailed studies have been made of the short, and the cells are subject to mitotic delay and there-
dose-rate effect [4], the parameters of the LPL model are fore inhibited from proliferating. As dose rate is reduced,
also given. both these factors become less severe and cell cycling
 Cell killing around an implanted radiation source 185

Table 12.1 Radiosensitivity parameters* for a number of human tumor cell lines

HX34 Melanoma 0.47 0.30 0.27 0.046 0.092

HX118 Melanoma 0.43 0.35 0.33 0.038 0.23
HX58 Pancreas carcinoma 0.25 0.53 0.47 0.052 0.80
HX156 Cervix carcinoma 0.59 0.32 0.30 0.022 0.54
HX147 NSCLC 0.82 0.20
HX148 NSCLC 0.55 0.07
HX149 SCLC 0.26 0.38
MGH-U1 Bladder carcinoma 0.57 0.26 0.26 0.17 0.80
RT112 Bladder carcinoma 0.73 0.19 0.12 0.027 0.85
GCT27 Teratoma 0.40 0.50 0.46 0.036 0.34
HX138 Neuroblastoma 0.11 0.84
HX142 Neuroblastoma 0.13 0.98 0.48 0.17 0.54
HC12 SCLC 0.39 0.47
IN859 Glioma 0.57 0.22 0.17 0.055 0.49
IN1265 Glioma 0.73 0.30 0.28 0.027 0.58
SB Glioma 0.47 0.15 0.15 0.034 0.97

* SF2 is the surviving fraction for a dose of 2 Gy at high dose rate.

LDR sens, indicates the slope of the survival curve at 1-2 cGy min"1 (Gy1). a (Gy1), P (Gy2) and Ti (h)
are parameter values of the Lethal-Potentially Lethal model, determined from low dose-rate experi-
ments.
NSCLC = non-small-cell lung cancer; SCLC = small-cell lung cancer.

takes place during irradiation, thus counteracting the
effect of irradiation. At what dose rate does this happen?
Hall [1] concluded that HeLa cells did not proliferate
above 0.2 cGy min'1. Mitchell et al. [14] estimated the
critical dose rate for cell proliferation in six mammalian
cell lines: this ranged widely, from 0.1 cGy min~' in a
lymphoma cell line to over 4 cGy mirr1 in pig kidney and
V79 Chinese hamster cells.
A study by Skladowski et al. [15] illustrates the com-
plexity of the concept of a dose-rate effect on cell prolif-
eration. Human bladder carcinoma cells (MGH-U1)
were irradiated at dose rates ranging from 0.1 to 1.4 cGy
min"1. The mitotic index was scored at frequent intervals
and flow-cytometry was used to quantify the number of
cells in the Gl, S, and G2 phases of the cell cycle. Mitotic
activity was immediately suppressed, to a greater degree
at the higher dose rates, but this recovered after irradia-
tion had continued for about 24 h and, surprisingly, the
time of this recovery was independent of dose rate.
Thereafter, the mitotic index overshot to above the nor-
mal level and at the higher dose rates there was evidence
of synchrony. So proliferation in these cells, though ini-
tially disturbed, did continue when the dose rate was as
high as 1.4 cGy min'1.
Cell survival data were also available for this cell line
as a function of dose rate. It was possible to calculate that
irradiation for 24 h would lead to a surviving fraction of
approximately 0.2 at 0.4 cGy min"1, 0.1 at 0.7 cGy min 1 ,
0.03 at 1 cGy min"1, and 0.008 at 1.4 cGy min-1. So the
irradiation just during the initial 24 h of mitotic arrest
led to sterilization of more than 90% of the clonogenic
cells at dose rates above 0.7 cGy min-1. The flow-
cytometric data on cell-cycle progression may therefore
be misleading, for, at the higher dose rates, most of the
cells observed by this method may be dead from a
colony-forming point of view. It is impossible by such
methods to learn about the cycling of the surviving
colony-forming cells on which tumor recurrence will
depend. Skladowski et al. [15] concluded that cell-cycle
effects in tumor cells are unlikely to be of any great sig-
nificance in relation to the cell-killing effect at different
distances from an implanted radiation source. Overall
treatment times in brachytherapy tend to be short com-
pared with external-beam treatment and proliferation
effects are correspondingly of less significance.
12.6 CELL KILLING AROUND AN IMPLANTED
RADIATION SOURCE
The non-uniformity of radiation field around an
implanted source has important radiobiological conse-
quences. Close to the source, the dose rate is high and the
amount of cell killing will be close to that indicated by
the acute-radiation survival curve. As the distance^from
the source is increased, two changes take place: cells will
be less sensitive at the lower dose rates, and within a
given period of implantation the accumulated dose will
also be less. These two factors lead to a very rapid change
of cell killing with distance from the source [16].
This is illustrated in Figure 12.6 for the case of a point
186 Dose-rate effects with human cells

curves derives in part from the underlying assumed

Poisson relationship between the average number of sur-
viving cells per shell and the control probability. As is the
case with tumor control by external-beam irradiation,
there will in reality be factors that make the tumor con-
trol curves less shallow: heterogeneity, for instance.
Within tissues (tumor or normal) that are close to the
source, the level of cell killing will be so high that cells of
any radiosensitivity will be killed. Further out, the effects
will be so low that even the most radiosensitive cells will
survive. Between these extremes there is a critical zone in
which differential cell killing will occur. In this critical
region the radiation dose rate will be low. For this reason
we would argue that the low dose-rate survival curves as
shown in Figures 12.3 and 12.4 are more clinically real-
istic than the high dose-rate curves, certainly for
brachytherapy [13].
Figure 12.7 contrasts this situation with external-
beam radiotherapy, where the aim is to deliver a uniform

Figure 12.6 The likelihood of cure varies steeply with distance

from a point radiation source. The radius at which failure
occurs depends upon the steepness of the survival curve at low
dose rate (upper panel). (From Steel [18].)

radioactive source. A source strength was chosen that

gives 75 Gy in 6 days at a range of 2 cm. Three different
tumor-cell sensitivities were assumed, as shown in the
upper panel. It is the low dose-rate sensitivities that mat-
ter for this calculation. For spherical shells containing 109
clonogenic cells at different distances from the source, it
was possible to calculate the surviving fraction from 6
days' irradiation, the absolute number of surviving
clonogenic cells, and thus the probability that all cells in Figure 12.7 Variation of cell kill around a point source of
the shell would be killed. The results are shown in the radiation. The source gives 0.87 Gy min~1 at 2 cm (i.e. 75 Gy in 6
lower panel. For cells of any given level of radiosensitiv- days); there are 109 cells per cm3, for which -a - 0.35 Gy1,
ity there will be cliff-like change from high to low local P = 0.035 Gy2, ha If-time for recovery is 1 h. (a) The hatched
cure probability, taking place over a radial distance of a area indicates the volume within which the surviving fraction is
few millimeters. Note that the order of the lines in the below 10~20. The stippled area indicates the volume where
upper and lower panels of this figure is reversed: very survival is between 10-20 and 10-6, which is the critical region for
sensitive tumor cells (lines A) can be cured out to a tumor control. For comparison, panel (b) shows the type of
greater radius than less sensitive cells (B) or very radio- profile that would be aimed for with external-beam
resistant cells (C). The steepness of the tumor control radiotherapy.

radiation dose across the tumor. Only in a narrow zone
around an implanted source (where the surviving frac-
tion changes from, say, 10-20 to 10-6) will radiobiological
considerations be of interest or importance in relation to
tumor control. The same principle will apply to normal-
tissue damage: serious damage to normal structures
depends on making sure that they are outside the corre-
sponding 'cliff.'
12.7 IMPLICATIONS FOR CLINICAL
BRACHYTHERAPY
The radiobiology of low dose-rate irradiation is now
fairly well understood. Although data are not available
on a wide range of human tumors, the data that we have
do indicate the range of responses that are seen for
human cells in tissue culture. It is likely that these will be
realistic for effects on well-oxygenated cells in the
patient. Much less is known about the effects of low
dose-rate irradiation on hypoxic cells in vivo. These are,
of course, less sensitive to high dose-rate irradiation. The
work of Ling et al. [17] showed that the sparing effect of
low dose-rate irradiation as a function of oxygen con-
centration was complex. Lowering the dose rate initially
had more effect on the oxic cells than on the hypoxic
cells. Further lowering of dose rate then had more effect
on the hypoxic cells. Although for such reasons there is
much that still needs to be understood about the tumor
effects of brachytherapy, some simple conclusions can be
drawn:
1. In the dose-rate range from a few Gy min-1 down to
a few cGy mnr1, repair of radiation damage is the
main modifying process on radiosensitivity. The
effects are large, leading to a change in the
isoeffective radiation dose by a factor of 2 or more.
Below 1 cGy mhr1, cell proliferation will play an
increasingly strong role in making tumors or normal
tissues less sensitive to radiation damage.
2. There is evidence for a dose-rate effect in the region
of 1 Gy mhr1. If, in external-beam radiotherapy, a
change of machine or of source-skin distance leads
to a substantial lowering of dose rate, then a dose-
rate correction should be considered.
3. The biological effect of irradiation changes rapidly at
dose rates around 10 cGy min'1. This may mean that
greater precision in dosimetry and dose prescription
is required in high dose-rate brachytherapy than
when a low dose rate is used.
4. Tumor cells of different origins show very different
response to low dose-rate irradiation. Theoretical
calculations suggest that as we move out from an
implanted radiation source the local tumor control
probability will change rapidly, i.e., there will be
sudden failure to eradicate all clonogenic tumor
cells. The prediction that the range at which this
References 187
occurs will depend strongly on the low dose-rate
radiosensitivity of the tumor cells could be clinically
important [6]. There is a strong case for predictive
testing of tumors that are to be treated with curative
intent by brachytherapy in order to predict those
that require a greater or lesser range of dose-
distribution.
REFERENCES
1. Hall, E.J. (1972) Radiation dose-rate: a factor of
importance in radiobiology and radiotherapy. Br.J.
/tarf;o/.,45,81-7.
2. Steel, G.G., Down, J.D., Peacock, J.H. and Stephens, T.C.
(1986) Dose-rate effects and the repair of radiation
damage. Radiother. Oncol., S, 321-31.
3. Steel, G.G. (1997) The dose-rate effect: brachytherapy. In
Basic Clinical Radiobiology, ed. G.G. Steel. London,
Edward Arnold, 163-72.
4. Steel, G.G., Deacon, J.M., Duchesne, G.M., Norwich, A.,
Kelland,LR. and Peacock, J.H. (1987) The dose-rate
effect in human tumour cells. Radiother. Oncol., 9,
299-310.
5. Kelland, LR. and Steel, G.G. (1988) Differences in
radiation response among human cervix carcinoma cell
lines. Radiother. Oncol., 13,225-32.
6. Bjbrk-Eriksson,T., West, C., Karlsson, E. and Mercke, C.
(1998) Discrimination of human tumor radioresponsiveness
using low-dose rate irradiation. Int.J. Radiat. Oncol. Biol.
P/jys.,42,1147-53.
7. Amdur, R.J. and Bedford, J.S. (1994) Dose-rate effects
between 0.3 and 30 Gy/h in a normal and a malignant
human cell line. IntJ. Radiat. Oncol. Biol. Phys., 30,
83-90.
8. Oliver, R. (1964) A comparison of the effects of acute and
protracted gamma-irradiation on the growth of seedlings
of vivia faba. Int.J. Radiat. Biol., 5,475-88.
9. Szechter, A. and Schwarz G. (1977) Dose-rate effects,
fractionation and cell survival at lowered temperatures.
Radiat. /?., 71, 593-613.
10. Dale, R.G. and Jones, B. (1998) The clinical radiobiology of
brachytherapy. Br.J. Radial., 71,465-83.
11. Thames, H.D. (1985) An 'incomplete-repair' model for
survival after fractionated and continuous irradiations.
IntJ. Radiat. Biol.,47,319-39.
12. Curtis, S.B. (1986) Lethal and potentially lethal lesions
induced by radiation -a unified repair model. Radiat.
Res., 106,252-70.
13. Steel, G.G. (1991) Cellular sensitivity to low dose-rate
irradiation focuses the problem of tumour radio-
resistance. Radiother. Oncol., 20,71-83.
14. Mitchell, J.B., Bedford, J.S. and Bailey, S.M. (1979) Dose-
rate effects on the cell cycle and survival of S3 HeLa and
V79 cells. Radiat. Res., 79, 520-36.
188 Dose-rate effects with human cells
15. Skladowski, K., McMillan, T.J., Peacock, J.H., Titley, J. and
Steel, G.G. (1993) Cell-cycle progression during
continuous irradiation of a human bladder carcinoma
cell line. Radiother. Oncol., 28,219-27.
16. Steel, G.G., Kelland, LR. and Peacock, J.H. (1989) The
radiobiological basis for low dose-rate radiotherapy. In
Brachytherapy 2, Proceedings of the 5th International
Selectron Users' Meeting 1988, ed. R.F. Mould. Leersum,
The Netherlands, Nucletron International BV, 15-25.
17. Ling, C.C., Spiro, I.J., Mitchell, J. and Stickler, R. (1985) The
variation of OER with dose rate. Int.}. Radial. Oncol. Biol.
P/?ys.,11,1367-73.
18. Steel, G.G. (ed.) (1997) Basic Clinical Radiobiology.
London, Edward Arnold.

Radiobiology of high dose-rate, low dose-rate,
and pulsed dose-rate brachytherapy
DAVID J. BRENNER, ROGER DALE, COLIN ORTON, AND JACK FOWLER
13.1 BIOPHYSICAL MODELING IN
RADIOTHERAPY
In the 1970s, before the observations about the differen-
tial response of early-responding and late-responding
tissues had been made, the technique in widespread use
for predicting alternative fractionation schemes was the
Nominal Standard Dose (NSD) approach, developed by
Ellis [ 1 ]. This concept introduced for the first time the
idea of separating overall time from the number of frac-
tions, but did not include the important differential
response to fraction size/dose rate of early and late
effects.
Following the initial suggestion by Barendsen [2],
since the 1980s, the NSD (or time-dose factor, TDF)
approach has been largely replaced by the linear-
quadratic (LQ) model. The reasons for this change were
reviewed by Fowler [3]. Essentially, the NSD model,
which is an empirically based approach, was useful when
used to interpolate regimens with fraction numbers
comparable to those from which its parameters were
derived, but unsuccessful when used outside this range.
When used to extrapolate, neither the assumed depen-
dence on overall time nor the fraction size proved reli-
able in late-responding normal tissues.
The LQ model is different from the NSD approach in
two fundamental ways:
13
1. The LQ model is based on mechanistic radio-
biological notions about how cells are killed by
radiation, so extrapolation of clinical results, though
always to be viewed with caution, is a more
reasonable option than with NSD, which represents
an empirical fit of a convenient, but non-
mechanistically based, formula to a limited data set.
2. The LQ approach allows a clear separation to be
made between effects in early-responding and late-
responding tissues.
As described in this chapter, after more than a decade
of investigation and use, the basic ideas and parameters
in the LQ model have held up surprisingly well in the
clinic.
The large dose gradients and inhomogeneous dose
distributions associated with brachytherapy present
problems in deciding where to specify the dose prescrip-
tion point for such treatments. There are, however, two
general points which may be made, and which simplify
some of the considerations:
1. Tumor control probability (TCP) is determined
mostly by the minimum dose received by the tumor.
Provided all parts of the tumor are within an isodose
surface, which is sufficiently large to achieve a
reasonable TCP, and provided there are no pockets
of underdosage within that critical surface, the
190 Radiobiology of HDR, LDR, and PDR brachytherapy
degree of dose variation within that surface is not a
major consideration.
2. In all types of radiotherapy, the normal tissue
complication probability (NTCP) is volume related.
In the case of a brachytherapy treatment, the dose
gradients ensure that there is no clearly delineated
treatment volume, and the NTCP is therefore more
likely to be related to the integral dose received by
critical structures.
Because of these two considerations, no 'one number'
dose specification can give an adequate indication of
both the likely TCP and the likely NTCP. By the same
token, attempts to compare the results of several treat-
ments in terms of 'one number' dose specifications are
fraught with difficulty and may be exceedingly mislead-
ing.
Figure 13.1 helps to quantify the nature of the prob-
lem. The curves show how the biologically effective dose
(BED) required for 50% TCP changes with increasing
tumor radius, firstly for tumors containing only 1% of
clonogenic cells, and then for tumors consisting of 100%
clonogens. The curves have been derived by direct appli-
cation of the LQ model to concentric shells around a
central source. The net TCP associated with any particu-
Figure 13.1 Illustration to show how the tumor surface dose (Gy) required for 50% tumor cure probability varies relatively slowly
with increasing tumor radius (cm). Three sensitivities (a values) are considered: a,=0.45 Gy7, a2=0.35 Gy', a3-0.25 Gy1. (a) Tumor
volume consisting of 1% clonogenic cells, (b) Tumor volume consisting of 100% clonogenic cells.
lar tumor is determined by the net surviving number of
clonogens. Two points emerge from the graphs:
1. As in other types of radiotherapy, radiosensitivity
and the percentage of tumor clonogens are the most
important determinants of the dose necessary to
cure a tumor with brachytherapy.
2. For a tumor of given radiosensitivity and percentage
of clonogens, the BED required for a given TCP
increases only slowly with increasing size, i.e.,
provided the dose (and hence BED) is specified at
the tumor surface.
To judge properly the quality of brachytherapy appli-
cations, and to allow some degree of treatment opti-
mization, new methods and parameters are now being
proposed. Some of the indices which have been sug-
gested relate only to the physical dose uniformity [4-6],
whereas others relate to both the dose uniformity and
the degree of overlap between the reference isodose sur-
face and the normal tissue volume [7]. Whilst such
indices are currently related to the physical characteris-
tics of brachytherapy, their future development will
undoubtedly require extensions which involve radiobio-
logical parameters, thus opening the way to biologically
optimized brachytherapy.

13,2 THE LINEAR-QUADRATIC MODEL
13,2*1 Mechanistic basis of the LQ model
Central to the LQ approach is a biological model of radi-
ation action, which was spelled out in detail over 50 years
ago by Lea and Catcheside [8,9], based on a mechanistic
analysis of chromosomal-aberration induction in
Tradescantia spores. The application of this formalism to
radiation therapy has been reviewed by Hall [10],
Thames and Hendry [11], Dale [12], Fowler [3], and
many others.
Central to the approach is that radiotherapeutic
response is primarily related to cell survival (or perhaps
survival of groups of cells). This concept is itself not nec-
essarily true, but there is now a wealth of evidence that
cell killing is the dominant determinant of radiothera-
peutic response, for both early-responding and late-
responding endpoints [10,11].
In the most basic LQ approach, cellular survival, S, at
a dose D is written as:
The mechanistic interpretation of equation 13.1 is
that cell killing results from the interaction of two ele-
mentary damaged species - probably DNA double-
strand breaks - to produce a species - perhaps a
dicentric chromosomal aberration - which may cause
lethality. The two terms in equation 13.1 indicate that
the two elementary damaged species may be produced
by the passage of the same track of radiation (linear term
in dose) or by two different tracks (quadratic term).
Clearly, if some time elapses between the passage of the
first and second tracks, there exists the possibility of the
first damaged site being repaired before interacting with
the second. This repair will result in the reduction of the
second, quadratic term in equation 13.1 (but not the
first), by a factor denoted G by Lea and Catcheside [8]:
where, for acute exposures, G>l, and for very long
exposures G>0. In this context, 'acute' and 'long' are
defined relative to the half-time for repair of sublethal
damage (Ti). In general, the G factor in equation 13.2
will depend on the details of the temporal distribution of
the dose, as well as on TI. As discussed before, for many
simple cases, G can be calculated analytically. For exam-
ple, for n short, equal fractions, where the separation
between fractions is much longer than T|, Gl/n.
Formulae for many other standard schemes have also
been derived [8,12,13], as has a general formalism for
any possible scheme [14].
It is important to note the mechanistic basis of equa-
tion 13.2 so that it is not simply an equation which hap-
pens to fit cellular survival curves. It has been suggested,
for example, that the LQ model can be considered sim-
The linear-quadratic model 191
ply as the first two terms (i.e., dose and dose squared) of
a power-series expansion [15]. If LQ were just another
empirical model, there would be no good reason for con-
sidering the linear dose term to be independent of pro-
traction/fractionation, and the quadratic term in dose to
be fractionation dependent. This distinction between the
linear and the quadratic terms is at the heart of the LQ
model and its application.
Based on equation 13.2, we can proceed in two ways.
We can either try to equate schemes, i.e., produce a regi-
men with the same, say, tumor response, as a 'tried and
tested' regimen, or we can try to predict absolute
responses. Both routes are discussed here, though it is
argued elsewhere in the chapter that equating schemes is
a far more reliable procedure.
Thus, assuming tumor repopulation (described
below) is negligible, to match a new fractionation
scheme (labeled n) to a given ('old') fractionation
scheme (labeled o), we must calculate the dose (DJ in
scheme n such that:
Assuming we know how to calculate G, and that we
know a suitable value for a/f3, equation 13.3 can clearly
be solved to yield Dn.
If we wish to proceed to the other route, and actually
calculate absolute tumor control probabilities (TCP) or
normal-tissue complication probabilities (NTCP), we
need models relating cellular survival (S) with TCP or
with NTCP.
The standard model derives from the suggestion of
Munro and Gilbert [16] that TCPs can be calculated
from the probability that, after radiation treatment, there
are no remaining stem cells capable of initiating tumor
regrowth. Let us suppose that a dose, D, delivered in a
given fractionation pattern, produces a stem-cell survival
probability S. We define K to be the initial number of
potential stem cells in the tumor, i.e. the number of cells
that have the independent capability to initiate tumor
regrowth. Then each initial stem cell will have a proba-
bility of not initiating tumor regrowth of (1-S), and thus
the TCP is simply:
which, for small values of S, is approximately
The surviving fraction, S, is given by the LQ model as
equation 13.2 or 13.7, and so the TCP is:
This same formula may also be used to calculate
NTCPs, except that now the parameter K does not refer
192 Radiobiology of HDR, LDR, and PDR brachytherapy

to the number of tumor cells which need to be sterilized,

but rather to the number of groups of cells in the normal
tissue ('tissue-rescuing units' [17]), whose destruction
would result in the late complication.
The problem with using formulae such as equation
13.6 to calculate absolute, de novo, values of TCP or
NTCP is that the results are exquisitely sensitive to the
parameter values, particularly the K parameter, and, in
general, the utility of these equations for absolute, de
novOy calculations is quite limited. Rather, the main
application of the LQ model is for comparisons between
regimens equation 13.3, which are much less sensitive to
the LQ parameter values.

13*2.2 Our knowledge of LQ parameters

Around 1980, Withers and colleagues [18] made the key

Figure 13.2 The dose-response curve for late-responding tissue
observation that early-responding and late-responding
is 'curvy', i.e., has a small a/b ratio; for early-responding
tissues differed in their responses to fractionation (and, by
endpoints such as tumor control, the dose-response curve is
implication, low dose rate, LDR). Essentially, Withers and
straighter, i.e., the a/b ratio is larger. Consequently, dose
colleagues showed that, for a given dose, increasing the
fractionation spares late-responding tissues more than early-
fraction size (or, by implication, decreasing the number of
responding tissues. (Adapted from reference 63.)
fractions or increasing the dose rate) will increase late
effects much more than it will increase tumor control.
Conversely, decreasing the fraction size (or increasing the
number of fractions, or decreasing the dose rate) will Consequently, when using the LQ model, it is essential
decrease late effects much more than it will decrease to be clear about whether the calculation is designed to
tumor control. Thus the 'therapeutic ratio' (ratio of refer to early-responding or late-responding tissue. From
tumor control to complications) will increase as the num- equation 13.3, it is clear that use of different values of
ber of fractions increases, or as the dose rate decreases. a/P will result in different answers for the isoeffect dose.
In terms of the LQ model, these observations can be
interpreted in terms of the a/p ratio. In terms of survival
curves (see Figure 13.2), the a/b ratio essentially 1.3.2.3 New extensions to the LQ model
describes the degree of 'curviness' of the acute survival
curve. A small value of a/b means that the P (dose REPOPULATION
squared) term is dominating at radiotherapeutic doses,
Equation 13.2, which is the basic LQ equation, addresses
resulting in a curvy survival curve (bottom curve in
only the inactivation of a homogeneous population of
Figure 13.2). A large value of a/b means the a (linear in
cells. There is no doubt, however, that accelerated repop-
dose) term is dominating, resulting in a straighter sur-
ulation of tumor clonogens during radiotherapy is often
vival curve. Now, as a first approximation, the
an important factor in determining tumor control
dose-response relation for a fractionated (or LDR) regi-
[19,20].
men can be thought of as simply the result of multiple
The LQ formalism can also take into account the
repeats of the initial part of the survival curve. Clearly
effects of tumor repopulation, i.e., the effects on tumor
(see Figure 13.2), repeating the early part of a curvy sur-
control of changes in the overall time. Following the
vival curve many times will result in far more sparing
original formulation by Travis and Tucker [21], overall
than repeating the early part of a straighter survival
time is taken into account by increasing the surviving
curve. fraction by a factor exp(y[T-TD]), where T is the overall
Thus, late effects, which are very sensitive to changes
treatment time, and TD is the delay after the beginning of
in fractionation, are characterized by small values of a/b,
the treatment before tumor-cell proliferation begins.
and early effects (tumor control or early-responding
Then, the survival is given by:
normal sequelae) are characterized by large values of
oc/p. As clinical data accumulated during the 1980s and
1990s from which a/P ratios can be derived, the
where
dichotomy between a/b ratios for early and late effects,
originally inferred from animal data, has held up
remarkably well.

The parameter y determines the speed of the repopu-
lation, and is given by:
y=0.693/7;, (13.8)
where Tp is the effective doubling time of cells in the
tumor. If we can ignore spontaneous cell loss, Tp is
approximately the same as the measurable in-vitro dou-
bling time of the tumor cells.
In summary, then, to match a fractionation scheme
(labeled 2) to a given fractionation scheme (labeled 1),
we must calculate the dose (DJ in scheme 2 such that:
with the same convention as equation 13.7.
It should be noted that, for late-responding tissues, y
is effectively zero. In other words, late-responding seque-
lae do not vary significantly with changes in overall
treatment time.
REDISTRIBUTION AND REOXYGENATION
The LQ model as used in equation 13.7 incorporates
sublethal damage repair and repopulation. These two
factors are often referred to as two of the '4Rs' of radio-
therapy. Recently, an extension has been proposed to the
LQ model, termed LQR, to include also the other two
'Rs': cell cycle redistribution and reoxygenation [22].
In the LQR approach, redistribution (due to progres-
sion through the cell cycle) and reoxygenation are both
regarded as aspects of a single phenomenon, termed
resensitization [23]. Resensitization occurs when a radi-
ation exposure preferentially kills the more radiosensi-
tive cells in a diverse population, producing a decreased
average radiosensitivity just after the dose is adminis-
tered; subsequent biologically driven changes then tend
gradually to restore the original population average
radiosensitivity.
The LQR model represents a generalization of the
LQ model. In contrast to some multi-parametric
approaches, it uses only two additional adjustable para-
meters, an overall resensitization time and overall resen-
sitization amplitude. Its essential feature is to replace the
LQ cell survival equation (equation 13.7) with the equa-
tion:
Here, all the terms except the last are the same as for
the LQ survival equation (13.7); they again model lethal-
ity, repair, and repopulation. The new term is the last,
+ {(72 (jD2. This term contains the resensitization magni-
tude, which is positive and is written }a2. This resensiti-
zation magnitude is regarded as an average for the
dominant resensitization effects present in a heteroge-
neous tumor. The influence of fractionation on resensi-
tization is contained in the factor (j of the above
equation and depends on a characteristic resensitization
time, TS. When simplifying assumptions were introduced
The linear-quadratic model 193
for cell-cycle distribution and reoxygenation [22,23], G
turned out to have exactly the same form as the G func-
tion for sublethal damage repair, i.e., in the term GfSD2,
with the characteristic repair time replaced with the
characteristic resensitization time, Ts. However, in con-
trast to repair, resensitization tends to increase sensitiv-
ity as the overall time increases. For example, tumor cells
which were in a resistant part of the cell cycle at the time
of one fraction and were thus preferentially spared may
move to a more sensitive part of the cell cycle. This dif-
ference between repair and resensitization is manifest in
equation 13.10 by the'+' sign in the resensitization term
compared with a'' sign in the repair term.
While mechanistically driven, the model is designed to
be sufficiently simple that it can be practically applied to
isoeffect calculations in radiotherapy. Its idealizations in
the consideration of resensitization parallel those inher-
ent in the standard LQ model relating to repair. The
model gives reasonable fits to relevant experimental data
in the literature [22].
THE EFFECTS OF TUMOR SHRINKAGE
When there is a significant degree of ongoing shrinkage
throughout a course of brachytherapy, and when the
radiation sources are centrally situated within the tumor
volume, the BED to the tumor may be higher than that
calculated with standard equations. Because the physical
dose in a brachytherapy treatment varies rapidly with dis-
tance from the source(s), radiation oncologists usually
select a prescription point (itself an element of a three-
dimensional isodose surface designed to enclose the
assumed tumor volume) at which the reference dose for
the treatment is specified. If that reference surface dimin-
ishes in size as a result of tumor shrinkage, an increase in
physical dose results, because those cells at the dose spec-
ification point will move closer to the source(s) during
treatment, and will receive a higher dose than that pre-
scribed. The radiobiological consequence of this has been
examined in some detail by Dale and Jones [24,25].
By assuming that the linear dimensions of the tumor
shrink exponentially with time, the effective BED of a
high dose-rate (HDR) brachytherapy treatment consist-
ing of N fractions of dose d (to the dose prescription
point) is given by:
where
X = 1 +(N/-1)zf
and z is the rate of linear tumor shrinkage (day1), and t
is the time between fractions (days). For a continuous
low dose-rate (CLDR) treatment delivering a dose rate of
1? Gy h'1 over T hours, the BED is:
where
194 Radiobiology of HDR, LDR, and PDR brachytherapy
Y = 1 + zT/24
The similarity of form between equations 13.11 and
13.12 should be noted.
For late-responding normal tissues adjacent to the
tumor, there will be little or no repopulation during the
treatment (i.e., K= 0). If the normal tissues move toward
the source(s) as a result of the shrinking of the tumor,
then the late-reacting BED will always increase with
increasing fraction interval.
The interesting point about equations 13.11 and 13.12
is that they indicate that an increase in BED is not an
inevitable consequence of tumor shrinkage. In the case
of HDR, increasing the time interval (?) between frac-
tions allows for more shrinkage, but this will improve the
BED only if the following inequality is satisfied:
Equation 13.13 confirms what is to be intuitively
expected, i.e., that such favorable conditions are more
likely to exist when the dose equivalent of the repopula-
tion rate (fC) is small, and/or when the shrinkage rate (z)
is large.
Because equation 13.13 incorporates the ratio K/z,
and not merely z, it serves as a reminder that ongoing
shrinkage is not, by itself, enough to guarantee that the
BED will be favorably increased by the use of larger frac-
tion intervals, i.e., whether or not there is an increase in
biological effect with shrinkage is dependent on the ratio
of K/z.
Dale and Jones [24,25] have examined the possible
radiobiological consequences of tumor shrinkage, in
terms of the optimal interfraction spacing of HDR
brachytherapy. They concluded:
1. When the shrinkage rate (z) is small, then, largely
irrespective of the value of K, there will be few
benefits associated with the use of a long time gap
(?) between fractions. For most values of Kthe BED
always reduces with increasing time interval.
2. For higher values of z and moderate or low K values,
BED can be usefully increased by increasing the time
gaps.
3. Increasing t between fractions is beneficial only
when the shrinkage constant and the daily
repopulation factor are favorably related. When
there is doubt about the radiobiological parameters,
or in the absence of predictive assays (of SF2 and Tpot,
for example), and if the tumor regression rate
cannot be determined during the initial phase of
treatment, then relatively close spacing of fractions
minimizes the possibility of large variations about
the prescribed value of BED. Close fraction spacing
is therefore the 'safe' option in such cases.
Following from conclusion (3), it is possible to inves-
tigate the radiobiological conditions which will allow the
BED to increase with increasing fraction interval. In
mathematical terms, this is equivalent to saying that the
slope of the curve of BED versus time - given by the dif-
ferential d(BED)/dt - will be positive for all values of t in
this condition. The conditions for which this is true lead
to the following conclusion.
For critical cases (high K value and/or small shrinkage
rate), the ratio K/z will be large, and in such cases the
interfraction intervals should be kept as small as possi-
ble. This is because the BED finally delivered in such
cases will always be less than that intended (primarily
because of the dominant effect of the high rate of repop-
ulation), causing the loss of biological effect to increase
as the interval between fractions increases, i.e.,
d(BED)/dt will usually be negative over the range of
fraction intervals which are likely to be used in practice.
These considerations concerning tumor shrinkage
may also impact on the optimal time spacing between
external-beam radiotherapy and brachytherapy. The
precise time at which tumor shrinkage begins during a
course of radiotherapy is an important consideration in
judging how teletherapy and brachytherapy should be
juxtapositioned. In practice, it is unlikely that dynamic
tumor shrinkage will commence immediately after the
first radiation delivery and, for this reason, it is likely that
equation 13.11 overestimates the increase in BED when
the K/z ratio is small. Similarly, there may be under-
estimation of the decrease in BED associated with a large
K/z. The equations in this section may therefore have
greater validity when the brachytherapy treatments have
been preceded by teletherapy, or other anticancer
modalities such as cytotoxic chemotherapy, which also
causes tumor volumes to decrease exponentially [26]. It
is therefore appropriate to consider separately
brachytherapy used alone and brachytherapy used in
combination with teletherapy.
For radical brachytherapy, relatively large doses will be
prescribed, and the conditions of the inequality in equa-
tion 13.13 are more likely to be satisfied because the
product Nd is large, so that the tumor BED will probably
increase with time once tumor shrinkage is initiated.
Although difficult to implement in practice, there might
be advantages in initially using relatively short interfrac-
tion intervals and then increasing them once the tumor
regression has attained a steady state. However, even with
a small K and/or large z (i.e., small K/z), excessively
extended intervals may not be feasible if HDR applica-
tors require to remain in situ throughout the whole
course of treatment [27]. It is also possible that over-
extension of t may allow for accelerated repopulation in
squamous cell carcinomas [19,20] or, alternatively, a
reduction of the spontaneous cell-loss rate [28], either of
these phenomena requiring the delivery of additional
dose to restore isoeffectiveness.
Brachytherapy is most commonly used in combina-
tion with external-beam radiotherapy. For high K/z
ratios, the brachytherapy should be included within the
overall time required for delivery of the teletherapy

regime. Where a small K/z ratio is known to be obtain-
able, the application of brachytherapy should be
deferred until steady-state tumor shrinkage has been ini-
tiated, i.e., brachytherapy will always be more effective if
it follows teletherapy in this case. Further improvements
can be achieved by optimizing the time gap between the
cessation of teletherapy and initiation of brachytherapy,
but the overall TCPs remain dependent on tumor size
[29,30].
If the tumor shrinkage rate following teletherapy is
very small, the brachytherapy BED is unlikely to be sig-
nificantly enhanced. In such cases, particularly for larger
tumors, debulking surgery can be used to reduce clono-
gen number, followed by brachytherapy to the tumor
bed. Alternatively, cytotoxic chemotherapy can be used
to reduce tumor repopulation during continued tumor
regression, and brachytherapy given at a later stage to the
smaller tumor [29,31].
Other considerations may apply for clinical situations
in which the tumor center is distanced away from the
treatment catheter, as in the case of intraluminal HDR
treatments for carcinomas of the bronchus and esopha-
gus. This form of treatment geometry has been consid-
ered by Bleasdale and Jones [29], but the overall
principles are the same as described in this chapter. With
an offset tumor center, any regression will not produce
the same degree of physical dose advantage, so that
extensions of overall time will not always be advanta-
geous. If the clinical constraints are such that HDR bron-
choscopic applications can only be performed every 2
weeks, and the tolerable number of fractions is only
three, then brachytherapy should be commenced rela-
tively early within a 6-7-week teletherapy regime [32]. If
the three HDR brachytherapy fractions can be delivered
over a period of 1 month, when the repopulation factor
is likely to be unfavorable, consideration should be given
to shortening the external-beam therapy to the same
overall treatment time.
In all cases it must be remembered that tumor shrink-
age may cause adjacent normal tissues to move closer to
the treatment source(s). For radical treatments, any deci-
sion to increase the tumor BED by prolonging the frac-
tion interval must be tempered by the possibility that the
normal tissue tolerance dose may be reached or
exceeded. Whether or not this is the case can only be
determined by careful measurement or estimation of the
movement of the critical normal tissues at the time of
delivery of each dose fraction.
It is clear that the development of improved
brachytherapy treatment requires a greater knowledge of
the radiobiological processes which govern treatment
outcome, and in this chapter the importance of the
opposing effects of tumor shrinkage and repopulation
particularly have been highlighted. Predictive assays and
serial imaging techniques are already available and are
likely to be powerful tools in allowing the mathematical
models to be more effectively applied for the benefit of
The linear-quadratic model 195
individual patients. The wider availability and use of
such methods would seem to be the obvious next step in
the further development of brachytherapy.
MOVING ISODOSE SURFACES
Because brachytherapy doses are traditionally prescribed
at a specific point, it has become commonplace also to
compare radiobiological effects at a defined anatomical
point. This has led to the notion that, if therapeutic ratio
is not to be seriously compromised, considerable care
must be exercised when replacing LDR techniques by
fractionated HDR. Many articles have dealt with this
aspect of radiobiology, but, as discussed later in this
chapter, in certain special situations (of which
brachytherapy of the uterine cervix is the most com-
mon), it may be demonstrated that HDR brachytherapy
in small numbers of fractions may be less detrimental
than is sometimes supposed. Dale [33], Brenner and Hall
[34], and Orton [35] have shown that, even without rel-
atively favorable radiobiological parameters, a modest
extra amount of geometrical spacing of critical normal
tissues at HDR allows the use of small numbers of frac-
tions without loss of therapeutic ratio. Improved geom-
etry is easiest to achieve in the case of intracavitary
treatments, less so with intraluminal brachytherapy.
A refreshing new analysis of the problem has recently
been conducted by Deehan and O'Donoghue [36], who
considered how the relative positions of isodose surfaces
are changed in switching from LDR to HDR. Although
the issue is seemingly complex, it may be summarized
quite simply.
Once a fractionated HDR regime has been designed to
match an LDR regime at a particular reference point, the
LQ model may be used to calculate the biological effects
(BEDs) at other sites closer to, and further away from,
the sources. Figure 13.3 illustrates a typical case. It will be
noted that, at all points closer to the sources, the HDR
treatment delivers a higher BED than the LDR treat-
ment. Conversely, at those sites on the distal side of the
matching point, the BEDs with HDR are always lower
than in the LDR case. The important point here is that
the gradients of the BED versus distance curves differ
between HDR and LDR, even though the effects have
been matched at the reference point. The separation
between these curves, in fact, becomes greater as the
fraction number is reduced.
The individual elements making up the curves in
Figure 13.3 are parts of smooth isoeffect surfaces sur-
rounding the treatment sources. Thus, for sites close to
the sources, any particular LDR isoeffect surface moves
further out when HDR is used, i.e., the volume of
enclosed tissue receiving more than a given biological
dose is increased. Similarly, at surfaces beyond the
matching point, the isoeffect surfaces move inwards, and
the volumes of tissue receiving a given biological dose
are reduced. Because the more proximal sites are likely to
196 Radiobiology of HDR, LDR, and PDR brachytherapy
Image Not Available
Figure 13.3 Illustration to show how radiobiological
equivalence between LDR and HDR is achievable only at the
chosen matching point. At sites closer to the sources, the HDR
delivers a higher biological dose (BED) than LDR; at sites on the
distal side of the matching point, the BED from the HDR is
lower than from the LDR. The lateral separation between the
two curves increases as the number of HDR fractions is
decreased. Because the curves are two-dimensional
representations of three-dimensional isoeffect surfaces, the
switch from LDR to HDR brings about a (possibly useful)
increase in the tissue volume irradiated to more than a given
biological dose at sites close to the sources, but a favorable
decrease in the volume receiving more than a given biological
dose at sites beyond the matching point. (Reproduced from
reference 36, with permission.)
be in the vicinity of tumor cells, and the more distal sites
are likely to be in the vicinity of normal tissues, this rel-
ative shifting of the isodose surfaces will tend to enhance
the integral dose (i.e., dose x volume product) for tumor,
whilst diminishing that for the normal tissues. Such
trends may be ideally expressed in terms of effect-
volume histograms.
Further extension of Deehan and O'Donoghue's work
allows assessment of the linear displacements in the iso-
dose surfaces, and hence of the changes in the included
tissue volumes. It thus paves the way to a better under-
standing of radiobiological differences between HDR
and LDR in terms of changes in irradiated volumes, and
opens up a new avenue for investigating one of the most
elusive aspects of brachytherapy - the modeling of
volume effects. For intraluminal treatments in particu-
lar, consideration of surface movement shows that
fractionated HDR may offer benefits over LDR.
133 HIGH DOSE-RATE VERSUS LOW DOSE-
RATF RRAfHYTHFRAPY
13.3.1 From LDR to HDR: general principles
Basic radiobiological principles tell us that the optimal
strategy for any radiotherapeutic regimen requires:
1. Use of large numbers of fractions or LDR to
maximize sparing of late-responding normal tissues,
and to allow reoxygenation;
2. Use of short overall times to limit tumor
repopulation;
3. Use of long overall times to reduce early normal-
tissue sequelae, especially to the skin and mucosa.
Because of the physical dose distributions in
brachytherapy, the last point is not normally a major
concern, and it becomes clear why brachytherapy is often
the treatment of choice for those tumors which are rea-
sonably accessible for an implant.
It is also clear that moving from LDR to HDR must
generally involve a loss in therapeutic advantage. To put
it in terms of LQ calculations, if an HDR dose is calcu-
lated using, say, equation 13.3, based on producing equal
tumor control to an LDR regimen, that HDR dose will
not be isoeffective in terms of late effects, but will pro-
duce increased late sequelae. Conversely, if an HDR dose
is calculated to produce, say, equal late sequelae to an
LDR regime, the HDR dose would be expected to pro-
duce less tumor control than the corresponding LDR
regime.
Thus, in general, HDR represents a compromise
between therapeutic advantage, which decreases, and
some other factor (such as patient convenience, treat-
ment repeatability, etc.), which may increase.
133.2 A special case: cancer of the cervix
It is clear from the previous discussion that many frac-
tions are necessary in order for HDR treatments to be
radiobiologically equivalent to LDR, all other things
being equal. However, for the treatment of carcinoma
of the uterine cervix, it has been well documented that
equal, and maybe even superior, results (same local
control and survival but with fewer complications) can
be obtained with as few as about five fractions
[33-35].
This apparent discrepancy between radiobiological
theory and clinical evidence is probably because not all
other things are equal for cervical cancer radiotherapy.
Clearly, one of the major reasons why brachytherapy is so
 High dose-rate versus low dose-rate brachytherapy 197

effective and therefore widely utilized in these treatments

is that the radiation sources are placed in and around the
tumor and away from the normal tissues most susceptible
to late radiation damage, specifically the rectum and blad-
der. In the previous sections, it was assumed that the doses
to tumor and normal tissues were the same, whereas, with
cervical cancer brachytherapy, packing and/or retraction,
'optimal' source distributions, and applicator shielding
are all strategies that can be applied to keep normal tissue
doses below those applied to the tumor.
As discussed earlier in this chapter, because cervical
cancer brachytherapy dose distributions are so inhomo-
geneous, it is not really appropriate to consider the dose
Image Not Available
to just a single point, e.g., Point A, to represent the
'tumor dose' [37]. Doses to single rectal or bladder
'points' similarly do not truly represent 'normal tissue
doses' [38]. What are required are the 'effective doses' to
tumor and normal tissues derived by analysis of three-
dimensional dose-volume histograms, where the 'effec-
tive dose' is that dose which, if delivered uniformly to the
tissue in question, would result in the same probability
of effect (TCP or NTCP) as the inhomogeneous dose
distribution present in that tissue. Several techniques,
though not ideal, have been devised to reduce dose-
volume histogram data to a single number, such as 'effec-
tive dose' [39]. For brachytherapy treatments for cervical
cancer, it has been demonstrated that the vast majority
of the cervix tissue receives substantially higher doses
than most of the rectal and bladder tissues [38]. This is
Figure 13.4 Typical differential dose-volume histograms: (a) for
illustrated for rectal tissues in Figure 13.4. Hence, the
cervix, and (b) for rectal tissues obtained using the University of
'effective doses' to normal tissues are significantly lower
Michigan CT-compatible Fletcher-type applicator for the
that the 'effective tumor dose.'
treatment of carcinoma of the cervix [37]. The prescription
This needs to be taken into account when applying
called for a minimum dose of 11 Gy to the cervix, which, for a
radiobiological modeling, such as with the LQ theory, for
conventional LDR application, would correspond to a Point A
comparison of LDR and HDR. However, such 'protec-
dose of about 20 Gy [38]. The solid curves are the dose-volume
tion' of normal tissues is a benefit with both HDR and
histograms for non-optimized source loadings typical of those
LDR treatments, so some additional 'protective' attrib-
employed in LDR treatments. The dashed curves are the dose-
utes of HDR must be contributing to the low complica-
volume histograms obtainable with the HDR stepping-source
tion rates observed. One of these is illustrated in Figure
technology using optimization of dwell positions. (Reproduced
13.4b, which shows that optimization of the dwell posi-
with permission of Dr Mary Martel, personal communication.)
tions of the single HDR stepping source can significantly
reduce the effective dose to rectal tissues compared to
when 'fixed' LDR sources are used. A similar effect is
observed for the bladder [37]. Hence, the almost infinite extensive retraction during the short HDR treatments
variety of source distributions obtainable with a step- can readily be tolerated, especially if the patient is anes-
ping source makes it possible to achieve superior dose thetized or medicated appropriately.
distributions to those attainable with conventional LDR Another less obvious potential benefit of HDR relates
fixed sources. (Note, however, that pulsed-LDR to differences in rates of repair between tumor and late-
brachytherapy - PDR, discussed later in this chapter - reacting normal tissue cells. It appears that, on average,
which also uses a single stepping source, will have a sim- tumor cells tend to repair sublethal damage faster than
ilar advantage.) normal cells [40]. This will be an advantage for HDR
A second potential advantage of HDR over LDR is the because almost no repair will be possible during short
ability to make better use of packing or retraction. It has HDR exposures, whereas, during protracted LDR treat-
been reported frequently that the short duration of HDR ments, tumor cells will be better able to take advantage
treatments enhances the effectiveness of packing or of the time available for repair, so repair at low dose rates
retraction techniques. For example, gauze packing is will be enhanced more for tumor than for normal tissue
known to shrink during long LDR irradiations. Also, cells.
198 Radiobiology of HDR, LDR, and PDR brachytherapy

These qualitative physical and biological potential

advantages of HDR can be quantified by the use of the
LQ model.

LQ MODEL CALCULATIONS FOR CARCINOMA OF

THE CERVIX: HDR VERSUS LDR

For radiobiological comparisons of LDR and HDR

brachytherapy for cervix cancer, the following terminol-
ogy will be applied. Let:
/represent the fractional geometrical sparing of
normal tissues due to employment of brachytherapy,
and therefore obtainable with both HDR and LDR,
Figure 13.5 LQ model predictions of the therapeutic advantage
i.e.,/= effective normal tissue dose/effective tumor
of HDR over a 60 Gy in 72 h LDR regime as a function of the
dose;
number of HDR fractions employed and the extra geometrical
/ be the extra fractional geometrical sparing of
spa ring factor (Y) achievable with HDR. A therapeutic advantage
normal tissues attainable with HDR due to
>1 means that HDR is superior to LDR. Assumptions for this
advantages of stepping source technology and better
figure are: no normal geometrical sparing, i.e., f = 1; repair rates
retraction or packing, i.e., j/' is the total geometrical
of tumor and late-reacting normal tissue cells are equal, with
sparing factor for HDR treatments;
repair half-times 1.5 h; tumor o/P = 10 Gy; late-reacting
|it and |l be the repair-rate constants for tumor and
normal tissue o/p = 3 Gy.
late-reacting normal tissue cells, respectively;
'therapeutic advantage' (TA) of HDR over LDR be
the ratio of the tumor log cell-surviving fractions,
HDR versus LDR, for the same late-reacting normal-
tissue log cell surviving fractions, i.e.,

We can apply the basic LQ formula (equation 13.2) to

determine the number of HDR fractions necessary to be
equivalent to an LDR regime with effective tumor dose
rateO.833 Gyh~'(60 Gyin72 h), assuming the same repair
rate constant of 0.46 h~] for tumor and normal tissues (cor-
responding to repair half-time of 1.5 h) and no conven-
tional brachytherapy geometrical sparing (/=!). This
leads to the curves shown in Figure 13.5 for four values of
/'. Thisfigureshows that the extra geometrical sparing that
can be achieved with HDR, represented by the factor /',
plays a very significant role. In this example, which illus-
trates the least favorable scenario for HDR (no normal
geometrical sparing (/= 1) and no difference in repair
rates), more than 17 fractions are needed before HDR
becomes superior to LDR (TA>1) if /'=!, whereas this
number of fractions reduces to 12,8, and 4 as/' decreases
to 0.95, 0.90, and 0.85, respectively. With the additional
advantages of faster repair of tumor cells and some degree
of normal geometrical sparing of normal tissues (/<!),
one would expect the number of HDR fractions necessary
for equivalence to decrease even further. On the other
hand, the number of fractions should increase as the LDR
dose rate is reduced. The effect of these other parameters is
illustrated in Figure 13.6, which shows the various combi-
nations of/and/' that make five fractions of HDR equiva-
lent to 60 Gy at LDR, i.e.,'break-even'(TA= 1).
Figure 13.6 Combinations of f and f required for five fractions
of HDR to be equivalent (therapeutic advantage = 1) to LDR
regimes of either 60 Gy in 72 h (dose rate, R = 0.833 Gy h'1) or
60 Gy in 144 h(R = 0.417 Gy h~1), for two different tumor-cell
repair rate constants (\i) 1.4 h-1 or 0.46 h~\ corresponding to
repair half-times of 0.5 h or 1.5 h, respectively. For
combinations of f and f below each curve, HDR is superior to
LDR for the parameters assumed, and vice versa above each
curve. Assumptions are: for late-reacting normal tissues,
ji = 0.46 h~\ o/p = 3 Gy; for tumor, o/p = 10 Gy.
Each of the four curves in Figure 13.6 represents a dif-
ferent combination of tumor repair rate constant (|n)
and LDR dose rate. For combination of / and /' below
each curve, HDR is superior to LDR for the parameters
assumed; and above, LDR is superior. For example, if |it
is assumed to be 1.4 h~', and the LDR tumor dose rate is
0.833 Gy Ir1, HDR will be better than LDR for all combi-
nations of/and/' below the top curve in Figure 13.6,
 Low dose-rate versus pulsed dose-rate brachytherapy 199

i.e., for most values of / or /' less than unity, which icc
highly likely. At the other extreme, if tumor cell repair
rates are assumed to be the same as normal cells (mt =
0.46 h-1), and the LDR dose rate is only 0.417 Gy h'1,
there are many combinations of/and/' for which LDR
will be the superior treatment, although HDR will always
be better if/'<0.8, regardless of the value of f.
Clearly, replacing LDR with HDR is more difficult if
the LDR dose rate is very low and/or the rate of repair of
tumor cells approaches that of normal cells. Because it is
desirable to obtain results at least as good as achievable
with LDR at very low dose rates, and because repair rates
of tumor cells are reported to vary widely but are not
known for individual patients [41], it becomes essential
to maximize geometrical sparing of normal tissues when
converting from LDR to HDR. The superior results Figure 13.7 Gamma-ray doses for multi-fractioned stereotactic
obtained with HDR for the treatment of cervical cancer radiotherapy, which are calculated to be equivalent, in terms of
are presumably due to this additional geometrical spar- tumor control, to single-fractioned radiosurgical doses. (Adapted
ing of normal tissues, with possible enhancement for at from reference 63.)
least some patients attributable to a fortuitous combina-
tion of repair rates of normal tissue and tumor cells.

1333 From HDR to LDR: fractionated

stereotactic radiotherapy

Primarily because of therapeutic convenience, there has

been a trend in favor of moving from LDR to HDR.
There is one situation in which the reverse is true,
namely in fractionated stereotactic radiotherapy. The
background to this development is the technique of
single-treatment stereotactic radiosurgery, originally
designed to treat arteriovenous malformations, which
has been adapted to the treatment of primary and sec-
ondary brain tumors. For the reasons outlined above,
namely because of the lack of sublethal damage repair
and of reoxygenation in a single treatment, such single-
fraction treatments are probably inappropriate for treat-
ing malignancies.
The LQ model (in the form of equation 13.3) has been
Figure 13.8 Isoeffect data for late response from three
used to calculate fractionated regimes which are pre-
(D,O, A) different regions of the rat spinal cord [42], and for
dicted to be isoeffective to currently used single-
acute skin reactions ( ) in mice [43]. All the points at
fractioned regimens (Figure 13.7).
> 20 Gy/fraction correspond to single acute exposures. The data
There is some question, however, of whether the LQ
are plotted in a form [43] such that, if they follow a linear-
model actually applies in situations in which a single
quadratic relationship, the points would fall on a straight line.
fraction of, say, 20 Gy is the baseline regime. Figure 13.8,
The ratio of the slope to the intercept of this straight line then
for example, shows some well-known isoeffect results
provides an estimate of the o/p ratio.
from Van der Kogel [42] for late-responding damage to
the rat spinal cord, and from Douglas and Fowler [43]
for acute damage in mouse skin. The form of the plots is
13.4 LOW DOSE-RATE VERSUS PULSED DOSE-
such that, if the LQ formalism applies, the data would
RATE BRACHYTHERAPY
fall on a straight line [43]. Although there are more
sophisticated methods available for assessing agreement
with the LQ model [44], given the inherent uncertainties 13.4.1 Introduction to PDR
in the data, it is clear that all these data, including those
for single fractions of ~ 20 Gy, are not inconsistent with Because of its practicality and its logistic similarity to
the LQ model. continuous low dose-rate (CLDR) brachytherapy, use of
200 Radiobiology of HDR, LDR, and PDR brachytherapy

pulsed dose-rate (PDR) brachytherapy is increasing regimen, but have comparable or better therapeutic
[46-48]. In PDR, a CLDR brachytherapy regimen is ratios than responding tissues. The suggested protocols
replaced with one involving a series of high dose-rate allow all of the advantages of a computerized, remote-
pulses, typically (though not always) taking about 10 min controlled afterloader while preserving the benefits of
h~' and typically (though not always) with the same over- low dose rate. In addition, the protocols could allow the
all dose and time as the corresponding CLDR regimen. patient to go home overnight, or to stay overnight in an
PDR is achieved with a remote afterloader containing adjacent medical inn or hospital-associated hotel, rather
a single high-activity source which is stepped through than in a hospital bed - which could have major eco-
the catheters of an implant, with dwell positions and nomic benefits. In such an economic situation, an extra
times adjusted under computer control to achieve the treatment day for the daytime PDR could well be consid-
required dose distribution. ered, which would virtually guarantee an improved clini-
The advantages of PDR have been discussed elsewhere cal advantage relative to CLDR.
[41,49,50]. The patient has much more mobility - dur-
ing the 'off' periods - than in a conventional CLDR reg-
13*43 Equivalent regimens for PDR
imen, during which nursing and visiting can be safely
accomplished. There are two clinical advantages. First, by
The key radiobiological question for PDR revolves
varying dwell times and locations of the source as it
around the question of equivalence between the results
shuttles through the tumor, dose distribution can be
of CLDR and those of a corresponding PDR regimen.
optimized for the actual locations of the implanted
Initial calculations [41,50], based on equation 13.3 and
catheters relative to the tumor and normal tissues.
LQ parameters from in-vitro systems, suggested that, as
Second, the overall dose rate can be maintained even as
long as the time between, say, 10-min pulses was not
the source decays, by increasing the length of individual
increased much beyond 1 h, early-responding normal
pulses. Finally, from a practical viewpoint, the use of a
tissues would not show significant differences in
single source has both logistic and radiation protection
response between CLDR and PDR (for the same overall
advantages compared with the usual inventory of
dose and time). An example of the result of such a cal-
sources.
culation is shown in Figure 13.9. Subsequent in-vitro
experimental results [51,52] have corroborated this con-
clusion, as have in-vivo studies with an early-responding
13.4,2 'Daytime'PDR
endpoint [53]. The limited clinical experience with PDR
reported to date also suggests that early response is not
The original PDR protocols have been for day and night
markedly different from CLDR [45-48].
irradiation. It would clearly be advantageous to design
Several authors, however, have pointed to the need for
pulsed-brachytherapy (PDR) protocols that are expected
caution with regard to late effects [41,54-57].
to be at least as clinically efficacious (in terms of both
tumor control and late sequelae) as CLDR regimens, but
that involve irradiation only during extended office
hours. The LQ formalism has been used [49] to design
PDR schemes in which pulses are delivered during
'extended office hours' (8 a.m. to 8 p.m.), with no irradi-
ation overnight. Generally, the proposed PDR regimes
last the same number of treatment days as the corre-
sponding CLDR regimen, but the PDR treatment lasts
longer on the final day (i.e., until 8 p.m.). PDR doses were
calculated such as to produce a tumor control which is
equivalent to standard CLDR protocols, and the corre-
sponding predicted late complication rate was compared
with that for CLDR. Ranges of plausible values for the
half-times of sublethal damage repair for tumors and for
late-responding normal tissues were considered. The effi-
cacy of PDR relative to CLDR depends considerably on
the repair rates for sublethal damage repair. The clinical Figure 13.9 Combination of pulse widths and periods between
and experimental evidence suggests that average repair pulses that will yield an equivalent survival to a continuous low
half-times for early effects (e.g., tumor control) are less dose irradiation of 30 Gy in 60 h. For this particular cell line,
than about 0.5 h, and for late sequelae are more than any combination of pulse width and period within the marked
about 1 h (but see below). If these estimates are correct, boundary is predicted to yield equivalent cell killing. The figure
daytime PDR regimes can usually be designed which take shows representative data for one of 38 cell lines analyzed in
the same number of days as the corresponding CLDR reference 41. (Redrawn from reference 41.)

Essentially, this is because of the fact (discussed above)
that late-responding tissues are more sensitive than
early-responding tissues to changes in fractionation pat-
terns. These authors pointed out that changes in late
effects when moving from CLDR to PDR are essentially
determined by the rate of repair of sublethal late-
responding damage - and that these repair rates are sim-
ply not well known. Essentially, the trend, schematically
illustrated in Figure 13.10, is that rapid repair rates in
late-responding tissues would lead to increased late
effects in PDR compared with CLDR [58]. On the other
hand, slow repair rates would imply that PDR might well
produce fewer late effects than the corresponding CLDR
regimen.
Experimentally, changes in late-responding sequelae
are hard to quantify, particularly when these changes
may well be relatively small. This is true both in the clinic
and in the laboratory. In the clinic, a variety of reports
have generally reported no significant difference in late
sequelae between PDR and CLDR [45-48]. In a model
late-responding system (cataract induction in the rat
lens), no significant difference was observed between
15 Gy of X-rays delivered over 24 h and in various PDR
regimens with the same overall dose and time [59].
Similar results have been obtained using as an endpoint
rectal toxicity in the rat [60,61].
Figure 13.10 Calculated fractional change in cell survival for
PDR compared with LDR as a function of the assumed half-time
for sublethal damage repair. Both treatments consist of 30 Gy
delivered in 60 h, either continuously (LDR) or in 60 10-min
50 cGy pulses delivered every hour (PDR). The calculated
quantity is fSPDR - S Ldr) S LDR ; here, the survival (S) is calculated,
using the linear-quadratic formalism (3,8), asS = exp(-ccD
-GpD2) where D is the total dose, a and P are the linear-
quadratic formalism parameters, and G is the quantity
describing sublethal damage repair (see equation 13.2), which
depends on the half-time of sublethal-damage repair, TJ/2. Thus,
the quantity calculated is actually exp/-(GPDR - GL JpD2/ -7. In
the calculation, it was assumed that (3=0.025 Gy~2, though
similarly shaped graphs are obtained for other values of p.
(Redrawn from reference 58.)
Conclusions 201
The equality of late effects from CLDR and PDR in the
laboratory must imply that sublethal damage repair is
quite slow in this model late-responding system, in
agreement with trends observed in the clinic for sub-
lethal damage repair of late sequelae. Such trends would
suggest that PDR is unlikely to produce significantly
worse late effects than the corresponding CLDR regime,
which is in agreement with early clinical data using PDR.
Caution, however, is strongly indicated.
13.5 CONCLUSIONS
In this chapter we have discussed the principles underly-
ing the use of the LQ model, and some examples in
designing equi-effect doses, for either early-responding
or late-responding tissues. The main application of the
LQ model is likely to be for comparisons of schema, or
designing isoeffective schema. Such applications are
much less sensitive to the values of LQ parameters than
are absolute, de novo, predictions of TCP or NTCP.
While it is important to be appropriately critical of the
LQ model and its application to radiotherapy, it is
equally important to recognize that it is the best model
we have. It is a mechanistically based model of cell
killing, with parameters that have a clear radiobiological
interpretation, and there is a wealth of evidence that cell
killing dominates radiotherapeutic response.
Of course, the simplest form of the LQ model (equa-
tion 13.3) is not necessarily the most appropriate to
apply. When repopulation is important, the LQ formal-
ism can be appropriately modified [21]. If redistribution
or reoxygenation is important, the LQ formalism can
again be appropriately modified [22]. Similarly, if there
is evidence that the LQ model is underpredicting sur-
vival at high doses, appropriate saturation-related mod-
ifications to the LQ formalism have been described
[62,63].
A recent study [64] looked at the relationship of the
LQ formalism to other commonly used radiobiological
models, particularly in terms of their predicted
time-dose relationships. It was shown that a broad range
of radiobiological models is described by formalisms
which result in the standard LQ relationship for dose
fractionation/protraction, including the same general-
ized time factor, G (see equation 13.2). This approximate
equivalence holds not only for the formalisms describing
binary misrepair models, which are conceptually similar
to LQ, but also for formalisms describing models
embodying a very different explanation for time-dose
effects, namely saturation of repair capacity. In terms of
applications to radiotherapy, it was shown that a typical
saturable repair formalism predicts practically the same
dependencies for protraction effects as does the LQ
formalism, at clinically relevant doses per fraction.
Overall, use of the LQ formalism to predict dose-time
202 Radiobiology of HDR, LDR, and PDR brachytherapy
relationships is a notably robust procedure, depending
less than previously thought on knowledge of detailed
biophysical mechanisms, because various conceptually
different biophysical models lead, in a reasonable
approximation, to the LQ relationship including the
standard form of the generalized time factor G.
GLOSSARY
oc/P ratio The ratio of the parameters a and P in the
linear-quadratic model (qv). a is considered to be a mea-
sure of the probability that a single radiation event will
cause lethal cellular damage; (3 is a measure of the prob-
ability that two sublethal events will combine together to
create lethal damage. In clinical radiotherapy, the value
of a is the principal determinant of overall radiation
sensitivity of a tumor or normal issue; the p component
governs the fractionation and dose-rate characteristics of
a particular cell line. In terms of the underlying cell sur-
vival curve, a is the initial slope and P is a measure of the
downward 'bendiness' of the curve.
Biologically effective dose (BED) A measure of biologi-
cal effect as calculated by the LQ model. BED values are
additive, and are therefore useful in calculating the over-
all effectiveness of treatments which consist of two or
more components. The BED is tissue-specific as its value
is dependent on the oc/P ratio and the recovery half-life.
BED may be thought of as the dose necessary for a given
effect when the treatment consists of an infinite number
of infinitely small fractions.
Early-responding tissues Those normal tissues in which
the radiation damage is normally apparent within weeks
or months of exposure; characterized by a relatively large
oc/P ratio.
High dose rate (HDR) A dose rate such that the time
required to deliver a given dose is very short in compar-
ison with the cellular recovery half-lives.
Late-responding tissues Those normal tissues in which
the radiation damage only becomes apparent months or
years after exposure; characterized by a relatively small
oc/P ratio.
Linear-quadratic (LQ) model Cell-killing model based
on the assumption that there are two components to cell
killing: a linear component which is directly propor-
tional to the delivered dose, and a quadratic component
which is proportional to the square of the delivered dose.
In the simplest case of a single instantaneous dose of
magnitude dy the cell survival (S) is given by: S =
exp(-ad - P^2). The model has been extensively devel-
oped to describe many other patterns of radiation
delivery.
Low dose rate (LDR) A dose rate such that the time
required to deliver a given dose is long compared with
the cellular recovery half-lives.
Medium dose rate (MDR) A dose rate such that the
time required to deliver a given dose is comparable with
the cellular recovery half-lives.
Potential doubling time (Tpot) The predicted cell dou-
bling time in the absence of cell loss.
Pulsed dose rate (PDR) A technique whereby the bio-
logical effects associated with continuous LDR irradia-
tion are simulated by the use of 'pulses' of HDR
irradiation delivered at approximately 1 -h intervals over
a long time period.
Radiosensitivity A measure of the radioresponsiveness
of a particular cell line. Possible measures of radiosensi-
tivity are the surviving fraction after a single dose of 2 Gy
(SF2), and the initial slope of the cell-survival curve (a).
Recovery The process whereby the amount of injury to
irradiated cells or tissues is able to reduce with time after
irradiation.
Recovery half-life The half-life which determines the
(exponential) rate at which simple sublethal cellular
injury may recover.
Repopulation effect The concomitant growth of tumor
clonogens during a course of radiotherapy.
Repopulation factor (K) The daily dose necessary to
offset tumor repopulation. In terms of the LQ model, K
is defined as: K = 0.693/ccrpot.
Sublethal damage That component of cellular injury
which is capable of repair. When sublethal damage is
accumulated within a given cell, lethal damage may
result from an interaction between the sublethal compo-
nents.
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63. Hall, E.J. and Brenner, D.J. (1993). The radiobiology of
radiosurgery: rationale for different treatment regimes
for AVMsand malignancies. InlJ. Radial Oncol. Biol.
Pfcys.,25,381-5.
64. Brenner, D.J., Hlatky, L.R., Hahnfeldt, P.J., Huang, Y. and
Sachs, R.K. (1998) The linear-quadratic model and most
other common radiobiological models result in similar
predictions of time-dose relationships. Radial Res., 150,
83-91.

Predictive assays for radiation oncology
JOHN A. COOK AND JAMES B.MITCHELL
14.1 INTRODUCTION
In 1895, Wilhelm Roentgen contributed to the medical
profession perhaps one of its most widely used and ben-
eficial diagnostic tests. With the discovery of the X-ray
and the rapid development of radiographs, Roentgen's
discharge tube enabled physicians non-invasively to
visualize anatomical structures quickly and establish
sound diagnosis of a variety of medical problems.
Diagnostic tests used in medical practice have progressed
a long way since the early 1900s, both in type and sophis-
tication. An elaborate array of tests now greatly aids the
physician in making a rational diagnosis of a particular
medical problem. Expeditious diagnosis is extremely
important in the field of oncology and, unquestionably,
if certain tumors are detected early enough, successful
treatment and eradication of the tumor can be achieved.
Unfortunately, not all tumors are detected early and,
despite there being a wide variety of treatment options
available, including surgery, chemotherapy, and radia-
tion therapy, successful eradication of tumor with
acceptable normal-tissue toxicity remains a major chal-
lenge to the practicing oncologist.
Since the 1980s, radiation oncologists and biologists
have recognized the need for additional assays on an
individual patient basis that would select the most
advantageous treatment approach [1]. We emphasize
assays for individual patients for several reasons. First,
the cellular radiation sensitivity of the tumor may differ
among individuals, even for tumors of the same histo-
logical type. If the radiosensitivity of the individual's
14
tumor were precisely known, perhaps total radiation
doses could be adjusted before the end of therapy to
maximize tumor response. Alternatively, the option of
using radiation sensitizers for 'radioresistant' tumors
would have a more rational basis. Second, normal-tissue
radiation sensitivity may differ among individuals. This
is an important point because the total radiation dose
that can be delivered to a patient's tumor is often limited
by normal tissue tolerance. Stated differently, frequently
radiation oncologists are compelled to treat a patient's
tumor with radiation doses that are dictated not by
tumor sensitivity but by normal-tissue tolerance, which
in many instances results in inadequate dose to the
tumor. If one assumes there is a Gaussian distribution of
normal-tissue radiosensitivities among humans, then
the most sensitive individuals in the population may
well dictate radiation tumor doses utilized in the clinic.
Because the radiation tumor control dose response
curve is quite steep for many tumors, modest increases
in the total radiation dose delivered would be expected
greatly to enhance tumor control. If it were determined
that the patient's normal-tissue radiation response were
toward the 'radioresistant' edge of the Gaussian distribu-
tion, consideration could be given to administering
higher radiation doses. Alternatively, if the patient's
normal-tissue radiation response were toward the
'radiosensitive' edge of the Gaussian distribution, the use
of radioprotectors could be considered. Unfortunately,
selective normal-tissue radioprotectors have yet to be
identified. Third, biological, environmental, and physio-
logical factors of tumors may differ among individuals.
Factors such as tumor pH, hypoxia, blood flow, and
206 Predictive assays for radiation oncology
growth of the tumor in terms of cell-cycle parameters
and potential tumor doubling times (Tpot) can influence
the overall radiation responsiveness of the tumor. If
these factors were known prior to therapy, the use of
hypoxic cell radiosensitizers or, in the case of Tpot values,
alteration of fractionation/time schedules could be con-
sidered.
Numerous predictive assays have been developed over
the past two decades to address many of the points cited
above and several have been evaluated in a clinical set-
ting. This chapter briefly reviews the current status of
several different predictive assays and discusses their
advantages and shortcomings. These assays, while evalu-
ated on patients receiving external-beam radiotherapy,
are also highly relevant for patients receiving various
forms of brachytherapy.
14.2 REQUIREMENTS OF CLINICALLY USEFUL
PREDICTIVE ASSAYS
A number of diagnostic tests already aid the oncologist
in designing the course of treatment. These include:
tumor type, histological grade, tumor biochemical
markers, size and anatomical location of the tumor
(which can be determined by various X-ray procedures),
rate of tumor growth, receptor status, ploidy of the
tumor cells, and patient performance status and age [2].
A major advantage of these tests is that they can be per-
formed rapidly and are available when options for treat-
ment are considered. The tests have proven to be
predictive for both tumor responsiveness to therapy and
ultimate survival of the patient. Ideally, predictive assays,
particularly those for radiation oncology, should be
rapid (ideally within a week) and predictive with low
false negativity [3].
143 SURVIVAL ASSAYS
143*1 Tumor-cell radiosensitivity
Intrinsic cellular radiosensitivity of cell lines established
from patients' tumors has provided interesting correla-
tions with respect to the radioresponsiveness of specific
tumor types in the clinic. Fertil and Malaise, in an analy-
sis of published radiation survival curves, found that cell
lines derived from, for example, glioblastoma and
melanoma exhibit a high surviving fraction at 2 Gy
(SF2Gy) [4]. These tumor types are less responsive to
radiotherapy than, for example, tumors such as lym-
phomas and small lung cancer, which exhibit low SF2Gy
values [4]. While there is a semi-qualitative relationship
between SF2Gy values of given tumor types and clinical
radioresponsiveness, a range of radiosensitivities has
been noted in cell lines derived from the same tumor
type [5]. As an example, cell lines isolated from glioblas-
toma tumors exhibit a broad range of SF2Gy values
(0.2-0.9) [5], yet glioblastoma uniformly respond
poorly to radiation. If heterogeneity in cellular radiosen-
sitivity exists in human tumors of the same histological
type, the need for an accurate individualized assessment
of cellular radiosensitivity becomes extremely important
if altered treatment approaches are to be considered in
the clinic based on predictive assays. Raaphorst has
pointed out that the reproducibility of SF2C}, determina-
tions of an established cell line can be quite variable [6].
Using the radiosensitivity parameter of SF2Gy means that
cell killing is usually confined to the first log of survival.
Low doses of radiation which result in low levels of cell
killing are difficult to resolve statistically due to the sum-
mation of statistical errors inherent in conducting sur-
vival assays for low radiation doses [7]. Thus, concerns
relating to tumor-cell radiosensitivity assessments from
a patient's tumors include: (a) whether the radiosensitiv-
ity of cells taken from the biopsy sample is representative
of the entire tumor; (b) whether the single determina-
tion of radiosensitivity is so variable that it would not be
useful; and (c) whether radiosensitivity would remain
constant during a full course of 25-30 fractions of radio-
therapy.
While such concerns are reasonable (and perhaps
sobering) with regard to tumor-cell biology, it is difficult
to second-guess results until experiments are conducted.
However, the studies discussed above formed the basis to
explore the possibility of determining the inherent cellu-
lar radiosensitivity of primary cultures of tumor cells
taken directly from the patient. There are several assays
available to assess cellular radiosensitivity [8-17], but
only those for which most clinical data have been
obtained are discussed below.
143*2 Cell adhesive matrix assay
The cell adhesive matrix (CAM) assay is conducted on
tissue culture dishes coated with a substance that facili-
tates cell attachment and cell growth [18]. Single-cell
suspensions of tumor cells are plated onto CAM dishes,
incubated for 24 h, and then exposed to varying doses of
radiation (1-6 Gy). After a growth period of 10-14 days,
the cell monolayer is stained with crystal violet. The den-
sity of cell monolayer is assessed by the amount of stain
taken up by the surviving cells as recorded by image
analysis techniques. By comparing the density of staining
of unirradiated cultures to that of irradiated cultures,
growth-rate-based cell survival curves can be obtained
[18]. Using this assay, Brock et al, determined SF2Gy val-
ues of cells derived from biopsies of head/neck tumors
prior to radiation therapy [19]. Figure 14.1 shows the
cumulative frequency histograms of SF2Cy values for 72
patients evaluated [19]. The range in SF2Gy values in
patients achieving local control was from 0.10 to 0.91.

Image Not Available
The plot also displays SF2Gy values from 12 patients with
local recurrence following radiation treatment. SF2Gy val-
ues from this subset of patients ranged from 0.20 to 0.91.
Note that patients' tumors with low and high SF2Gy values
recurred. The authors concluded that SF2Gy values were
not suitable prognostic indicators for this set of patients
[ 19]. Preliminary data from Girinsky, et a/., who used the
same assay to evaluate head/neck tumor-cell radiosensi-
tivity, reached similar conclusions for SF2Gy values; how-
ever, using the calculated a values of the radiation
survival curves, a correlation was found between patients
with an a value > 0.07 Gy ' and local control [20]. That
there was no correlation between tumor sensitivity and
clinical response is particularly troublesome, because the
assay is both simple and reasonable. A technical diffi-
culty inherent in the CAM assay is the observation that
normal host fibroblasts (included in the tumor biopsy)
can also grow on the matrix-treated dishes, thus poten-
tially complicating the interpretation of tumor-cell
radiosensitivity [20].
1433 Courtenay-Mills soft agar assay
This clonogenic assay is conducted by plating single-cell
suspensions from patients' tumors into medium con-
taining soft agar [21]. Standard clonogenic radiation
survival curves are conducted from which survival curve
parameters such as SF2Gy can be determined. From the
time of the initial biopsy to the evaluation of the radia-
tion survival curve is approximately 4 weeks. Using the
assay, West et a/., determined SF2Gy values of tumor cells
taken from 88 patients with cervical carcinoma [22]. In
Survival assays 207
Figure 14.1 Cumulative
frequency histograms of SFXy
values for 72 head and neck
cancer patients (patients
controlled locally + patients who
failed locally) compared to
patients with local recurrences.
(Redrawn with permission from
reference 19.)
the study, a significant correlation was found between
SF2Gy values and both local control and survival, as shown
in Figure 14.2. Patients with SF2Gy values > 0.4 had both a
lower local control rate and a lower survival when com-
pared to patients with SF2Gy values < 0.4 [23]. 5F2Gy values
were independent of disease stage, tumor grade, and
patient age [22]; however, there was a loose correlation
with tumor volume and diploid status, which suggests
that SF2Gy alone may not be a completely independent
predictor of local control and survival. As shown for the
CAM assay, fibroblasts have also been shown to grow in
this soft agar assay [24].
Of all the cell-survival predictive assays presently
under evaluation, the data from the Courtenay-Mills
assay clearly provide the most encouragement. It will be
most interesting to determine if SF2Gy values determined
by this assay correlate with local control and survival for
different tumors. Likewise, it would be informative to
determine if the CAM assay applied to cervical carci-
noma would give similar results to the Courtenay-Mills
assay. A potential improvement that could be applied to
both assays might be to use fractionated radiation (i.e.,
five 2-Gy fractions) to maximize the importance of
repair, which is not apparent for a single 2-Gy dose of
radiation [6].
Both assays require several weeks to obtain results.
This represents a possible disadvantage, particularly if
radiation sensitizers or protectors were to be considered
an option as treatment commences. However, both
assays can be completed before the end of therapy, thus
permitting total tumor dose modification. The finding
that host fibroblasts grow in both assays raises concern as
to their contribution to the overall radiosensitivity
208 Predictive assays for radiation oncology

Image Not Available

Figure 14.2 Local control and survival probability as a function of time after treatment of cervical carcinoma patients. Local control
and survival were further separated by examining patients with SF2Gy values greater than or less than 0.4. (a) Local control probability
as a function of time after radiation, (b) Survival probability as a function of time after radiation. (Redrawn with permission from
reference 23.)

assessment, although such a concern would only be
important if tumor-cell and fibroblast radiosensitivities
differ.
143*4 Normal-tissue cellular
radiosensitivity
Is there a correlation between the radiosensitivity of nor-
mal tissues and tumor cells from the same animal or
patient? The answer to this question is not known for
humans. If the answer were yes, then the determination
of normal-cell radiosensitivity might be easier to per-
form and more reliable than tumor-cell radiosensitivity
assessments, given that a homogeneous population
(with respect to DNA content or chromosome stability)
of cells from readily accessible normal tissues could be
studied. Data from at least one animal model suggest
that normal-tissue and tumor radiosensitivities are
indeed similar. Budach et al. showed that tumors arising
in severe combined immunodeficient (SCID) mice
exhibited the same radiosensitivity as their normal skin
fibroblasts [25]. The study, however, represents an
extreme example, in that SCID mice are approximately
threefold more radiosensitive than normal mice. In
recent human studies, however, Stausbol-Gron et al.
examined the SF2Gy of both fibroblasts and tumor cells
from 71 head and neck patients and found no statistical
correlation between the fibroblast and tumor SF2Gy [26].
The question as to whether there is a similarity of
radiosensitivities between tumor and normal tissues in
'normal' mice and humans remains unanswered.
Another question that warrants consideration is
whether normal-cell radiosensitivity (fibroblasts, lym-
phocytes, etc.) correlates with radiation-induced
normal-tissue complications. Several studies have
attempted to address this question [27-33]. Geara et al.
evaluated the radiosensitivity of fibroblasts taken from 21
patients with head/neck tumors who subsequently
received radiation therapy [34]. Fibroblast SF2Gy values
were compared to the acute and late effects of skin and
oral mucosa during and after radiation treatment, as
shown in Figure 14.3 [34]. SF2Gy values correlated well
with late normal-tissue reactions (Figure 14.3a). That is,
patients whose fibroblast radiosensitivity was character-
ized by high SF2Gy values exhibited fewer late reactions.
Likewise, low SF2Gy values correlated with more severe late
effects. No correlation was found between SF2Gy values
and acute reactions (Figure 14.3b). Russel et al. studied
the sensitivity of dermal fibroblast from 79 breast cancer
patients and attempted to correlate the SF2Gy with the
degree of breast fibrosis [33]. Although there was signifi-
cant variation in intrinsic radiation sensitivity, there was
only a weak correlation between the SF2Gy and breast
fibrosis. Other studies have suggested that acute effects
may correlate with fibroblast radiosensitivity, but these
studies are preliminary and require further verification
[35]. Despite differences, collectively the studies suggest
that radiation-induced,'late' normal-tissue reactions cor-
relate to some extent with fibroblast radiosensitivity [32].
It is hoped that study of larger populations of patients
will confirm and extend the preliminary findings to other
tissues and organs at risk for radiation damage.
Recently, the gene for ataxia telangiectasia (AT) has

Image Not Available
Figure 14.3 SF2Gy values as a function of the grade of either late or acute normal-tissue reactions, (a) Late reactions scored after the
radiation treatments, (b) Acute reactions of the skin and mucosa scored weekly during the radiation treatments. (Redrawn with
permission from reference 34.)
been cloned [36]. Fibroblast cultures derived from
homozygous AT patients have long been known to
exhibit extreme radiosensitivity [37]. Likewise, ataxia
telangiectasia patients also exhibit severe normal-tissue
reactions if given a standard course of radiotherapy [38].
Dunst et al. examined chromosome breaks in lympho-
cytes from cancer patients undergoing radiotherapy.
This study included three individuals who had proven
ataxia telangiectasia (AT homozygotes) [31]. It found a
higher number of chromosomal breaks in the lympho-
cytes from patients who had extreme normal-tissue reac-
tions to the radiation, while the ataxia patients had the
highest break frequency of all. There is also evidence that
ATheterozygotes exhibit slightly increased radiosensitiv-
ity [39] compared to fibroblasts from normal individu-
als. What makes the observation clinically important is
that approximately 18% of patients with breast cancer
may be heterozygous for the AT gene [40]. Application of
molecular techniques may allow for the rapid identifica-
tion of AT heterozygotes, thus allowing for a more
precise attempt to correlate radiosensitivity and normal-
tissue damage. In the future, as more insight into human
genetics and radiation responsiveness is gained, it maybe
feasible to screen quickly for selective markers.
14.4 OXYGEN MEASUREMENTS AND TUMOR
RESPONSE
Inherent cellular radiosensitivity may not necessarily
correlate with clinical radioresponsiveness because the
tumor microenvironment may influence radiation
response. A major modifier of the radiation response is
Oxygen measurements and tumor response 209
molecular oxygen [41]. Cells exposed to X-rays at low
oxygen levels are more resistant than fully oxygenated
cells by a factor of about three. Should hypoxic cells exist
in tumors, they might pose a potential obstacle to suc-
cessful tumor eradication. The ability to determine if
hypoxic cells are present in human tumors has been
facilitated by the use of sensitive oxygen electrodes.
These tiny glass electrodes are inserted directly into the
tumor and many oxygen measurements are made as the
electrode is mechanically moved along a track of tissue
(2-40 mm). The procedure can be done several times
through different parts of the tumor, does not cause pain
or discomfort to the patient, and can be completed in
approximately 1 h. Oxygen levels in normal tissue can
also be determined for comparison. Disadvantages of the
technique include the invasive nature of the procedure
and the inaccessibility of some tumors. Several studies
using the oxygen-sensitive electrode to measure PO2 lev-
els in head and neck carcinomas, cervical carcinomas,
breast carcinomas, soft tissue sarcomas, and in squa-
mous cell carcinoma metastases have been reported
[42-46]. In squamous cell carcinoma metastases prior to
radiation treatment, Gatenby et al. showed a relationship
between tumor response and tumor PO2 levels [43].
Patients who achieved a complete response to radiation
therapy had higher PO2 levels (< 26% of the tumor vol-
ume measuring < 8 mm PO2) in their tumors than did
patients who did not respond (> 26% of the tumor vol-
ume measuring < 8 mm PO2). More recent clinical expe-
rience with oxygen electrodes has confirmed and
extended the observations by Gatenby. Vaupel and
Hockel published a series of studies in which PO2 levels
were measured in patients with breast and cervix cancer
and related to survival and/or recurrence-free survival
210 Predictive assays for radiation oncology

[44,45]. Examples from their studies are shown in

Figures 14.4 and 14.5. Figures 14.4a and b showPO2 dis-
tributions for normal breast tissue (N = 16) and breast
tumors (N = 15, Stage T1-T4), respectively [45]. The
median PO2 level in normal breast was 65 mmHg com-
pared to 30 mmHg for breast tumors. Notice that for
breast tumors there was a significant number of values
< 10 mmHg, whereas normal breast tissue had no mea-
surements < 10 mmHg. A level of oxygen < 10 mmHg is
within the range in which the oxygen enhancement ratio
(OER) changes from a value of 1 (aerobic) to a maxi-
mum of 3 (hypoxic). Thus, values < 10 nimHg might be
considered 'hypoxic.' The PO2 profiles shown in Figures
14.4a and b are mean values for a group of patients. Image Not Available
Interestingly, PO2 profiles of individual breast cancer
patients appear to have normal PO2 readings (Figure
14.5a) and yet other profiles that contain significant
hypoxic readings < 10 mmHg (Figure 14.5b) [44].
Adams et al. examined the PO2 profiles of 37 head and
neck cancer patients and also found a significant degree
of hypoxia in these tumors as compared to subcutaneous
PO2 readings [42]. Dunst et al. examined 49 cervical car-
cinoma patients both before and during radiotherapy

0 100

Figure 14.5 P02 profiles from two individual breast cancer

patients. In both panels, n = number of oxygen measurements
made. (Redrawn with permission from reference 45.)

[47]. They found PO2 changes occurred during radio-

Image Not Available
Figure 14.4 P02 profiles from breast tumors and normal breast
tissue. (A) P02 profiles of normal breast tissue (N = 16). (B) P02
profiles of breast tumors (M = 15). In both panels, n = number
of oxygen measurements made. (Redrawn with permission from
reference 45.)
therapy, with a majority of those patients with either a
pretreatment median PO2 > 10 mmHg or a median PO2
> 10 mmHg at 19.8 Gy having complete response to the
radiation treatments. The example serves to reinforce the
importance of individualized assessment of hypoxia in
human tumors, particularly in the context of evaluating
or considering the use of hypoxia-cell radiosensitizers.
Figure 14.6 shows survival curves of patients with cervi-
cal carcinoma whose median PO2 profiles were either
greater than or less than 10 mmHg. These preliminary
data clearly show that survival is enhanced for those
patients whose tumors had median PO2 profiles
> 10 mmHg prior to treatment. This was true for
patients receiving radiotherapy alone as well as for those
who received surgery, chemotherapy, or combined ther-
apies. The data, while of interest to radiation oncologists,
are also of interest to tumor biologists, in that patients
with tumors with PO2 profiles < 10 mmHg did not
respond well to any therapy. The reason for the response
profile is not clear, but it indicates that hypoxia is a
marker of aggressive, poorly responsive tumors [48].
Likewise, the presence of hypoxia in soft tissue sarcomas
may be predictive for metastatic potential [46].
Several other techniques to measure tissue PO2 levels

Image Not Available
Figure 14.6 Survival probability of cervical carcinoma patients
as a function of time after treatment (either radiation, surgery,
or chemotherapy alone, or a combination of these treatments).
Survival was separated based on whether the median ?02 was
either less than or greater than 10 mmHg. (Redrawn with
permission from reference 44.)
are currently under development [49]. Oxygen electrode
measurements do not yield the complete PO2 profile of
the entire tumor. Ideally, it would be advantageous to
have a technique that could provide non-invasive assess-
ment of PO2 levels for the entire tumor. The use of
nitroimidazoles, which bind to macromolecules under
hypoxic conditions [50,51 ], is one approach toward non-
invasive imaging of hypoxic tissue. The nitroimidazole
can be labeled with radioactive iodine-123 and evaluated
by single photon emission computed tomography
(SPECT) [52], labeled with an isotope of fluorine (fluo-
rine-18) and evaluated by positron emission tomography
(PET) [53] or detected histochemically [54]. Other tech-
niques include the use of electron paramagnetic reso-
nance (EPR) coupled with free radical probes [55,56] or
India ink [57] and fluorine (fluorine-19) magnetic reso-
nance spectroscopy [58]. These techniques hold great
promise, but are still in the early stages of development.
14.5 CELL-CYCLE ANALYSIS AND TUMOR
RESPONSE
Because tumors are known to grow at different rates, it
might be beneficial to have an assay to access the poten-
tial doubling time (Tpot) of the tumor. Such an assay has
the potential to identify those patients with rapidly
growing tumors who might benefit from accelerated or
hyperfractionated radiation treatment. Technology has
rapidly advanced over the past few years, making estima-
tion of the rpot of a patient's tumors relatively simple and
straightforward. The assay involves bolus injection of a
halogenated pyrimidine (bromodeoxyuridine or iodo-
Cell-cycle analysis and tumor response 211
Image Not Available
Figure 14.7 Actuarial survival of head and neck patients as a
function of time after treatment (either accelerated
fractionation or conventional fractionation). Survival was
separated based upon a Jpot < 4 days (fast) or a T^, > 4 days
(slow). (Redrawn with permission from reference 60.)
deoxyuridine). Over the next 2-4 h the halogenated
pyrimidine is incorporated into the tumor-cell DNA.
The tumor is biopsied and a single-cell suspension is
prepared. The cells are then treated with a fluorescent-
labeled antibody that recognizes the specific halogenated
pyrimidine incorporated in the DNA. Following this
treatment, the cells are analyzed by flow cytometry. From
the DNA flow cytometry histogram, an estimate can be
made of the rpot of the tumor [59]. Recent clinical stud-
ies have shown that local tumor control (using conven-
tional fractionation) in patients with tumors with Tpot
values < 4 days was significantly worse than that for
tumors with Tpot values > 4 days, as shown in Figure 14.7
[60]. However, patients whose Tpot values were < 4 days
and received accelerated fractionation achieved local
control comparable to that of patients with Tpot values
> 4 days who received either conventional or accelerated
fractionation. Similar findings have been reported by
other investigators [61]. In contrast, a recent study with
74 patients with head and neck tumors failed to show a
correlation between Tpot values and local regional control
using conventional radiotherapy [62]. These studies
serve to demonstrate how important Tpot determinations
might be in identifying candidates for altered fractiona-
tion schedules and perhaps high or low dose-rate
brachytherapy. A cautionary note must be sounded
because the number of patients analyzed in this fashion
has been small, and verification with larger patient pop-
ulations and different tumor types is needed. In addi-
tion, relying on a single biopsy for determination of Tpot
values may be misleading. A recent study showed that
when five biopsies were taken from individual
esophageal tumors and rpot values determined, hetero-
geneity in T values were obtained [63].
212 Predictive assays for radiation oncology
14.6 CONCLUSIONS
Predictive assays are far from being incorporated into the
routine radiation treatment decision-making process.
Yet progress has been made and indeed much can be
learned about tumor and normal-tissue biology and
physiology through the development of such assays.
Perhaps what will evolve from the cited initial studies is
a battery of predictive assays that, when used together,
will aid the radiation oncologist better to individualize
treatment. There is no doubt that molecular techniques
will aid ultimately in identifying new markers that will
facilitate accurate and individualized predictive assays.
There are indications that predictive assays have the
potential to revolutionize the way in which the radiation
oncologist will approach patient treatment. What is
needed now is continued support by the radiation com-
munity of research and development that will lead to
effective and practical assays.
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Principles of the dose-rate effect derived from
clinical data
ERICJ. HALL AND DAVIDJ. BRENNER
15,1 INTRODUCTION
The dependence of the biological effect of a given dose
on dose rate has been demonstrated unequivocally in
experiments with cells cultured in vitro as well as in ani-
mal studies [1-3]. A decrease in biological effect as dose
is protracted over time is universally observed for radia-
tions of low linear energy transfer (LET) and for cells
that die a mitotic as opposed to an apoptotic death. This
is attributed to repair of sublethal damage and to repop-
ulation (i.e., to cell birth) if the total exposure period is
sufficiently long. Many experiments have been per-
formed and the mechanisms worked out.
In the case of clinical data, the situation is not as clear
cut, despite the fact that interstitial implants typically
involve the range of dose rates for which the variation of
biological effect with dose rates is substantial in experi-
mental systems.
15.2 DOSE-RATE CORRECTIONS IN THE ERA
OF RADIUM NEEDLE IMPLANTS
It was pointed out by Paterson in the 1960s [4] that the
dose-limiting factor in the case of interstitial implants is
the tolerance of normal tissues. His philosophy was to
15
push to the maximum the dose tolerated by the normal
tissues in order to maximize tumor control. Paterson
published a curve relating total dose to overall time, with
limiting normal-tissue tolerance as the endpoint.
Regarding 60 Gy in 7 days as the standard, he proposed
that an implant of shorter duration should have a lower
dose, and an implant of longer duration an augmented
dose. The published curve represented his considerable
clinical experience, accumulated over many years, and
was unequivocally based on equalizing late effects in nor-
mal tissues. The experience was based on treatments with
radium needles implanted according to the Manchester
System. Ellis [5] proposed an essentially identical scheme
for use in clinical practice; the data upon which his curve
was based were attributed to TA Green. The curve of
Paterson and Ellis is reproduced in Figure 15.1, together
with theoretical curves relating equivalent dose to overall
time based on radiobiological data for early-responding
and late-responding tissues, normalized to 6000 cGy in 7
days. The oc/P and T{ for early-responding tissues were
taken from the in-vitro data for cell lines of human origin
[6]. The oc/P and T{ for late-responding tissues were taken
from the limited experimental clinical data available,
specifically from those of Turesson and Thames [7]. It is
interesting to note that the calculated curve based on the
radiobiological parameters for late-responding tissues is
virtually indistinguishable from the curves of Paterson
216 Principles of the dose-rate effect derived from clinical data
Figure 15.1 Dose equivalent to 60 Gy in 7 days calculated in
different ways: based on clinical experience of normal tissue
tolerance (Paterson [4], Ellis [5]); calculated from o/p and 7)
values related to late effects; and calculated from the average
oc/P and 7| values for cells of human origin cultured in vitro,
i.e., early effects.
and of Ellis, who unequivocally based their judgment on
obtaining equal late effects. The curve relating equivalent
dose and overall time is steeper for late-responding than
for early-responding tissues because of the smaller value
ofot/p.
153 THE INTRODUCTION OF IRIDIUM WIRE
IMPLANTS
The introduction of iridium wire as a substitute for
radium needles in interstitial brachytherapy allowed
greater flexibility and patient comfort, but also resulted
in a much larger variation of dose rate between individ-
ual implants. Two factors contribute to this:
1. As a consequence of the relatively short half-life of
iridium-192 (74 days), the linear activity will vary
significantly during the period of several months
that the wires may be used or re-used.
2 The Paris System of dosimetry [8] developed for
iridium-192 implants, where all sources have the
same linear activity with varying separation between
wires for different lengths (i.e. greater separation for
larger wires), results in a wider range of dose rates
than was characteristic of radium implants using the
Parker-Paterson dosimetry system, where internal
needles had half or two-thirds of the linear activity
of outer needles. Because all wires have the same
linear activity, there is a correlation between
implanted volume and dose rate, with larger
volumes being associated with higher dose rates.
The combination of those two factors results, in practice,
in a threefold variation in the overall irradiation time for
the delivery of a given tumor dose. Nevertheless,
Pierquin and his colleagues [9] came to the conclusion
that, in iridium-192 implants, the time factor (and there-
fore the dose rate) was unimportant or at least less
important than others had suggested. Consequently, the
Paris school recommended the same prescribed dose
irrespective of overall time within the range 3-8 days.
They were careful to point out that their conclusions
were preliminary, but nevertheless concluded: 'We can
however say with certainty that the variation in overall
treatment time for the same tumor dose from 3 days to 8
days does not appear to influence the frequency or recur-
rence or necrosis.'
Based upon this conviction, many hundreds of
patients were treated with iridium-192 implants using
standard doses uncorrected for treatment time or dose
rate, despite the fact that this conflicts with the previ-
ously published clinical experience of Paterson and of
Ellis, and does not agree with the experimental radio-
biological data that would predict a substantial dose-rate
effect over the dose-rate range in question.
15.4 DOSE-RATE EFFECTS FROM A
RETROSPECTIVE ANALYSIS OF THE IRIDIUM
IMPLANT DATA
The large series of patients treated with iridium wire
implants has been followed carefully over the years and
constitutes an invaluable resource. Two important
papers have appeared in recent years describing a retro-
spective analysis of these data. In the first, Mazeron et
al. [10] studied the incidence of local tumor control
and necrosis in T1 and T2 squamous cell carcinoma of
the mobile tongue and floor of mouth treated with
interstitial iridium-192. The data are shown in Figure
15.2. This represents one of the largest cohorts of
patients that has been analyzed after treatment with a
standardized implantation technique, but the numbers
still preclude a detailed analysis of dose rate and can
distinguish only between dose rates above and below
0.5 Gy h'1. Two principal conclusions can be drawn
from this analysis:
1. There is little or no difference in local control
between the two dose-rate ranges provided a
sufficiently high total dose is used (65-70 Gy), but
there is a clear separation at lower doses (around 60
Gy), with the lower dose rate being significantly less
effective.

Figure 15.2 Incidence of local tumor control and necrosis for
T 1-2 squamous cell carcinoma of the mobile tongue and floor
of mouth, treated with interstitial radiotherapy using iridium-
192. (Based on the published results of Mazeron et al. [10].j
2. Over the entire range of doses used, there was a
higher incidence of necrosis associated with the
higher dose-rate range.
The clinical data are in line with the predictions that
would be expected based on radiobiological considera-
tions, particularly the more critical dependence on dose
rate of late-responding tissues. Figure 15.3 shows the
theoretical expectations using representative values for
Figure 153 Local tumor control and necrosis rate at 5 years as
a function of dose in patients treated for T1-2 squamous cell
carcinomas of the mobile tongue and the floor of the mouth
with interstitial iridium-192 implants. The patients were
grouped according to whether the implant was characterized by
a high dose rate (above 0.5 Gy h~') or low dose rate (below 0.5
Gy h~1). The necrosis rate is higher for the higher dose rate at all
dose levels. Local tumor control did not depend on dose rate
provided the total dose was sufficiently large. (Redrawn from the
data of Mazeron et a I. [10].,)
The bias of tumor size and dose rate 217
oc/p and T| for early-responding and late-responding tis-
sues. The radiobiological predictions mirror the essential
characteristics of the clinical data, i.e., adequately explain
what was observed.
In a second study, Mazeron et al. [11] analyzed data
from a large group of patients with carcinoma of the
breast who received iridium-192 as a boost to external-
beam radiotherapy. These results allow an assessment of
the effect of dose rate on tumor control, but provide no
information on the effect of dose rate on normal tissues,
because there was only one case that involved necrosis,
probably because the interstitial implant comprised only
part of the radiotherapy. A fixed standard total dose was
used, regardless of the dose rate, and there is a clear cor-
relation between the proportion of recurrent tumors and
the dose rate, as illustrated in Figure 15.4. For a given
total dose, there were markedly fewer recurrences when
the radiation was delivered at higher as opposed to lower
dose rates. A clear difference in tumor control could be
seen between 0.3 and 0.9 Gy h"1, as predicted from radio-
biological experiments with cells in vitro.
Figure 15.4 Fraction of patients who showed no local
recurrence as a function of dose rate amongst patients with
breast carcinoma treated by a combination of external-beam
radiation plus iridium-192 interstitial implant. The implant was
used to deliver a dose of 37 Gy; the dose rate varied by a factor
of 3 due to different linear activities of the iridium-192 wire,
and to different size volumes implanted. (Drawn from the data
of Mazeron et a I. [11].,)
15.5 THE BIAS OF TUMOR SIZE AND
DOSE RATE
A complication and confounding variable in the inter-
pretation of clinical data relating dose to produce an
equivalent effect to implant time (and therefore to dose
rate) is the fact that, for interstitial implants, the dose
rate tends to increase as the size of the implant increases.
This correlation is particularly true for implants using
iridium-192 wires, as used in the Paris System, which are
218 Principles of the dose-rate effect derived from clinical data
all of the same linear activity, but less so when there is a
variation in linear activity, as in the Parker and Paterson
system [12]. The bias of larger tumors and larger
volumes being associated with higher dose rates, while
smaller tumors and smaller treatment volumes are asso-
ciated with lower dose rates, was pointed out by Pierquin
and his colleagues [9]. Larger tumors of course require a
larger dose for a given level of local control, whereas the
maximum dose that can be tolerated by normal tissues
decreases as the volume implanted increases.
This volume/dose-rate bias has an interesting effect on
the isoeffect curves, as illustrated in Figure 15.5. The
lower curves are isoeffect curves for late-responding nor-
mal tissues, while the upper curves relate to an early-
responding tissue, which includes tumor control. The
isoeffect curve for late-responding normal tissues is
steeper than for tumor control, showing a greater depen-
dence on overall time (or dose rate) in keeping with the
smaller oc/f3 ratio characteristic of such tissues as
described by Withers et al. [13]. The dashed lines in
Figure 15.5 illustrate, in a qualitative way only, the effect
of the variation of dose rate with tumor size and there-
fore with implanted volume.
At one extreme, higher dose rates are associated with
large tumors and therefore large implanted volumes.
Larger tumors require a larger dose to produce local con-
trol, while larger volumes can tolerate lower doses to
produce a given level of necrosis. The bias of higher dose
Figure 15.5 The correlation between implant volume and dose
rate has an influence on the shape of the isoeffect curves for
both early and late effects. Solid lines: calculated isoeffect curves
for in-vitro data representing tumors and for in-vivo data
corresponding to late-responding normal tissue. Dotted lines
illustrate qualitatively the way in which the isoeffect curves
change owing to the bias of higher dose rates being associated
with larger tumors. Larger tumors require a larger dose for a
given level of local control; this tends to flatten the isoeffect
curve for tumor control. By contrast, the isoeffect curve for late
effects in normal tissues is steeper, because larger implanted
volumes can tolerate smaller doses.
rates being associated with larger tumors (and, con-
versely, lower doses associated with smaller tumors) has
opposite effects on the isoeffect curves for tumor control
and for normal-tissue tolerance. It will tend to flatten the
isoeffect curve for tumor control and steepen the iso-
effect curve for normal-tissue tolerance, as shown by the
dashed lines in Figure 15.5. It should be stressed that the
dashed lines are qualitative only, showing a trend, but
cannot be quantitative at this time because data relating
tumor control dose to tumor volume, or tolerance dose
to treatment volume, are very limited.
Based on these considerations, then, it is clear why the
Paris school and the Paterson/Ellis school differed so
radically in their prescriptions for dealing with dose-rate
changes. Firstly, the Paterson/Ellis recommendations
were based on equalizing only late effects, where there is
a clear change of equi-effect dose with dose rate (solid
curves in Figure 15.5). However, the Paris recommenda-
tions were based on an attempt to equalize late and early
effects (with hindsight, it certainly seems that when the
dose rate changes it is not possible to match both late
and early effects). Secondly, the Paterson/Ellis recom-
mendations date from the era of radium needles when
there was less correlation between volume and dose rate
because needles of varying linear activity were available.
However, the Paris recommendations were based on
iridium wire implants, for which there is strong correla-
tion between tumor volume and dose rate, which would
tend to make the equi-effect curve for tumor control
vary even less with dose rate.
15.6 EARLY-RESPONDING AND LATE-
RESPONDING TISSUES
A basic tenet of radiotherapy is that delivering the overall
dose in many fractions, or at low dose rates, improves
therapeutic outcome. The rationale for this originally
empirical observation was provided by Withers and col-
leagues [13], who showed that, for a given dose, increasing
the number of fractions will decrease late effects much
more than it will decrease tumor control. Withers and col-
leagues quantified the difference in response between
late-responding tissues and early-responding tissues,
such as tumors, in terms of the linear-quadratic formal-
ism, and the parameter oc/p (see below), which is generally
smaller for late-responding than for acutely responding
tissue. What goes for multifraction protracted treatments
applies too to continuous low dose rate.
Because in most instances tumor cells are cycling
rapidly and qualify as early responding, whereas the
dose-limiting normal tissues are late responding, a pro-
tracted treatment regime consisting of many fractions of
external beam, or continuous low dose rate in an
implant or intracavitary procedure, leads to an improved
therapeutic ratio. There is, however, at least one excep-
 Exploiting differences in repair rates to optimize brachytherapy 219
tion to this general rule, namely carcinoma of the
prostate. This is a very slowly growing tumor for which
the oc/P ratio is about 1.5 Gy, similar to that for late-
responding normal tissues. This value was derived by
Brenner and Hall [14] from an analysis of two sets of
mature data on the radiotherapeutic control of prostate
cancer, one using external-beam therapy and the other
permanent seed implants. Because the tumor and dose-
limiting normal tissues have similar oc/(3 values, high
dose-rate (HDR) brachytherapy should be a highly
appropriate modality for treating prostate cancer.
15.7 SUBLETHAL DAMAGE REPAIR RATES
In the past decade, it has become increasingly clear that
there is a second type of difference in radiation response
between late-responding and early-responding tissues,
namely the rate of repair of sublethal damage. If late-
responding normal tissues and early-responding tissues
such as tumors do repair at different rates, this could be
used to produce improved radiotherapeutic protocols.
Specifically, just as differences in cc/|3 are currently
exploited to design schemes with improved therapeutic
advantage between early and late damage, it might be
expected that differences in repair rates could be
exploited to the same end.
The suggestion that repair rates might be slower in
late-responding compared to early-responding tissue
originated with Thames, Withers, and Peters in 1984
[15]. In rodents, they compared half-times for sublethal
damage repair (TO for damage to bone marrow,
jejunum, and colon (early-responding tissues) with
those for lung and spinal cord (late-responding tissues).
They concluded that Ti for the late-responding tissues
were significantly greater than 1 h, whereas for the early-
responding tissues the T{ were less than 1 h.
This suggestion was subsequently corroborated in the
clinic by analyzing the results of hyperfractionated
radiotherapy, where treatments were given at intervals of
only a few hours. Following some early indications from
Nguyen etal. [16],Edsmyr etal. [17], Morgan eta/. [18],
and Marcial etal. [19] that treatments with 2-h to 4.5-h
intervals were producing excess late effects, Cox et al.
[20] produced a definitive analysis of the results of the
Radiation Therapy Oncology Group (RTOG) protocol
8313; this protocol allowed hyperfractionation intervals
of 4-8 h for treatment of cancers of the upper respira-
tory and digestive tracts. The results were divided into
interfraction intervals of < 4.5 h versus > 4.5 h. Both
acute toxicity and tumor control were unaffected by the
interfraction interval, suggesting a relatively short Ti of,
roughly, < 100 min. On the other hand, the < 4.5-h
group showed a significant increase in late toxicity, sug-
gesting that repair was not complete between fractions,
implying a T{ of, roughly, > 200 min.
Further evidence from the clinic comes from the
results of Turesson and Thames [7] on early-responding
and late-responding skin damage after fractionated
radiotherapy. They found two-component repair
processes, both early-responding and late-responding
damage having an estimated fast repair TI of ~ 25 min.
However, the slow repair for early-responding damage
had an estimated T} of ~ 75 min, whereas the corre-
sponding estimated slow Ti for late-responding tissue
was ~ 250 min, with confidence limits from 210 to 320
min. In both cases, the slow and fast repair channels each
repaired about half the repairable damage.
The interpretation of laboratory-based animal data on
repair rates in late-responding tissues is still a matter of
some debate. Recent laboratory evidence has emerged
from analyses of late radiation damage in rodents in
which, following the clinical results of Turesson and
Thames, a possible two-component (fast and slow)
mechanism for late tissue damage repair was investi-
gated. Ang et al. [21] found two components of repair
for spinal cord damage in rodents (T{ values estimated at
0.7 h and 3.8 h) with an estimated 62% of the repair
occurring through the slow channel. Moulder and Fish
[22] have reported two components of repair for kidney
damage in rats (Tf estimated at 30-40 min and 130-200
min), with an estimated 70-75% of the repair proceed-
ing through the slow channel. Finally, van Rongen et al.
[23], re-analyzing the data of Travis et al. [24] for rodent
lung damage, also found two components of repair (Ti
estimated at 0.4 h and 3.6 h), with an estimated 24% of
the repair proceeding through the slow channel.
15.8 EXPLOITING DIFFERENCES IN REPAIR
RATES TO OPTIMIZE BRACHYTHERAPY
SCHEDULES
Differences in repair rates between early-responding and
late-responding tissues, if real, open up new possibilities
for optimizing brachytherapy schedules: in this situa-
tion, it can be shown that continuous low dose rate
(CLDR) no longer represents the optimal schedule pro-
ducing the maximum therapeutic ratio between tumor
control and late sequelae. For example, pulsed brachy-
therapy, with doses separated by several hours, would
result in a bigger differential between tumor and normal
tissue than CLDR [25]. It can also be shown that loading
the early and late parts of brachytherapy schedules with
larger doses, whilst keeping the overall dose and time
fixed, should improve therapeutic ratios still more.
These ideas suggest that the difference in repair rates
between early-responding and late-responding tissues
can be exploited to produce clinically practical protocols
of considerably greater therapeutic advantage than cur-
rently achieved. In this regard, the considerations here
complement the concepts expounded by Withers and
220 Principles of the dose-rate effect derived from clinical data
colleagues, who showed that the difference in the cc/P
ratio between early-responding and late-responding tis-
sues could be exploited to advantage. In this case, how-
ever, it is the difference in repair rates, as well as that in
oc/P, which can be exploited.
Under the assumption that late-responding tissues
repair more slowly than do early-responding tissues, for
the same overall dose and time, it is possible to design
optimized protocols which have significantly less late-
responding tissue cell killing, and slightly more early-
responding cell killing [26]. Thus, in comparison with
conventional CLDR protocols of the same overall dose
and time, the optimized protocols designed here should
produce: (a) significantly fewer late-tissue complica-
tions, and (b) comparable or slightly increased tumor
control and early normal-tissue sequelae.
Temporal optimization - that is, systematic optimiza-
tion of fractionation protocols - is a new concept in
radiotherapeutic design. There is an extensive literature
on spatial optimization in radiotherapy, in terms of
delivering maximum dose to the tumor relative to nor-
mal tissue. Temporal optimization, however, has not
received adequate consideration, and may allow major
therapeutic gains.
Finally, we add several caveats. First, the magnitude of
the potential gains that can be made depends on the rate
of repair for late-responding damage. The evidence for a
component of repair of several hundred minutes is sum-
marized above, and is reasonably convincing. However,
details, such as the ratio of a slow to fast component of
damage, are not well known. Second, the concepts
described here will not allow improvement of conven-
tional external-beam radiotherapy, where the time
between fractions (-24 h) is much longer than all known
repair times. Rather, the ideas here are relevant to all
accelerated protocols, be they brachytherapy or acceler-
ated hyperfractionated external-beam radiotherapy.
Finally, it is stressed that not all potential fractionation
protocols can be usefully optimized. In particular, as dis-
cussed above, pulsed protocols with long interfraction
intervals (such as ~15 h overnight gaps) probably can
never produce a therapeutically advantageous therapeu-
tic ratio, although optimization will still produce the best
possible therapeutic advantage for such protocols.
In conclusion, there is likely to be another biological
parameter, sublethal damage repair rates, which we may
exploit to produce a therapeutic advantage, and which
would open up a variety of new directions for
brachytherapy.
REFERENCES
1. Hall, E.J. and Bedford, J.S. (1964) Dose rate: its effect on
the survival of HeLa cells irradiated with gamma rays.
Radial Krc.,22,305-15.
2. Bedford, J.S. and Mitchell, J.B. (1973) Dose-rate effects in
synchronous mammalian cells in culture. Radial. Res.,
54,316-27.
3. Fu, K., Phillips, T.L, Kane, LJ. and Smith, V. (1975)
Tumour and normal tissue response to irradiation in vivo:
variation with decreasing dose-rate. Radiology, 114,
709-16.
4. Paterson, R. (1963) The Treatment of Malignant Disease by
Radiotherapy, 2nd edn. London, Edward Arnold.
5. Ellis, F. (1968) Dose time and fractionation in
radiotherapy. In Current Topics in Radiation Research, Vol.
4, ed. M. Elbert and A. Howard. Amsterdam, North
Holland, 359-97.
6. Brenner, D.J. and Hall, E.J. (1991) Conditions for the
equivalence of continuous to pulsed low dose rate
brachytherapy. Int.J. Radial Oncol. Biol. Phys., 20,
181-90.
7. Turesson, I. and Thames, H.D. (1989) Repair capacity and
kinetics of human skin during fractionated radiotherapy:
erythema, desquamation, and telangiectasia after 3 and
Syears'followup. Radiother. Oncol., 15,169-88.
8. Pierquin, B. (1971) Dosimetry: the relational system.
Proceedings of a Conference on Afterloading in
Radiotherapy. Rockville, New York. US Department of
Health, Education and Welfare, Publication number (FDA)
72-8024,204-27.
9. Pierquin, B., Chassagne, D., Baillet F. etal. (1973) Clinical
observations on the time factor in interstitial
radiotherapy using iridium-192. Clin. Radiol., 24, 506-9.
10. Mazeron, J.J., Simon, J.M., Le Pechoux. C. etal. (1991)
Effect of dose-rate on local control and complications in
definitive irradiation of TI squamous cell carcinomas of
mobile tongue and floor of mouth with interstitial
iridium-192. Radiother. Oncol., 21,39-47.
11. Mazeron, J.J., Simon, J.M., Crook, I etal. (1991) Influence
of dose-rate on local control of breast carcinoma treated
by external beam irradiation plus iridium-192 implant.
InlJ. Radial Oncol. Biol. Phys., 21,1173-7.
12. Meredith, W.S. (ed.) (1967) Radium Dosage: The
Manchester System, 2nd edn. Baltimore, Williams and
Wilkins.
13. Withers, H.R. Thames, H.D. and Peters, LJ. (1982)
Differences in the fractionation response of acutely and
late-responding tissues. In Progress in Radio-oncology,
Vol. II, ed. K.H. Karcher, H.D. Kolgelnikand G. Reinartz.
New York, Raven Press, 287-96.
14. Brenner, D.J. and Hall, E.J. (1999) Fractionation and
protraction for radiotherapy of prostate carcinoma. Int. J.
Radial Oncol. Biol. Phys., 43,1095-101.
15. Thames, H.D.Jr, Withers, H.R. and Peters, LF.(1984)
Tissue repair capacity and repair kinetics deduced from
multifractionated or continuous irradiation regimens
with incomplete repair. BrilJ. Cancer, 49,263-9.
16. Nguyen, T.D., Demange, L, Froissart, D., Panis, X. and
Loirette, M. (1985) Rapid hyperfractionated radiotherapy.
Cancer, 56,16-19.
17. Edsmyr, F., Andersson, L, Espoti, P.L, Littbrand, B. and

Nilsson, B. (1985) Irradiation therapy with multiple small
fractions per day in urinary bladder cancer. Radiother.
Oncol., 4,197-203.
18. Morgan, DAL, Bradley, P.J. and MacLennan, K.A. (1987)
Radiotherapy of advanced laryngeal cancer using three
fractions per day (abstract). Brit.J. Radial., 60,606.
19. Marcial, V.A., Pajak, T.F., Chang, C., Tupchong, L and
StetzJ. (1987) Hyperfractionated photon radiation
therapy in the treatment of advanced squamous cell
carcinoma of the oral cavity, pharynx, larynx, and
sinuses, using radiation therapy as the only planned
modality: (preliminary report) by the Radiation Therapy
Oncology Group. Int.}. Radial Oncol. Biol. Phys., 13,41-7.
20. Cox, J.D., Pajak, T.F., Marcial, V.A., Coia, L, Mohiuddin, M.
and Fu, K.K. (1991) Interfraction interval is a major
determinant of late effects, with hyperfractionated
radiation therapy of carcinomas of upper respiratory and
digestive tracks: results from Radiation Therapy Oncology
Group protocol 8313. InLJ. Radial Oncol. Biol. Phys., 20,
1191-5.
21. Ang, K.K., Guttenberger, R., Thames, H.D., Stephens, L.C.,
Smith, C.D. and Geng, Y. (1992) Impact of spinal cord
References 221
repair kinetics on the practice of altered fractionation
schedules. Radiother. Oncol., 25,287-94.
22. Moulder, J.E. and Fish, B.L (1992) Repair of sublethal
damage in the rat kidney (abstract) In Radiation Research:
a Twentieth-century Perspective, Vol. 1, ed. J.D. Chapman,
W.C. Dewey and G.F. Whitmore. San Diego, Academic
Press, 238.
23. van Rongen, E., Thames, H.D. and Travis, E.L (1993)
Recovery from radiation damage in mouse lung:
interpretations in terms of two rates of repair. Radial
Res., 133,225-33.
24. Travis, E.L, Thames, H.D., Watkins, T.L. and Kiss, I. (1987)
The kinetics of repair in mouse lung after fractionated
irradiation. Int.J. Radial Biol., 52,903-19.
25. Brenner, D.J. and Sachs, R.K., (1995) Potential reduced
late effects for pulsed brachytherapy compared with
conventional LDR. Int.J. Radial Oncol. Biol. Phys., 31,
201-2.
26. Brenner, D.J., Hall, E.J., Huang, Y. and Sachs, R.K. (1994)
Optimizing the time course of brachytherapy and other
accelerated radiotherapeutic protocols. Int.J. Radial
Oncol. Biol. Phys., 29,893-901.
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 PART
Ill
Clinical practice

16 Endobronchial brachytherapy in the treatment of

lung cancer 225
17 Brachytherapy in cancer of the esophagus 243
18 High dose-rate afterloading brachytherapy for
prostate cancer 257
19 Low dose-rate brachytherapy for breast cancer 266
20 Brachytherapy in the treatment of head and
neck cancer 284
21 High dose-rate interstitial and endocavitary
brachytherapy in cancer of the head and neck 296
22 Brachytherapy in the treatment of pancreas
and bile duct cancer 317
23 Brachytherapy for treating endometrial cancer 333
24 Low dose-rate brachytherapy for treating cervix
cancer: changing dose rate 343
25 High dose-rate brachytherapy for treating cervix
cancer 354
26 Brachytherapy for brain tumors 373
27 Interstitial brachytherapy in the treatment of
carcinoma of the cervix 379
28 Interstitial brachytherapy in the treatment of
carcinoma of the anorectum 387
29 High dose-rate brachytherapy in the treatment of
skin tumors 393
30 Hyperthermia and brachytherapy 400
31 The costs of brachytherapy 410
32 Quality management: clinical aspects 423
33 Safe practice and prevention of accidents in
afterloading brachytherapy 433
34 Pulsed low dose-rate brachytherapy in clinical
practice 443
This page intentionally left blank

Endobronchial brachytherapy in the treatment
of lung cancer
BURTON LSPEISER
16.1 INTRODUCTION
The treatment of lung cancer by radiation has consisted
primarily of the use of standard external-beam radia-
tion. The use of endobronchial brachytherapy (EBBT) in
the form of manual afterloading low dose-rate (LDR)
began to emerge in the early to mid 1980s. It was not
until the mid and late 1980s that high dose-rate remote
afterloading brachytherapy began to be utilized increas-
ingly. At the present time, it is the most prevalent means
of treating endobronchial disease with brachytherapy
throughout the world.
Endobronchial brachytherapy for lung malignancies
consists of the placement of a catheter into the involved
bronchus, with the radiation source placed with remote
or manual afterloading. After-loaded implants can deliver
LDR, intermediate dose-rate (IDR), or high dose-rate
(HDR) ionizing radiation at less than 1 Gy h"1 (low dose
rate, LDR), 1-12 Gy h'1 (IDR), or greater than 2 Gy miir1
(HDR). A typical afterloading system utilizes hollow
catheters and iridium-192 seeds embedded in nylon rib-
bon for LDR, or a single iridium-192 source (nominal
activity of 10 Ci or 370 GBq), which 'dwells' within the
lumen of the treatment catheters.
Endobronchial brachytherapy, however, has been used
16
primarily for palliation, for recurrent disease. Although
it is used curatively, this usage is not as prevalent. Even
less common is its use for occult carcinomas of the lung,
where, as the sole modality, or used in conjunction with
either photodynamic therapy or limited external radia-
tion, it can lead to high cure rates with low morbidity.
16.2 BACKGROUND
Brachytherapy was first used at the turn of the twentieth
century when the Curies gave a small radium tube to Dr
Danlos for insertion into a malignancy. In the ensuing
years, further progress was made in the area of
brachytherapy. Kernan [1] first reported the implanta-
tion of radon-222 seeds into carcinomas of the trachea
and bronchus utilizing a rigid bronchoscope. He
reported on ten cases treated with radon-222 seed
implantation combined with diathermy treatment. Of
interest was his comment in the report that, 'It was pos-
sible to destroy the tumors with diathermy and Radon
implantation, and there have been no local recurrences
as yet, although one case has been followed for five years.'
For the next 10 to 20 years, work was being performed
on standardization of dose calculation and prescription
226 Endobronchial brachytherapy in the treatment of lung cancer
for brachytherapy. The publication of the Manchester
System of Paterson, Parker, and Meredith (1934) set the
foundation for brachytherapy dosimetry. This was fur-
ther advanced with the publication of the manual,
Radium Dosage [2]. Pool [3] reported on radon-222
used at Memorial Hospital, New York City, in a total of
42 patients implanted during the time period of
1936-1960. The implanted seeds consisted of a sealed
gold capillary tube filled with radon-222 gas. The tech-
nique reported by Pool, 'proved to benefit patients with
primary tracheal tumors, and patients with bronchial
stump recurrences following pulmonary resection.'
Radon-222 seed implantation was also used during tho-
racotomy, with the first reported case by Graham and
Singer [4].
In order to decrease the radiation safety problems
with radon-222, efforts were made to identify radioac-
tive isotopes of shorter half-life and lower decay ener-
gies, as well as developing afterloading techniques, in
order to reduce medical personnel and patient expo-
sures. Henschke [5] introduced standardized afterload-
ing techniques with gold-198 and, subsequently,
iridium-192. With the shorter half-life of iridium-192
and afterloading techniques, interstitial implantation
showed a rapid increase in medical utilization, both in its
range of application and its overall usage in the USA.
However, despite this rapid increase, there were very few
changes in the limited use of brachytherapy for carci-
noma of the lung. Early transbronchial implantation
techniques, initially utilizing radon-222 and then iodine-
125 through the rigid bronchoscope, were difficult and
associated with a considerable expenditure of physician
time and effort. With the advent of the flexible broncho-
scope, a new flexible applicator system was designed by
Martinez and colleagues [6]. The use of intraluminal
brachytherapy by the placement of an afterloading flexi-
ble applicator bronchoscopically was first reported in the
American literature by Mendiondo et al [7]. In addition,
the new neodymium-YAG laser was introduced into
clinical use for the treatment of tracheal and endo-
bronchial obstructions for both primary and metastatic
lung malignancies in 1984. It is this convergence of med-
ical technologies that led to a rapid increase in the use of
intraluminal brachytherapy utilizing the afterloading
techniques, usually in concert with YAG laser photore-
section.
163 ENDOBRONCHIAL CATHETERS
A variety of commercial catheters is available for use.
Basically, the physical characteristics of each catheter
must allow for easy placement and removal from the
endobronchial tree and immobilization when in place.
The catheter must fit through the biopsy channel of the
endoscope and the internal diameter must be source
compatible (most commonly used are 5 or 6 French with
a 1.7 or 2 mm internal diameter, respectively). Finally,
the distal end of the catheter is closed-end to prevent
dummy seeds or the active source from coming into con-
tact with tissues and/or fluids.
The placement of the catheter is conducted after
assessing the cardiac and pulmonary status of the patient
to ensure his or her ability satisfactorily to tolerate an
endobronchial procedure. With a pulmonologist, the
catheter is placed in an endoscopy suite. This is per-
formed with constant vital sign monitoring, the use of
topical anesthesia and intravenous sedation. Under
video bronchoscopy, the malignant lesion is identified by
the pulmonologist and radiation oncologist. Photo-
graphic documentation is acquired and the anatomical
characteristics of the malignancy are noted, including
distance from anatomical landmarks such as bronchial
branch points and carina. The extent of the malignant
lesion can be further localized utilizing radio-opaque
markers placed on the patient's thorax corresponding to
the most distal and proximal extents of the malignancy
as identified by the bronchoscope under fluoroscopy.
After this visual inspection and fiuoroscopic confirma-
tion, a guidewire in a catheter is placed through the
biopsy channel. Its placement is confirmed visually and
fluoroscopically. The bronchoscope is removed and,
simultaneously, the catheter is positioned such that the
tip is several centimeters distal to the most distal point of
the malignancy. After complete removal of the broncho-
scope, the proximal end of the catheter is secured to the
nose. The guidewire is removed and replaced by a set of
markers. Orthogonal treatment planning simulation
films are obtained and the markers in the catheter and
fiducial points are digitized into the treatment planning
computer.
16.4 TREATMENT PRESCRIPTION
The prescription depth is calculated for the three-
dimensional volume by multiple points perpendicular to
the axis of the catheter or source train to which the min-
imum target dose is prescribed. The prescriptions that
are reported in the literature range from 0.5 cm to 2 cm.
To ensure treatment of the entire tumor volume, with
consideration for possible source or tumor movement
secondary to respiratory excursions, the maximal dis-
tance from the source center to the margin of the malig-
nancy must be considered during three-dimensional
brachytherapy planning. A longitudinal margin of 2 cm
proximal and distal to the malignant margins is com-
monly used. A prescription depth within the range 0.5-2
cm, which allows for effective dose distribution to
encompass the tumor volume depth without exceeding
bronchial mucosa tolerance dose, is employed, with a
recommendation that dose standardization be used
 Strategies for treatment of occult carcinomas of the endobronchus 227
(i.e., use or report the 1 cm depth from source axis for
comparison to other studies).
16.5 STRATEGIES FOR TREATMENT OF
OCCULT CARCINOMAS OF THE
ENDOBRONCHUS
Occult carcinomas of the lung are a subpopulation
defined as carcinomas diagnosed by sputum cytology,
and bronchoscopy using brushings, washings, and/or
biopsy. Less commonly, patients with cough and/or
hemoptysis undergo bronchoscopy and are diagnosed in
that fashion without a prior sputum cytology being pos-
itive. Their defining concept is that they cannot be
detected by conventional radiographic means before or
immediately after the initial diagnosis.
In 1974, Sanderson et al. published 'Bronchoscopic
localization of radiographically occult lung cancer' [8].
In 1980, Cortese et al. published their study,
'Roentgenographically occult lung cancer' [9]. In the
same year, Martini and Melamed published 'Occult car-
cinoma of the lung' [10]. Initially, the treatment of
choice was surgery, either lobectomy or pneumonec-
tomy. However, as experience with photodynamic ther-
apy (PDT) and then EBBT increased, the 'menu' of
treatment modalities increased.
This subpopulation of roentgenographically occult
carcinomas of the lung is associated with interesting
characteristics. First, the time interval from the initial
abnormal sputum cytology to bronchoscopic confirma-
tion, as reported by the Mayo Lung Project [9], ranged
from 1 to 1014 days (median, 70 days; 75th percentile,
169 days). Second, the disease is most often Tis, Tl and
NO [11] (Saito etal. [12] found that of 94 patients, 17%
were Tis and 77% were Tl). Third, most cases are squa-
mous cell carcinomas; in a significant number, dysplasia
initially had been the only finding [9]. Fourth, adverse
prognostic factors (i.e., weight loss) that predict lower
survival rates, are rarely present [13-16]. Finally, syn-
chronicity and metachronicity are significant. In a surgi-
cal series, Nagamoto et al. [17] reported a rate of 1.09
lesions per patient, Kato etal. [18] found 1.21 lesions per
patient, and Saito et al. [12] found 1.2 lesions per
patient. In the Mayo Lung Project Study [9], a metachro-
nous rate of 5% per year was reported. Saito et al. [19]
reported a rate of 0.022 lesions per patient-year; the rate
was 0.041 lesions per patient-year when synchronous
and metachronous tumors were combined. If a patient
had a second lesion, there was a 47% probability that,
within 5 years, a third lesion would be identified, at a rate
of 0.11 lesions per patient-year [19]. The 5-year survival
rate for patients with a single lesion and no evidence of
synchronous or metachronous lesions was 90%. If, how-
ever, other metachronous or synchronous lesions were
present, the 5-year survival rate was 59%. In 108 patients
who underwent surgical resection for occult carcinoma,
Nagamato etal. [17] identified ten (9.3%) who had addi-
tional squamous cell carcinomas <1 mm in size. These
lesions were associated with either dysplasia or marked
atypia.
Another important prognostic factor is the size of the
lesion. Many studies have found that lesions <10 mm in
size are associated with the most favorable outcomes. In
a surgical study of 127 patients [20], 55 patients had
lesions of this size, and no metastatic lymph nodes were
identified. Of 46 patients with lesions >10 mm but
<20 mm, there were four patients (9%) with nodal
metastasis. Of 26 patients with lesions that were >20 mm
but <55 mm, four patients (15%) had nodal disease.
Overall, for lesions >10 mm, the incidence of nodal
involvement was 11%.
In an earlier study by Saito [12], extrabronchial inva-
sion was documented by pathological analysis in 16
(17%) of 94 patients. Five (31%) of these 16 patients had
metastatic spread to nodes. Only one (1%) of 78 patients
had nodal disease without evidence of extrabronchial
invasion. No recurrences were identified in 75 patients
who had intrabronchial disease with no lymphatic
spread who underwent a complete resection. Overall, the
cause-specific 5-year survival rate was 93.5% (versus
80.4% for all causes combined).
Kato et al. [18] treated 45 lesions fulfilling the criteria
for occult carcinomas in 40 patients (1.13 lesions per
patient). PDT was the only treatment used for 30 lesions
in 20 patients, and the complete response rate was 100%.
Three patients (15%) had recurrences, one of whom
(5%) died of the disease. An additional nine patients
(45%) died of unrelated causes.
Considerably fewer patients with occult carcinomas
have been treated with EBBT than with PDT or surgery.
Sutedja et al. [21] reported two patients with Tl squa-
mous cell carcinoma who were treated with high dose-
rate EBBT. Three fractions of 10 Gy were delivered at a
1 cm depth. Both patients were alive without disease at
follow-up examinations at 54 and 25 months.
Tredaniel et al. [22] treated 29 patients with a diversity
of lesions, whose common denominator was that their
carcinomas were limited to the bronchus (radiographi-
cally occult), such that the disease could be encompassed
by intraluminal brachytherapy. In contrast to other
reported series, however, these patients had undergone
prior treatment, which included surgery, external radia-
tion, and/or chemotherapy. The patients were treated
with high dose-rate EBBT using a dose of 7 Gy calculated
at a 1 cm depth for six fractions (42 Gy). The median
actual survival of these patients had not been reached
after 23 months of follow-up.
Saito et al. [12] treated 49 occult carcinomas in 41
patients (1.2 lesions per patient) with external-beam
radiation using 40 Gy in 20 fractions plus EBBT of 25 Gy
in five fractions. Doses were customized and the pre-
scription point ranged between 3 mm and 9 mm depth,
228 Endobronchial brachytherapy in the treatment of lung cancer
based on the average diameter of the airway being
treated. With a median follow-up of 24.5 months, only
two patients (5%) experienced recurrences.
A prospective non-randomized study reported by
Perol and coworkers [23], utilized the following selec-
tion criteria in the treatment of occult lung cancer with
EBBT. All cases were proximal non-small cell lung carci-
nomas, <1 cm, in an area not previously irradiated. All
lesions were roentgenographically occult, and the
patients had severe chronic respiratory failure or had
already had surgery or external radiation for previous
lung carcinoma. An escalating dose protocol was
employed, and doses were prescribed at 1 cm. The first
two patients received three fractions of 7 Gy each, the
next four patients received four fractions of 7 Gy each,
and the last 13 patients received five fractions of 7 Gy
each. Two months after the completion of treatment, 15
(83%) of the 18 evaluable patients were locally con-
trolled with negative biopsies. At 1 year, 12 (75%) of 16
evaluable patients revealed no evidence of disease.
Actuarial 1-year and 2-year survival rates were 78% and
58%, respectively, with a median survival of 28 months.
Two patients who received five fractions of 7 Gy devel-
oped necrosis of the bronchial wall. Two of these
patients died of hemoptysis, one with no evidence of
carcinoma.
The substantial synchronous and metachronous rates
and the finding of additional small lesions with dysplasia
or marked atypia all lead to the concept of a 'field defect.'
It is quite likely that the entire bronchial mucosa is at
risk, with a high probability of more than one lesion
developing. Any treatment strategy should address this
basic issue. Although lobectomy and/or pneumonec-
tomy will cure a certain percentage of patients, the
remaining lung will continue to be at risk. Another strat-
egy for properly selected lesions (i.e., those <10 mm, no
Figure 16.1 Treatment schema for a proposed clinical trial for occult lung carcinoma with randomization between photodynamic
therapy (PDT) and endobronchial brachytherapy (EBBT). (Ext. = external radiation.)
evidence of extrabronchial extension, and squamous cell
histology) is to consider therapies designed to preserve
pulmonary function (PDT or EBBT). Lesions >10 mm
or with evidence or suggestion of extrabronchial exten-
sion or non-squamous histologies, however, should be
considered for surgery, if patients are medically oper-
able. If they are inoperable, prophylactic nodal external
radiation plus EBBT should be employed.
A suggested strategy is outlined in Figure 16.1. Lesions
that are <10 mm and with squamous cell histology
would be treated by one of the two therapeutic modali-
ties most conserving of pulmonary function. Such a
strategy would facilitate the clinical development of
EBBT for occult lung cancers.
At our institution, we have treated more than 600
patients on protocols utilizing EBBT, which are
described in detail later in the chapter. Of these patients,
only 19% were treated by the curative intent protocol
and, of these, only five (4%) met the criteria to be classi-
fied as radiographically occult carcinomas (Table 16.1).
The symptom index score is listed in Table 16.6. This is a
semi-quantitative symptom index (described later in the
chapter), which allows for description and scoring of the
symptoms of the patients during their medical course.
Five patients are included, with a total of six lesions
treated, for a rate of 1.2 lesions per patient. Two out of
five patients (40%) died from intercurrent disease. One
patient died of recurrence at 676 days. At the time of
analysis, two of the patients were alive with no evidence
of disease (NED) at 1228 and 650 days. In contrast to
other reported studies, these patients were treated with a
more conventional approach utilizing the current cura-
tive intent protocol described later in detail, which
allowed for the delivery of 60 Gy or 64 Gy, with external
radiation therapy given concurrently with their EBBT. In
this group of five patients treated with the combination
 Endobronchial brachytherapy for stages I, II, and III or recurrent lung cancer 229
Table 16.1 Brachytherapy for radiographically occult carcinoma
1 TisRUL Dyspnea (1) PDTx4
T1RLL Cough (1)
2 T1 LUL Hemoptysis (2) COPD- severe
Dyspnea (2)
Cough (1)
3 T1 RUL Hemoptysis (1) COPD -severe
Dyspnea (4)
Cough (1)
4 T2RLL Cough (2) COPD -severe
5 T2RMS Hemoptysis (1) COPD -severe
Dyspnea (3)
Cough (4)
a
The numbers in parentheses refer to grade and symptom as described in Table 16.6.
Rx = radiation treatment; NED = no evidence of disease; RUL = right upper lobe; RLL = right lower lobe; LUL = left upper lobe; RMS = right main
stem; COPD = chronic obstructive pulmonary disease.
of external-beam radiation and EBBT, there were no
complications.
16.6 RESULTS OF ENDOBRONCHIAL
BRACHYTHERAPY FOR STAGES I, II, AND III
OR RECURRENT LUNG CANCER
Bronchogenic carcinoma often leads to symptoms sec-
ondary to airway involvement. These can include
obstructive pneumonia, atelectasis, hemorrhage, cough,
or interference with airflow. YAG laser photo resection has
immediate results, but is restricted to central airways and
to use by highly experienced operators. Unfortunately,
conservative photoresection of the tumor without other
interventions usually results in a fairly rapid re-obstruc-
tion of the airway. The principle of endobronchial
brachytherapy is that a very high dose of radiation is
delivered in a short period of time to the tumor, with
sparing of normal adjacent tissues. Historically, it is of
interest that as early as 1922, Yankauer [24] placed cap-
sules of radium through a rigid bronchoscope into the
region of bronchogenic carcinoma in two patients with
airway obstruction. In 1933, Kernan [1] used radon seed
implantation. With the advent of fiberoptic bron-
choscopy, new techniques became possible. The first
reported use for transbronchial implantation was by
Moylan [25] in 1983, using gold-198 seeds. Also in 1983,
Mendiondo [7] used an afterloading tube placed with the
aid of the fiberoptic bronchoscope and then placed an
iridium-192 source into the tube. A total of 3000 cGy
delivered at a 5 mm depth was prescribed, with an average
treatment time of 10 h. Using this technique, it was noted
that patients had 'significant improvement' in bronchial
obstruction. Schray et al. [6,26] reported on afterloading
with iridium-192 in 1985 and again in 1988. A single
7.5Gyx3/60Gy 202 Died-intercurrent None
7.5Gyx3/60Gy 1228 Alive NED None
5Gyx4/60Gy 676 Died -local recurrence None
5 Gy x 3/64 Gy 650 Alive NED None
5Gyx3/64Gy 104 Died-intercurrent None
catheter was used in 65 patients. Fifty-nine of his patients
had either prior or concurrent external radiation, and 40
of the patients underwent YAG laser photoresection.
Approximately 60% of the patients showed a response,
20% were stable, and 20% had progression at follow-up
bronchoscopy. In his second report in 1988, 11 patients
had developed either fistulas or massive hemorrhage,
seven of which he felt were secondary to treatment. He
also noted that six of the seven patients had undergone
YAG photoresection and that this may have contributed
to the complications.
High dose-rate (HDR) remote afterloading was first
reported in the American literature by Seagren et al. in
1985 [27]. All patients in this reported series had endo-
bronchial carcinoma and had previously received a min-
imum external-beam radiation therapy dose equivalent
to 5000 cGy prior to brachytherapy. Each patient had
bronchoscopically documented disease with local symp-
toms and a Karnofsky performance status of 50 or
greater. The HDR remote afterloading unit was a
Brachyton using a 3 mm diameter cobalt-60 source with
an average strength of 0.7 Ci. The unit had the ability to
oscillate the source up to a maximum of 16 cm. A single
catheter was used and a dose of 1000 cGy in a single frac-
tion was delivered at a prescription depth of 10 mm. The
total time for treatment ranged between 12 and 27 min-
utes. Seagren et al. reported on a total of 20 patients
treated between 1982 and 1983. Four patients had first
received YAG laser photoresection prior to the
brachytherapy procedure. Complete palliation of symp-
toms was seen in 25% of the patients, partial in 69% for
a combined partial, or complete palliation of symptoms
in 94% of the patients. In six of these patients, palliation
was long lasting, with no recurrence of symptoms. In 12
patients, these symptoms recurred or progressed, with a
mean time to recurrence of 4.3 months.
Table 16.2 Compilation of endobronchial HDR studies

Seagren(AI) 1985 20 10at10mm 1 94 NA 100 28

Macha (A2) 1987 56 7.5 at 10 mm 3 74 88 75 7
Nori (A3) 1987 15 20 at 10 mm 3 80 88 NA 0
Burf (A4) 1990 50 15-20 at 10 mm 1 50-86 46 88 0
Pass (A5) 1990 15 5-36 at 10 mm 1-6 75 NA NA 0
Miller (A6) 1990 88 10at10mm 3 NA NA 80 0
Stout" (A7) 1990 100 15-20 at 10 mm 1 50-86 46 NA 0
Khanavkar(AS) 1991 12 Sat 5 mm 2-8 67 NA 100 50
Aygun (A9) 1992 62 5at10mm 3-5 NA 36 76 15
Bedwinek(A10) 1992 38 6 at 10mm 3 76 64 82 32
Gauwitz(A11) 1992 24 15at10mm 2 88 83 100 4
Mehta(A12) 1992 31 4 at 20 mm 4b 88 71-100 85 3
Sutejda(A13) 1992 31 10at10mm 3 82 NA NA 32
Speiser(A14) 1993 144 10at10mm 3 85-99 NA 80 7
151 7.5 at 10 mm 3 8
Zajac(A15) 1993 82 10^7 at 10 mm 1-5 82 NA 74 0
Tredaniel(A16) 1994 51 7 at 10 mm 2-8 55-85 NA 84 10
Chang(A17) 1994 76 7 at 10 mm 3 79-95 NA 87 4
Gollinsa(A18) 1994 406 10-20 at 10 mm 1 (94%) 88 (H) 62 (C) 46 NA 8
2 (6%) 60 (D) 92 (S)
Cotter (A1 9) 1993 65 (17 intermediate, 48 HDR 2.7-10 at 10 mm 2-4 66 (PS) 46 63 2
Goldman (A20) 1993 20 15at10mm 1 37(C)89(D)100(H) 58 55 0
Marsh (A21) 1993 12 26-53 at 10 mm; high 1 92 (tumor response) 8
activity125I
Nori (A22) 1993 32 4-5 at 10 mm 3-4 100(H)86(C)100(P) Local control 83 0
Pisch (A23) 1993 39 10at10mm 1-2 93 (H) 80 (C) 20 (P) NA NA 3
Macha (A24) 1995 365 5-7.5 at 10 mm 1-6 69 NA NA 21
Huber(A25) 1995 93 3.8 at 10 mm or 4 Improved local control 21
7.2 at 10 mm 2
Gustafson (A26) 1995 46 7 at 10 mm 3 74 69 92 7
Sur(A27) 1995 14 10at10mm 1-2 100(H) NA NA 7
Speiserc (A28) 1995 485 total
47IDR 10 at 5 mm 3 99 (H) NA 53 (CR) 4.4 (CUR)
144 HDR 10at10mm 3 99 (P) 29 (PR) 7.3 (PAL)
82 (TR)
151 HDR 7.5 at 10 mm 3 86 (D) 9.1 (REC)
 143 HDR 7.5at10mm 3 85 (C) 7.3 (all)
5at10mm 4
Saito (A29) 1996 40 5 at 3-9 mm 5 NA NA 100 0
Delclos (A30) 1996 81 15at6mm 2 32 excel lent
31 moderate
21 minimal
84 total NA NA 0
Huber(A31) 1997 98 median survival
42 External only
60" 22-30 30 week 14
56 External + internal
Internal 4.8 at 5 mm 2 43 week 19
Corsa (A32) 1997 29 5-15at10mm 1-4 100(H)70(D)46(C) 83 79 6.9
Perol (A33) 1997 19 76 at 10 mm 3-5 79 biopsy (-) 10.5
actual survival
1 year = 78
2 years = 58
median = 28 months
Ornadel (A34) 1997 117 15at10mm 1 46 (C) 50 (D) 9.4
62 (H) 54 (PS) 20 2 years
actuarial
Ofiara (A35) 1997 30 8at10mm 3 46 (C) 33 (D) 43 63 NR
20 (P) 79 (H)
Hennequin (A36) 1998 149 4-7 at 5-1 5 mm 2-6 60 79 6.7
(Multivariate
analysis,
endobronchial
tumor length was
significant
p = 0.02)
Total 1985-1998 3176 20-100 36-88 55-100 0-50
Mean 10.1

C = cough, CR = complete response, CUR = curative, D = dyspnea, H = hemoptysis, IDR= immediate dose rate, P = pneumonia, HDR = high dose rate, NR = not recorded, PAL = palliative, PR = more than 50%
response, PS = performance status, REC = recurrent, S = stridor, TR = CR + PR.
Patients in more than one publication were counted once.
a
Same institution.
b
Four treatments in 2 days.
c
Speiser reporting different protocols.
d
Mean dose ~ 50 Gy 13 Gy.
For references A1-A36, see p. 241-2.
232 Endobronchial brachytherapy in the treatment of lung cancer

Joyner and colleagues [28] first reported on the use of
iridium-192 solid wire afterloading for endobronchial
treatment. They treated 14 patients with stage III non-
small cell lung cancer with a combination of
neodymium-YAG laser photoresection followed by
endobronchial radiation and external-beam radiation
therapy treatments. Brachytherapy treatment times were
approximately 8-20 h to deliver 3000 cGy at a prescrip-
tion depth of 5 mm. Rooney and colleagues [29] dis-
cussed their protocol for anesthesia in the use of HDR
endobronchial treatment utilizing a Gamma Med unit
with an iridium-192 source. This technique allowed for
the stepping sequence of the source in up to 12 dwell
positions spaced at either 0.5 or 1.0 cm. The patients
were treated on a weekly basis, receiving 600 cGy per
week at a prescription depth of 1 cm with a maximum of
five treatments. This was a technique paper, and clinical
results were not presented. Macha et al. [30] published a
report in 1987 of HDR afterloading with an iridium-192
source in which the treatment was fractionated into
three treatments through a single catheter. The total dose
was 1500 cGy at a 5 mm prescription depth. Patients had
laser, external radiation, and/or chemotherapy and had a
high complication rate.
Patients who present with atelectasis may particularly
benefit from application of this approach. Re-expansion
of the lung after endobronchial brachytherapy may allow
for better-tailored external-beam radiation fields. Bastin
et al. [31] reported their ability to spare an average of
32% of the ipsilateral lung volume using this technique.
In most of the studies described above, the procedure
consisted of a single catheter for intraluminal
brachytherapy. Additional physics factors must be taken
into account, including the choice of the radioactive iso-
tope, the dose at the prescription depth relative to the
radius and inverse square law, as well as correction fac-
tors for the attenuation in water equivalent tissue versus
air. Iridium-192 can be fabricated in very small physical
sizes of high activity, allowing passage through catheters
with an internal diameter of 1.5 mm or less. In addition,
iridium-192 has virtually no significant correction for
attenuation in water versus air up to a distance of 5 cm
from the source. This makes iridium-192 an ideal
radioactive isotope to be used within tissues with mixed
air/water density interfaces, such as intraluminal
brachytherapy. The major drawback of iridium-192 is its
relatively short half-life of 74 days, such that over a
period of months, its activity changes considerably.
However, this disadvantage can be addressed by the fre-
quent replacement of the sources to keep the source
strength well within the high dose-rate range.
Table 16.2 is a compilation of most, but not all, of the
studies published on HDR remote afterloading endo-
bronchial brachytherapy. It covers the years 1985 to 1998
for a total of 3176 patients. The reader can see in the tab-
ulation the different doses used per fraction, the wide
range of fractions, as well as the dose prescriptions at
various depths. Of interest is that, while the variation for
fatal hemoptysis is extremely large (ranging from 0% to
50%), the mean is 10.1%. This rate appears to depend on
multiple factors, such as total number of patients stud-
ied, extensiveness of follow-up, and aggressiveness of the
treatment. For a small series, such as that of Khanavkar
[32], the complication rate - 50% incidence of fatal
hemoptysis in 12 patients - is probably not representa-
tive. Similarly, there are reports of no fatal hemoptysis,
such as that of Burt et al. [11], reporting on 50 patients.
However, when the same medical group updated their
series and reported on a total of 406 patients [33], their
rate of fatal hemoptysis was 8%. Some authors have
attributed fatal hemoptysis to aggressive treatment, such
as Bedwinek [34], who reported a 32% rate of hemopty-
sis. However, Macha [35] and Speiser [36] reported on
365 and 485 patients with lower rates of fatal hemopty-
sis, 21% and 8% respectively. Further information indi-
cated that many of these cases were secondary to biologic
progression of the carcinoma itself, suggesting that the
treatment may not have been aggressive enough.
In 1986, Speiser and Spratling developed a series of
scoring systems (Tables 16.3-16.6) for selecting patients
for treatment, as well as for outcome analysis. Their ini-
tial report [37] was based on experience with an inter-
mediate dose-rate unit, which was a modification of a
low dose-rate unit, to allow a higher specific activity of

Table 16.3 Influence of performance status on patients with inoperable lung cancer

100
1 80-90
2 60-70
3 40-50
4 20-30
Asymptomatic
Symptomatic: fully ambulatory
Symptomatic: in bed less than 50% of the day
Symptomatic: in bed more than 50% of the day but not bedridden
Bedridden

Table 16.4 Weight loss score based on percentage of loss of
body weight within 6 months preceding diagnosis
0 0
1 1^1.9
2 5-9.9
3 10-19.9
4 >20.0
Table 16.5 Obstruction score
Trachea 10 5 2
Main stem 6 3 1
Lobar bronchi 2 1 -
Atelectasis/pneumonia received additional 2 points per lobe.
Table 16.6 Symptom index scoring system
Dyspnea
0 None
1 Dyspnea on moderate exertion
2 Dyspnea with normal activity, walking on level
ground
3 Dyspnea at rest
4 Requires supplemental oxygen
Cough
0 None
1 Intermittent, no medication necessary
2 Intermittent, non-narcotic medication
3 Constant or requiring narcotic medication
4 Constant, requiring narcotic medication but without
relief
Hemoptysis
0 None
1 Lessthan2/week
2 Less than daily but greater than 2/week
3 Daily, bright red blood or clots
4 Decrease of hemoglobin and/or hemotocrit > 10%;
greater than 150 cm, requiring hospitalization or
transfusion
Pneumonia/elevated temperature
0 Normal temperature, no infiltrates, white blood
count less than 10 000
1 Temperature greater than 38.5 C and infiltrate,
white blood count less than 10000
2 Temperature greater than 38.5 C and infiltrate
and/or white blood count greater than 10000
3 Lobar consolidation on radiograph
4 Pneumonia or elevated temperature requiring
hospitalization
Protocol 233
iridium-192 for more rapid delivery of dose. In some of
the low dose-rate protocols, delivery of radiation took as
long as 60 h. The increase of iridium-192 activity
allowed the treatment time to be decreased to 1.5-4 h.
This range was based on (1) shorter times when the
sources were new versus longer times after the sources
decayed, and (2) the use, for the first time, of multiple
catheters to deliver treatment. All treatments were per-
formed in the outpatient setting and followed a protocol
that is outlined in the next section.
16.7 PROTOCOL
The protocol alluded to earlier in the chapter was initi-
ated in 1986 when EBBT was transformed from low
dose-rate manual afterloading to medium dose-rate
remote afterloading procedures. This was a transitory
step of short duration, lasting for 9 months. The HDR
remote afterloader was, in fact, a Nucletron Selectron
low dose-rate remote afterloader that was modified to
accept a longer source train and a higher level of radio-
activity. The activity was typically maintained at greater
than 740 MBq, or 20 mCi cm"1. Dose rates initially were
calculated at a 5 mm depth perpendicular to the source
train, and were in the range of 5-10 cGy min-1.
16.7.1 Eligibility
Eligibility for the protocol included the following.
1. Disease must involve the trachea, main stem, or
lobar bronchi. Involvement of the segmental bronchi
without involvement more proximal was not
considered sufficient for entry into the protocol.
2. The central airway disease must be intraluminal,
visualized and biopsied via bronchoscopy. Patients
requiring transbronchial biopsy were ineligible for
the protocol.
3. Patients must have significant symptomatology
within the four symptom groups consisting of
cough, dyspnea, signs and symptoms of obstructive
pneumonia, and/or hemoptysis.
Evaluation of the patients meeting eligibility criteria
for the EBBT protocol schedule was reviewed within the
context of all patients diagnosed with lung cancer in
the referral area from 1986 through 1996. This involved
the greater Phoenix/Maricopa County area and, based
on the Tumor Registry, an incidence of approximately
9000 cases of lung cancer during the 10-year period was
calculated. Of these, only 19% received radiation and
16% of that group, or 3% of all patients, were treated on
protocol, while an additional 11% of patients receiving
radiation (or 2% of all patients) were treated with
brachytherapy off protocol. Thus, 27% of all patients
receiving radiation, or 5% of all diagnosed lung cancer
234 Endobronchial brachytherapy in the treatment of lung cancer

patients, received brachytherapy. For patients on the
curative protocol, these figures were 3% and 0.5%,
respectively.
16.7.2 Indications
Indications for treatment are outlined in Table 16.7.
16.7.3 Protocol 1.0 curative intent
To be eligible for this protocol, patients must not have
had prior radiation within the thoracic area, which
would preclude the adequate delivery of a full dose of
external radiation. Patients must be inoperable and have
a primary lung carcinoma with non-small cell histology.
Stages accepted were Tl,2,3, Nl,2, MO. These correspond
to stage groupings I, II, and Ilia. Performance status
using the East Coast Oncology Group (ECOG) four-
tiered system must be 0, 1, or 2 and weight loss using a
four-tiered weight loss system, likewise, must be 0, 1, or
2 and correspond to weight losses of 0, less than 5% or
less than 10%, respectively, of the patient's weight in the
6 months prior to diagnosis. The rational for selection of
this level of weight loss is described in 'Oncologic assess-
ment using the four-tiered scoring system' [38].Patients
were treated within groups 1-4, with dose modifications
as described in Table 16.8.
16.7.4 Protocol 2.0 palliative intent
PROTOCOL 2.1
Eligibility for these patients includes: primary lung can-
cer with non-small cell histology, and stage T4, N3
and/or Ml disease. These corresponded to stage group-
ings Illb and IV. In addition, the patients ineligible for
protocol 1.0 because of performance scores of 3 or 4 or a
weight loss of 3 or 4 (>10% >20%) were reallocated to
this protocol. Patients were treated within groups,
characterized by dose, as described in Table 16.8.
PROTOCOL 2.2
Primary lung cancer consisting of small cell histology,
both limited and extensive; primary lung cancer with
contralateral metastatic disease involving the endo-
bronchial mucosa; and non-lung primaries with metas-
tases primarily to the mucosa were treated within this
category. Patients were treated within the group charac-
terized by dose as described in Table 16.8.
16.7.5 Protocol 3.0 recurrent patients
All patients who had received prior radiation for a cura-
tive intent for carcinoma of the lung were included
within this category. Patients were treated within the

Table 16.7 Indications for treatment with endobronchial brachytherapy

Tumors must be seen and biopsied by
bronchoscopy (intraluminal)
Tumors presenting with extrinsic
compression of the airway as seen by
bronchoscopy and the biopsy must be
performed transbronchially
(extraluminal)
Intraluminal brachytherapy delivers a very
high dose to tumor close to the source axis;
extraluminal disease due to its much
greater distance from the axis, would lead
to unacceptable doses to the bronchial
mucosa and surrounding structures

Tumors must be in the central airways Tumors in peripheral airways which Significant symptomatology is most often
which are defined as the trachea, main are defined as segmental bronchi or caused by disease in central airways;
stem, and lobar bronchi beyond treatment of small peripheral airways
leads to stenosis of those airways

Tumors in central airways causing Patients with significant pre-existing Patients with symptoms second to disease
significant symptomatology dyspnea unrelated to carcinoma; other than central airway disease are not
patients with dyspnea secondary to expected to improve with intraluminal
effusion, or large extrinsic masses brachytherapy

In-situ carcinoma for inoperable Patients entered into national protocols Preserves lung and pulmonary function;
patients using other modes of treatment, i.e., excellent treatment for multifocal disease
photodynamic

Pre-op. for submucosal spread from Patients should be good candidates Treatment provides a clear margin for
a peripheral/central lesion for lobectomy or pneumonectomy surgery
 Protocol 235

Table 16.8 Modification of doses by year for the curative, palliative and recurrent protocols

Curative protocol
1 1986-1988 6000 30 1000 5 3 MDR
2 1988-1990 6000 30 1000 10 3 HDR
3 1990-1992 6000 30 750 10 3 HDR
4 1992-1994 6400 32 500 10 3 HDR
Palliative protocol
1 1986-1988 3750 15 1000 5 3 MDR
1000 5 3 MDR
2 1988-1990 3750 15 1000 10 3 HDR
1000 10 3 HDR
3 1990-1992 3750 15 750 10 3 HDR
750 10 3 HDR
4 1992-1994 3750 15 500 10 3 HDR
500 10 4 HDR
750 10 3 HDR
Recurrent protocol
1 1986-1988 1000 5 3 MDR
2 1988-1990 1000 10 3 HDR
3 1990-1992 750 10 3 HDR
4 1992-1994 500 10 4 HDR

group characterized by dose, as described in Table 16.8.
Group I patients were treated with medium dose rate. In
the palliative protocol, the brachytherapy was constant
and the use of external radiation was optional, at the dis-
cretion of the treating oncologist. Its use was restricted
to patients with extrinsic disease that caused a significant
contribution to the level of obstruction and/or sympto-
matology.
16.7.6 Results
The following results incorporate 600 patients treated in
the curative, palliative, and recurrent protocols outlined
previously. In each of the successive periods of the oper-
ation of the protocol, the eligibility factors for the cura-
tive, palliative, and recurrent protocols have remained
constant.
All patients treated in curative protocols with external
radiation received 2 Gy per fraction and, in palliative
protocols, 2.5 Gy per fraction. If patients received con-
current brachytherapy and external radiation, the two
treatments were not given on the same day. For the cura-
tive protocol, brachytherapy was delivered during weeks
one, three and five. For palliative or recurrent protocols,
brachytherapy was delivered weekly for three or four
fractions, depending on the protocol.
The distribution of patients into the protocol groups
was as follows: curative 19%, palliative 48%, and recur-
rent 33%. The age distribution of the patients had a
median of 68 years and a mean of 67.1 years. Most of the
patients fell within the range of 60-80 years old. The
gender distribution was 62% male and 38% female. The
percentage of female patients increased from 28% in
Group 1 to 41% in Groups 3 and 4. The breakdown for
male/female patients was similar to that of all patients
presenting with carcinoma of the lung within the geo-
graphical treatment area.
Squamous cell carcinoma is by far the most common
cell type, overall, in the study (49%), and even to a
greater extent for those treated in the curative protocol
(70%). This percentage is considerably higher than is
currently being seen in newly diagnosed outpatients
with lung cancer (27%). This fits with prior observations
that squamous cell carcinomas tend to be more central
and adenocarcinomas more peripheral.
The use of laser photoresection predated the wide use
of HDR brachytherapy for airway carcinoma. In this
study there was a gradual decrease in photoresection
from an initial 32% to 16% in the latter part of the study.
It is currently estimated that less than 5% of patients
with central airway disease require laser photoresection.
The protocol required that patients must have one or
more of the four primary symptom complexes in order
to be included in this study. The incidence of the symp-
toms in the study were: cough, 99%; dyspnea, 97%;
hemoptysis, 64%; and the signs and symptoms of
obstructive pneumonia, 49%. Using the Four-tiered
symptom index as outlined in Table 16.6, the severity of
the symptoms was weighted and the total weighted
scores was subsequently normalized to 100%. Response
for each symptom score is related to each brachytherapy
236 Endobronchial brachytherapy in the treatment of lung cancer
procedure and the first follow-up bronchoscopy (Figure
16.2).
Hemoptysis had the most dramatic and rapid of the
responses with improvements of 70%, 90%, and >99%
at each intervention point. Pneumonia improvement
was only slightly less dramatic, with responses of 57%,
85%, and >99%. Improvement in dyspnea occurred in
36%, 54%, and 86% respectively. The fourth symptom,
cough, showed improvements of 32%, 52%, and 85%,
respectively. The improvements in hemoptysis and
pneumonia were commonly seen within the first 24 h
following the first brachytherapy procedure. Patients,
who were admitted to the hospital with obstructive
pneumonia and/or sepsis, or with severe bleeding
requiring transfusion, generally had a prompt response.
In the palliative protocol, the use of concurrent exter-
nal radiation with brachytherapy was optional. When
the weighted responses were measured for brachyther-
apy only, versus brachytherapy and external radiation,
the results in terms of improvement at follow-up were as
follows: hemoptysis, 94% and 97%; pneumonia, 86%
and 82%; dyspnea, 54% and 48%; and cough, 51% and
57%. There was no statistical difference in response for
each symptom group for each of these two therapies.
The use of brachytherapy only was sufficient to provide
palliation, without the need to add supplemental exter-
nal radiation.
Airway obstruction scores (as seen in Figure 16.3),
were analyzed in a different fashion. All of the scores
were converted into median scores, which were normal-
ized to 100%. These were obtained for each brachyther-
apy procedure and at the first follow-up bronchoscopy.
The median score was normalized to 100% and the
residual level of obstruction expressed as a percentage.
Any tissue including inflammatory tissue was included
as part of the obstruction score. The curative patients
and the palliative groups fared better than the recurrent
group, with scores of 12%, 12.5%, and 19% respectively
(Figure 16.3). This is not unexpected, considering that
patients with recurrent carcinoma have had previous
external radiation, which may select for a slightly more
radioresistant carcinoma. It is interesting that neither the
use of concurrent external radiation nor the use of laser
photoresection led to improved clearing of obstruction.
Thus, as in the symptom index results, the addition of
external radiation or laser resection did not add to clear-
ing endobronchial disease.
The survival of patients by protocol group was, for the
curative patients, 10%, and for palliative-recurrent, 5%
at 5 years. The cause of death shows a significant local
failure rate in all categories. These rates were 31% and
30%, respectively, for the curative and palliative-
recurrent protocols. As has been seen in numerous other
studies, despite gradual increasing doses of radiation
Figure 16.2 Response in the
symptom index as measured by
the decrease of the symptom
index scores comparing the
initial score at the first
brachytherapy (normalized to
100%) and the scores at
subsequent encounters as the
percent residual.
Figure 16.3 Response in the obstruction score with
the mean initial score normalized to 100% at the
first brachytherapy and the percent residual at the
first bronchoscopicfolloW-up (F/U).

over the last several decades, local disease continues to be
a significant problem.
Survival curves for curative versus the palliative-
recurrent patient illustrated in Figure 16.4 are calculated
from the date of diagnosis and date of the first
brachytherapy procedure. There was no statistically dif-
ferent result between these two groups when analyzed
Figure 16.4 Survival cures and p values for curative, palliative, recurrent, and combined group measured from diagnosis and from
date of first treatment.
Protocol 237
from the date of diagnosis (p = 0.1). However, from the
date of the first brachytherapy treatment, thep-value was
<0.0001 comparing the curative versus the palliative-
recurrent patients. The recurrent patients are self-
selected by the fact that they lived long enough to
develop a symptomatic recurrence. This bias was elimi-
nated when analyzing survival by date of treatment.
238 Endobronchial brachytherapy in the treatment of lung cancer
16.8 COMPLICATIONS
The complication most often described when discussing
endobronchial carcinoma and its treatment is that of
fatal hemoptysis. This is defined as bleeding which is
usually caused by erosion into the right or left pul-
monary artery, with subsequent exsanguination within
the tracheal bronchial tree. This is a known complication
of the progression of untreated or inadequately treated
carcinoma involving the tracheal bronchial tree, usually
in the region of the upper lobe bronchi, due to their
proximity to the pulmonary arteries. With the advent of
intraluminal treatment, it must also be considered as a
possible complication of this modality.
In the study of Speiser and Spratling [37], the overall
rate of fatal hemoptysis is 6%, with the median time
from diagnosis until death of 14 months. However, when
measured from the date of the first brachytherapy until
death, the median for the entire group is only 5 months.
Recurrent patients, as would be anticipated, have the
highest rate of fatal hemoptysis, at 9%, while the curative
and palliative patients have rates of 5%. Of interest is
that, in the different dose groups, there was an increase
in fatal hemoptysis as the dose was increased from
Group 1 to 2. However, there was paradoxically a slight
further increase in the rate of hemoptysis as the dose was
initially reduced, and then a decrease in the rate of fatal
hemoptysis (2%) with further dose reduction. No clear
dose-response relationship could be identified. In the
palliative protocol, 41% of the patients were treated with
brachytherapy only, and 59% with brachytherapy and
external radiation. The rate of fatal hemoptysis was 5.5%
in the brachytherapy-only group, versus 4% in the com-
bined group who received higher doses of radiation.
The most common side-effect related to intraluminal
treatment is radiation bronchitis and stenosis. This was
first described by Speiser and Spratling [37].Table 16.9 is
a definition of the various grades of radiation bronchitis
and stenosis. The incidences of radiation bronchitis and
stenosis by group were 9%, 12%, 14%, and 14%, respec-
tively. By protocol, they were 23%, 12%, and 8%, respec-
tively, for the curative, palliative, and recurrent
protocols. The rate is clearly highest in the curative
patients. However, the only significant factor predicting
for this response was length of follow-up. Although the
true incidence of this complication is not known for
patients receiving external radiation only, it appears to
be a complication primarily of intraluminal brachyther-
apy, with its very high mucosal doses.
For palliative patients, this complication was studied
in those patients receiving brachytherapy only versus
those receiving brachytherapy with concurrent external
radiation, and the incidences were 17% and 10%, respec-
tively. Whereas the incidence was slightly higher in the
brachytherapy-only group, the median time to occur-
rence was slightly longer in this group, at 3.6 months
Table 16.9 Grades of radiation bronchitis and stenosis (RBS)
1 Fibrinoid membrane without significant luminal
obstruction: no symptoms
2 Increase of exudation and fibrous membrane
with mild obstructive symptoms requiring
therapeutic intervention such as simple
debridement or medical treatment
3 Characterized by severe inflammatory response
with marked membranous exudate including
fibrosis requiring multiple debridements
4 A greater degree of fibrosis resulting in stenosis
with decreased luminal diameter requiring laser
photo resection, balloon or bougie dilation,
and/or stent placement
versus 2.5 months for the patients receiving combined
treatment.
16.9 MANAGEMENT OF COMPLICATIONS
The treatment of brachytherapy-related hemoptysis is
the same as that of hemoptysis from other causes. This
includes bed rest, codeine, and/or transfusion for hemo-
dynamic stability, avoidance and/or reversal of anticoag-
ulants, and vascular embolization, electrocautery or
lasocautery to reduce bleeding volume.
One of the largest reported series of 406 patients
treated with palliative brachytherapy alone is from the
Christi Hospital in Manchester, England [39]. Of these
patients, 322 with inoperable non-small cell lung cancers
were treated with a single fraction of HDR, with a total
dose of 15-20 Gy delivered intraluminally, with the dose
prescription 1 cm from the central axis of the catheter.
Patients were evaluated 6 weeks after completing the
HDR treatment regarding their symptoms, including
stridor, hemoptysis, cough, dyspnea, pain, and pul-
monary collapse. In addition, at various times following
the brachytherapy procedure, 83 bronchoscopies were
conducted on 55 patients. Massive hemoptysis leading to
death occurred in 8% of the patients (32/406). Cox mul-
tivariate analysis revealed that treatment-related factors
associated with subsequent massive hemoptysis were
brachytherapy dose >15 Gy, prior laser therapy, second
brachytherapy treatment, and concurrent external-beam
radiation therapy. Twenty of the 25 patients whose deaths
were assessable and related to hemoptysis had recurrent
and/or residual tumor suspected at the hemoptysis site.
The chronology of the massive hemoptysis leading to
death occurred between 9 and 12 months after comple-
tion of the HDR procedure. This was in stark contrast to
deaths from all other causes, which usually occurred 3-6
months after completion of the HDR procedures [40].

Brachytherapy-related bronchitis and stenosis are
managed depending on the level of severity of the reac-
tion and/or stenosis. This can include observation for
mild treatment-related bronchitis for the least sympto-
matic presentation, versus active treatment for its more
debilitating form, with oral and/or aerosol administra-
tion of steroids, aerosol-administered bronchodilators,
codeine-based or narcotic-based cough suppressants,
and antifungal or antibiotic therapies as indicated. More
aggressive interventional management for debilitating
and/or life-threatening levels of bronchitis and/or steno-
sis may be managed with balloon and/or bougie dilata-
tion, laser photoresection, bronchoscopic debridement,
and/or placement of intraluminal stents.
Although lung brachytherapy has been advocated by
radiation oncologists for the past 20 years, recent techno-
logical developments in the area of HDR brachytherapy,
such as the design of small, high-activity iridium-192
sources and remote afterloading machines, have
prompted renewed interest in HDR endobronchial
brachytherapy. The specific role of lung EBBT is not
clearly defined within the standard and/or uniform com-
munity practice. There is an ongoing evolution for the
selection criteria to identify those patients most likely to
benefit from EBBT as part of definitive therapy. The
American Brachytherapy Society (ABS) HDR Consensus
Guidelines [41] currently state that, although endo-
bronchial brachytherapy has demonstrated efficacy for
the symptomatic relief of bronchial obstructions and
hemoptysis, either alone or in combination with external-
beam radiation therapy, the curative benefit of
brachytherapy in addition to conventional external-
beam radiation therapy and/or chemotherapy has not
been proven. The ABS recommends that brachytherapy
for the definitive treatment of lung cancer is done within
the context of controlled clinical trials. Outside of clinical
trials, the ABS suggests that brachytherapy be reserved for
palliative treatments alone. Although the guidelines do
not clearly state the indications for additional external-
beam radiation in newly diagnosed lung cancer patients,
EBBT alone is recommended for recurrences after full-
dose external-beam radiation therapy treatments have
been administered. No single-dose fractionation scheme
has been identified which provides a superior therapeutic
ratio. Dose specifications to be prescribed have been rec-
ommended to a depth of 1 cm from the source center for
uniform prescription dosimetry comparisons.
A study by the Radiation Therapy Oncology Group
(RTOG) evaluated the palliation provided by external-
beam radiation to patients with newly diagnosed non-
metastatic, non-small cell lung cancers [42].This study,
by Simpson et al, demonstrated that a short course of
external-beam radiation therapy delivering 30 Gy in ten
fractions provided relief of hemoptysis in 74% of
patients, of cough in 55% of patients, and of dyspnea in
43% of patients. Median survival was around 6 months.
Compared to this RTOG study, brachytherapy alone
Pros and cons 239
appears to provide palliation equivalent to or better than
external-beam radiation, with a similar survival out-
come. Given this fact, brachytherapy may give more
prompt symptomatic relief of obstructive symptoms, in
a more cost-effective manner. In a small group of 19
patients treated with HDR to a total dose of 15 Gy [43],
a detailed assessment with rigorous testing was per-
formed both before and after administration of the HDR
brachytherapy. This enlisted chest X-rays, computerized
tomography scan of the thorax, direct bronchoscopic
evaluation, objective obstruction index scoring, 5-min
walking stress tests, isotope ventilation and profusion
lung scanning, and formal pulmonary function tests
with maximum inspiratory and expiratory full volume
measurements. Symptomatic relief was reported in 17 of
the 19 patients. Atelectasis of a collapsed lobe or lung
reported in 13 patients was demonstrated to have
reinstituted ventilation in nine cases by radiographic
imaging. Bronchoscopic evaluation of luminal patency
demonstrated improvement in 18 of the 19 patients.
Isotope lung scans showed significant increase in the
percentage of total lung ventilation and perfusion in
the abnormal lung. This rigorous study demonstrated
the high correlation between objective and subjective
improvement of the presenting symptomatology in these
patients. In addition, it confirmed the palliative benefit
of brachytherapy, which has been described in larger
groups of patients. Further prospective studies of
brachytherapy and external-beam radiation therapy are
clearly needed to rigorously document treatment effi-
cacy and toxicity, as well as cost-benefit and quality of
life analyses in this setting.
16.10 CONCLUSIONS
Endobronchial brachytherapy is an excellent method of
palliative treatment for patients who are symptomatic
from endobronchial disease as part of definitive therapy
for curative intent patients; however, a survival advan-
tage is not shown. This group of patients should be ran-
domized to external-beam radiation therapy versus
external-beam plus intraluminal radiation to evaluate
prospectively any survival advantage. Further studies will
also be necessary to determine the optimal dose and
number of fractions that will provide the greatest patient
benefit, the lowest morbidity, and the lowest cost of
treatment.
16/11 PROS AND CONS
Pro Endobronchial brachytherapy is ideal for
delivering very high doses of radiation to
neoplastic tissue in or within a 1 cm radius of the
main airway.
240 Endobronchial brachytherapy in the treatment of lung cancer
Con Because brachytherapy doses depend on the
inverse square law (that is, the dose decreases by
the square of the distance), neoplastic tissue
>1 cm from the airway is not effectively treated.
Pro Endobronchial brachytherapy provides relief of
airway obstruction to a greater extent and
significantly faster than external radiation.
Con Obstruction of airways by extrinsic compression
is best treated by external radiation.
Pro Endobronchial brachytherapy can be used in the
trachea main stem, lobar and segmented bronchi
to an extent greater than feasible with the YAG
laser.
Con YAG laser works immediately (endobronchial
brachytherapy takes 4-24 h for a partial response)
and is sometimes necessary for very bulky
exophytic tumors.
Pro For palliation of airway signs and symptoms due
to intrinsic disease, endobronchial brachytherapy
provides excellent relief with minimal morbidity.
Con Extrinsic compression such as nodal or
parenchymal masses or pleural effusion can
nullify benefits of brachytherapy, unless these
other factors are adequately dealt with.
Pro Endobronchial brachytherapy can cure occult
cancer of the lung.
Con Occult cancer has a high rate of synchronous
lesions that must also be identified and treated.
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A35 Ofiara, L, Roman, T., Schwartzman, K. et al. (1997)
Local determinants of response to endobronchial high-
dose rate brachytherapy in bronchogenic carcinoma.
Chest, 112(4), 946-53.
A36 Hennequin, C., Tredaniel, J., Chevret, S. et al. (1998)
Predictive factors for late toxicity after endobronchial
brachytherapy: a multivariate analysis. Int. J. Radial
Oncol. Biol. Phys., 42(1), 21-7.

Brachytherapy in cancer of the esophagus
A.D. FLORES
17.1 INTRODUCTION
It is estimated that, in the year 2001,13200 new cases will
be diagnosed with carcinoma of the esophagus in North
America and, of these, 12 500 will die as a result of the dis-
ease during the same year. This number corresponds to
only 1 % of all cancer cases seen in this particular year [ 1 ].
Whereas the incidence of cancer of the stomach in the last
40 years has been declining, the incidence of adenocarci-
nomas arising in the esophagus has substantially
increased, and now comprises 20-40% of all esophageal
malignancies seen in North America and Western Europe
[2-5]. Similarly, there has been a significant increment in
the incidence of cardioesophageal lesions in relation to
carcinomas developing in the distal portion of the stom-
ach [2-5]. Higher incidence rates (40-50 per 100000
population) have been reported in certain regions of Iran,
South Africa, China, and the former Soviet Union.
Although etiological factors are still unknown, many
environmental factors (alcohol, smoking, dietary, etc.)
have been associated with the disease [6].
The clinical presentation, behavior, and prognosis of
cancers arising in the esophagus and/or the cardio-
esophageal junction are similar. Unfortunately, conven-
tional treatments have not altered the poor prognosis
these patients have and survival rates of 5-7% have
remained unchanged in the last four decades [7-9].
Most patients have advanced disease when first diag-
nosed and only palliative treatment is available to them.
17
Only 20% of all new patients seen could be eligible for
treatment with an intention of cure. However, the treat-
ment for these patients presenting with early disease is
controversial. Although, historically, surgical treatments
have produced a poor overall survival similar to that of
radiation treatments [7-9] trials designed to compare
these two treatments have been difficult, not enough
patients could be recruited and they therefore had to be
abandoned [10].
Results of investigations using preoperative or postop-
erative conventional radiotherapy have been mixed
[11-15]. Cooperative efforts employing multimodality
conventional treatments have also been disappointing.
Chemotherapy regimens have not affected metastasis or
stopped the development of metastasis in recent studies.
Similarly, encouraging preliminary results using
chemotherapy as an adjuvant treatment to surgery or
radiation have been associated with increased toxicity
and have resulted in neither significant improved sur-
vival nor better quality of life [16-28].
Clearly, new innovative treatment protocols will be
required to enhance the cure rate for cancers arising in
the esophagus and cardioesophageal junction.
17.2 NATURAL HISTORY OF THE DISEASE
The majority of patients with carcinoma of the esophagus
are diagnosed with dysphagia, which is a manifestation of
244 Brachytherapy in cancer of the esophagus

extensive local disease causing malignant obstruction. In Table 17.1 Linear activities of radioactive sources
the western world, 80% of patients are diagnosed when
the tumor is larger than 5 cm or extended beyond the
esophageal wall (T2-T3). Even in early operable cases, Cesium-137 tubes 21 mCi cm-1 or 770 MBq cnr1
lymphatic spread is recognized in 70% of the resected Cesium-137 pellets 1
126 mCi cm or 4660 MBq crrr1
esophageal specimens 9 Anatomically, the esoph- lridium-192(10Ci/4 mm) 20 Ci cm-1 or 74000 MBq cm-1
agus does not have a serosal layer and the neoplasm could
easily reach the adjacent peri-esophageal tissues and
spread through the rich submucosal lymphatics to the technology made brachytherapy in general a more
most proximal esophageal wall and to the mediastinal, acceptable treatment modality for esophageal cancer and
perigastric, and cervical lymph nodes. malignancies at other sites.
The study of patterns of failure in several institutions The basic rationale for choosing brachytherapy in
confirms that the overwhelming majority of patients esophageal cancer is that while the amount of irradiation
(more than 80%) with esophageal cancer fail and die that can be given by external irradiation is limited by
with persistent local or loco-regional disease and metas- the tolerance of the normal tissues in the chest (lung,
tasis [26,27,32-36]. From these facts, it is reasonable to spinal cord, mediastinal structures, etc.), intraluminal
assume that if local control of the disease could be brachytherapy places the highest concentration of irra-
enhanced by innovative treatments, better quality of life diation directly into the intraluminal disease but delivers
and possibly even longer survival will result. It is, there- significantly lower doses to the adjacent normal tissues
fore, imperative that new protocols be designed with the (due to the rapid dose fall-off). In view of this physical
specific aim of enhancing the local therapeutic ratio of advantage, therefore, it is possible to increase the dose to
external irradiation. the cancer with the use of brachytherapy without affect-
ing the adjacent normal tissues, thus enhancing the
therapeutic ratio.
173 HISTORY AND TREATMENT RATIONALE
FOR INTRALUMINAL BRACHYTHERAPY
17.4 CLINICAL STAGING AND
The potential therapeutic value of intraluminal PRETREATMENT INVESTIGATIONS
brachytherapy for esophageal cancer was already recog-
nized at the beginning of the twentieth century. As early
The TNM classification for esophageal malignancies has
as 1909, some investigators had reported useful pallia-
changed. Tumor size and degree of circumferential
tion of dysphagia by directly placing radium beads in the
involvement are no longer criteria to define the extent of
esophagus housed in a nasogastric plastic tube [37,38]. It
the primary tumor. The new staging classification is
was, however, not until 1969 that successful intraluminal
based on the histopathological assessment of the depth
brachytherapy was reported in a selected group of eight
of tumor penetration in the esophageal wall (Table 17.2).
patients by Rider and coworkers in Toronto [39].
Because it is not always possible to obtain a representa-
Although these investigators stressed the usefulness of
tive sample of the full thickness of the esophagus by
brachytherapy for esophageal malignancies, this type of
procedure was unfortunately not actively pursued. The
lack of interest was due to many factors, among them: Table 17.2 TNM classification: esophagus
the introduction of megavoltage units and deviation of
interest towards external irradiation, technical difficul- Primary tumor (T)
ties of the brachytherapy procedure, and, most impor- TX Primary tumor cannot be assessed
TO No evidence of primary tumor
tantly, the poor tolerance of patients due to longer
Tis Carcinoma in situ
treatment times. The Second World War and legitimate
T1 Tumor invades the lamina propria or submucosa
concerns regarding radiation exposure also delayed the T2 Tumor invades the muscularis propria
development of new radioactive isotopes for medical use T3 Tumor invades adventitia
until 1948, when cobalt-60 was introduced. In 1953, T4 Tumor invades adjacent structures
Henschke developed the idea of afterloading and
Lymph node (N)
designed plastic tube devices in an attempt to reduce the
NX Regional lymph nodes cannot be assessed
radiation exposure of the medical personnel [39a]. NO No regional lymph node metastasis
In more recent years, the production of safer and N1 Regional lymph node metastasis
higher specific activity radioactive sources (Table 17.1)
facilitated the fabrication of miniaturized sources, signif- Distant metastasis (M)
MX Presence of distant metastasis cannot be assessed
icantly decreased treatment times, introduced automatic
MO No distant metastasis
remote control radiation delivery, and completely elimi-
M1 Distant metastasis
nated the problem of radiation exposure. This improved

endoscopic biopsy, pretreatment clinical staging of this
cancer has been difficult.
Recently, endoscopic ultrasonography, a new diagnos-
tic procedure, has produced satisfactory imaging of the
different layers of the esophageal wall and regional lym-
phatics. Several investigators have demonstrated good
clinico-pathological correlation, with ultrasonography
suggesting superiority over computerized tomography
(CT) or magnetic resonance imaging (MRI) scans in the
clinical staging of esophageal cancer [40]. The routine
use of endoscopic ultrasonography to assess the extent of
esophageal malignancies has been endorsed by the
International Society of Gastroenterology [41].
If the diagnosis of cancer of the esophagus is sus-
pected, the initial evaluation should include routine
blood tests and full physical examination, including an
evaluation of the lymph node regional bearing areas.
Then, adequate radiological studies of the upper gas-
trointestinal tract and endoscopic examination for direct
biopsy of a suspicious area should follow. If the lesion is
located above the tracheal bifurcation, a bronchoscopic
examination at the same setting is advisable. This will
permit a better evaluation of the tumor extension and
exclude invasion to the membranous portion of the
adjacent bronchus or trachea. Once the diagnosis of a
malignancy has been confirmed, CT scan of the chest
and upper abdomen is performed to assess the extent of
the primary disease and exclude metastasis. As discussed
earlier, endoscopic ultrasound is desirable to determine
with certainty the extent of the local and regional disease
and for clinical staging prior to definitive treatment.
Only 20% of the patients diagnosed with cancer of the
esophagus have their disease confined to the esophageal
wall (T1NO, T2NO) and could be suitable for treatment
with curative intent. In most patients, the esophageal
disease has already extended beyond the wall and cannot
be resected adequately (T3, T4). The presence of regional
lymph node metastasis (Nl, N2) is also a sign of poor
prognosis, even if the esophagus is resected, as only 15%
or fewer patients with positive nodes will survive
[7,8,30,31]. Because, overall, 5-year survival rates with
conventional treatments are extremely poor, a careful
and adequate assessment of the clinical staging prior to
treatment is essential. This information is extremely use-
ful when selecting the most suitable treatment according
to prognosis and to avoid unnecessary complications
associated with radical treatments [42,43].
The addition of intraluminal brachytherapy to exter-
nal irradiation is a good treatment strategy, as it is sim-
ple, well tolerated, and can enhance the local control and
quality of life of most of these patients.
17.5 TREATMENT STRATEGIES
Attempts to improve local control by increasing the
amount of external irradiation have failed due to poor
Therapy decision process 245
tolerance of the normal tissues adjacent to the esopha-
gus. Newer schedules of fractionated radiotherapy
(accelerated, superfractionation, etc.), concurrent
chemotherapy, chemical modifiers, or sensitizers aiming
to enhance the effect of external irradiation are also
likely to fail for the same reasons. Because the local fail-
ure is high, it is sensible to assume that better control can
be obtained by combining radiotherapy and surgery.
Results of studies using postoperative irradiation have
been negative and those of preoperative irradiation trials
have been mixed. Two European phase III studies
[11,12], comparing esophagectomy alone and preopera-
tive conventional external irradiation showed no advan-
tage for either group. In these trials, the radiotherapy
schedule was unusual (4000 cGy in ten fractions) and a
high rate of complications resulted. Three other studies
[13-15], comparing esophagectomy alone with a more
conventional preoperative external irradiation, reported
significant benefits in the preoperative irradiation arm.
Due to concerns regarding perioperative complications,
current trials have not considered a preoperative irradi-
ation treatment arm. Instead, newer programs involve
studying the value of neoadjuvant or concurrent
chemotherapy added to either surgery or external irradi-
ation. However, the impact of these new programs
should be expected to be minimal and a larger number
of patients will be required to show differences between
the treatment arms.
The esophagus above the tracheal bifurcation lies con-
tiguous and posterior to the membranous portion of the
trachea and the proximal aspect of the left main
bronchus. These anatomical characteristics show the
obvious weakness of esophagectomy alone as a rational
treatment for cancers of the esophagus. Furthermore,
the morbidity and mortality associated with esophagec-
tomy are higher for upper esophageal lesions. The lower
end of the esophagus is relatively free and more accessi-
ble for adequate removal. Conventional external irradia-
tion produces similar results to surgery in early cases and
may be better for palliation in more advanced tumors.
The morbidity associated with external irradiation com-
pared to surgery is mild and similar for all levels of the
esophagus, and no additional toxicity should be
expected with intraluminal brachytherapy [44].
17.6 THERAPY DECISION PROCESS
Patients with cancer of the esophagus could be candi-
dates for either palliative or curative treatment, depend-
ing on the extent of their disease, performance status,
associated illnesses, and age. Patients with distant metas-
tasis have an average lifespan of only 3-6 months, and
the palliative treatment should be short, simple, and
specifically designed to improve their quality of life in
terms of swallowing and pain. The same philosophy
246 Brachytherapy in cancer of the esophagus

should be applied to elderly patients with locally tube. Catheters of 8 mm or less external diameter can be
advanced disease and poor condition. easily placed through the nose and are, in general, better
Because dysphagia and nutrition are the main con- tolerated. Larger diameter catheters require the oral
cerns at presentation, most patients require dilatations route and adequate sedation (xylocaine spray and val-
and/or parenteral feeding prior to their treatment for ium 3-5 mg intravenously is usually sufficient). With
palliation or curative intent. either route, the suctioning of oral secretions and/or sali-
In palliative conditions, a single intraluminal treat- vation is essential to maintain patient comfort and avoid
ment alone or combined with a short course of external aspiration. The following is a step-by-step plan and out-
irradiation (1800 cGy in three fractions given by parallel line of the procedure.
and opposed fields) may be sufficient to restore and
1. The precise anatomical location and extension of the
maintain swallowing and improve the quality of life of
cancer are determined by reviewing the barium
these patients.
swallow X-rays, endoscopic and CT scan findings.
Patients with only loco-regional disease (as per CT scan
2. Localization and planning of the treatment area are
and endoscopic sonogram findings) and in good overall
performed in the simulator unit using a limited
condition are suitable for a form of radical treatment
barium swallow study, at least 24 h prior to the
designed to control the disease. They could be eligible for
procedure. The treatment centers and fields for
trials of investigation using radiotherapy or esophagec-
external irradiation and intraluminal brachytherapy
tomy and adjuvant treatments. Patients with esophageal
are chosen, and points of reference (bony
malignancies located above the tracheal bifurcation may
landmarks, skin tattoos, etc.) identified (Figure
be best treated with radiotherapy programs alone or in
17.1).
combination with chemotherapy in prospective trials.
Lower esophageal lesions can be treated also by radiother-
apy regimens, reserving esophagectomy for persistent or
recurrent disease. Primary esophagectomy should only be
considered in prospective clinical trials and opposed to
radiotherapy programs.
Radiotherapy with curative intent requires adequate
planning and several weeks of external irradiation using
multiple portals. Intraluminal brachytherapy can be
given before, during, or after the course of external irra-
diation. Treatment planning should be tailored to each
patient needs and to whether concurrent chemotherapy
is used. It would be preferable to give part of the external
treatment by parallel AP/PA opposed portals to prevent
lung toxicity when chemotherapy is given concurrently.
Tumor doses given by external irradiation are usually
4000 cGy in 15 fractions, or 5000 cGy in 20 fractions in
4 weeks to an 8 x 8 x 16 cm treatment volume. The intra-
luminal brachytherapy dose is estimated at 1 cm of the
axis of an 8-12 cm linear source and consists of
3000 cGy in 48 h with low dose-rate sources (radium,
cesium), or a single 1500 cGy with intermediate and high
dose-rate sources (in 1.5h or a few minutes respec-
tively). The radiobiological reasons for these doses are
discussed below. General guidelines for esophageal
brachytherapy have been published recently [45].

17.7 INTRALUMINAL BRACHYTHERAPY

TECHNIQUE

The placement of the endoesophageal catheter for intra-

luminal brachytherapy is a very simple outpatient proce-
dure and it is usually performed under local anesthesia Figure 17.1 Simulator film showing treatment center and fields
and mild sedation. The catheter can be placed via the for external and intraluminal brachytherapy. Note bony
oral or nasal route, depending on the diameter of the landmarks and skin tattoo.
 Intraluminal brachytherapy technique 247

3. In a fluoroscopy room, the patient is sedated and his

or her nose and throat are adequately anesthetized in
the sitting or supine position. It is important to have
a suction unit available to assist the patient during
the procedure.
4. A thin, cut-end (French 8 or 10) nasogastric tube
containing a fine, soft, atraumatic Teflon-coated
guide wire is passed or swallowed into the stomach,
under fluoroscopy. If the obstruction is significant,
the nasogastric tube is passed only to the level of
stricture, and then, under fluoroscopy, the guide
wire alone is maneuvered through the stenosis to the
stomach and its position anchored in the body of
this organ (Figures 17.2, 17.3 and 17.4).
5. The esophageal stricture is dilated, either by a
balloon or a Savory dilator, through the guide wire if
required before the placement of the applicator tube
for brachytherapy (Figure 17.5).
6. The exact positioning of the intraluminal treatment
is verified using dummy sources according to plan,
and the applicator position is secured to the mouth
guard or taped to the nose. X-ray films are then
obtained for planning and dosimetry (Figures 17.6
Figure 17.3 The guide wire is negotiated through the stenotic
and 17.7).
esophagus.
7. The patient is treated, preferably using a remote
afterloading medium dose-rate (MDR; i.e.,
1000 cGy h-1) or a high dose-rate (HDR; i.e.,
50000-20000 cGy h-1) unit (Figures 17.8 and 17.9).

Figure 17.2 An 8-mm nasogastric tube containing a guide wire Figure 17.4 The position of the guide wire in the stomach is
at the level of strictured esophagus. verified.
248 Brachytherapy in cancer of the esophagus
Figure 17.5 Balloon dilatation.
17.8 RADIOBIOLOGICAL AND CLINICAL
CONSIDERATIONS
Prior to 1980, intraluminal brachytherapy for esophageal
malignancies was only sporadically used, and mainly to
treat patients with recurrent disease. In the 1980s, the
Vancouver Clinic utilized radium and later cesium tubes
(four tubes, each with 2 cm active length and 10 mg
radium equivalent). These elements were placed in tan-
dem within an esophageal plastic tube with the aim of
delivering a dose of 3000 cGy at 1 cm from the axis in
48 h, and a low dose rate (LDR) of 75 cGy Ir1 (Figure
17.10). This treatment was used only in selected patients
who had not responded to conventional external radio-
therapy. Although this treatment required hospitaliza-
tion, it was well tolerated and an adequate temporary
palliation of the dysphagia was achieved. An esophageal
applicator [46] became available in February 1985 that
Figure 17.6 Passage of the intraluminal applicator through
the esophagus, using the guide wire. Note the dummy cesium
(MDR) pellets in the applicator, used as reference for the
intraluminal treatment position.
could be connected to a remote afterloading unit
(Selectron). This unit operated radioactive cesium pel-
lets, each of 2.5 mm in diameter and 40 mCi of radium
equivalent; 40 pellets placed in tandem generated a lin-
ear source of 10 cm in length with a dose rate of
1000 cGy h'1 at 1 cm from the axis (MDR). Similar appli-
cators are now available for HDR iridium-192, which
uses a stepping but smaller radioactive source of only
1.1 mm in diameter, which produces a higher dose rate
(50000-20000 cGy h-1) (see Figures 17.7 and 17.9).
Because higher biological effects should be expected
with higher dose rates, a linear quadratic model [47] was
used to estimate equivalent doses to standard LDR
brachytherapy. Assuming a recovery time to sublethal
effects of irradiation of 2 h and an a/p ratio of 4 for late
effects and 10 for acute effects, this model showed that
3000 cGy given with LDR radioactive materials were
equivalent to 1500 cGy given by HDR sources (Figure
17.11). It can also be seen that, according to this formula,

Figure 17.7 Verification of position of the intraluminal
applicator using dummy sources for an iridium (HDR) stepping
source, in a similar patient to Figure 17.6.
Radiobiological and clinical considerations 249
tissue effects do not change for dose rates higher than
lOOOcGylr 1 .
The isodose distribution of intraluminal brachyther-
apy and rapid dose fall-off in depth can be appreciated
from Figure 17.12.
The outer diameter of the applicator is also important
when considering intraluminal brachytherapy. It deter-
mines the dose to the surface of the tumor or normal
mucosa in contact with the applicator. The dose is usu-
ally prescribed at 1 cm from the axis of the source. The
actual dose to the mucosa lying adjacent to the surface of
an applicator with smaller outer diameter (i.e., 6 mm)
will be significantly higher than when a larger outer
diameter applicator is used (i.e., 10 mm). Higher mor-
bidity, mucositis, ulceration, and fibrosis should be
expected with smaller outer diameter applicators if the
patient survives. Therefore, the use of larger outer diam-
eter applicators and confining the brachytherapy boost
only to the area affected by the disease could minimize
complications.
Intraluminal brachytherapy for esophagus can be
used alone for palliation of dysphagia in advanced or
metastatic cases. It can also be used as a complement to
external irradiation in earlier cases with the intention of
cure. In these situations, brachytherapy can be given
before, during, or after external irradiation. If the
obstruction is significant, it may be advantageous to start
with brachytherapy as dysphagia could be improved and
tolerance to external treatment thus enhanced. On the
other hand, intraluminal brachytherapy may be more
effective after external irradiation, as the bulk of the dis-
ease will be reduced and the depth dose given to the base
of the tumor by brachytherapy is significantly better. In
a study conducted in Vancouver there was, however, no
Figure 17.8 A patient
undergoing treatment with an
oral-esophageal applicator.
Note the head support and
mouth route. MDR cesium
pellets.
250 Brachytherapy in cancer of the esophagus
Figure 17.10 X-ray film showing an endoesophageal tube
containing four radium tubes in tandem. LDR treatment and
8 cm active length.
significant difference in outcome when brachytherapy
was used either before or after external irradiation. A sin-
gle brachytherapy boost of 1500 cGy (MDR or HDR)
had been preferred at the Canadian Vancouver Cancer
Clinic, and proved to be an effective, well-tolerated treat-
ment in more than 700 patients. Brachytherapy has been
given in three or more fractions in other centers, but
multiple applications need to be balanced against
Figure 17.9 A patient
undergoing treatment with a
naso-esophageal applicator.
Note the patient comfort and
suction unit. HDR iridium
source.
Figure 17.11 Dose equivalencies for different dose rates
according to the linear quadratic equation, (i - recovery time to
sublethal effects of irradiation.)
repeated discomfort and the probability of more compli-
cations due to trauma and inconvenience for a patient
whose quality of life has already been significantly
affected by the disease.
17.9 TREATMENT RESULTS
In China, where the incidence of esophageal carcinoma
is high, a mass screening program was conducted in the
rural areas of Linxian in 1970-1974. This program
detected a large number of patients with esophageal
malignancy, not all of whom could be treated conven-
tionally with external irradiation due to the scarcity of
machines [48]. Thus, 203 patients were treated only with

intraluminal brachytherapy using cobalt-60 wires with
two to four applications and variable doses. Seventeen
out of 203 patients survived 5 years or more and were
apparently cured [49]. A randomized study of 200
patients, performed at the Shanxi cancer hospital
between 1982 and 1986 [50], comparing external radio-
therapy alone versus external plus intraluminal
brachytherapy, showed significant difference in favor of
the treatment arm with brachytherapy (17% versus 10%
5-year survivals, respectively).
Hishikawa, from Japan, also using a cobalt linear
source and external radiotherapy, reported an 18%
5-year survival rate in a group of 66 patients with disease
limited to the esophagus [51].
In Vancouver, a phase I-II study was conducted
between 1985 and 1987 to evaluate the toxicity and effi-
cacy of a combined treatment consisting of 4000 cGy in
15 fractions given by external irradiation plus 1500 cGy
at 1 cm given by intraluminal brachytherapy. All patients
(171) seen during that period, except for those with
impending tracheal or bronchial fistula, were treated in
that manner. This was a feasibility study and to assess the
toxicity and response of additional intraluminal
brachytherapy to external irradiation. It was concluded
that this combined treatment was feasible, well tolerated,
and could be done as an outpatient procedure.
Morbidity was only related to temporary mucositis, and
there was no associated treatment-related mortality. A
quality-of-life assessment after treatment in relation to
patients' performance status, ability to swallow, weight,
and pain demonstrated improvement in all of these
parameters [29]. A subsequent phase III study, with a
similar group of patients, but designed to compare the
value of brachytherapy before and after external irradia-
tion in 219 patients, showed no significant difference
Treatment results 251
Figure 17.12 Isodose
distribution for a linear
radioactive source.
between these two treatment arms. From 1985 to 1993,
over 700 patients with cancer of the esophagus and car-
dia were treated with intraluminal brachytherapy at the
Cancer Agency in Vancouver. The first 150 patients were
treated with a linear source made of radioactive cesium
pellets that generated a dose rate of 1000 cGy tr1 (MDR)
at 1 cm. All subsequent patients were treated using a
stepping radioactive source of iridium (HDR), produc-
ing a dose rate between 50 000 and 20 000 cGy Ir1
(depending on the activity/age of the source) at 1 cm.
The treatment dose chosen for both radioactive sources
was the same or 1500 cGy at 1 cm from the axis, as esti-
mated by the linear quadratic model [46]; however, the
treatment time was significantly shorter with the HDR
unit.
The clinical evaluation of the acute and late effects of
patients treated by LDR (radium or cesium), MDR
(cesium pellets), or HDR (iridium) showed similarity of
effects, suggesting good correlation with the predicted
values by the linear quadratic equation for the different
dose rates.
Two hundred and ninety-seven patients with cancers
of the esophagus and cardia treated in Vancouver with
external and intraluminal irradiation were eligible for an
analysis and a minimum follow-up to 5 years. Ninety-
three patients (31%) had an upper esophageal cancer
above the carina, and 204 had esophageal tumors below
the tracheal bifurcation. Forty upper esophageal cancers
had only palliative treatment (five of them had distant
metastasis and 35 had advanced disease and were in poor
condition). Only two of the 93 patients with upper
esophageal cancers survived 5 years. Of the 204 (69%)
patients who had lower esophageal cancers, 114 (56%)
had an inoperable disease (29 had distant metastasis and
85 locally advanced disease). Eight out of 85 (9.4%)
252 Brachytherapy in cancer of the esophagus

patients with local advanced disease survived 5 years,

whereas none of the patients with distant metastasis sur-
vived. Ninety patients were explored, but only 66 (73%)
were resected. Of the 24 patients who were considered
inoperable at the time of exploration, none survived.
Only three patients had palliative resection (all had liver
metastasis), none survived more than 4 months. Of the
63 patients who had curative esophagectomy after exter-
nal and intraluminal irradiation, 31 (49%) had survived
the disease for 5 years or more after treatment. A sum-
mary of the clinical presentation, treatment, and results
for all patients is shown in Table 17.3.
The study of the 63 pathological specimens after
external and intraluminal radiotherapy permitted an
evaluation of the changes induced by brachytherapy in
the esophageal tissues. The macroscopic effect in the
specimen was obvious, and the localized changes seen in
the mucosa reflected the effect of the intraluminal treat-
ment. The historical examination revealed marked
pyknotic changes, with no evidence of viable tumor at
different levels of the wall of the esophagus (Figure
17.13). The radiation effects and the depth of tumor
penetration were determined separately for each speci-
men and subsequently correlated with local control and
survival. The depth was expressed according to the four
layers of the esophagus: level 1 when penetration was no
deeper than the muscularis mucosa; level 2 when there
was more penetration but no deeper than the submu-
cosa; level 3 when it was deeper than the muscularis pro- Figure 17.13 Pathological specimen of esophagus showing
pria; and level 4 when it involved the peri-esophageal esophageal layers and radiation effect of intraluminal
tissues [52]. A ratio of 1 (radiation effect/tumor pene- brachytherapy.
tration) was present in 43 cases and this correlated with
local tumor control in 95% of them. The survival was
superior when there was complete sterilization of malig- there was no associated mortality in over 700 patients. A
nancy in the surgical specimens, as can be seen in Table summary of treatment complications is shown in Table
17.4. The histopathological findings of radiation effects 17.5. Acute radiation mucositis, although common, was
in regional lymph nodes were surprising. Peri- usually transient. Persistent mucositis was due to exten-
esophageal nodes considered to have been involved by sive disease or associated factors (candidiasis, etc.) and
the cancer were pathologically sterilized in 11 cases by dysphagia was related to persistent disease. Bleeding as a
the treatment combination and this was also reflected in complication following brachytherapy is extremely rare
survival, as can be seen in Figure 17.14. in our experience; however, it should be expected if the
The combined treatment of external and intraluminal tumor is advanced or significant trauma occurred dur-
radiotherapy was well tolerated, morbidity was low, and ing the insertion of the applicator. Fibrosis and stenosis

Table 17.3 Cancer of the esophagus: treatment results in 297patients

Above carina Advanced 88 2 2

Below carina Advanced 85 8 9.4
Below carina Resected3 63 32 49
Number of patients with distant metastasis 34 0
Number of patients explored and found inoperable 24 0
Palliative resection (liver metastasis)3 3 0
All cases (overall) 297 42 14
3
Total esophagectomy after external + intraluminal brachyth< rapy.
External + intraluminal brachytherapy, Vancouver (1985-198!J).
 Conclusions 253

are common in long-term survivors, and occurred in 17.10 CONCLUSIONS

42% of our patients with advanced cancers surviving
more than 5 years. Dilatations at regular intervals were
required in most of these cases.
From the results obtained, it can be seen that intralu-
minal brachytherapy enhances the therapeutic ratio
when added to external irradiation for this disease. A
comparison of results with other recent combined treat-
ment modalities showed superiority of external and
intraluminal radiotherapy over esophagectomy plus
chemotherapy or external irradiation combined with
adjuvant chemotherapy (Table 17.6).
Because the prognosis and survival of patients with
esophageal cancer are poor, an adequate evaluation of
these patients prior to any treatment is essential. The
emphasis of treatment in advanced cases should be pal-
liation and improving the quality of life of these patients.
A short course of external irradiation alone or combined
with a single intraluminal brachytherapy may be suffi-
cient for most patients.
A recent prospective, randomized trial has shown no

Table 17.4 Cancer of the esophagus: radiation pathology

Sterilized (no recognizable disease) 16 3 1 12 75

Ratio 1 (radiation damage to all levels) 24 7 3 14 58
Ratio < 1 (radiation damage to superficial layer only) 23 16 2 5 21
Totals 63 26 6 31 49

NED = no evidence of disease.

Table 17.5 Cancer of the esophagus: complications of external irradiation +

brachytherapy

Mild Moderate! Severe

Radiation esophagitis 358 72 (14%) 60 (12%)
Radiation pneumonitis 1a
Broncho-esophageal fistula 30 (6%)b
a
Unrelated to intraluminal brachytherapy.
b
Related to disease; occurred 6 months or more after treatment.
Mild: transient, requires symptomatic medication only.
Moderate: transient but may require supplementary care.
Severe: requires hospitalization or intervention.

Table 17.6 Cancer of the esophagus: summary of treatment results

Non-surgical
(a 11 cases)
XRT + chemotherapy [18] 61 2 30 ?
XRT +brachytherapy [51]
Extensive disease 82 0 7 0
Limited disease 66 0 37 18
XRT + brachytherapy [*]
Extensive disease 138 0 33 7.2

Surgical combined
(early cases or limited)
Preoperative chemotherapy [23] 48 11 25 18
Preoperative chemotherapy + XRT [20] 43 8 50 34
Preoperative XRT + brachytherapy 63 0 65 49

? Data are not available.

[*] Vancouver series.
XRT = irradiation.
254 Brachytherapy in cancer of the esophagus
Figure 17.14 Survival versus peri-esophageal lymph node
status.
benefit from chemotherapy prior to esophagectomy in
early operable cases [28]. The combination of external
and intraluminal radiotherapy has obvious advantages
over other treatments in esophageal cancer: it is simple,
cost effective (hospitalization is not required), and has
lower morbidity than adjuvant chemotherapy and/or
esophagectomy. As it does not increase the operative
morbidity associated with esophagectomy, it should be
the treatment of choice in early cases, radical surgical
treatment being reserved only for persistent or recurrent
disease.
Future prospective trials must consider combined
external and intraluminal brachytherapy as the main
treatment arm in early operable esophageal cancer cases
to determine the best local therapy. These future trials
must also evaluate morbidity and the quality of life of
survivors.
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High dose-rate afterloadingbrachytherapy for
prostate cancer
P.J. HOSKIN
18.1 INTRODUCTION
Brachytherapy as a treatment modality for prostate can-
cer has been used with varying degrees of enthusiasm for
many years. Early techniques used direct open implanta-
tion with live source permanent implants, typically gold
grains or iodine seeds [ 1 ]. The relatively poor results of
this treatment from the 1960s led to disenchantment
with this approach, but in the last decade developments
in both imaging techniques and brachytherapy equip-
ment have led to this form of high dose radiation ther-
apy becoming an important integral part of the
management of localized prostate cancer.
Manual afterloading using iridium wire to deliver a
medium dose-rate (MDR) implant has been employed
in prostate cancer. The largest published series from
Long Beach, California, reports 450 patients treated with
30-36 Gy external-beam radiotherapy in 3.5-4 weeks
followed by an iridium interstitial implant boost deliver-
ing 30-40 Gy in 40-60 h. A local control rate of 92%
with a 76% 10-year disease-free survival and 6% moder-
ate to severe morbidity rate was obtained [2].
High dose-rate (HDR) afterloading enables small
diameter catheters of around 2 mm external diameter to
18
be used for interstitial implantation, with the great flexi-
bility of dose delivery inherent in the stepping source
system. Catheter placement exploiting the advantages of
transrectal ultrasound and computed tomography (CT)
imaging to provide accurate positioning and reconstruc-
tion of the implant can ensure high-quality implants and
precise dosimetry related to anatomical structures. The
advantages of high dose localization inherent in
brachytherapy can therefore be fully exploited and, in a
situation in which a dose response has been demon-
strated for radiation therapy [3], an improvement in
local rates of control without additional normal tissue
morbidity is a realistic expectation.
Delivery of radiation at high dose rate, however, car-
ries biological implications which demand careful atten-
tion to dose fractionation and dose distribution. The
challenge with HDR brachytherapy in prostate cancer is
to deliver a safe, effective dose using a technique which
will enable several fractions of treatment to be given over
several days whilst retaining the high quality of the
implant throughout.
Unlike low dose-rate (LDR) brachytherapy for
prostate cancer, a biological advantage cannot be claimed
for HDR over external-beam treatment. The better
geographical localization of dose with brachytherapy is
258 High dose-rate afterloading brachytherapy for prostate cancer
a major advantage, but its clinical implementation is
probably optimized by using it in conjunction with
external-beam treatment. The natural history of prostate
cancer includes early invasion of the prostatic capsule
and seminal vesicles. A high proportion of patients pre-
senting with apparently localized disease will already
have microscopic disease within the immediate vicinity
of the prostate gland. Predictors for this include a
prostate-specific antigen (PSA) level greater than 10, a
Gleason score greater than 7, and a clinical stage of T2b
or higher, all of which would carry a greater than 30%
chance of regional microscopic disease [4]. In this sce-
nario, external-beam treatment is undoubtedly superior
in covering the wider field necessary to incorporate these
patterns of spread. In a manner analogous to many other
sites where brachytherapy is shown to be a vital compo-
nent of successful radical treatment, HDR afterloading
brachytherapy can then be used as a high dose localized
boost treatment to the primary bulk of tumor.
18.2 IMPLANT TECHNIQUES
Open procedures are no longer used for prostate implan-
tation. The common route is transperineal, although
transrectal approaches are also described. Transperineal
implants typically use a template on the skin to define
catheter position of entry. A common approach in current
use is to combine this with transrectal ultrasound to pro-
vide direct real-time imaging as the implant is inserted.
Two types of applicator are in common use: rigid needles
or flexible plastic catheters. The rigid needles may have
the advantage of easier positioning, being less readily
deflected by the tissues after skin entry, but they may be
more traumatic to the tissues and less well tolerated when
an implant remains in place for several days. Fixation of
the needles on the perineal skin is also a challenge.
183 PROCEDURE: GENERAL
CONSIDERATIONS
1. All patients will require general or spinal anesthesia.
The patient is placed in the lithotomy position with
the pelvis tilted anteriorly as far as possible. This aids
the passage of the applicators below the pubic arch
into the more anterior portion of the prostate gland.
However, for patients who are elderly, perhaps with
degenerative hip disease, care must be taken in
positioning the patient while anesthetized to avoid
damage to the pelvis and hips.
2. An indwelling urethral catheter will be required and
will be retained until removal of the catheters at the
end of the last fraction of treatment. This is both to
facilitate urinary drainage and also to provide a
marker for urethral position, which is an important
consideration in catheter placement and dosimetry.
3. The skin is prepared and full sterile theater
precautions should be used throughout for the
implant to avoid the introduction of infection.
4. The prostate gland is subject to considerable
movement, in particular rotation about its axis, if
steps are not taken to avoid this. Fixation needles are
inserted as the first step in most implant procedures.
Positions in the template away from those likely to
be immediately implanted are chosen. Two needles,
one in each lateral lobe, are usually adequate,
although some advocate a third needle anteriorly.
5. A blunt needle to define the length of implantation
and position of the bladder neck has also been
advocated. The advantage of this is that it gives an
additional gauge against which the applicator
position can be checked, particularly if imaging
quality is variable, as can happen where there is
interference from adjacent planes on the ultrasound
as the implant builds up.
18.4 FLUOROSCOPIC IMPLANTATION
PROCEDURE
1. The C-arm of the imaging intensifier requires
careful positioning to enable imaging of the prostate
implant to be seen together with the bladder base. As
it is difficult during the procedure to move the
C-arm, an antero-posterior or lateral view will be
chosen. In general, the lateral view provides better
information, particularly for multiplane implants,
although some prefer an oblique or direct antero-
posterior view.
2. The urinary catheter balloon will be filled with
hypaque or a similar contrast-enhancing medium so
that it can be readily visualized on the fluoroscope
screen. This then defines the bladder base. Ideally,
previous CT images will have been obtained in a
diagnostic setting to define the position of the prostate
in relation to the bladder base. Often, the prostate will
be seen to impinge above a catheter balloon in the
bladder and it is important this is known so that
coverage of the apex of the gland is adequate.
3. Applicators will then be inserted transperineally
through a template, if used, and their cranial
position, defined by their relation to the bladder
base, marked by the catheter balloon. Fluoroscopy
will help enable the catheters to be inserted in
parallel, although this may become more difficult to
judge as sequential planes are built up.
18.5 TRANSRECTAL ULTRASOUND
IMPLANTATION TECHNIQUE
1. Transrectal ultrasound (TRUS) is now the standard
means of guiding applicators accurately into the
 Catheter insertion and fixation 259

prostate gland. For implantation, a probe mounted

on a frame with a stepping platform enables
reproducible positioning of the catheters. Onto the
frame is fixed a template, the image of which can be
superimposed on the ultrasound images to relate a
catheter position to the anatomy seen, as shown in
Figure 18.1. A further feature is to have a dual crystal
probe which can produce both transverse and
longitudinal images. This then enables catheter
placement to be followed in both planes.
2. The role of a pre-implant ultrasound study to define
the treatment volume and design an ideal implant
prior to the procedure is not mandatory with this
technique. Whilst necessary for LDR iodine seed
implants, for which the seeds have to be ordered and
loaded in a fixed array, the flexibility of HDR
afterloading dosimetry means that, provided
catheters are inserted in a fixed format - that is, in
parallel rows as defined by the template - covering
the prostate volume, post-implant dosimetry is
adequate to define the dwell positions for coverage of
the volume. Pre-implant imaging and dosimetry are
not necessary for HDR afterloading, although
diagnostic CT or MR images are of value both to give
information on the size of the prostate gland and also
to predict pelvic arch interference, notwithstanding
their role in providing accurate staging information.
3. Setting up of the TRUS prior to implantation is very Figure 18.2 Transrectal ultrasound images of the prostate
important and, if not done carefully and accurately, gland showing how shape may change with angle of probe at
will greatly detract from the final quality of the the same position in the gland.
implant. Important criteria to observe are that the
inferior border of the gland is as flat as possible, and
considerable variation in gland contour can be
of the implant and followed throughout its course
achieved simply by altering the angle of the probe, as
into the bladder neck to ensure that the prostate is
shown in Figure 18.2. A flat inferior border with the
lying straight in its axial plane along the probe.
most inferior row of applicators parallel and just
inside the gland is required.
4. The urethra should be identified and positioned
18.6 CATHETER INSERTION AND FIXATION
between vertical rows of applicators around the center

Typically, the stepping TRUS technique is used with a 1 cm

Figure 18.1 Transrectal ultrasound probe and stepping frame
set up as used for HDR prostate implant showing template,
stabilizing needles, and HDR applicators.
grid template developing parallel rows of catheters in a
square multiplane array. A second template maybe used in
addition to the one attached to the ultrasound frame to
guide skin entry. Manipulation of the catheters after skin
entry may be achieved manually, using the ultrasound
images to guide direction. Parallel multiplane implants are
generally required; typically, three or four planes will be
necessary to cover the depth of the gland.
The pubic arch and pelvic side walls may present
physical obstacles in placing the most peripheral
catheters. Whereas the template technique generally
improves geometry, a rigid template against the perineal
skin reduces the ability to move the catheter slightly out
of plane to avoid the pubic arch or other bony interfer-
ence. The advantage of flexible catheters is that they may
be seen to bend around the pubic arch and then regain
260 High dose-rate afterloading brachytherapy for prostate cancer

their plane in the more anterior aspects of the prostate ance for the implant as it is measured on each occasion
gland. Extreme pubic arch interference should be pre- treatment is given to identify any catheter movement. A
dicted prior to the implant from CT images or a pre- completed implant in situ is shown in Figure 18.3.
planned ultrasound, and in some circumstances this may
be a contraindication to proceeding with the implant if a
satisfactory source distribution cannot be anticipated. 18.8 IMPLANT RECONSTRUCTION
Once in position, fixation of the catheters to ensure
reproducible positioning on sequential fractions is one Following recovery from the anesthetic, reconstruction
of the more difficult aspects of this technique. A rigid of the implant is required. Although this may be done
applicator may be sutured to the skin and rigid needles using the TRUS images obtained during the procedure,
fixed into this using a locking device within the template. we have found that post-implant CT imaging provides
Rigid needles may be individually sutured to the skin, better reconstruction of the implant, allowing volume
but where a typical implant may comprise 12 to 20 definition on the basis of the anatomical information on
needles, this becomes somewhat tiresome and difficult. the CT scan. It also readily interfaces with the planning
system to provide accurate volume and catheter position
transfer. Transrectal ultrasound images in general will
18.7 MOUNT VERNON APPLICATOR AND
require manual digitization to import the volumes into
TEMPLATE TECHNIQUE
the planning system. There are changes following
implantation and, in particular, prostate volume
At Mount Vernon Hospital we have developed an HDR increases are recognized when comparing post-implant
implant technique using a flexible template and flexible CT images to TRUS taken during the implant, which
HDR applicators. A standard TRUS system with stepping may need to be taken into account, and CT gives accu-
unit is used for imaging, with the template attached to the rate positioning of the rectum which may be very differ-
ultrasound frame, as shown in Figure 18.1. The template ent once the TRUS probe has been removed.
has been modified by increasing the diameter of the guid- Conventional orthogonal film reconstruction of the
ing holes to enable the flexible catheters to pass through implant is, of course, possible and will give adequate
them so that the applicator maybe removed over the prox- information regarding the catheter positions, but none
imal ends of the catheters at completion of the implant.
Once the ultrasound is placed in position and set up
as defined above, a flexible latex template is placed
against the perineal skin. This is aligned to be exactly
matching the ultrasound template. The flexible template
has rubber 'O' rings incorporated in it in a 1 cm grid
identical to that of the ultrasound template. It is fastened
to the skin using adhesive, the skin having previously
been shaved to make removal less painful.
The implant procedure then continues with place-
ment of the applicators guided by the ultrasound tem-
plate passing through the corresponding 'O' ring of the
flexible template against the perineal skin. An added
advantage of this approach is to give clearance between
the two templates which enables digital guidance of the
applicators where necessary, the flexible template allow-
ing movement at skin entry.
At completion of the implant the ultrasound probe is
removed and the ultrasound template is removed over
the proximal ends of the flexible applicators. These are
then held in position, gripped by the 'O' rings of the flex-
ible template. Retaining sutures in each corner of the
flexible template are used to prevent it buckling when the
legs are brought together, and this can be trimmed to
improve comfort around its edges. The flexible catheters
are kept capped to avoid contamination of the HDR
channel, their length from the 'O' ring to their distal con-
necting end is carefully measured, and each catheter is
labeled with its grid position. This length is carefully
documented and is vital in maintaining quality assur- Figure 18.3 HDR implant of prostate.

in relation to the prostate gland and rectum. Although
adequate, therefore, in terms of implant reconstruction,
it does not provide the information required for opti-
mization of the implant in relation to the soft tissue.
Once the implant has been reconstructed and the
catheter positions defined, the dose distribution can begin
to be calculated. All the modern HDR systems have associ-
ated planning programs with them to facilitate this process.
The principles of dosimetry are to deliver a homogeneous
dose within the denned volume, with rapid fall-off partic-
ularly posteriorly towards the anterior rectal wall, and with
a relative cold spot around the urethra. Catheter placement
usually takes into account these requirements, with periph-
eral grid positions being filled, but leaving one or two cen-
tral positions empty around the urethra.
Dwell positions will be defined along the catheters,
initially using one of two conventions, either Paris
dosimetry or Manchester dosimetry. From this baseline,
individual optimization may then be required [5].
Paris dosimetry has the advantage of simplicity in that
uniform linear activity, achieved by equal times in each
dwell position, is the requirement. Inevitably, however,
because an ideal Paris implant requires catheters longer
than the volume to be treated, it will, unless the distal end of
the implant has been taken well beyond the apex of the
prostate, be cold around the apex. In contrast, Manchester-
based dosimetry, with weighting of the dwell positions at
the ends and periphery of the implant volume typically
aiming for a 2:1 weighting, reproducing the Manchester
rule requiring two-thirds of the dose to be delivered to the
periphery, will give a more homogeneous dose to the limits
of the catheters. Current planning systems have more com-
plex optimization techniques which can then be intro-
duced, although they may not give superior results to
conventional individualized planning and often result in
marked ranges of dwell time along the catheter.
Once satisfactory dose distribution has been obtained,
this will be transferred into the HDR control program as
a series of dwell times for each catheter. A typical distri-
bution with corresponding dwell times is shown in
Figure 18.4. The treatment delivery is relatively simple,
although careful and meticulous attention to identify
any catheter movement and having a rigorous protocol
to ensure that the correct channels are attached to the
appropriate catheter are vital. Typical treatment times
are very short, most catheters having a total dwell time of
only a few seconds, and total treatment times for the
implant being of the order of 5 min, depending upon the
total number of catheters.
18.9 COMPUTED TOMOGRAPHY-BASED
THREE-DIMENSIONAL PLANNING
A novel technique has been described from the group in
Offenbach [6], relying on three-dimensional reconstruc-
Dose prescription 261
tion of an implant inserted under ultrasound control
using four rigid steel needles placed transrectally. Two
crossing needles are placed in the upper and lower left and
two in the upper and lower right peripheral regions of the
gland. An optimized distribution is then defined using
three-dimensional reconstructed CT images for HDR
afterloading. Because only four needles are used to cover
the entire volume, extensive high dose regions are intro-
duced, with up to 50% of the volume receiving 200% of
the reference prescription dose. Early clinical results have
not revealed significant additional morbidity.
18.10 DOSE PRESCRIPTION
HDR afterloading implants for prostate cancer are rarely,
if ever, used as sole treatment. Their use is generally
designed to be part of a treatment program in which
external beam accounts for two-thirds of the total dose,
equivalent to a dose sufficient to eliminate microscopic
disease, followed by the remaining one-third of the rad-
ical dose delivered by the implant. However, a review of
the actual doses prescribed in the various centers using
this technique reveals considerable variation, particu-
larly in relation to the implant dose. There appears to be
general agreement that a dose of 40-45 Gy in 4-5 weeks
or its equivalent is an appropriate external-beam sched-
ule, no doubt reflecting experience from other sites
where this approach to radical treatment is successful,
for example the head and neck, and cervix. As can be
seen in Table 18.1, however, the implant doses typically
given in two to three fractions vary enormously [7-12].
This may, in part, be explained by the lack of conformity
in dose definition for interstitial implantation and, per-
haps more critical in assessing the dosimetry, is the
actual dose distribution and relative dose to normal
structures compared to the high dose volume.
A better comparison of the different dose fractiona-
tion schedules may be achieved using the biological
equivalent dose (BED) formula, acknowledging the lim-
Table 18.1 Prostate HDR brachytherapy doses
Michigan [7] 18 3
Oakland,CA [8]
Seattle [9] 16.5 3
Goteborg[12] 20 2
Kiel [10] 30 2
Berlin [11] 18 2
Offenbach [6] 28 4
Melbourne" 20 4
MVH 17 2
" Personal communication, Professor G. Duchesne.
NB: where centers have quoted a range of doses, the most recent
schedules have been stated here.
262 High dose-rate afterloading brachytherapy for prostate cancer

Figure 18.4 Dose distribution

(a) and catheter dwell times in
nominal seconds (b) for
completed implant.

c.hanrtel
Channel
1 2 3 4 5 6 7 8 9 10 II 12 1
Dwell
position
1 0 5 5 5 4 0 2 5 5 5 0 5 0
2 5 4 3 4 4 5 3 3 3 3 0 2 0
3 3 3 4 1 0 4 4 1 1 3 3 3 0
4 3 3 3 0 1 3 3 0 0 3 2 2 4
5 3 3 3 2 0 3 3 1 1 3 2 2 3
6 3 3 3 2 1 3 3 0 0 3 2 1 2
7 3 3 3 . 1 0 3 3 0 0 3 0 1 2
8 3 3 3 1 1 3 3 0 0 3 0 1 1
9 3 3 3 0 0 4 3 1 1 3 0 1 2
10 2 3 3 1 0 3 3 0 0 4 1 1
II 1 3 3 1 0 4 3 1 0 3 2 1 2
12 2 4 4 4 0 3 4 0 0 4 2 2 2
13 3 2 4 4 2 3 4 1 I 3 2 2
14 2 3 3 3 3 2
15 3

itations of this when applied to a two-fraction or three-
fraction implant using large doses per fraction. This is
shown in Table 18.2, together with equivalent 2 Gy frac-
tion doses, which are perhaps a more familiar format to
consider the dose equivalence of the different schedules.
The rectal tolerance in this setting is also uncertain.
The nearest analogy would be to gynecological
brachytherapy, in which rectal dose is also one of the
major limiting normal tissue effects. Indeed, the external-
beam and HDR combination doses used in the prostate
cancer schedules are very similar to those for cervical can-
cer, where the limit for rectal dose would be a 2 Gy equiv-
alent of 64-66 Gy. This, of course, does not take into
account the volume effect, whereby a much higher dose
may be tolerated to a small volume provided there is ade-
quate recovery in surrounding areas. This may be more
apparent in prostate implantation where 5 mm CT slices
or TRUS images are being used to define the dose distrib-
ution. The general rule of thumb, however, is to keep the
rectal dose within 60% of the tumor dose. This is
reflected in the Mount Vernon schedule, in which, from a
tumor dose of 8.5 Gy using the HDR implant, the target
rectal dose is 5 Gy or less. Equivalent rectal doses from the
published schedules are shown in Table 18.3.
Similarly, urethral tolerance is poorly denned. It
would appear that the urethra is able to tolerate far
higher doses than the rectum, but experience from LDR
iodine-125 implants confirms that urethral problems
can arise if steps are not taken to reduce the central dose
of the implant [13].
 Complications and toxicity 263

Table 18.2 HDR brachytherapy doses: biological equivalent doses (BED) and 2 Gy equivalents for different oc/P ratios

Michigan [7] 90.0 38.6 48.0 28.8 28.8 24.0

Oakland,CA[8]
Seattle [9] 77.0 33.0 46.7 28.0 25.6 21.3
Goteborg[12] 153.3 65.7 86.7 52.0 40.0 33.3
Kiel [10] 330 141.4 180 108 75.0 62.5
Berlin [11] 126 54.0 72.0 43.2 34.2 28.5
Offenbach [6] 158.7 68.0 93.3 56.0 47.6 39.7
Melbourne3 86.7 37.2 53.3 32.0 30.0 25.0
Mount Vernon Hospital 113.3 48.6 65.2 39.1 31.5 26.3
b
Personal communication, Professor G. Duchesne.

Table 18.3 Rectal dose from HDR schedules (assuming 60% of tumor dose and o/p = 3)

Michigan [7] 28.8 17.3 103.3 62.0

Oakland, CA [8]
Seattle [9] 28.0 16.8 103.0 61.8
Goteborg[12] 52.0 31.2 135.3 81.2
Kiel [10] 108 64.8 191.3 114.7
Berlin [11] 43.2 25.9 115.2 69.1
Offenbach" [6] 56.0 33.6 131.0 78.6
Melbourne* 32.0 19.2 108.7 65.2
Mount Vernon Hospital 39.1 23.5 107.5 64.5

"Quoted mean rectal dose is 3 Gy, i.e., 42.8% of prescription dose.

''Personal communication, Professor G. Duchesne.

The disparity and uncertainty regarding dose pre-
scription for this technique make it imperative for all
centers undertaking this work to carefully document and
report normal tissue toxicity in addition to tumor con-
trol rates.
18,11 TREATMENT RESULTS
Reporting of results from this technique is still at an
early stage, with most data being relatively immature,
particularly in a tumor which has a natural history span-
ning 10 or 15 years untreated. A summary of the pub-
lished data is shown in Table 18.4. The only conclusions
that can be drawn are that this is an effective form of
treatment, that high control rates from locally advanced
disease as well as early prostate cancer can be achieved,
and that, to date, morbidity is within acceptable limits
for a high dose radical radiotherapy schedule, although
later normal tissue effects require clarification.
While single center reports are of value, the ultimate
question that will arise is how this technique relates in its
outcome to LDR iodine-125 seed implantation and opti-
mized external-beam treatment alone using conformal
and possibly intensity modulated radiotherapy tech-
niques. Currently, only one randomized trial is under-
way at Mount Vernon Hospital, comparing a standard
external-beam technique of 55 Gy in 20 daily fractions
with the HDR schedule shown above.
18.12 COMPLICATIONS AND TOXICITY
In general, this technique appears well tolerated, with no
additional complications other than those which would
be anticipated from high dose pelvic radiotherapy.
The implant procedure itself appears straightforward,
notwithstanding the inevitable risks of anesthesia in a
patient population which is predominantly elderly. This
is, of course, amplified with techniques and programs
264 High dose-rate afterloading brachytherapy for prostate cancer

Table 18.4 Clinical results

Michigan 33 [7] T2:26 91 Bowel: 5

T3: 7
59 [14] 86 7
Oakland, CA [8] 110 85 Rectal: 1
Urinary: 4
Seattle [9] 104 84 Bowel: 0
Urethra I: 7
Goteborg[12] Not reported
Kiel [10] 171 72:110 T2:89 Bowel: 3
T3: 59 T3: 85 Bladder: 7
Berlin [11] 82 T2:21 All: 53 Bowel: 3.6
T3:61
Offenbach [6] 59 Not reported None
3
Melbourne Not reported
Mount Vernon Hospital Not reported

Personal communication, Professor G.Duchesne.

which deliver successive fractions with a new implant on
each occasion.
During the implant itself, there may be minor dis-
comfort, but this is usually controlled with simple or
moderate analgesia. Indeed, after the first hour or so of
recovering from the anesthetic, most patients require no
additional anesthesia. Hematuria is common, but rarely
of great consequence. Rectal symptoms are few. Some
disturbance of bowel function often follows, our own
schedule incorporating an enema preoperatively to
empty the bowel followed by a constipating regime for
24 h to prevent bowel motions whilst the implant is in
situ. Many men then find it takes a week or two for bowel
motions to return to a normal pattern and may require a
gentle laxative for a few days. Urinary symptoms once
the catheter is removed may persist for a week or two,
with mild dysuria and hematuria. Occasionally, patients
who have had significant outflow obstruction with
symptoms prior to the implant may require catheteriza-
tion for a period of a week or two after the implant
whilst the initial edema settles. Long-term catheteriza-
tion, however, has not been encountered in our experi-
ence. Urinary incontinence as a complication is not
reported. Experience from LDR implants suggests that
transurethral resection is a risk factor for urinary symp-
toms and incontinence after implantation [13] and we
regard this as a contraindication at present, although
data on HDR implants after transurethral resection
(TURP) are not currently forthcoming.
The incidence of expected late complications such as
rectal fibrosis and stenosis, bladder telangiectasia, and
urethral stricture is unknown on examination of the lit-
erature. The most mature data to report this from Kiel
[10] and Berlin [11] suggest the incidence will be of the
order of 3% for severe bowel complications, with per-
haps a similar or slightly higher incidence of severe uri-
nary symptoms.
18.13 CONCLUSION
HDR afterloading implants to the prostate gland can be
achieved with a high level of technical accuracy and
enable the delivery of a concentrated high dose radiation
treatment to a defined volume encompassing the
prostate gland. Doses to the rectum can be limited to
remain within normal tissue tolerance and adjustment
of catheter placement and dwell positioning can also
minimize the dose to the urethra. In combination with
external-beam treatment, this approach offers a treat-
ment program which combines a moderate radiation
dose sufficient to control microscopic disease along pat-
terns of regional spread with a central high dose treat-
ment to known sites of macroscopic tumor. As such, it is
both conformal and intensity modulated, and early
results suggest it is highly effective in the management of
localized prostate cancer.
REFERENCES
1. Khan, K.( Crawford, D.E. and Johnson, E.L (1983)
Transperineal percutaneous iridium-192 implant of the
prostate. Int.J. Radial Oncol. Biol. Phys., 9,1391-5.
2. Puthawala, A., NisarSyed, A.M., Austin, PA.etal. (1996)
Combined interstitial iridium-192 implant and external
beam irradiation in the treatment of carcinoma of the
prostate. Radiother. Oncol., 39 Suppl. 1, S1.
3. Hanks, G.E., Kerring, D.F. and Kramer, S. (1985) Patterns of

care studies: dose-response observations for local control
of adenocarcinoma of the prostate. Int.J. Radiat. Oncol.
Biol.Phys., 51,153-7.
4. Partin, A.W., Subong, E.N.P., Walsh, P.C. etal. (1997)
Clinical stage and Gleason score to predict pathological
stage of localized prostate cancer. JAMA, 277,1445-51.
5. Hoskin, P.J. and Rembowska, A. (1998) Dosimetry rules for
brachytherapy using high dose rate remote afterloading
implants. Clin Oncol., 10,226-30.
6. Martin, T., Kolotas, C, Dannenberg, T. etal. (1999) New
interstitial HDR brachytherapy technique for prostate
cancer: CT based 3D planning after transrectal
implantation. Radiother. Oncol., 52,257-60.
7. Stromberg, J., Martinez, A., Gonzalez, J. et al. (1995)
Ultrasound-guided high dose rate conformal
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description and preliminary results of a Phase l/ll clinical
trial. Int.J. Radiat. Oncol. Biol. Phys., 33,161-71.
8. Rodrigues, R. and Demanes, D.J. (1997) HDR
brachytherapy: ultimate in conformal radiotherapy for
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Interstitial Remote Controlled Brachytherapy, ed. N.
Zamboglou. Munich, WZuckschwerd undVerlag, 119-25.
9. Mate, T., Gottesman, J., Hatton, J. et al. (1998) High dose
rate afterloading iridium-192 prostate brachytherapy:
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10. Kovacs, G., Wirth, B., Bertermann, H. etal. (1996) Prostate
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- an intermediate analysis after ten years experience. Int.
J. Radiat. Oncol. Biol. Phys., 36 (Suppl.) S80,198.
11. Dinges, S., Deger, S., Koswig, S. etal. (1998) High-dose rate
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Oncol., 48,197-202.
12. Borghede, G., Hedelin, H., Holmang, S. etal. (1997)
Irradiation of localized prostatic carcinoma with a
combination of high dose rate iridium-192 brachytherapy
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definitions and dose levels inside the prostate gland.
Radiother. Oncol., 44,245-50.
13. D'Amico, A.V. and Coleman, C.N. (1996) Role of interstitial
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14. Rodriguez, R.R., Demanes, D.J. and Altieri, G.A. (1999)
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503-23.

Low dose-rate brachytherapy for breast cancer
JULIA R. WHITE AND J. FRANKWILSON
19.1 INTRODUCTION
Low dose-rate (LDR) brachytherapy has had a long his-
tory of use for the treatment of breast cancer. Its primary
use has been as a boost following whole breast radiation
therapy (WBRT) as part of breast conserving treatment
(BCT) for early-stage disease. Additionally, it has had
some broader application for the treatment of locally
advanced as well as locally recurrent breast cancer. As a
result of both technical and philosophical changes in the
radiation treatment of breast cancer, the use of LDR
brachytherapy has declined significantly. Despite this,
there remains a role for LDR brachytherapy in breast
cancer treatment.
19.2 HISTORICAL PERSPECTIVE
LDR brachytherapy played an important part in the dra-
matic practice shift over the past three decades toward
BCT as the preferred local therapy for eligible breast can-
cer patients [1]. While most of the transition to BCT
happened over the last two decades, it was actually just
shortly after the turn of the twentieth century that
visionary investigators began the insertion of radium
needles into primary and recurrent breast cancer as an
alternative to surgical resection [2]. As early as 1910, Dr
Henry Janeway, a surgeon at Memorial Hospital in New
York, gained experience treating primary and metastatic
breast cancer with the insertion of capillary glass seeds
containing radon [3]. In 1924, a British surgeon, Sir
19
Geoffrey Keynes, began systematically treating primary
breast cancer with radium needle insertion instead of
radical mastectomy. He routinely included the breast, as
well as the supraclavicular, infraclavicular, axillary, and
internal mammary regional nodal areas in his treatment
volume (Figure 19.1) [4]. In 1929, reporting his results of
treating 90 women with definitive interstitial irradiation,
he proclaimed, 'at the present time we regard treatment
by buried needles as preferable to operation,' for opera-
ble breast cancer. Subsequently, in 1937 Keynes modified
his technique to include tylectomy of the primary breast
mass prior to radium needle insertion [5]. Similarly, in
1932, Dr George Phaler, a Philadelphia radiologist,
reported his experience using radium 'for intensive local
effect by interstitial implantation' in combination with
roentgen rays for primary treatment of 127 breast cancer
patients [6]. He reported an 81% control rate at 'well
over 5 years' for 40 patients with resectable breast cancer
treated with radiation alone because they had either
refused surgery or were medically inoperable. This early
work with interstitial LDR implants became the founda-
tion of experience upon which BCT would be built, and
preceded the first published reports of external-beam
therapy with or without tylectomy by at least 10 years
[7,8]. The development of better X-ray generators and
greater understanding of radiobiologic principles, com-
bined with frustration with the stagnant results and
physical deformity from radical mastectomy, led to the
emergence of more reports utilizing external radiation
for BCT [9-11]. Shortly after the Guy's London Trial
[12] comparing tylectomy and breast radiation to radical
mastectomy was initiated in 1955, Pierquin et al. began

Figure 19.1 Distribution of radium needles used by Sir
Geoffrey Keynesfor the definitive treatment of operable breast
cancer between 1924 and 1929 [4].
routinely treating operable breast cancer with radical
radiation therapy alone, consisting of whole breast exter-
nal-beam irradiation (WBRT) and an LDR interstitial
implant into the tumor-bearing quadrant [13]. Similar
work combining WBRT and brachytherapy after tumor
excision for BCT began in the USA as well [14]. These
single institution experiences, by consistently demon-
strating comparable survival and good local control in
comparison to treatment with radical mastectomy,
helped further the acceptance of BCT for treatment of
early-stage breast cancer. Their work ultimately led to
the prospective randomized trials [15-20] which estab-
lished BCT as the preferred alternative to mastectomy in
eligible patients. LDR brachytherapy remains a part of
the radiation management of breast cancer some 80
years after its inception.
193 EARLY-STAGE BREAST CANCER
193.1 Low dose-rate brachytherapy as
boost treatment
The predominant use of LDR brachytherapy has been in
the setting of BCT to deliver a 'boost' or supplemental
dose of radiation to the tumor-bearing quadrant of the
Early-stage breast cancer 267
breast after WBRT. This was an ideal application for an
interstitial implant, given that the anatomy of the breast
is readily accessible to an implant and the resulting dose
distribution allows a localized area of high dose, while
sparing much of the remaining breast, underlying chest
wall, and lung. Until linear accelerators capable of gener-
ating high-energy electron beams became generally
available, an interstitial LDR implant was the method of
choice for delivering the boost dose for patients treated
with BCT. The wide acceptance of LDR brachytherapy as
a boost technique is evidenced by the fact that in two of
the randomized trials comparing BCT to mastectomy for
early-stage breast cancer, an LDR interstitial implant was
part of protocol radiation [18,19]. There has been con-
siderable variation in terms of the surgery, radiation, and
implant techniques utilized among different institutions
(Table 19.1). However, in general, 10-30 Gy was deliv-
ered by LDR irradiation over 1-3 days, either before or
after WBRT of 45-50 Gy had been given over a 4-5-
week time period. This yielded local breast recurrence
rates varying from 3.7% to 16%, after 5-15 years of fol-
low-up (Table 19.2).
Over the past decade, many institutions have aban-
doned using an LDR implant for the boost dose. Results
from the 1983 Radiation Oncology Patterns of Care
Study in the USA for definitive breast irradiation
demonstrated 29.8% of boost doses were delivered with
an LDR implant [32]. In comparison, the 1989 US
Patterns of Care Survey included 449 cases from acade-
mic (30%), hospital-based (38%), and free-standing
(32%) radiation oncology practices. Ten percent, 2%,
and 13% of these respective practices used an LDR inter-
stitial implant for the boost technique [33]. This change
in practice pattern probably reflects a combination of
the availability and convenience of high-energy electron
technical capabilities and the controversy associated with
routinely boosting the lumpectomy bed after WBRT.
The rationale for boosting the tumor-bearing quad-
rant is supported by the work of Holland et a/., who per-
formed histologic examination of 282 mastectomy
specimens from breast cancer patients with solitary
tumors less than 5 cm in size who would otherwise have
been good candidates for treatment with BCT. The
amount and distribution of microscopic tumor foci out-
side the index mass in the adjacent normal breast tissue
were mapped. This demonstrated that in 177 (63%) of
cases, tumor foci were found outside of the index lesion,
with 20% of these being within a distance of 2 cm, and
43% at distances greater than 2cm [34]. In view of
the high risk of residual microscopic tumor burden in
the 2-4 cm of tissue surrounding the index mass, and
the cosmetic deformity of such a large excision margin in
most cases, boosting the affected area with higher local-
ized doses of radiation seemed a logical solution.
Multiple prospective and retrospective series utilizing
more limited surgery in combination with WBRT and a
boost have demonstrated breast recurrence rates of
Table 19.1 Techniques from various institutions using LDR brachytherapy as a boostfollowing whole breast treatment for breast conserving therapy

Netherlands Cancer Institute [21 -24] WLE Positive 9

Close 15 50/2 15-25 Paris3 2 15 2.5
Negative 46
Unknown 30

Thomas Jefferson University/ WLE Positive 15

University of Kansas [25] Negative 56 45/1.8 15-20 0.30-0.5 2 17.5 N/A
Unknown 2.9

Hopital Henri Mondor, Institut Tumorectomybfor N/A 25-37 25 Paris 2 N/A N/A
Gustave-Roussy [26] T size <3 cm 37
Harvard University, JCRTC [27,28] Excisional biopsyd N/A 45-50/1.8-2 10-30 0.4-0.5 1-2 24 N/A
2

West Mead Hospital Australia [29] Excisional biopsy- N/A 50/2 30 0.4-0.5 1 7.6 3
quad rantectomy

EORTC1081[18] WLE 50/2 25 Paris 2 N/A

NCI [17] Excisional biopsy 48.6/1.8 15-20 N/A N/A N/A

William Beaumount Hospital [30] WLE N/A 45-50/1.8 15 0.625 N/A 19 5

WBRT, whole breast radiation therapy; WLE, wide local excision - removal of tumor with 2 cm margin of normal adjacent breast tissue; N/A information not available.
'Paris: reference dose rate was prescribed according to the Paris System, i.e., 85% of the basal dose rate [31].
Tumorectomy - excision of tumor with a margin of normal tissue not exceeding 1 cm.
The Joint Center for Radiation Therapy.
d
Excisional biopsy - complete gross tumor excision.
Table 19.2 Outcomes from various institutions using LDR brachytherapy as a boost following whole breast treatment for breast conserving therapy

Netherlands Cancer Institute [21 -24] 774 66 T1 64 N/A 3.1 91 86

(1026) T2 36
Thomas Jefferson University/University of 655 48 T1 71 88 V 93 79
Kansas [25] T2 29
Hopital Henri Mondor, InstitutGustave- 245 T1 25 13 T1 63
Roussy [26] 180b T2 56 66 T2 51
T3 19 T3 28
Harvard University (JCRT) [27,28] 688C T1 54 11
(783) 80 T2 46 60 N/A
West Mead Hospital, Australia [29] 131 T1 69 8.5
83 T2 31 N/A 83 77
EORTC1081[18] 456 72 T1 38 10
T2 62 67
NCI [17] 98 120 T1 43 N/A 16 77
(121) T2 51
William Beaumont Hospital (30) 277 81 T1 68 89 lodine-1252 86 81d
T2 32 lridium-1927
"Actuarial.
b
Minimum follow-up.
C
24 patients had mixed electron + implant boost.
"8-year survival.
N/A Not available.
270 Low dose-rate brachytherapy for breast cancer
3-10% at 5 years, and 10-18% at 10 years
[15-21,25,29,35-42]. This is significantly less than
would be predicted from limited excisions alone by
Holland's data and has supported the concept that radi-
ation can eradicate microscopic residual tumor burden
left in the remaining breast. The most convincing evi-
dence against the routine use of a boost dose after WBRT
comes from the NSABP B06 trial that compared modi-
fied radical mastectomy, lumpectomy, and lumpectomy
with radiation for breast cancers up to 4 cm in size [17].
For this trial, the radiation dose was 50 Gy, delivered
over 25 fractions to the whole breast without systematic
boosting of the tumor-bearing quadrant. After 12 years
of follow-up, the 10% breast relapse rate after lumpec-
tomy and WBRT is comparable to that in other trials in
which boosting of the tumor bed was routinely
employed [15-20]. The NSABP B06 recurrence rates
may reflect that negative microscopic margins of resec-
tion were a prerequisite or a mastectomy was performed.
There are retrospective series which have corroborated
the NSABP B06 experience, demonstrating good local
control without boosting for patients with negative
resection margins [35,36]. So far, the preliminary results
from three randomized trials addressing this issue have
begun to clarify whether a boost to the tumor bed should
be routinely used when resection margins are negative.
In the Lyon, France, trial, 1024 women were randomized
to receive a 10 Gy boost delivered with electrons after
WBRT of 50 Gy given over 20 fractions. With a median
follow-up of 3.3 years, the local failure is 3.6% versus
4.5% (p=0.044), with and without the addition of the
boost, respectively [43]. In contrast, a similar trial from
Nice, France, found no difference in local recurrence
after 6 years follow-up in 664 women randomized after
50 Gy WBRT in 5 weeks with cobalt-60 to either a 10 Gy
boost or observation: 4.3% versus 6.8% (p = 0.13) local
recurrence, respectively [44]. An EORTC randomized
trial (22881/1882) has been done to identify the optimal
radiation dose after lumpectomy in 5569 patients.
Patients with negative margins (n = 5318) of resection
were randomized to no boost versus 16 Gy boost after
50 Gy/2 Gy fractionation WBRT. After 5.1 years follow-
up, the 5-year actuarial recurrence rate is 6.8% with the
boost versus 4.3% without one (p = 0.0001). The full
results from this trial are anxiously awaited.
Boosts to the tumor-bearing quadrant are consistently
recommended in the setting of microscopic margin
involvement after local excision of the breast cancer.
While many reports support that there is an increased
risk of local failure after BCT when microscopic surgical
margins are positive [35,37-40,46], others have found
no correlation between positive microscopic margin sta-
tus with subsequent breast relapse [41,42]. This may be
partially explained by the relatively higher cumulative
total doses to the excision cavity from boosting when
microscopic margins were positive in these studies
[41,42]. The association of adverse pathologic features
with higher rates of breast relapse has been reported
from prospective randomized trials [44-48], as well as
many retrospective series [21,22,27,31,37,38]. For exam-
ple, a review of the pathologic findings from the NSABP
B06 trial revealed a non-significant correlation between
the presence of lymphovascular invasion and increased
local breast recurrence (8% versus 3%, p=0.07) [49].
Other factors which have been associated with a higher
likelihood of breast relapse after BCT when present
include tumor size, nuclear grade, histologic grade, and
an extensive intraductal component [21,27,46-48].
Along with adverse pathologic features, other patient-
related and tumor-related factors, such as young age and
hormone receptor-negative tumors, have been associ-
ated with higher breast relapses after BCT [21,27,38]. All
of these factors need to be taken into consideration when
determining the planned final dose to the tumor-bearing
quadrant.
What is known is that the addition of a boost is safe
and will not compromise cosmesis if administered
appropriately, with either an implant or electrons (Tables
19.2 and 19.3). The characteristics of electron external-
beam therapy, with the sharp drop-off in dose beyond its
useful range, makes it ideal for treating superficial vol-
umes. It is very suitable for delivering a boost dose to a
tumor bed located in a small to moderate sized breast or
in the superficial aspect of a large breast. Typical electron
energies used for delivering a boost range from 8 to
12 MeV, with the goal of encompassing the volume
within the 80% isodose line. Energies higher than
12 MeV have been associated with a poorer cosmetic
outcome [50], related to more frequent telangiectasis
and fibrosis. Electron boosts also provide the important
advantages of not requiring a surgical procedure or a
hospital stay, as is necessary for an LDR interstitial
implant.
A few institutions have examined their experience ret-
rospectively to evaluate the influence of the type of boost
on the outcomes of local breast recurrence and cosmesis
(Tables 19.3 and 19.4). The breast recurrence rates were
comparable whether an LDR implant or an electron
boost had been delivered, despite the differences between
the series regarding surgical techniques, radiation doses,
and degree of resection margin assessment. Perez et al,
in their series from Washington University, USA,
observed improved local control for a small subset of
patients with T2 lesions when boosted with an LDR
implant to a cumulative dose of 70.2 Gy (1/24, 4%) ver-
sus lower doses (4/14, 28.6%) [52]. Mansfield et al.
reported an advantage in local control for stage II
patients who received an LDR implant boost versus elec-
trons [25]. Similarly, Deore et al. noted more local recur-
rences among T2 patients who received an electron
boost (4/13,31%), versus an LDR implant (15/157,10%)
[55]. In contrast, Wazer et al. reported more local recur-
rences at 7 years in patients treated with an implant
boost versus non-implant boost (9% versus 2.2%) [56].
Table 19.3 Comparison of outcomes from implant versus electron boost for breast conserving therapy

Hopital Tenon, Hopital Pitie, Salpetriere [51] 82 45-46/2-2.5 169 15.3 8.1 61 160 14.6 13.5 82.5
Washington University [52] 67.2 48-50/1.8-2.0 119 10-20 6.7 81.5 493 10-20 6 81
3 3
Thomas Jefferson University, University 40 45/1.8 654 1 5-20 7 (5 years) 91 416 20 8 (5 years) 95
of Kansas [25] 12 (10 years) 19 (10 years)
William Beaumont Hospital [30] 81 45-50/1.8 87(iodine-125) 15 2a 89 104 N/A 5a 90
190(iridium-192) 7
Beth Israel Medical Center [54] 46 50/2 35 15 8.6 N/A 45 15 0 N/A
'Actuarial recurrence.
N/A Not available.
272 Low dose-rate brachytherapy for breast cancer
However, implants were performed only for cases with
indeterminate or final microscopic margins < 2 mm.
Breast relapses were not significantly different between
implant versus non-implant boosts when this higher risk
group of patients was analyzed separately. In these series,
cosmetic results were equivalent, irrespective of which
boost method was employed. Touboul et al. found
poorer cosmesis in their group of patients who had an
LDR implant boost, but attributed this difference to the
fact that patients who received an implant boost had
WBRT with Cobalt-60, which delivers a greater skin dose
than the 4-6 MV photons used to treat the patients
boosted with electrons [51]. Olivotto etal. also reported
an initially worse cosmetic outcome in association with
larger volume implants that was defined surrogately
based upon the number of iridium-192 seeds utilized
[28]. A later series, which included this cohort of
patients, failed to demonstrate a negative impact on cos-
metic outcome associated with an implant boost [57]. As
seen in Table 19.3 and reported by others [58,59], cos-
metic results are not compromised by an LDR implant
boost when careful attention is paid to technical and
dosimetric factors.
Two distinctly different randomized trials have evalu-
ated the outcomes from delivering an LDR implant ver-
sus an electron boost. The first of these is RTOG 83-06,
which accrued 285 patients between 1983 and 1988 in an
attempt to compare electron versus LDR implant boost
for breast cancer patients with pathologically negative
axillary nodes and Tl, T2 tumors [60]. The breast
surgery was an excisional biopsy to obtain clear gross
margins of > 1 cm. After WBRT was delivered to a total
dose of 46 Gy over 23 fractions using 4 or 6 MV pho-
tons, a 16 Gy or 20 Gy boost was delivered, depending on
the status of the microscopic margins of resection.
Unfortunately, to date no results have been reported. The
other trial, performed at the Institute Curie, was con-
ducted in more advanced cases of primary breast cancer
with tumor sizes of 3-7 cm treated with radiation ther-
apy alone after incisional or core needle biopsy for diag-
nosis. After 57.6 Gy at 1.8 Gy fractionation WBRT,
patients were randomized to receive an additional 37 Gy
with either an iridium-192 LDR implant or cobalt-60
external therapy. After a median follow-up of 8 years,
there was a higher breast relapse rate in patients who
received the cobalt-60 external therapy boost compared
to those boosted by an implant: 45/129 (35%) versus
28/126 (22%), (p = 0.024) [61]. Therefore, while the
boost modality probably does not influence outcome
after lumpectomy and WBRT, in the setting of radical
radiation, an LDR interstitial boost appears necessary to
improve local control.
Despite the efficacy and convenience of electrons,
there is a specific role for LDR implants as a boost after
WBRT. Brachytherapy is the preferred boost method for
a deep tumor within a large breast. Tumor beds that are
greater than 4-5 cm from the skin surface are generally
beyond the useful range for electron irradiation.
Electron boosting in this setting leads to significantly
higher doses to both the overlying skin and underlying
chest wall and lung in comparison to an LDR implant
[62]. A brachytherapy boost is advocated by some inves-
tigators for patients at a higher risk of local failure after
CSRT [25,51-53]. This generally includes patients with
involvement of microscopic resection margins, an exten-
sive intraductal component, or other poor pathologic
risk features. The main rationale for an implant in these
higher risk patients is that it permits intensification of
radiation doses into a localized area with less morbidity
than is seen with electrons or photons. Krishnan et al.
have proposed that there is, in addition, a radiobiologic
advantage to boosting with an LDR interstitial implant,
particularly when performed at the time of breast
surgery [63,64]. Specifically, these theoretical advantages
include the dose differential of greater than 50% at the
center of the implant versus the periphery, continuous
irradiation provides greater dose per cell cycle than con-
ventionally fractionated external-beam radiation, and
greater recruitment of cells into more radiation-sensitive
phases of the cell cycle [63].
At The Medical College of Wisconsin, the patient
charges for an electron boost are nearly half of those
generated for an LDR implant. It should be noted that
patient billing practices vary widely among institutions.
However, when indicated, the use of an LDR implant
may represent an overall economic advantage when the
cost of treating a local recurrence or poor cosmetic out-
come is factored into the equation.
193.2 Brachytherapy as the sole radiation
treatment
The 5-6-week treatment duration necessary for WBRT
makes BCT prohibitive for certain women who either
live a great distance from a radiation center or are elderly
and/or disabled. In order to reduce the overall treatment
time and improve utilization of BCT, phase I/II trials uti-
lizing interstitial implants to the tumor-bearing quad-
rant as the sole method of radiation after lumpectomy
have been conducted [65-69]. The rationale for this
approach is based upon the local failure pattern within
the breast after lumpectomy with or without breast irra-
diation. Multiple randomized trials examining treatment
with lumpectomy alone versus lumpectomy and radia-
tion therapy consistently demonstrated a significantly
reduced risk of local recurrence with the addition of
radiation therapy [17,20,45,70,71]. In examining the
local failure patterns in these trials, it is noted that
the local recurrences occur most commonly at the site of
the original tumor excision and recurrences elsewhere
in the breast are relatively uncommon [70-72]. Follow-
ing this argument, it may be that the dominant benefit
derived by the addition of radiation therapy is primarily
 Early-stage breast cancer 273

from reducing local recurrences at the original excision none to three axillary lymph nodes involved, and must
site. have negative surgical margins after lumpectomy.
Radiation to the tumor-bearing quadrant alone fol- Tumors with an extensive intraductal component and
lowing lumpectomy was evaluated in the Christie invasive lobular histologies were excluded. Implants were
Hospital Breast Conservation Trial, which randomized either LDR or HDR based upon institutional preference.
breast cancer patients with tumors smaller than 4 cm to The LDR dose was 45 Gy/3.5-6 days.
tumor bed radiation with electrons versus WBRT after
lumpectomy [65]. No attempt was made to obtain clear
193.3 Brachytherapy for local recurrences
surgical resection margins. With a 65-month median
after breast-conserving therapy
follow-up, the overall survival is similar between the two
groups. The local-regional recurrence rate was signifi-
Standard treatment for local recurrence after conserva-
cantly higher in the local-field-alone arm (19.6% versus
tive surgery and radiation therapy is mastectomy. When
11%, p = 0.0008), particularly in patients with infiltrat-
a patient is medically inoperable or refuses mastectomy,
ing lobular histology or an extensive intraductal compo-
brachytherapy alone or after a simple excision represents
nent. The authors concluded that, with more stringent
a potential alternative. Maulard et al. reported their
selection criteria, radiation to the tumor-bearing quad-
experience with 38 patients utilizing brachytherapy
rant alone might be sufficient.
either alone (n = 23) for tumors > 3 cm or after excision
The necessity for careful selection of patients to receive
(n = 15) for tumors < 3 cm in size [73]. A total dose of
treatment to the tumor-bearing quadrant alone after
30 Gy was delivered by a single LDR implant after exci-
lumpectomy is illustrated by the Guy's trial [66]. After
sion. For treatment with brachytherapy alone, two sepa-
tumorectomy with no attempt made to achieve clear
rate insertions were done, delivering cumulative total
resection margins, an iridium LDR implant of the tumor
doses of 60-70 Gy. For the entire group, the second local
bed was performed delivering 55 Gy over a 5-day time
recurrence rate was 21% after a mean follow-up of 40
period to 27 patients. The mean tumor size was 3.5 cm
months. With a mean follow-up of 48 months, 4/15
and 10/27 (37%) had margin involvement. After a 6-year
(27%) of the excision and brachytherapy group had a
median follow-up, the local failure rate was 36%. This
second local recurrence, in comparison to 4/23 (17%) in
unacceptably high rate of local failure probably reflects
the brachytherapy-alone group after a mean follow-up
the poor selection criteria and limited surgical excision.
of 36 months. The 5-year overall and disease-free sur-
Other investigators have used stricter selection criteria
vivals were 61% and 31% respectively, for the entire pop-
for doing an interstitial implant as the sole radiation
ulation. Local control in the group treated with
method after lumpectomy. At the Oschner Clinic, 51
brachytherapy after excision might have been better had
patients have received an implant after lumpectomy as
a higher dose than 30 Gy been used. Toxicity included
the sole radiation treatment [67]. Twenty-six of these
necrosis in one patient and chronic breast pain in
were with an iridium-192 LDR implant administering
another, both requiring mastectomy. In comparison,
45 Gy in 3.5-6 days. At 20 months' median follow-up,
Kurtz et al. reported a 32% second local recurrence rate
no local recurrences have been observed. At William
after a median follow-up of 51 months for 50 patients
Beaumont Hospital, 50 patients have received an LDR
with breast failure after BCT treated with local excision
implant with iodine-125, giving 50 Gy at 0.52 Gy h~'
alone [74]. While mastectomy remains the recom-
after lumpectomy [68]. There have been no local
mended treatment for recurrence after BCT, brachy-
regional failures after 47 months' median follow-up. In
therapy after local excision represents a potential
each of these trials the average tumor size was 1.5 cm
alternative in selected cases.
and negative microscopic resection margins were a pre-
requisite. Excellent or good cosmesis was noted in 71%
and 98% of cases at the Oschner Clinic and William
19.4 LOCALLY ADVANCED BREAST CANCER
Beaumont Hospital, respectively. A similar pilot study
using high dose-rate (HDR) brachytherapy has been
performed at the London Ontario Regional Cancer In an attempt to expand the benefits of BCT to patients
Center using comparable selection criteria but with with locally advanced breast cancer, LDR interstitial
somewhat smaller volume implants. It reports one local implants have been used as a boost after induction
recurrence in 39 patients after 20 months' median chemotherapy and WBRT alone or in combination with
follow-up [69]. These results are promising, but longer lumpectomy (Tables 19.4 and 19.5). The total implant
follow-up is needed to determine if this method yields dose delivered tended to be slightly higher in this setting,
results comparable to WBRT after surgery. The ranging from 25 Gy to 40 Gy (Table 19.4). Local control
Radiation Therapy Oncology Group (RTOG) has rates from these series range from 74% to 91%, with the
recently completed a Phase II trial to test the repro- majority of patients treated with exclusive radiation.
ducibility of these results in a multi-institutional setting. Breast preservation rates were 78-94% of attempted
Patients eligible for this trial had tumors < 3 cm in size, cases. This held true even when larger tumors and more
274 Low dose-rate brachytherapy for breast cancer
Table 19.4 Techniques from various institutions using LDR brachytherapy as a boost following whole breast treatment for more
locally advanced breast cancer
Hopital Tenon, Hopital Pitie Induction:3 4 cycles
Salpetriere [75] Adjuvant:1312 cycles
Centre Hospitaller et Induction:0 3 cycles
Universitaire[76] Adjuvant:" 6 cycles
Neckar Hospital [77] Induction:6 4-6 cycles
Adjuvant:'5-12 cycles
Hopital Pitie Salpetriere [78] Induction only
Memorial Medical Center None
of Long Beach [79]
a
5-Fluorouracil, adriamycin, cyclophosphamide.
b
Cyclophosphamide, methotrexate, 5-fluorouracil.
c
Mitoxantrone, vincristine, cyclophosphamide, 5-fluorouracil.
"As above, with epirubicin.
'Vinblastine, thiotepa, methotrexate, 5-fluorouracil, prednisone with adriamycin.
WLE, wide local excision; MRM, modified radical mastectomy.
advanced stages were treated. Survival was comparable
to those series with similar chemotherapy regimens
which routinely employed mastectomy [80]. As reviewed
earlier, the Institute Curie has demonstrated improved
local control from an LDR interstitial implant versus an
electron boost in a prospective randomized trial [61]
when treating primary breast cancers 3-7 cm in size
with radiation therapy alone without definitive surgery.
Therefore, in this setting, an LDR interstitial implant is
the recommended and preferred boost method.
19.5 TECHNIQUE
Iridium-192 is the most commonly used isotope for
LDR breast implants (see Table 19.1). Alternatively, a few
institutions have used iodine-125 and reported clinical
advantages in comparison to iridium-192 in terms of
easier shielding and dose optimization [53]. However,
iodine-125 requires significant physics time and exper-
tise for the assembly and dismantling of custom ribbons.
In most cases, a minimum of two planes is necessary
for appropriate coverage by the implant of the lumpec-
tomy site. A double-plane implant can generally be used
to treat volumes with thicknesses up to 2.5-3 cm. For
treatment volumes with thicknesses > 3-3.5 cm, a
three-plane implant is generally warranted to improve
dose homogeneity [81]. Single-plane implants are
reserved for treatment volumes with a thickness of 1 cm
None 33 45/1.96 25-30
WLE 27
MRM 37
None 32 45/2.25 15-35
WLE 45
MRM 81
None 23/5.0-6.3 20-30
None 45/1.8 25-30
23/1.5-6.5
Incisional biopsy 50/2.0 Breast 30-40
Axil la 20-30
or less, which may occur in very small breasts or in the
periphery of the breast, particularly the upper inner
quadrant. Spacing between planes and the individual
ribbons within a plane typically varies between 1 and
2 cm. The planes can be arranged so that the needles in
opposing planes are parallel, creating a square configu-
ration between needles in different planes. For breast
implants, the needles in adjacent planes are commonly
staggered. This means that the needles in one plane are
situated at half the in-plane separation of the opposing
plane, so that there is a triangular configuration
between needles in different planes (Figure 19.2a). This
latter arrangement has been used extensively in the Paris
System for interstitial radiation therapy, for which the
recommended spacing between individual needles in
the same plane is 15, 18, or 20 mm and the interplanar
separations are 13, 16, and 18 mm, respectively, or
nearly equidistant [82]. There is substantial clinical
experience supporting the efficacy of the Paris-type
arrangement for LDR interstitial implants in the breast
(see Table 19.2). In using the Paris System the operator
should be aware that, as the distance between needles
and planes increases to cover larger target volumes, so
does the relatively higher dose region in the center of
the implant [83]. For this reason, others have recom-
mended varying needle and plane separations to
improve dose homogeneity [84,85]. As an example,
Zwicker et al. use a Quimby-like system which main-
tains a constant needle spacing of 1 cm within the plane
as the interplanar spacing varies with target thickness in
Table 19.5 Outcomes from various institutions using LDR brachytherapy as a boost following whole breast treatment for more locally advanced breast cancer.

Hopital Tenon, Hopital F'itie-Salpetriere[75] 97 IIIA-IV 6.6 86 78 78 16/60 80 69

(17)

Centre Hospitalier et Universitaire [76] 158 T2-T3 5.6 38 48.7 N/A 6/77 73.2a -
(8)
Necker Hospital [77] 137 IIA-B 3-15 62 94 85 337196 IIA 95 -
94 IIIA-B" (17) KB 80 -
IMA 60 -
1MB 58 -

Hopital Pitie-Salpetriere [78] 135 T3-T4b 8.5 96 90 72 26d/135 All 64 50

(19)d T3 66 52
T4 56 47

Memorial Medical Center of Long Beach [79] 78 III N/A 48-84 90 65 7V85 47
(8)
'Disease-free survival.
"Including inflammatory limited to part of the breast.
C
27 isolated with metastasis, 23 breast, 4 axillary.
d
11 with DCIS.
e
5 breast failures, 2 axillary.
BCT, breast conserving treatment.
N/A Not available.
276 Low dose-rate brachytherapy for breast cancer
order to reduce the high-dose region at the center of the
implant [85].
Interstitial breast implants are generally placed with
the patient under general anesthesia. In some cases, con-
scious sedation combined with local infiltration is ade-
quate. The patient is positioned to match what was
utilized for her preplanning, or otherwise is generally
positioned so that the ipsilateral arm is abducted to
approximately 90. The entire breast, with a generous
margin, should be sterilely prepped and draped. In gen-
eral, 15-20 cm hollow, stainless-steel needles are used.
The deep plane is generally placed first. The orientation
of the needles depends on the location of the tumor bed
within the breast. Care is taken that the superficial plane
is sufficiently deep to the skin (0.5-1 cm) to avoid exces-
Figure 19.2 Isodose distributions in (a) transverse, (b) coronal,
and (c) sagittal planes for a rigid implant demonstrating
staggered interplane needle arrangement.
sive skin dose. Once all the needles are in position, they
can be replaced with flexible plastic catheters. Flexible
catheters have the benefit of improving patient comfort.
The major disadvantage is the potential for change in the
implant geometry and dosimetry with patient move-
ment [86]. To maintain ideal geometry, some have advo-
cated that the needles or catheters be fixed in position by
either endplates [82] or a bridge [87] (Figure 19.2). Once
the implant is completed, a small amount of antibiotic
ointment can be placed around the needle puncture sites
and the implant covered with loose-fitting gauze until
loading. After the patient has recuperated sufficiently
from her anesthesia, post-implant treatment planning
proceeds. In general, prophylactic antibiotics are not
required unless the patient has a comorbidity such as

cardiac valve disease. Usually, the patient can be com-
fortably maintained with mild analgesics throughout her
treatment. Patients are allowed bathroom privileges, but
activity should be restricted so that the implant geome-
try is maintained. It has been shown that the implant
dosimetry can change with the patient position [86].
Once the radiation is completed, removal of the implant
is done at the bedside, using a sterile technique.
19.6 TREATMENT PLANNING
Typically, an LDR interstitial implant boost can be per-
formed 1-2 weeks before or after initiation of WBRT.
Significant time delays between WBRT and the implant
should be avoided, as this was correlated with a greater
risk of local breast recurrence by Dubray et al. in the
Creteil experience. In that analysis, the mean time delay
between the WBRT and the LDR implant was prolonged
at 5.9 1.7 weeks [88]. Because most patients in this
series were treated by exclusive radiation without breast
surgery, it is not clear whether this finding is applicable
to WBRT plus implant following excision as well. For
patients receiving an LDR implant as the sole radiation
modality following lumpectomy, implants should prob-
ably be performed within 4-6 weeks of the final breast
surgery.
Performing the implant at the time of excision or re-
excision has the important advantage of allowing direct
visualization of the surgical bed, ensuring that it is cov-
ered by the needle geometry. Furthermore, implants
done at the time of the re-excision or the axillary node
dissection have the added benefit of avoiding a separate
surgical procedure and anesthesia. The disadvantage of
implanting at the time of the breast surgery is that the
presence of any adverse pathologic feature and status of
the final resection margins are unknown. For this reason,
delayed loading of the implant for 48 h after peri-
excision placement is recommended, to allow for wound
healing and availability of the pathologic review and
margin assessment [89]. Others have loaded the implant
within 6 h after peri-excision placement and reported no
greater occurrence of wound complications and have
adjusted total dose for any adverse pathologic features
found at the time of pathology review [56,90]. Another
disadvantage of performing the implant at the time of
the excision or re-excision is that it is limited to those
patients who are treated at centers with both surgical and
radiation oncology capabilities on site. At many large
referral centers, this would preclude an interstitial
implant for the numerous patients who have had their
breast surgery performed elsewhere.
Patients who do not have the interstitial implant per-
formed at the time of breast surgery require careful
localization of the excision cavity. This includes all
implants done at the time of the axillary node dissection
Treatment planning 277
before WBRT, as well as those performed after WBRT.
De Biose et al. found that clinical examination (physical
examination, operative report, and mammograms)
underestimated the full extent of the lumpectomy cavity
87% of the time in comparison to preoperative and
intraoperative ultrasound definition [91]. Sedlmayer et
al. demonstrated a potential error rate of 51% from esti-
mating the location of the tumor bed based upon the
clinical criteria of preoperative mammography, surgical
reports, and palpation of postoperative indurative
changes in comparison to radiographs of surgical clips
outlining the excision cavity [92]. This potential error
rate rose to 78.5% for large pliable breasts. As a result,
this group advocates that the excision cavity be marked
with surgical clips. Demarcating the lumpectomy site
with surgical clips has also been shown to be equally
important when planning WBRT and electron boost vol-
umes to ensure adequate coverage [93,94]. For this rea-
son, it is our belief that the lumpectomy cavity should
always be marked with surgical clips to avoid geographic
misses by any radiation modality, not just in the setting
of an implant.
When the lumpectomy cavity has not been demar-
cated with surgical clips, localization with either com-
puterized tomography (CT) scan and/or ultrasound is
necessary. Both of these modalities are dependent on the
presence of a seroma and/or hematoma to outline the
cavity. Therefore, it is necessary to perform these studies
for localization purposes as close to the breast surgery as
possible, as postoperative changes can resolve within a
few weeks. Prior to going to the operating room, the
treatment volume to be implanted should be determined
and mapped on the skin of the breast. Also, the depth of
the deepest plane necessary to adequately cover the exci-
sion cavity should be planned preoperatively as this is
frequently also underestimated by clinical examination
[91].
One proposed method to ensure accurate tumor local-
ization and intraoperative reproduction of a preplanned
implant is to make a mould of the breast that will provide
fixed geometry for the implant. Teo and Chung first
reported using a cobex cast of the breast to aid in the
planning of LDR implants that were a component of rad-
ical radiation for locally advanced breast cancer [95].
Once the cobex cast of the breast was made, a CT scan was
performed for tumor localization with the cast in place. A
geometrically ideal implant for tumor coverage was
planned from the CT scan, and the entry and exit points
for the needle placement drilled into the cast preopera-
tively. Intraoperatively, the cast was refitted to the
patient's breast and the implant constructed via needle
placement through the predrilled holes. This technique
was modified by Perera et al. for use together with surgi-
cal clips marking the lumpectomy cavity. The surgical
clips were added because of difficulty separating the
tumor bed from normal dense breast tissue with the use
of CT alone [96]. Their technique used the simulator first
278 Low dose-rate brachytherapy for breast cancer
to localize the tumor bed based on the position of the
clips within the breast. This area was then mapped out on
a breast mould and marked by radio-opaque catheters
attached to the mould. Similarly, after CT localization,
the optimal implant for coverage of the treatment volume
was planned and the exit and entry points for the implant
needles placed on the mould in relation to the radio-
opaque markers. Reconstruction of the implant was then
done intraoperatively after the mould had been refitted to
the patient's breast. Vicini et al. have used a similar tech-
nique to preplan implants using ultrasound to initially
map the lumpectomy cavity prior to a CT done with
radio-opaque markers placed directly on the breast
instead of a mould or cast. The positions of the radio-
opaque markers were subsequently drawn directly on the
breast. Using a three-dimensional treatment planning
system, they were able to create a volumetric model of
their fixed template system and virtually plan the ideal
position of the implant on the CT. Digitally reconstructed
radiographs of the skin surface were generated demon-
strating the needle exit and entry points relative to the
radio-opaque markers to guide intraoperative placement
[97]. Sedlmayer reported a technique for preplanning
implants based solely on simulator localization of the
clips marking the excision cavity to determine the depth
and trajectory of the implant planes [92]. This informa-
tion is then mapped directly on the affected breast with
the patient in the same position to be used at the time of
surgical placement. At The Medical College of Wisconsin,
we have adopted a similar technique, preoperatively map-
ping the position of clips onto the skin of the breast and
estimating the depth of the planes in the simulator with
the patient in a position that will mimic what will be used
intraoperatively. In addition, we routinely use a C-arm
fluoroscopic unit intraoperatively to confirm inclusion of
the clips marking the excision cavity within the needle
geometry after the first few needles have been placed
prior to completing the entire implant.
Multiple dosimetry systems for preplanning intersti-
tial implants have been formulated. These are meant to
guide seed activity and spacing, as well as intraplanar
and interplanar needle spacing, so as to deliver a certain
dose rate over a given volume. These include a nomo-
gram [84], which specifies ribbon spacing based upon
the linear activity of the sources and target volume, and
planning tables [85], which determine the seed activity
and interplanar separation needed to achieve a desired
dose rate at the boundaries of the treatment volume of
dimensions specified in the table. These preplanning
tables and monographs have been particularly useful for
implants performed at the time of lumpectomy. They
should not replace post-implant treatment planning as
the actual geometry of the implant performed at the
time of surgery can vary significantly from what was pre-
planned.
Post-implant treatment planning should consist of a
minimum of two variable angle films, typically 60-90
apart. Ribbons containing radio-opaque dummy seeds
are loaded into all the implanted needles or catheters
and, by their different appearances, allow identification
of the separate needles. The positions of the dummy
seeds and the surgical clips demarcating the cavity on the
orthogonal films are digitized into the planning system,
allowing reconstruction of the implant. The radiation
oncologist should specify the volume to be covered by
the reference dose rate on the treatment planning films.
Evaluation of isodose curves in the sagittal and coronal
as well as in the transaxial planes gives a better under-
standing of the volume irradiated and the dose hetero-
geneity (Figure 19.2a-c). Ideally, isodose curves should
be generated in more than just the central plane. It is
particularly important to evaluate other planes if a non-
rigid implant was performed, as central plane dosimetry
will not reliably represent any convergence or divergence
of the needles that may have occurred. CT scan-based
dosimetry is very useful for planning and documenting
tumor volume coverage of multiplane implants [98]. It
reduces the time necessary for reconstruction from the
orthogonal radiographs, reliably demonstrates areas of
uneven spacing, and can evaluate the isodose coverage of
the lumpectomy site.
Dose prescription includes selection of the dose rate
and total dose to be delivered to a specified volume.
Doses for boost therapy after lumpectomy and WBRT
range from 10 Gy to 25 Gy, with dose rates typically
varying from 0.4 Gy to 0.8 Gy h~' (see Table 19.1). Doses
for boost therapy after WBRT in cases of exclusive radi-
ation therapy for locally advanced disease tend to range
from 20 Gy to 40 Gy given over similar dose rates (see
Table 19.4). For the Paris System, the reference dose rate
is 85% of the basal dose, or the average minimum dose
between the sources [31]. A dose-rate effect for local
control was reported by Mazeron et al. in a review of 398
T1-T3 adenocarcinomas of the breast treated by exclu-
sive radiation therapy without surgery. An LDR intersti-
tial implant of 37 Gy was done after WBRT of 45 Gy.
Significantly higher rates of breast relapse were noted
when the implant dose-rate was < 0.6 Gy rr1 [99]. Deore
et al. demonstrated a similar effect for LDR implant
boosts after lumpectomy and WBRT [55]. In this series
of 273 patients, an increased rate of local recurrence was
seen in a small number of cases in which the dose rate of
the implant boost was 0.2-0.29 Gy (4/17, 24%) versus
>0.3 Gy h-1 (16/253, 6.3%). However, little information
is available in this report regarding the presence of other
adverse prognostic features in this group of 17 patients.
Overall, dose rates > 0.4 Gy h"1 have yielded very high
local control rates after lumpectomy (see Table 19.2).
Special attention should be paid to the skin dose dur-
ing the implant treatment planning. Excessively high
skin doses may result in telangiectasis and skin retrac-
tion as a late outcome. For this reason, the most super-
ficial sources should be at least 5-10 mm beneath the
skin surface. Implants with large interplane separations

may need up to 10 mm to avoid excessive skin dosage.
Van Limbergen studied the location of the dermal vas-
cular structures of 30 healthy skin samples from ten
mastectomy specimens and found that the dermal vas-
cular structures responsible for telangiectasia are located
in the first 5mm under the skin surface [100].
Thermoluminescence dosimetry (TLD) measurements
made over several points on the skin surface of the breast
during the implant and WBRT suggested that doses
> 50 Gy to the skin are associated with a higher proba-
bility of late telangiectasia [86]. At The Medical College
of Wisconsin, two to three BBs are placed over the skin
at the time of post-treatment planning in the simulator.
These are then digitized into the planning system along
with the dummy seeds and the surgical clips. This pro-
vides us with an estimate of skin dose.
While it is necessary that the desired dose accurately
covers the treatment volume to secure local control, it
should be kept in mind that the parameters of total dose
and treatment volume can influence the cosmetic and
toxicity outcomes. The irradiated boost volume and total
dose significantly influence the formation of late fibrosis.
A very carefully executed study evaluating breast fibrosis
was performed in 404 patients with early-stage breast
cancer who underwent BCT [23]. This study demon-
strated that the odds of developing moderate to severe
fibrosis were dependent on overall dose, particularly for
doses > 70 Gy. Furthermore, for any given dose, there was
a proportional increase in late fibrosis with increasing
irradiated volumes, (see Figure 19.3). Specifically, for
each 107 cm3 added to the irradiated volume, the risk of
fibrosis increased by a factor of 4. Similarly, McRae et al.
correlated soft-tissue complications with the implant vol-
ume in 56 breast implants [ 101 ]. In contradiction to these
findings, others have not found a correlation between
implant volume and cosmetic or toxicity outcome [59].
Figure 19.3 Relationship of dose and implant volume to
probability of breast fibrosis. (Adapted with permission from
Borger et al. [23].)
References 279
Implicit in the prescription of dose with LDR intersti-
tial implants are those volumes of tissue that will receive
markedly higher doses due to dose heterogeneity. Several
investigators have proposed methods for quantifying
dose uniformity. These include the dose homogeneity
index (DHI), dose non-uniformity ratio (DNR), and
double dose volume ratio (DDVR) [81,102,103]. The
DHI represents the percentage of the target volume
receiving dose rates between 100% and 150% of the ref-
erence dose rate [81]. The DNR is defined as the ratio of
the high-dose volume relative to the reference volume
[ 102]. Lastly, the DDVR is the ratio of the volume of tis-
sue receiving twice the prescribed dose divided by the
volume of tissue receiving the prescribed dose [103].
Acceptably homogeneous implants are recommended to
have a DHI of > 0.8, a DDVR of < 0.1, and the minimum
DNR. The value of these indices is that they allow com-
parison of implants in terms of dose actually delivered
versus prescribed dose. Ideally, the 150% isodose line
should be broken up and visible around individual rib-
bons only. The importance of the interaction between
total treatment volume and dose heterogeneity for deter-
mining cosmetic and toxicity outcomes further demon-
strates the need for careful treatment planning.
19,7 CONCLUSION
Low dose-rate brachytherapy for the treatment of breast
cancer has a well-established track record for providing
high levels of local control and good cosmetic outcomes.
Careful quality control with special attention to target
localization and dose specification has proved crucial in
the success of LDR implants. While its role as a boost
after WBRT is diminishing in cases of BCT, newer appli-
cations are emerging. In particular, brachytherapy as the
sole radiation modality following lumpectomy appears
promising. Even as HDR brachytherapy becomes more
prevalent for the treatment of breast cancer, the wealth
of LDR experience and data provides an important
benchmark for success in terms of local control and late
outcomes.
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method of interstitial brachytherapy. Int.J. Radial
Oncol. Biol. Phys., 40(3), 629-35.
98. Regional Medical Physics Department (1986) The use of
simulator-based computed tomography in iridium-192
dosimetry. Br.J. Radiol., 59,1035-6.
99. MazeronJ.J., Simon, J. and Crook, J. (1991) Influence of
dose rate on local control of breast carcinoma treated by
external beam irradiation plus iridium 192 implant. Int.
J. Radial Oncol. Biol. Phys., 21,1173-7.
100. Van Limbergen, E., Briot, E. and Drijkoningen, M. (1990)
The source - skin distance measuring bridge: a method
to avoid radiation telangiectasia in the skin after
interstitial therapy for breast cancer. Int.J. Radial Oncol.
Biol. Phys., 18,1239-44.
101. McRae, D., RodgersJ.and Dritschilo, A. (1987) Dose-
volume and complication in interstitial implants for
breast carcinoma. IntJ. Radial Oncol. Biol. Phys., 13,
525-9.
102. Saw, C.B., Suntharalingam, N. and Wu, A. (1993) Concept
of dose nonuniformity in interstitial brachytherapy. Int.
J. Radial Oncol. Biol. Phys., 26, 519-27.
103. Metcalf, D.R., Lewinsky, B.S., Fingerhut, A.G. etal. (1988)
A ratio of volumes technique for analyzing interstitial
implants. Int.J. Radial Oncol. Biol. Phys., 15 (Suppl. 1),
143.

Brachytherapy in the treatment of head and
neck cancer
A.GERBAULETANDM.MAHER
20.1 HISTORICAL BACKGROUND
Since the discovery of radium in 1898 by Pierre and
Marie Curie, there have been many advances in the use
of radioactive sources for brachytherapy procedures. The
first reported cases of interstitial therapy were published
in 1914 from Dublin, Ireland [1-3]. Subsequent devel-
opment of radium needles allowed easy implantation of
skin tumors, lip tumors, and cancers of other accessible
sites. Advances in dosimetry saw the development of
units such as threshold erythema dose, millicurie
destroyed and milligram-hours. In the 1930s Patterson
and Parker devised a series of rules for single-plane,
double-plane, and volume implants governing the use of
radium needles. Milligram-hours were at that time the
unit of measurement in common use for such applica-
tions [4,5].
In head and neck cancers the most common sites to be
treated by such implants were lip, tongue, floor of
mouth, and buccal mucosa. Radium needles had the dis-
advantage of significant radioprotective problems.
Artificial radioactivity, however, was discovered by Irene
Curie and Frederic Joliot in 1933 and shortly thereafter
new materials suitable for clinical use became available.
The introduction of iridium-192 wire brought with it
greater flexibility and a major reduction in the hazards
posed to both staff and patients by radium brachyther-
apy. From the 1960s onwards, the Paris school led by
20
Pierquin, Dutreix, and Chassagne [5-7] laid the founda-
tions of the Paris system of implantation. Enormous
clinical experience coupled with scientific endeavor
resulted in what became known as the Paris System. This
refers to a system of implantation and dosimetry which
is predictive, reliable, consistent, and clinically safe [8,9].
With the development of linear accelerators in the
1950s and 1960s, the popularity of brachytherapy as a
treatment modality began to decline. However,
brachytherapy is currently undergoing a resurgence in
use due to the widespread availability of isotopes which
offer more flexibility and few radioprotective problems
and the introduction of remote afterloading machines
into many treatment departments [6,9].
20.2 PRETREATMENT ASSESSMENT AND
INVESTIGATIONS
20.2.1 Primary tumor
Pretreatment assessment is without doubt the single
most important step in any planned brachytherapy pro-
cedure. In order to be able to decide whether a
brachytherapy procedure is appropriate, one must be
able to define with confidence the limits of the tumor
volume and the limits of the proposed target volume
[1,5,7,9].

In most instances, brachytherapy is contraindicated as
an initial therapeutic procedure for T3-T4 cancers of
the head and neck. On the other hand, brachytherapy is,
in the majority of clinical situations, perfectly appropri-
ate as an initial or indeed exclusive local therapeutic pro-
cedure for T1-T2 cancers of the head and neck. The key,
therefore, to the correct and effective use of brachyther-
apy in head and neck cancers lies in the pretreatment
assessment and investigations. Pretreatment assessment
includes detailed history, full physical examination,
appropriate investigations, and multidisciplinary con-
sultation. With regard to the primary tumor, this process
refers to loco-regional tumor evaluation, routine search
for metastatic disease, investigation for synchronous sec-
ond primaries and, in the case of oral cavity implants,
gingival/dental examination and recommendations
[5,10].
Loco-regional tumor evaluation defines the exact lim-
its of the primary tumor, allowing the brachytherapist
precisely to appreciate the tumor volume. This may be
an entirely clinical assessment for lesions on the lip, buc-
cal mucosa, floor of mouth, or mobile tongue. In some
situations, however, further delineation is provided by
computerized axial tomography (CAT) scanning and/or
magnetic resonance imaging (MRI) scans, which may
more accurately assess the primary tumor volume and
the integrity of adjacent structures such as bone and car-
tilage [8,11-13].
20.2.2 Neck assessment
For patients with oral cavity tumors for whom the
planned treatment is brachytherapy, assessment of nodal
neck disease is primarily clinical. Even if clinically nega-
tive, all such patients treated in Gustave-Roussy system-
atically undergo elective neck dissection provided they
are deemed fit for general anesthesia and surgery. In sit-
uations in which patients are deemed to be unfit for gen-
eral anesthesia, the draining neck nodes may be assessed
clinically and by serial CAT scanning.
20.23 Dental assessment
Gingival and dental assessment is of vital importance
prior to any brachytherapy procedure which will result
in radioactive sources lying in close contact with the
teeth, gums, or mandible. Teeth with extensive caries and
gross gingival disease are better extracted prior to
brachytherapy if osteoradionecrosis is to be avoided.
Following extraction, sufficient time to allow adequate
gum healing must elapse (usually 2-3 weeks) before the
brachytherapy treatment is carried out.
For patients with healthy teeth and gums, efforts must
be made to protect the dentition. In our institution, a
shielding system made of 2 mm of lead is used to cover
the teeth and gums. An identical denture shield made of
Treatment methods 285
acrylic resin, which is radiotransparent, is put in place
when the orthogonal X-ray films for dosimetry are taken
following the brachytherapy procedure. This allows
reproduction of the actual source positions during irra-
diation with the dental radioprotective lead shield in
place. This shielding system confers a reduction in dose
of 50% to the teeth and mandible.
203 TREATMENT METHODS
203.1 lridium-192
Iridium-192 is the radioisotope used in our institution
for head and neck low dose-rate (LDR) brachytherapy.
Some institutions continue to use cesium needles in cer-
tain clinical situations, such as lip and tongue cancer.
Iridium-192, however, is flexible, pliable, and can be cut
to prerequisite lengths. It is available as a continuous
wire coil of iridium-platinum alloy (25-75) and can be
purchased in diameters of 0.3 or 0.5 mm, depending on
the technique for which it will be employed. Iridium has
a half-life of 74 days, is a gamma ray emitter with aver-
age energy of 0.35 MeV, and has a half value layer of
2 mm lead [4-7].
203.2 Iridium-192 hairpins
Iridium-192 is also available in the form of single pins or
hairpins. The hairpin consists of two lengths of iridium
wire connected by a bridge, rather like the three sides of
a rectangle. The 'legs' can be cut to any desired length
and the separation between them is a constant 12 mm,
thereby assuring parallelism. This iridium has a diameter
of 0.5 mm.
Iridium hairpins are implanted using specially made
stainless-steel guide gutters. These guide gutters have a
similar geometric shape to the hairpin, but the 'legs' are
hollow and bevelled. The bridge of the guide gutter is
everted and can be gripped by a long-handled or short-
handled Pierquin forceps, which allows better leverage
for accurate placement. Guide gutters/iridium-192 hair-
pins are ideally suited to brachytherapy for floor of
mouth and lateral border of mobile tongue tumors. For
implantation of such tumors, the patient sits in a dental
chair and the procedure is carried out under local anes-
thetic. Ideally, the theater should be equipped with a C-
arm fluoroscopic X-ray control unit. The area to be
implanted is anesthetized, the guide gutters are intro-
duced, and their geometric arrangement is verified by
fluoroscopy. When found to be in a satisfactory position,
a silk suture is passed underneath the bridge of the guide
gutter, taking in a generous amount of tissue. The active
iridium hairpin is then slipped into the bevelled edges of
the guide gutter and advanced until the bridge reaches
the surface tissue. A skin hook is placed over the hairpin
286 Brachytherapy in the treatment of head and neck cancer
bridge to maintain its position while the guide gutter is
being withdrawn. The silk suture is then tied to ensure
the hairpin does not become displaced during the irrida-
tion. Orthogonal X-ray films are taken, with, if appro-
priate, the previously described acrylic dental protector
in place. Dosimetry is determined by both computer and
manual planning [5,7,8,14].
2033 Plastic tube technique
The plastic tube technique is an elegant system of
implantation, but requires considerable operator skill
and expertise. It is an afterloading technique which fixes
the tissues encompassed by loops of plastic tubing. It is a
technique of implantation which is suited to tumors of
the floor of the mouth spreading onto the ventral surface
of the tongue, and vice versa, for tumors of the lateral
and posterior tongue, the tonsillar fossa, tonsillar pillars,
soft palate, and uvula. The technique is described here in
relation to a midline Tl tumor of the soft palate.
Having confirmed the indication for brachytherapy
treatment by preoperative assessment and investigations,
the patient is given a general anesthetic. The procedure is
carried out under aseptic conditions with the patient in
the supine position. A small tumor of the midline of the
soft palate is implanted by looping two hollow plastic
tubes from the submandibular neck region on one side,
through the tonsillar pillars, across the substance of the
soft palate, and exiting by the tonsillar pillar route on the
opposite side of the neck.
Step 1 is to pass a hollow stylette vertically through the
skin of the neck and posterior floor of the mouth, so that
it exits intraorally at the foot of the posterior tonsillar
pillar. A length of nylon monofilament is threaded
through the hollow stylette from outside and is recuper-
ated intraorally. The stylette is then withdrawn, leaving
the monofilament in place.
A length of hollow plastic tubing (which will eventu-
ally hold the radioactive iridium wire) is threaded over
the monofilament and advanced to the skin entry point
on the neck. This plastic tubing has an outer diameter of
1.6 mm and an inner diameter of 1.2 mm. Forceps are
applied at the distal end of the monofilament, which is
overlapped by the plastic tubing. The intraoral monofil-
ament is thereafter carefully pulled through the tissues in
vertical fashion until the plastic tubing emerges at the
foot of the tonsillar pillar. Great care must be taken when
pulling the monofilament/plastic tubing through the tis-
sues so that tearing and subsequent bleeding are avoided.
A Reverdin forceps (which is curved) is passed from
the contralateral side through the substance of the soft
palate to emerge at the superior pole of the posterior
tonsillar pillar. The monofilament is gripped by the
Reverdin forceps and pulled back through the soft palate.
The plastic tubing is then carefully advanced through the
soft palate tissue, following the same principles as before.
To exit the tubing and complete the loop, a hollow
stylette is passed as before in vertical fashion from the
submandibular neck area to emerge at the foot of the
contralateral posterior tonsillar pillar. The monofila-
ment is threaded through from inside to emerge exter-
nally and the stylette is then withdrawn. The plastic
tubing is pulled through very carefully as before, and the
monofilament is then withdrawn.
The tubing is now in place, forming a loop which
passes from one side of the neck through the posterior
tonsillar pillar, across the substance of the soft palate,
and emerging via the contralateral posterior tonsillar pil-
lar to the opposite neck. The plastic tubing is flushed
through with a heparin solution to ensure it remains
patent.
A second length of plastic tubing is implanted in
exactly the same manner, but on this occasion the ante-
rior tonsillar pillar is the intraoral point of entry and
exit.
Although the actual physical process of implantation
has been described above, no mention has been made of
the relation of the tubes to each other or, indeed, to the
tumor. Obviously, these factors are of vital importance if
the Paris System rules are to be observed. The loops must
be implanted so that they comfortably sandwich the
tumor between them, while simultaneously remaining
equidistant and parallel with respect to each other. In
terms of dosimetry, the optimal distance between the
two tubes is approximately 12-15 mm. This distance is
maintained externally as follows: plastic tube spacers
which have been drilled with holes separated by a dis-
tance equal to the separation between the two hollow
plastic tubes are passed over the free ends of the tubes
and advanced so that they come to lie in contact with the
skin of the neck. Dummy wire is then threaded through
the plastic tubes and is held in place by lightly clamping
metal buttons which slide over the plastic tubes.
Orthogonal X-rays are taken for dosimetric purposes
[4,5,15,16].
203*4 Hypodermic needle technique
Hypodermic needles are most often used for cancers of
the lip and nose, for which an element of rigidity in the
source carriers is required. They have an external diame-
ter of 0.8 mm and are bevelled at both ends.
When the target volume has been implanted and the
positions are deemed satisfactory, the needles are kept in
place by a template system. The templates, which are
made of perspex, are cut and drilled to the implant
requirements and are then slipped over the ends of the
needles. Lead caps are placed over the bevelled ends of
the needles on one side of the implant and are crimped
to secure them.
Appropriate lengths of radioactive iridium-192 wire
are manually afterloaded into the opposite ends of the
 Treatment planning 287

needles and lead caps are put in position and crimped as high dose uniformity within the target volume, and a
before [5,7,17]. rapid fall-off in dose outside it [5,6,8,19].

203.5 Silk suture technique

20.4 TREATMENT PLANNING
This technique is used predominantly for small tumors
on the skin and eyelids. Braided silk (4.0) into which
20.4.1 General assessment
0.3 mm diameter iridium wire can be threaded is the
vector for implantation. The silk thread is first canalized
As previously emphasized, the general assessment
by a small steel wire and then hardened by dipping into
includes an evaluation of the patient, the patient's tumor
an organic compound. The steel wire is withdrawn and
under consideration, and other relevant factors such as
replaced by iridium-192 of 0.3 mm diameter, which is
dentition. When a brachytherapy procedure is being
maintained in position by a knot on the silk thread.
proposed, consideration has to be given to the manner of
The tumor to be implanted is treated by passing the
anesthesia. Local anesthesia is quite adequate for well
silk thread through the target tissue so that the portion
limited tumors of the lip, for small tumors of the floor of
containing the iridium wire lies in an appropriate posi-
the mouth or lateral border of the tongue for implanta-
tion. Depending on the size of the lesion to be treated,
tion by the guide gutter technique. Advantages of local
several silk sutures may be threaded through the target
anesthesia are that normal muscle tonus is maintained
tissue, ensuring at all times that the rules of the Paris
and, with a conscious patient check, fluoroscopy screen-
System are respected [6,18].
ing is easily carried out. Patients undergoing intraoral
brachytherapy procedures under general anesthesia
203.6 The Paris System must be intubated by the nasal route to allow adequate
room for the brachytherapist to work [1,7-9].
To respect the rules of the Paris System, several criteria
have to be observed.
20.4.2 Tumor evaluation
1. The linear activity of the sources must be uniform
for all the sources used and must be uniform
At first clinical assessment the brachytherapist can gen-
throughout the length of each source.
erally envisage the treatment method to be employed. In
2. Source must be implanted parallel and equidistant
rare instances, the predicted implant technique may
to each other.
need to be modified due to further information gained
3. The distance between the sources may vary from
from CAT scans or MRI scans. Guide gutter, hypodermic
implant to implant, but, once decided, must be
needle and silk suture techniques require immediate
constant for each individual case.
loading in the operating theater. The operator does this
4. The plane which passes through the midpoints of
using long-handled forceps manipulated from behind
each source at right-angles to the axis of the implant
lead screens. The plastic tube technique, on the other
is defined as the central plane and is used for
hand, is an afterloading system, which allows dosimetry
calculating the basal dose rates.
to be calculated prior to loading of the active wire.
5. The basal dose rate is the minimum dose rate
All of these factors have to be kept in mind by the
between lines. When three straight lines are
brachytherapist when planning the treatment. In this
implanted for a small skin carcinoma on the cheek,
respect, the advantage of the Paris System can be
there will be two basal dose rates. When three lines
exploited. With clinical assessment of the tumor volume
are implanted in triangular fashion for a small lip
to be encompassed, a knowledge of the Paris System of
carcinoma, there will be just one basal dose rate.
implantation allows for provisional estimation of the
Depending on the number of active wires and their
number of lines to be implanted, the separation between
configuration, most head and neck implants can be
the lines, and the lengths/activity of iridium to be used.
subdivided geometrically into triangles. The basal
Tumor evaluation therefore includes the method,
dose rate for each triangle is calculated. The results are
spacing, and length/activity of sources to be used in
added and divided by the number of triangles, giving
accordance with the size, shape, and position of the
an average basal dose rate for the entire implant.
tumor.
6. The reference dose rate is equal to 85% of the mean
The tumor and a margin of security are enveloped by
basal dose rate. This isodose envelops the target
the target volume. The target volume is therefore the vol-
volume and is the isodose on which the treatment is
ume of tissue to which we intend to deliver the pre-
prescribed.
scribed dose. The treated volume is that included by the
A good implant that follows the rules of the Paris 85% reference isodose curve, and should be at least equal
System will give precise coverage of the target volume, a to the target volume [5,10,20].
288 Brachytherapy in the treatment of head and neck cancer
20.43 Geometric configuration
When a series of loops or hairpins are implanted in pre-
cise geometric fashion, parallel and equidistant, the fol-
lowing volume applies:
V=L x WxT
where V = volume, I = length, W= width, and T= thick-
ness.
Length treated = 0.8 x half total active length.
Width treated = 1.55 x spacing.
Thickness treated = distance between outermost branches +
0.5 x spacing.
As can be deduced from the above, the active wires
must extend beyond the target volume at each end in
order to compensate for dose fall-off at the limits of the
implanted sources. The reference isodose dips sharply
between the implanted wires or tubes at the ends of the
implant due to the linear source strength of the iridium,
and therefore the active ends must extend beyond the
target volume to ensure the reference isodose curve
equates with the volume to be implanted. Naturally, this
results in a volume of tissue outside of the target volume
receiving an appreciable dose of radiation, but this in
turn is offset by the rapid fall-off in dose as one moves
away from each source.
With practice, the predictive dosimetry pertaining to
each proposed implant can be envisaged, as can the influ-
ence of varying the number and spacings between the
sources. Dosimetric planning consists of determining
the dimensions of the target volume and choosing the
method of implantation that best assures an optimal dose
distribution within the treated volume. For single-plane
implants, the three volume dimensions - length, width,
and thickness - need to be considered. Length depends
on the length of the iridium used, whereas width and
thickness depend on the spacing between the sources.
20.4*4 Radioactive sources
For the specification of radioactive sources, the
International Commission on Radiation Units and
Measurements (ICRU) has recommended the use of
kerma. The kerma rate defines the strength of a radioac-
tive source and is measured in air at a distance of 1 m
from the midpoint of the radioactive source. The unit of
measurement for kerma rate is cGy rr1 m2.
For LDR brachytherapy, radioactive sources must be
of small diameter to allow them to be introduced into
suitable carrier systems, such as plastic tubing. Sources
must be to some degree pliable to conform to implant
geometry and must not pose difficult radioprotective
problems. Iridium is an element which fulfills these
criteria.
The activity of the radioactive source may have a bear-
ing on ultimate outcome, and several studies have
demonstrated a link between dose rate and local control.
Such factors, therefore, impinge on the brachytherapist's
therapeutic decisions.
After-loading techniques such as the plastic tube
method allow the brachytherapist to take great care over
the geometry of the arrangement, thereby increasing the
possibility of obtaining a perfect implant with uniform
dose distribution [5].
20.5 TREATMENT
20.5.1 Lip
For lip cancers, the hypodermic needle or plastic tube
technique is generally used. Lip cancers are easy to assess
clinically and allow one to visualize the implant tech-
nique and geometric arrangement prior to the proce-
dure. Choice of technique depends on tumor volume,
site, and anatomy. Large tumors and those involving the
labial commissure are better treated by the plastic tube
technique. Implantation follows the axis of the lip and
preperforated templates may be introduced at both ends
to maintain the geometric arrangement.
General recommendations about dental protection
apply and an appropriate shielding device should be
worn by the patient during irradiation [1,4,5,7].
20.5.2 Nose
Cancer of the nasal vestibule may be implanted by plas-
tic tubes, guide gutters/hairpins, or hypodermic needles.
For large tumors infiltrating the columnella or nasal
cartilage, plastic tubes may be used in a horizontal
arrangement of several planes which transfix the nose
and conform to the Paris System. Preperforated tem-
plates are used to maintain parallelism.
Infiltration of the columnella may be treated by the
guide gutter/hairpin technique [6,17,21].
20.5.3 Skin, ear, eyelid
The silk suture or the plastic tube techniques may be
used for carcinomas of the skin, ear and eyelid. As the
iridium contained within the silk suture has a diameter
of 0.3 mm, this technique is suitable for areas such as the
eyelid where the vector for the radioactive source needs
to be of the smallest possible diameter.
Carcinomas of the pinna and the external auditory
canal can be treated by a mould system which conforms
to the irregular anatomy [5,8,18,22].

20*5.4 Mobile tongue
Carcinomas of the mobile tongue may be treated by
either the guide gutter/hairpin or plastic tube technique.
The guide gutter/hairpin method is suitable for small
tumors and carries the advantage of avoiding general
anesthesia. It is also a speedy procedure, which results in
good parallelism and excellent dose distribution.
The plastic tube technique is generally reserved for
bigger tumors, requires general anesthesia, and transfixes
the tongue/floor of mouth in its loops. As it is an after-
loading system, there is less exposure to the operator and
other personnel than that encountered by the guide gut-
ter/hairpin technique, which requires 'live' loading in the
operating theater.
Choice of implant system is dependent on tumor
site, volume, accessibility, and physician preference and
experience [5,7,12,23-34].
20.5.5 Base of tongue
Whereas in the past the guide gutter/hairpin method was
employed for base of tongue tumors, they are now
treated by the plastic tube technique. The plane of
implantation is generally sagittal (three loops) com-
pleted often by a frontal loop. In phase 1, the entire base
of the tongue is the target volume when treating exclu-
sively by brachytherapy. Phase 2 involves boosting the
tumor and tumor bed volume by leaving the relevant
sources in place for a longer duration of time, appropri-
ate to the dose prescribed [14,19,35-38].
20.5.6 Floor of mouth
Either the guide gutter/hairpin or the plastic tube tech-
nique can be used in the treatment of cancer of the floor of
the mouth. As the separation between the 'legs' of the hair-
pin is a constant 12 mm, this method is reserved for small
tumors. Care has to be taken that the active sources do not
lie too close to the gingiva or mandible if subsequent late
complications such as necrosis are to be avoided. As a gen-
eral rule in this institution, brachytherapy is contraindi-
cated if the implant demands that more than two
radioactive lines lie in close contact with the mandible.
The plastic tube technique can be equally applied in floor
of the mouth cancers, but as this method transfixes the
tongue and requires general anesthesia, the guide gut-
ter/hairpin method is preferred providing tumor dimen-
sions are appropriate [6,11 -13,27,39,40,42].
20.5.7 Buccal mucosa
Again, the plastic tube or guide gutter/hairpin method
can be applied. Choice of implant system is dictated by
tumor dimensions and position. The guide gutter/hair-
The Institut Gustave-Roussy results 289
pin method is appropriate for non-infiltrating small
tumors. The implantation of plastic tubes can be either
in the vertical oblique or horizontal planes, depending
on tumor orientation and infiltration [6,43].
20.5.8 Tonsil, tonsillar pillar, and soft
palate
Nowadays, treatment of these sites by brachytherapy is
confined almost exclusively to the plastic tube technique.
Implantation follows the principles described earlier. For
lesions confined to the tonsil, the loop may just involve
the ipsilateral tonsillar bed. For central lesions of the soft
palate, a looping system that passes from one side of the
neck to the other may be used. In some instances, the
loop may be fashioned in such a way that the tumor and
the full width of the soft palate are enveloped by the
loop, thereby confining the skin exit and entry points to
one side of the neck [8,15,16,35,44].
20.5.9 Nasopharynx
Brachytherapy for nasopharyngeal carcinoma is a plesio-
therapy technique. It is indicated in very few patients
more often as a salvage treatment, as the maximum
thickness of tissue that can be irradiated by this method
without significant complications is 10 mm.
Treatment involves taking an impression of the
nasopharyngeal cavity using a very fine dental algate,
and from the negative of this an individualized mould is
constructed. The impression of the nasopharynx will
reveal the position and dimensions of the tumor and
from this the brachytherapist can decide where the plas-
tic tubing source carriers should be positioned in the
mould. The sources are afterloaded into the plastic tubes,
which are appropriately positioned on the inside of the
hollow acrylic applicator [6].
Tumor evaluation is of critical importance when this
technique is to be considered. CAT scanning and/or MRI
scanning are imperative in the assessment of the tumor
dimensions.
20.6 THE INSTITUT GUSTAVE-ROUSSY
RESULTS
The following results are from experience at Institut
Gustave-Roussy in treating head and neck cancers with
LDR brachytherapy. In all cases, the rules of the Paris
System were respected. The figures given are broken
down into population base, age, sex, TNM status,
implantation method used, and clinical results.
Treatment protocol 'A refers to initial brachytherapy
to the primary lesion (if indicated) cervical node dis-
section + (if indicated) external-beam irradiation.
290 Brachytherapy in the treatment of head and neck cancer

Treatment protocol 'B' refers to initial external-beam complications: mucosal necrosis = 11%; bone
irradiation followed by brachytherapy as a boost proce- necrosis = 8%.
dure [6].

20.6.4 Floor of mouth [6,11-13]

20.6.1 Lip [6]
Population: 206 patients.
Population: 231 patients. Mean age: 53 years (range 31-85).
Mean age: 65 years (range 28-90). Males: 72%; females: 28%
Males: 85%; females: 15%. TNM distribution: TI = 42%; T2 = 50%; T3 = 6%;
TNM distribution: TI = 82%; T2 = 13%; T3 = 3%; NO = 70%.
NO = 80%. Treatment protocol: A = 87%; B = 13%.
Treatment protocol: A = 97%; B = 3%. Method for protocol A: plastic tube technique A = 21%;
Method: plastic tube technique = 40%; hypodermic guide gutters/hairpin = 79%.
needles = 56%; silk threads = 14%. Mean dose delivered: 65 Gy.
Mean dose delivered = 76 Gy. Method for protocol B: plastic tube technique A = 19%;
Clinical results: guide gutters/hairpin = 81%.
overall 5-year disease-free survival = 66% Mean dose delivered: 27 Gy.
local control rate at 5 years = 95%. Clinical results:
Complications: mucosal necrosis = 13%. overall 5-year disease-free survival: A = 74%;
B = 30%
20.6.2 Nose [6] local control rate at 5 years: A = 89%; B = 59%.
complications: mucosal necrosis = 11%; bone
Population: 36 patients. necrosis = 21%.
Mean age: 66 years (range 44-82).
Males: 83%; females: 17%.
TNM distribution: TI = 45%; T2 = 45%; T3 = 10%; 20.6.5 Oropharynx [6,19,37]
NO = 93%.
Treatment protocol: A = 93%; B = 7%. Population: 312 patients.
Method: plastic tube technique = 20%; hypodermic Mean age: 58 years (range 38-86).
needles = 54%; guide gutters/hairpins = 40%; silk Males: 85%; females: 15%.
threads = 6%. TNM distribution: TI = 25%; T2 = 40%; T3 = 35%;
Mean dose delivered: 72 Gy. NO = 50%.
Clinical results: Treatment protocol: A = 11%; B = 89%.
overall 5-year disease-free survival = 68% Method: plastic tube technique = 26%; guide gutters/
local control rate at 5 years = 86%. hairpin = 74%.
Complications: grade 1 and 2 = 33%; grade 3 = 18%. Mean dose: 75 Gy (including external-beam radiation)
Clinical results: overall 5-year disease-free survival: base
of tongue = 26%; tonsil = 37%; anterior oropharynx
20.6.3 Mobile tongue [5,6,11] = 40%; soft palate = 37%.
Local control rate at 5 years: base of tongue = 68%;
Population: 269 patients. tonsil = 79%; anterior oropharynx = 69%; soft
Mean age: 55 years (range 25-87). palate = 93%.
Males: 77%; females: 23%. Complications: grade 1 and 2 = 27%; grade 3 = 7%.
TNM distribution: TI = 31%; T2 = 55%; T3 = 14%;
NO = 81%.
Treatment protocol: A = 72%; B = 28%. 20.6.6 Nasopharynx [6]
Method for protocol A: plastic tube technique = 21%;
guide gutters/hairpin = 79%. Population: 47 patients.
Mean dose delivered: 71 Gy. Mean age: 42 years (range 26-57).
Method for protocol B: plastic tube technique = 51%; Males: 70%; females: 30%.
guide gutters/hairpin = 49%. TNM distribution: 33 patients treated as 'boost'
Mean dose delivered: 27 Gy. following external irradiation (45 Gy); 14 patients
Clinical results: treated for recurrence in previously irradiated area.
overall 5-year disease-free survival: A = 62%; Method: moulded applicator.
B = 30% Mean dose for 'boost' treatment: 30 Gy.
local control rate at 5 years: A = 87%; B = 49% Mean dose for salvage treatment: 60 Gy.
 Future directions 291

Clinical results: 20.7 LITERATURE REVIEW

overall 5-year disease-free survival for 'boost'
treatment = 42%
overall 5-year disease-free survival for salvage
treatment = 17%
local control rate at 5 years for 'boost' treatment =
74%
local control rate at 5 years for salvage treatment =
50%.
20.6.7 Pediatric head and neck
malignancies [6]
Population: 39 patients.
Mean age: 5 years (range 3 months-15 years).
Main tumor sites: nasolabial sulcus = 31%; oral
cavity = 21%; neck = 15%; ear = 10%.
Percentage of cases with rhabdomyosarcoma: 70%.
TNM distribution: TI - 61%; T2 = 36%; TX = 3%;
NO = 56%; NI = 41%; NX = 3%.
Treatment protocol: for children, the approach was
quite different from that with adults and included
chemotherapy in most cases; external radiotherapy
was given in 31% of cases.
Brachytherapy procedure: brachytherapy was indicated
in two different situations: first-line brachytherapy =
64%; salvage brachytherapy = 36%.
Plastic tubes hypodermic needles and/or guide
gutters: 95%
Guide gutters hypodermic needles: 5%
Brachytherapy performed per-operatively: 31%.
Mean dose: first-line brachytherapy = 68 Gy; salvage
brachytherapy = 56 Gy.
Results:
5-year disease-free survival: first-line brachytherapy
= 76%; salvage brachytherapy = 50%
local control rate: first-line brachytherapy = 84%;
salvage brachytherapy = 64%.
severe complications: first-line brachytherapy = 24%;
salvage brachytherapy = 21%.
A literature review and comparison of results are pre-
sented in classified tables (Tables 20.1, 20.2, and 20.3)
according to the different tumor sites. In these tables, the
following abbreviations are used: Results: O = origin, TS
= tumor site, NP = number of patients, TP = treatment
protocol, CND = cervical node dissection, EB = external-
beam irradiation, BT = brachytherapy, PS = Paris System
LDR, LC = local control, CP = complications, STN =
soft-tissue necrosis, ORN = osteoradionecrosis, SV =
survival, OSV = overall survival, SSV: site-specific sur-
vival, DPS: disease-free survival; tumor sites: BM = buc-
cal mucosa, BT = base of tongue, FM = floor of mouth,
GPS = glosso palatine sulcus, L = lip, MT = mobile
tongue, NP = nasopharynx, NV = nasal vestibule, OC =
oral cavity, OP = oropharynx, P = pinna, SP = soft palate,
TO = tonsil, ToPi = tonsil + pillars.
20.8 FUTURE DIRECTIONS
While the techniques of implantation described for LDR
brachytherapy for head and neck carcinomas are well
established, efforts have been made to further refine
them. In an attempt to diminish the exposure to staff,
automatic afterloading devices for LDR isotopes are now
available. However, various technical problems have
hampered their universal introduction and manual
afterloading continues to be widely practiced. In partic-
ular, with a plastic tube technique that involves a loop,
the source needs to be able to negotiate a curved path.
Such technical problems require further investigation
and refinement.
Similarly, dosimetry pertaining to the Paris System is
also well established and its precision is reflected in the
high rates of local control and low rates of complica-
tions. However, with the advent of three-dimensional
planning, there exists an opportunity to better define the
treatment volume. Computerized dosimetric calculation
with exact definition of the target volume may afford an
opportunity to ameliorate the various source arrange-
ment possibilities and thus arrive at an optimized dose
distribution within a given volume. The generation of

Table 20.1 Nasal vestibule, pinna

Levendag, P.C. and Pomp, J. 21] NV 63 T1 NO 36 EB + BT OS 65 T1 97

T2 NO 24 BT DPS 80 T279
MazeronJ.J. [17] Nose 1676 BT PS 93.6 I, II,
Iridium III 6
Debois,J.M.[22] P 140 BT Cesium 95
MazeronJ.J. [18] P 70 BT PS 94 20
292 Brachytherapy in the treatment of head and neck cancer

Table 20.2 Oral cavity

MazeronJ.J. [17-19] FM 117 T1 47 BTCND PS T1 NO 94 93.5

T270 +EB/N T2 NO 61 74.5
T2N1-N228 65
Pernot.M. [16] FM 207 T185 T2 99 BT102 PS SSV T197T272 117,1112
T316T44Tx3 EB + BT105 Iridium T1 88 T2 47 T351 III 6,
NO 172 T336 IV 0.5
Volterrani, F. [41] FM 175 T147T287 BT92 PS DFS42 88 I, II 35
T319 T4 22 EB + BT 8 24 36 III 5
Benk,V. [24] MT 110 II BTCND85 PS DFS42 88 I, II 35
EB + BT25 24 36 III 5
Hareyama, M. [26] MT 110 II BT99 T1 94 T2 91 STN20
EB + BT25 T371 ORN13
MazeronJ.J. MT 166 T1 NO 70 PS 52 87
[17-19] T2 NO 83 44 92
T1-T2 N1-N213 8 69
Pernot, M. [29] MT 147 T2 NO BTCND70 PS SS 62.2 89.8
EB + BT 77 34.7 50.6
Pernot.M. [16] FM 207 T185 T2 99 BT102 PS SSV T1 97 T2 72 117,11
T316T44TX3 EB + BT105 Iridium T1 88 T2 47 T351 12,1116,
NO 172 T336 IV 0.5
Shibuya, H. [30] MT 370 I 90 Ma 196 BTCND 184 Ma 78 Spf 85 1138
lib 84 EB + BT lib 72 Exoph 79 1114
Infill 45
Wang, C.C. [20] MT 143 T1NO EB + BT lOOorthoKv 50
T2 NO 100elec.eB 86
BT 54
Wendt, C.T. [32] MT 103 T1 NO 18 BT18 66
T2 NO 85 EB + BT 77 92
EB8 38
Dearnaley, D.P. [25] MT 149 BT + Iridium-cesium T1 T2 90
FM ENI Radium
Thomas L [31] MT 40 T1 NO BT 52 65 T>20 mm
FM T2 NO PS
Volterrani, F. [41] OC 406 T1 132.T2245, BT Radium 41.4 T1-279 ORN22
T329 EB + BT3 T354
BeitlerJ.J. [47] TO 29 T1/T2 BT+EB Iridium 125 - 92
Matsuura K. [33] MT 173 75 Stage I EB + BT 66 Iridium Stage 1 93
98 Stage 1 1 BTalone107 hairpins (5 years)
Stage II 78
(5 years)
Fujita, M. [34] MT 207 93 T1 EB + BT 82 Iridium T193 11.5
114T2 BTalone125 hairpins T277
Rudoltz, M.S. [42] OC 55 T1 16 EB + BT(HDR) 79 (2 years)
T226 87forT1/2
T38 47forT3/4
T45

dose-volume histograms will, in time, allow correlations Other areas of worthwhile future investigation include
to clinical outcome, which should theoretically increase biological studies involving proliferation rates, oncogene
rates of cure and local control while simultaneously and tumor suppressor gene expression, which may, in
maintaining or diminishing current complication rates. time, better define the population base likely to benefit

Table 20.3 Oropharynx
Pernot, M. [10] VT 361 T190.T2141 BT 18
T3119.T42, EB + BT 343
Tx91,
NO 230
Esche, B.A. [15] SP 43 EB + BT
Lusinchi.A. [37] BT 108 T1 18T2 39 EB + BT
T3 51
Puthawala,A. [38] TO 80 111-IV81% EB + BT
from exclusive brachytherapy treatment. In our institu-
tion, the place of ultra-LDR brachytherapy is currently
under investigation for patients suffering recurrence of
previously irradiated head and neck cancers.
20.9 CONCLUSION
The aim of this chapter was not to be exhaustive but to
try to show the efficacy of brachytherapy based on LDR
technique.
Taking into account the Institut Gustave-Roussy
experience and most of the results collected from Group
European Curietherapy (GEC) multicentric studies, two
categories of patients can be identified: those treated
with brachytherapy alone (60% of cases), in which the
results are: disease-free survival (DPS) 65-75%, local
control 80-90%, complications 10%; and those treated
with brachytherapy boost: DPS 35-45%, local control
60-70%, complications 20%.
To conclude, LDR brachytherapy plays a major role in
the management of head and neck cancer: the local
control rate is high, the complication rate is low.
This treatment is well tolerated by the patient and can
be delivered in a short time. However, successful
brachytherapy depends much upon careful assessment
of the patient, close collaborative efforts, and finally on
the entire brachytherapy experience, which itself is
based on precise planning and technique respecting the
rules of the system used to implant and calculate the
dose distribution, thus being able to report the results
and compare them with those of other treatment
approaches.
It is likely that in the future, brachytherapy may be
combined with chemotherapy in certain clinical situa-
tions or as an intraoperative endeavor [45]. In addition,
it will continue to hold its proven role in the treatment
of recurrent carcinoma in previously irradiated patients
References 293
PS Specific SV 80 121,112,
Iridium 63 1112,
IV 0.2
PS 37 92
GGPT
PS 26 T1 85, T2 50
GGPT T369
Iridium 72 84 6
as serial reports confirm its usefulness in this regard
[46].
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High dose-rate interstitial and endocavitary
brachytherapy in cancer of the head and neck
PETER LEVENDAG, CONNIE DE PAN, DICK SIPKEMA, ANDRIESVISSER, INGER-KARINE KOLKMAN,
AND PETERJANSEN
21.1 INTRODUCTION
The development of manual afterloading techniques for
radioactive sources and the introduction of artificial
radionuclides have received considerable attention over
the last few years and have contributed significantly to
the renaissance of brachytherapy. The total elimination
of radiation exposure to the nursing, medical, and
physics staff as well as to patients' relatives by remote
controlled afterloading devices was a logical extension of
the manual afterloading concept. In 1961, the first high
dose-rate (HDR) remote-controlled afterloader was
introduced in the Memorial Sloan Kettering Cancer
Center group, using high-activity cobalt-60 pellets.
When the manufacture of small, cylindrical (<1 mm),
high-activity (100-400 GBq) iridium-192 sources
became feasible, the so-called 'stepping-source tech-
nique' was introduced. In this way, 'isodose-volumes' can
be created very flexibly by combining careful placement
of the afterloading catheters or applicators and adjust-
ment of the dwell positions and dwell times of the
iridium-192 point sources (i.e., optimization).
In the University Hospital Rotterdam/Daniel den
Hoed Cancer Center (UHR/DDHCC), the first HDR
afterloader (microSelectron-HDR) using such a high-
activity iridium-192 point source was introduced for
21
interstitial and/or endocavitary brachytherapy in cancer
of the head and neck in 1990. Early on, it was recognized,
however, that there might be a radiobiological disadvan-
tage in applying large HDR (1-3 Gy min"1) single frac-
tions, even if the catheters or applicators are carefully
positioned and good immobility is achieved. Realizing
this, one can, of course, try to fractionate the HDR
brachytherapy to some extent.
Ultimately, it was proposed to try to combine the
radiobiological advantage of low dose rate (LDR), as
opposed to HDR, with the practical advantages of com-
puterized stepping-source HDR afterloading techniques
in 'pulsed dose-rate' (PDR) brachytherapy, i.e., using
multiple small fractions (pulses) per day with a fixed
(small) interval in between the pulses. This necessitated
the availability of a second afterloader; this
microSelectron-PDR was obtained in 1992. In principle,
the design of the PDR afterloading machine is quite sim-
ilar to that of the microSelectron-HDR, except for the
fact that the iridium-192 source for the PDR machine is
about ten times weaker (37 GBq), enabling one to deliver
multiple (e.g., every 0.5-3 h), small (e.g., 0.5-3 Gy)
fractions to a composite implant. However, confusion
emerged as to what fraction size at what interval should
be considered optimal. We took the opportunity to
design and test two types of fractionation schedules, one
to be used in conjunction with the microSelectron-HDR

('fractionated HDR schedule;' i.e., a regimen with a rela-
tively low degree of fractionation), and one with the
microSelectron-PDR ('PDR schedule'; i.e., a regimen
with a relatively high degree of fractionation); for details,
see section 21.2.
These two fractionation schedules have been consis-
tently clinically tested with regard to tumor control and
side-effects for some years (and, in fact, will remain
under investigation for a number of years to come). This
chapter summarizes the rationale for using either the
microSelectron-HDR or microSelectron-PDR in our
department. Some aspects regarding the brachytherapy
techniques per se and the clinical brachytherapy proto-
cols of the Rotterdam Head and Neck Cooperative
Group are illustrated, and the preliminary findings
obtained with fractionated HDR and PDR brachy-
therapy in cancer of the base of tongue, mobile tongue
cancer, nasal vestibule (mould and interstitial
brachytherapy), tonsillar fossa and soft palate (intersti-
tial brachytherapy), and cancer of the nasopharynx
(endocavitary brachytherapy) are reported. Finally,
future possibilities regarding the implementation of
brachytherapy in the head and neck using an integrated
brachytherapy unit (IBU) are discussed.
21.2 BRACHYTHERAPY SCHEDULES IN
ROTTERDAM
21.2.1 Rationale for choice of type of
remote-controlled afterloaders
As stated in the previous section, in the DDHCC we have
consistently used for all brachytherapy cases in the head
and neck either the microSelectron-HDR or the
microSelectron-PDR, i.e., we have departed from LDR
totally since August 1990.
For both types of remote-controlled afterloaders, dif-
ferent fractionation schedules were designed: either
using a fraction size of 3 Gy, twice daily, with an interval
of 6 h (fractionated HDR; daytime regimen; HDR after-
loader), or 1, 1.5 or 2 Gy per fraction, four or eight frac-
tions per day, 3-h interval (PDR; daytime regimen in the
case of four fractions or 24-h per day schedule in the case
of eight fractions; PDR afterloader). For the calculation
of the fractionated HDR and PDR schedules to be equiv-
alent to LDR in tumor effect, the linear-quadratic (LQ)
model was used in an incomplete repair formulation (for
details, see section 21.2.2). The advantages of fraction-
ated HDR and/or PDR brachytherapy over LDR are
summarized in Table 21.1.
The reasons for the implementation of two afterload-
ing machines in conjunction with the different types of
fractionation schedules are summarized in Table 21.2.
The choice of when to use which afterloading machine is
somewhat arbitrary; however, given the potentially sig-
Brachytherapy schedules in Rotterdam 297
Table 21.1 Advantages of fractionated HDR or PDR
brachytherapy schedules
1. Afterloading-elimination of radiation hazard
2. High-activity point source (37-400 GBq) - no source
preparation
3. Stepping source-dose optimization (NPS/PLATO)
4. Disconnection of patients during interval between
fractions:
easy doctor/nursing/family/care
increased flexibility for patients (e.g., outpatient
brachytherapy)
potential for application of other modalities during
interval (e.g., interstitial hyperthemia, hypoxiccell
cytotoxins)
5. Continuation/automation brachytherapy over weekend
(PDR)
nificant differences in biological outcome, the choice was
made at least in a structured (protocolized) fashion. In
summary: when the microSelectron-PDR is available,
our preference will be the PDR schedule ('small fraction
size' and potential for continuation of the irradiation
over the weekend); if the PDR afterloader is connected to
another patient or if it is felt that clinically and/or tech-
nically the patient (i.e., implant) is more suitable for
fractionated HDR, we opt for the microSelectron-HDR
(for details, see section 21.3).
Of course, not every department can implement
(afford) two types of afterloading machines, in particu-
lar if the brachytherapy caseload is relatively small (e.g.
<100 cases/year). As, logistically and biologically speak-
ing, the fractionated HDR and PDR schedules are quite
different types of brachytherapy treatments, we hope
that at some point in the near future we will be able to
arrive at some kind of conclusion which can contribute
to making the 'right' departmental choice as to which
fractionation schedule (and type of afterloader) is to be
preferred (see also section 21.2.2).
21.2.2 Radiobiological considerations and
dose fractionation for fractionated HDR and
PDR schedules
The incentive to initiate fractionated HDR and/or PDR
brachytherapy, and to test its feasibility as a replacement
for 'classical' LDR brachytherapy, is the wish to combine
the (mainly radiobiological) advantages of LDR
brachytherapy with the (mainly physical and socio-
economic) advantages of modern HDR afterloaders, as
summarized in the previous section. The conditions
under which PDR brachytherapy may simulate LDR
brachytherapy are being investigated in experimental
models, both in vitro and in vivo in different laboratories
[1]. This section deals with the choice of treatment
schedules for fractionated HDR (with two fractions per
298 HDR interstitial and endocavitary brachytherapy in cancer of head and neck

Table 21.2 Considerations that might favor having two afterloaders (e.g., microSelectron -HDR and -PDR) in conjunction with two
different types of fractionation schedules - two fractions per day (daytime regimen, fractionated HDR), or eight fractions per day (24-h
regimen, PDR) - in a single radiation therapy department*

Some tumor sites benefit typically from an HDR single-fraction treatment (e.g., palliation in carcinoma of
bronchus, esophagus)
With integrated brachytherapy unit, HDR afterloader essential
From clinical experience, some implants (i.e., patients) are not suitable for a 24-h PDR schedule (implant
technical and/or medical reasons, e.g., implants brain, nasal vestibule)
Medical/physics support off-hours regarding safety precautions favor daytime HDR (depending also on national
regulations)
Brachytherapy on outpatient basis favors daytime HDR
PDR If LDR is radiobiologically more permissive regarding late side-effects, strong fractionation can be of
importance (in fact, the use of small fractions, e.g., 1-3 Gy, with short intervals, e.g., 1-3 h has been
proposed (PDR)
For some (volume) implants, when using small fractions, transit times of high-activity point source (e.g.,
100-400 GBq) are short; therefore, in the case of PDR (small fraction size), weaker point source (e.g.,
37 GBq) needed
Surgical demands might force brachytherapy procedure into end of week; because HDR afterloader can only be
used at daytime during week days, fractionated HDR brachytherapy as opposed to PDR sometimes cannot
start until after the weekend
HDR and PDR Large and variable brachytherapy caseload
* For details, see text.

day) and for PDR brachytherapy (with more than two Dale [6] and Thames, et al. [7]. Treatment schedules
fractions per day) as alternatives to 'classical' LDR treat- with varying pulse intervals or combinations of different
ments. treatment schedules can also be evaluated. In order to
compare treatment schedules for clinical practice, the
RADIOBIOLOGICAL MODEL results of model calculations are usually expressed in the
quantity:
The model which is used to calculate fractionated HDR
and PDR schedules is the linear-quadratic model in an InS
BED = (21.2)
incomplete-repair formulation as given by Brenner and
Hall [2]. As stressed by these authors, the model is essen-
This quantity (with the unit dose) was designated by
tially based on the formalism described by Lea and
Barendsen [4] as the ETD (extrapolated target [or toler-
Catcheside (1942), published more than 50 years ago [3].
ance] dose) and by Fowler [8] as the BED (biologically
For a full description of the model, the reader is referred
effective dose). We follow the latter nomenclature here.
to the paper of Brenner and Hall; only the main features
Apart from comparing treatment schedules in terms of
are summarized here. The expression used for the sur-
survival level, the effect of a treatment can also be
vival of clonogenic cells is the familiar linear-quadratic
expressed in terms of tumor control probability (TCP)
one [4,5]. In order to take into account incomplete
or, if normal tissue effects are concerned, in normal tis-
repair of sublethal damage, either during LDR irradia-
sue complication probability (NTCP). These quantities
tion or in the (limited) time between HDR/PDR frac-
have the advantage of being directly related to data
tions and during the (finite) duration of each radiation
obtained from clinical studies, i.e., local control proba-
fraction, the quadratic term in the expression for the sur-
bility and complication probability. The TCP/NTCP
viving fraction S(D) after a dose D is assumed to be
model is based on the assumption that the probability of
reduced by a factor G:
local control follows Poisson statistics, i.e., is an expo-
nential function of the mean number of surviving clono-
genic cells (Ns) after treatment:
Brenner and Hall have given the expressions for two
specific cases of interest, that is, LDR brachytherapy with
a continuous irradiation and PDR brachytherapy with a
series of equal fractions at equal intervals. The expres- where N0 is the average initial number of clonogenic
sion for LDR irradiation is identical to the one given by cells. Regarding the probability of normal tissue compli-
 Brachytherapy schedules in Rotterdam 299

cations, the analogous quantity could be the number of
'functional subunits' without which the organ would
lose its function.
In order to derive clinical HDR or PDR brachytherapy
schedules, we have applied the following procedure.
Because more clinical data are available for external
radiotherapy, it seems adequate to choose an external
radiotherapy schedule as a reference schedule, giving one
fraction of 2 Gy per day and five fractions per week. As a
practical example, we will study a case in which a
brachytherapy boost has to be given which should be
equivalent in tumor effect to an external radiotherapy
schedule of 11 fractions of 2 Gy, i.e., 22 Gy physical dose.
As we are dealing with the replacement of LDR
brachytherapy schedules, subsequently LDR schedules
equivalent to this reference external radiotherapy sched-
ule were calculated. It should be stressed that we con-
sider two treatment schedules 'equivalent' if both have
the same BED value for a specific end-point (tumor
effect or normal-tissue effect). That means that we have
not applied the additional condition that the total phys-
ical dose and/or the overall time of a PDR treatment
must be identical to the values for the corresponding
LDR treatment regime. This additional condition was
applied in proposals for PDR schedules by Brenner and
Hall [2] and by Fowler [8]; however, we see no signifi-
cant reason why (slight) variations in physical dose and
overall time between PDR and LDR brachytherapy
schedules should not be allowed for. A longer overall
treatment time might lead to an increased risk of tumor
cell repopulation, but for the rather short treatment
schedules in brachytherapy (mostly not longer than 1
week), the probability of increased tumor repopulation
seems limited.
The BED of an LDR schedule is determined using:
The model parameters used are given in Table 21.3.
For the LDR schedules a constant dose rate of
50 cGy rr1 was taken. In our case, an LDR schedule of
46.3 h application time (physical dose 23.2 Gy) should
have a tumor effect equal to that of the reference exter-
nal radiotherapy schedule of 22 Gy. To determine an
equivalent HDR or PDR schedule, first a fraction size
and a fixed interfraction interval are chosen and the
number of fractions can then be calculated, yielding a
BED closest to the BED of the reference LDR schedule.
The results are shown in Table 21.4.
It can be observed that this approach results in differ-
ent physical doses, i.e., with the LDR schedule a physical
dose of 23.2 Gy is given, and with the fractionated HDR
schedule a lower dose of 21 Gy, while for the PDR sched-
ule a somewhat higher dose of 24 Gy is applied.
EFFECTS OF DIFFERENT REPAIR HALF-TIMES AND
OF DIFFERENT cc/p VALUES
The values of the LQ parameters and the repair time
constant used in the calculations are given in Table 21.3.
Unfortunately, limited data are available for human
tumors and normal tissues and, furthermore, a large
variation can be expected for different tumors. Brenner
and Hall [2] presented the following values (arithmetic
mean SD) for a set of 36 human cell lines in vitro:
a = 0.36 0.21 Gy-1, oc/p = 7.3 5.4 Gy, repair half-time
(TO = 0.54 0.91 h. The human data regarding recovery
capacity ( a / b ) and repair kinetics (TO have been

Table 21.3 Values used for the model parameters

LDR dose rate 50 cGy h-1

o/P Early effect/tumor 10 Gy
late effects 3Gy
a 0.3 G>r1
Half-time of repair of Early effect/tumor 1.0 h
sublethal damage late effects 3.0 h

Table 21.4 Fractionation schedules for fractionated HDR treatments (i.e., two HDR fractions per day with a minimum interval of 6 h)
and PDR treatments (continuous treatment with a constant time interval of 3 h between pulses)*

11x2 = 22 Gy 26.4 46.3 h = 23.2 Gy 7x3.0 = 21.0Gy 27.1 24x1.0 = 24.0 Gy 27.0

* The schedules are intended to be equivalent in terms of tumor effects, applying the parameters as listed in Table 21.3.
300 HDR interstitial and endocavitary brachytherapy in cancer of head and neck

reviewed by Thames et al. [7]. The results show that the
differences observed for cc/P between early and late
effects in animals also hold for humans; for early reac-
tions cc/P is in the of range 7-11 Gy, and for late reac-
tions a/P is in the range of 2-4 Gy. Data on repair kinet-
ics are scarce, but the available data indicate that repair
in human normal tissues might be slower than in
rodents. For early skin reactions the repair half-time is
about 1 h, whereas for late telangiectasia it may be as
long as 3 h. Pop et al. (9) have pointed out that, from the
available clinical experience with head and neck cancer
treatments with LDR brachytherapy on the one hand
and with external radiotherapy on the other hand, con-
straints can be derived for the possible values of the
repair half-times. The assumption of a long repair half-
time (i.e. > 3 h) in combination with a high dose of LDR
brachytherapy would lead to extremely high BED values
which are rather improbable. Due to the uncertainties,
the choice of a single set of parameters is necessarily
rather arbitrary. Therefore, we have chosen not only to
calculate equivalent schedules for a chosen 'plausible' set
of parameter values but also to evaluate the effects of
varying the parameter values over a wide range.
For this purpose, an approach proposed by de Boer
[10] has been followed. By calculating equivalent HDR
or PDR schedules for a large range of values, graphical
'maps' of the PDR/LDR dose ratio can be constructed as
a function of the oc/P ratio (Figure 21.1, horizontal axis,
ranging from 1 to 15 Gy) and the repair half-time
(Figure 21.1, vertical axis, ranging from 0.1 to 5 h). For
each 'map', a specific LDR reference schedule is used, e.g.,
23.2 Gy given in 46.3 h, with a dose rate of 50 cGy h"1.
Next, a specific equivalent schedule (fractionated HDR
or PDR) is chosen by specifying the fraction dose and the
interval between fractions. For each combination of oc/P
and TI values, the number of fractions is calculated, giv-
ing an effect equal to that of the LDR schedule (i.e., equal
BED values). The curves in Figure 21.1 represent the
ratio of the PDR and LDR doses, expressed in percent-
ages.
These 'maps' of the PDR/LDR dose ratio can be uti-
lized to estimate the effect of different values for oc/P and
T^: if the PDR/LDR dose ratio is increasing going from
tumor effects (a/p = 10) to late effects (cc/P = 3), this
means that the chosen schedule can be considered 'safe,'
because the late effects in normal tissues appear not to be
dose limiting. If, however, the PDR/LDR dose ratio is
decreasing going from tumor effects to late effects, one

Figure 21.1 Ratio of total PDR (or fractionated HDR) dose to LDR dose as a function of oc/P (Gy) and the half-time for repair of
sublethal damage (7), in h)for different PDR/HDR schedules. The reference LDR schedule is the same for all three panels: 23.2 Gy in
46.3 h (i.e., a dose rate of 50 cGy h~1); this reference LDR schedule is a boost schedule, intended to have tumor effect equal to an
external-beam radiation therapy (ERT) schedule of 22 Gy in 11 fractions of 2 Gy. Over the area of the 'map', the PDR or fractionated
HDR dose has been calculated which would give an effect equal to that of the reference LDR schedule. Upper panel: PDR schedule
with a time interval of 3 h between fractions and a fraction dose of 1.0 Gy. Central panel: 'daytime PDR' schedule applying four
fractions of 2 Gy per day, with a time interval of 3 h between fractions. Lower panel: fractionated HDR schedule with two fractions of
3.0 Gy per day, with a time interval of 6 h between the two fractions on the same day. The hatched regions indicate parameter ranges
considered plausible for early effects (a/P of about 10 Gy) and late effects (o/P of about 3 Gy), with repair half-times varying,
respectively, from 1 h to 3 h and from 1.5 h to 3 h.
 Brachytherapy schedules in Rotterdam 301

should be cautious because late-responding normal tis- time for the ratio (ERT + BT)/ERT, i.e., a combined
sues may be overdosed, i.e., the probability of late effects treatment schedule in comparison to external radiother-
in normal tissues may increase compared to the refer- apy alone.
ence LDR treatment schedule. The reference external radiotherapy schedule is 35
In Figure 21.1, PDR/LDR dose ratio maps are shown fractions of 2 Gy given in 7 weeks. In the combined
(see legend to Figure 21.1). Plausible ranges for the val- schedule an external radiotherapy series of 23 fractions
ues of a/ (3 and TI are indicated by a cross mark and of 2 Gy is followed by a brachytherapy boost (see also the
hatched rectangular areas, respectively: for early effects legend to Figure 21.2). It can indeed be observed that the
(including tumor effects), a/(3 is taken to be 10 Gy and differences between the two brachytherapy regimes tend
TI is taken to be 1 h, as indicated by the cross mark. For to be smaller in the combined treatments, i.e., the dose
late effects, we assume that a/b will be about 3 Gy and ratio for late effects for both HDR and PDR schedules is
Ti slightly longer or equal to the value for early effects, less than 5% lower than the dose ratio for early effects (at
i.e., a range of 1.5-3 h. From Figure 21.1, one can con- the cross mark).
clude that when choosing a PDR schedule with equal
tumor effect, the PDR/LDR dose ratio is somewhat
higher than 100%, depending on the value of Tj cho-
sen. In other words, depending on the assumptions for
the values for cc/P and T{, the total dose of the PDR
schedule is somewhat larger than that of the reference
LDR schedule for an equal tumor effect. With regard to
late effects in normal tissues, the PDR/LDR dose ratio
for these PDR schedules varies from 110% to 120%.
This seems satisfactory: the PDR/LDR dose ratio for
late effects is higher than for tumor effects and there-
fore with this type of PDR schedules late effects in
normal tissues appear not to be dose limiting. In the
central and lower panels of Figure 21.1, similar dose
ratio maps are shown for schedules with fewer frac-
tions, i.e., 'daytime PDR' schedules (four fractions of
2 Gy during daytime) and fractionated HDR schedules
(two fractions of 3 Gy per day), respectively. It can be
concluded that with less fractionation the dose ratio for
late effects becomes closer to the dose ratios for early
(tumor) effects, but even for the HDR schedule, there
are no indications for overdosing late-responding
normal tissues.
A general trend in these maps is that, provided that
the repair half-time for late effects is equal to or longer
than that for tumor effects, the dose ratio for late effects
is equal or greater than the dose ratio for early effects.
The (PDR/LDR) dose ratios for late effects will decrease
if the repair half-time for late effects is smaller than for
tumor effects. However, current radiobiological data for
repair kinetics point to longer repair times for late Figure 21.2 Ratio of total dose for a combined ERT + BT
normal-tissue effects [11-13]. schedule and a treatment schedule using ERT alone, as a
function of o/p (Gy) and the half-time for repair of sublethal
damage (7i, in h)for two different BT schedules, i.e. fractionated
OVERALL EFFECT OF EXTERNAL RADIOTHERAPY
HDR and PDR. The reference ERT schedule is 35 fractions of 2 Gy
(ERT) AND A BRACHYTHERAPY (BT) BOOST
in 7 weeks. The ERT series in the combined treatment is 23
It should also be kept in mind that in clinical practice the fractions of 2 Gy. For each combination of a/$ and 7|, the
majority of patients receiving some form of brachyther- number of fractions of the BT schedule (fractionated HDR or
apy are treated with a combination of external radio- PDR) is calculated which would have a BED equal to that of the
therapy and brachytherapy. This will dilute the potential reference ERT schedule. Upper panel: a PDR schedule with a
differences between fractionated HDR, PDR, and LDR, time interval of 3 h between fractions and a fraction dose of
in particular in terms of risks of normal-tissue compli- 1.0 Gy. Lower panel: fractionated HDR treatment schedule
cations. This effect has been investigated in Figure 21.2, applying two fractions of 3 Gy per day, with a time interval of
where again dose ratio maps have been calculated, this 6 h between fractions.
302 HDR interstitial and endocavitary brachytherapy in cancer of head and neck

21.2.3 Dose fractionation: table of
reference, fractionated HDR and PDR
As already mentioned, for each fractionation schedule
(fractionated HDR or PDR) the fraction size, interfrac-
tion interval, and total number of fractions are fixed. We
had chosen at the time to tailor the total dose of
brachytherapy according to T-stage (Tl/2 versus T3/4). In
case of re-irradiation, we have deliberately coned down
the dose up-front, because it was felt from previous expe-
rience that we are only alleviating symptoms, i.e., we are
aiming for (temporary) local-regional control as only
rarely can patients be cured [17]. For cancer of the nasal
vestibule, due to the severe acute (skin) reactions caused
by brachytherapy (with tumors located in the skin) with
otherwise excellent local control rates, we also lowered the
total dose somewhat. Table 21.5 summarizes the fraction-
ation regimens in use as of January 1995 until 2000. As of
2001 we have again slightly modified our brachytherapy
schedules. This was done after rigorous evaluation of the
clinical results, including side effects.
For clinicians interested in our currently used table of
reference, the reader is invited to contact the first author
of this chapter (Levendag@Rtdh.azr.nl).
21.3 BRACHYTHERAPY TECHNIQUES AND
PRELIMINARY CLINICAL RESULTS
213.1 Introduction: clinical
brachytherapy
For afterloading fractionated HDR or PDR brachyther-
apy, either commercially available standard afterloading
catheters (outer diameter 2 mm), in the case of intersti-
tial implants, or a mould technique, for example in the
case of cancer in the nasal vestibule and nasopharynx,
are used. In general, brachytherapy techniques are not
(very) dissimilar to those used for LDR (see also Chapter
20). The following paragraphs briefly summarize some
relevant aspects of our techniques, dosimetry guidelines,
and preliminary clinical results in different clinical sites
in the head and neck.
213.2 Base of tongue and Mobile tongue:
technique of interstitial volume implant
Implants of the base of tongue (and mobile tongue) are
interstitial volume implants. The dose specification of
these implants can be considered as a variation of the
well-known Paris System used for LDR treatments. That
is, we specify the dose as being 85% of the average dose in
the local minima of the central plane. When treating this
type of implant with an HDR or PDR afterloader using a
single stepping-source, a dwell position separation of
5 mm is chosen. A sagittal view of a base of tongue
implant is shown in Figure 21.3 (taken from reference 18).
This type of implant usually consists of three sagittal
planes, each containing a 'looping' catheter running over
the dorsum of the base of tongue and two or three blind-
ending catheters with buttons sutured to the looping
catheter. After reconstruction from orthogonal radio-
graphs, a central plane is chosen more or less perpendic-
ular to the main direction of the blind-ended catheters
through the center of the active part of the implant, as
indicated in Figure 21.3. The minimal dose in the central
plane will, in general, be located in the geometric centers
of triangles which are constructed from the intersections
with the catheters. These centers of the triangles are used
as reference points and are designated as 'basal dose
points.' The reference dose is specified as 85% of the
average dose in the basal dose points. In order to increase

Table 21.5 Table of reference for fractionated HDR and PDR brachytherapy

Nasal vestibule T1 50 60 52.5 60 16x3 61.9

Nasal vestibule T2, 3 54 64.8 56.7 64.8 17x3 65.7
Nasopharynx
After 60 GyERT 20 24 21.1 24 6x3 23.2
After 70 GyERT 14 16.8 14.8 16.8 4x3 15.5
Any other site
T1/2 booster dose 22 26.4 23.2 26.4 7x3 27.1 24x1.0 27
T3/4 booster dose 26 31.2 27.4 31.2 8x3 30.9 26x1.0 29.2
Any other site
T1/2 full course 66 79.2 69.3 79.2 20x3 77.3 44x1.5 78.3
T3/4full course 68 81.6 71.4 81.6 21x3 81.2 46x1.5 81.9
Re-irradiation 58 69.6 60.9 69.6 18x3 69.6 39x1.5 69.4

Total number of fractions for cancer of the nasal vestibule and other tumor sites relative to T stage. (*): in the case of booster doses, generally
46 Gy are given by means of external-beam radiation therapy (ERT). Full course: radiation is only given by means of brachytherapy. The booster
dose for cancer in the nasopharynx is given after either 60 Gy ERT (endocavitary brachytherapy 6 * 3 Gy) or 70 Gy ERT (endocavitary brachytherapy
4*3 Gy). Please note that after reviewing clinical experience, we have slightly modified this table of reference. For detailed information regard-
ing the use of these experimental brachytherapy schemes, including our current schedules, refer to Levendag@Rtdh.azr.nl.
 Brachytherapy techniques and preliminary clinical results 303

Figure 21.3 Schematic view of the sagittal plane of a base of

tongue implant, showing a catheter running partly over the
dorsum of the tongue as well as catheters sutured to this
so-called 'looping' catheter. (From reference 18, with permission.)

the dose uniformity, the dose distribution is optimized

using geometric optimization, i.e., the volume mode
[18,19]. In this optimization method, the dwell time in a
dwell position is inversely proportional to the dose con-
tribution from all other dwell positions except the ones
in the same catheter [20-22]. This optimization method
is sensitive for deviations in spacing and/or divergence of
catheters. An example of the result is presented in Figure
21.4 (taken from reference 18), showing a sagittal view of
an optimized and a non-optimized dose distribution of
the base of tongue implant. After geometric optimiza-
tion, the overdosed region receiving at least 200% of the
reference dose is reduced, especially at the intersection of
the blind-ended catheters and the looping catheter.
Base of tongue cancers are, in general, treated with a
combination of a volume implant of the base of tongue
and an external radiotherapy dose of 46 Gy (conventional
fractionation) to the base of tongue and neck. In case of
positive neck nodes, the external radiotherapy of the neck
is followed by a therapeutic (radical) neck dissection at
the time of the implant. The same policy is followed for
N+ mobile tongue cancer patients. For Tl,2 NO mobile
tongue cancers, an interstitial implant of the mobile
tongue is combined with a functional neck dissection.
With regard to dose fractionation of base of tongue and
mobile tongue implants, the reader is referred to the
guidelines given in Table 21.5. At the time of writing, the
number of volume implants treated by fractionated HDR
and PDR brachytherapy in our cancer center, in particular
for mobile tongue cancer, is small. At present, an extensive
analysis in terms of local-regional control and acute
and/or late side-effects is being performed for base of
tongue cancer. For preliminary results, however, the
reader is referred to references 23 and 24.
Current treatment schedule (as of January 2001) for
all T-stages (Tl-4): external radiotherapy 23 X 2 Gy.
Brachytherapy in case of fractionated HDR 4 Gy + 4
times 3 Gy + 4 Gy (total dose 20 Gy; 2 fractions per day).
Figure 21.4 Sagittal plane through middle catheter running
over dorsum of base of tongue; (a) non-optimized and (b)
optimized dose distribution. (From reference 18 with permission.)
PDR: 2 Gy + 28 times 1 Gy + 2 Gy (total dose 22 Gy; 8
fractions per day).
2133 Nasal vestibule: technique of
interstitial single-plane implant
Although technically not obligatory, in the DDHCC,
general anesthesia is preferred when implanting the
nasal vestibule. After decongestion of the nose
(R/xylometazoline), the points of entry for the trocar are
demarcated on the skin. A hollow, stainless-steel guide
needle and trocar are introduced interstitially. After
removal of the trocar, afterloading catheters are inserted
approximately 4 cm into the guide needle; subsequently,
the guide needle is removed. Catheters are fixed and
sutured to the skin by standard buttons. The number of
catheters (generally four to five) is defined by the target
volume. If the tumor is extending into the upper lip, an
extra catheter is inserted 'horizontally' through the lip.
Due to the anatomy of the nose per se and the geometry
of the target, the catheter separation frequently varies over
the target volume after implantation (Figure 21.5). The
304 HDR interstitial and endocavitary brachytherapy in cancer of head and neck
Figure 21.5 Schematic diagram of an interstitial implant in the
nasal vestibule. (See also corresponding X-ray films in Figure 21.6.)
geometrical configuration of the implant is visualized on
orthogonal X-rays postimplantation (or on the image
intensifier in the Integrated Brachytherapy Unit (IBU),
see section 21.4), with the patient still under general anes-
thesia. If the dose distribution of the implant is not satis-
factory (i.e., anticipated coldspots and/or hotspots),
additional catheters can be introduced (Figure 21.6). The
dose is usually prescribed in so-called dose points at a dis-
tance of 0.5 cm from the catheters. This clinical example
demonstrates the advantage of optimization (compare B
and C to A, and D to E in planes I and II of Figure 21.7);
however, it also demonstrates that, even with optimiza-
tion, a 'poor' implant can never become a 'good' implant
(compare A and C in planes I and II). After optimization
of the implant (Figure 21.7), fractionated HDR is applied
(for number of fractions, see Table 21.5).
Current treatment schedule for all T-stages as of
January 2001 is: fractionated HDR 15 x 3 Gy (total dose
45 Gy; 2 fractions per day). Moreover, the mould tech-
nique has been abandoned and only an implant using
standard afterloading catheters is being used.
In cancer of the nasal vestibule, only very rarely is the
neck involved (less than 10%); we therefore do not treat
the neck electively.
213A Nasal vestibule: mould technique
In selected cases (e.g., contraindication for general anes-
thesia, small and very superficial lesions of the mucosal
lining of alae or septum, patient preference), a mould
technique can be used. After topical anesthesia of the
nasal vestibule, the hair in the nasal cavity (nostrils) is
cut away and posteriorly the nasal airway is blocked by a
cotton-wool plug. Subsequently, an impression is made
with alginate material (R/CA 37 superiorpink). From
this provisional model a 'negative impression' of plaster
of Paris is constructed. Three flexible aluminium wires
(outer diameter 2 mm) are positioned and fixed into the
plaster cast at the sites where afterloading catheters are to
Figure 21.6 Lateral X-ray films of a patient with an interstitial
implant in the nasal vestibule (left ala). During the operation, it
was realized that the implant with four catheters (A) was
suboptimal in terms of anticipated dose distribution.
Subsequently, an extra catheter was implanted (B). Lead
demarcation visualizes tumor core lateral surface nose (skin).
The stippled zone represents the planning target.
be positioned (see Figure 21.8). Using this mould tech-
nique, about midway through the series of fractions, the
insertion of the mould becomes painful and thus less
accurate. In our center, therefore, the interstitial tech-
nique is definitely the technique of choice.
213*5 Clinical results: nasal vestibule
brachytherapy
Brachytherapy of cancer of the nasal vestibule seems
very rewarding. Between 1990 and 1994, 18 primary
squamous cell carcinomas were treated, nine intersti-
tially and nine by a mould technique. Out of 18 patients,
two experienced a local relapse and one had a regional
relapse on both sides of the neck. All relapses were sal-
vaged surgically. It might be of interest that both local
failures were found in nasal vestibule cancers treated by
a mould technique. Although the mould technique
seems simple and is more convenient to the patient, the
positioning of the mould during each fraction is critical,
in particular, as stated before, when the nose (vestibule)
becomes more sore (Figure 21.9). Both techniques, when
performed properly, give excellent cosmesis.
 Brachytherapy techniques and preliminary clinical results 305

Figure 21.7 As an example,

planes I and II were taken
through the periphery of the
target. (See also the legend for
Figure 21.6.) Five types of dose
distributions (A, B, C, D, and E)
are compared. A: dose
distribution with four catheters
- constant dwell times and
dwell positions (= non-
optimized, 'LDR equivalent');
B: dose distribution with four
catheters, geometrically
optimized; C: dose distribution
of four-catheter implant,
optimized on dose points
0.5 cm from catheters; D: dose
distribution of five-catheter
implant, optimized on dose
points 0.5 cm from catheters;
E: dose distribution with five
catheters, constant dwell times
and dwell positions (= non-
optimized, 'LDR equivalent').
Fraction size was 300 cGy
(fractionated HDR schedule).

Figure 21.8 Plaster of Paris mould of carcinoma in the nasal
vestibule ('negative' impression) with aluminium wires (outer
diameter 2 mm) in situ. Subsequently, the definitive 'positive'
silicone mould is manufactured with the aluminium wires
replaced by afterloading catheters (see Figure 21.9). The mould
is placed in situ and held by a head strip (cord) during the
irradiation. Dosimetry and dose prescription are similar to
interstitial implant of the nasal vestibule.
213.6 Tonsil and soft palate: technique of
single-plane interstitial implant
The implant of the tonsillar fossa and/or the soft palate
can be performed as a single-plane or volume implant.
Figure 21.9 Final silicone mould for carcinoma of the nasal
vestibule suitable for fractionated HDR brachytherapy on an
outpatient basis. Three afterloading catheters are visible in the
silicone mould.
Before embarking on such an implant, it is of paramount
importance to investigate whether the target volume
can be covered adequately by the implant. This means
that computerized tomography (CT) and/or magnetic
resonance imaging (MRI) of the tumor mass and neigh-
boring structures (e.g., parapharyngeal space, nasopha-
ryngeal side of the soft palate, retropharyngeal nodes
etc.) are mandatory. If the target is considered suitable
for implantation, the primary visible lesion is tatooed
306 HDR interstitial and endocavitary brachytherapy in cancer of head and neck
under general anesthesia. The next question regards the
neck. In principle, for T1/T2 tonsillar carcinoma we treat
the ipsilateral neck electively (NO) by either surgery
(functional neck dissection) for small/superficial lesions
of the primary tumor or external radiotherapy to a dose
of 46 Gy (neck and primary) in case of bulky primary
tumors. Subsequently - that is, after the functional neck
dissection or external radiotherapy (46 Gy) - the pri-
mary tumor mass is implanted. The same policy applies
for NO soft palate tumors, except that the neck is treated
bilaterally. For N+ in the great majority of patients, the
neck and primary are treated by external radiotherapy
46 Gy, followed by a neck dissection in conjunction with
an implant of the primary tumor (soft palate and/or ton-
sillar fossa).
The implant per se is very straightforward. Basically,
by means of hollow guide needles, catheters are intro-
duced into the tonsillar fossa (anterior and posterior
tonsillar pillars) and soft palate. In general, two to three
parallel running catheters are needed (Figure 21.10). The
target is demarcated by permanent implantation of sur-
gical clips or metallic seeds.
For dose prescription, dose points are positioned at a
distance of 0.5-0.75 cm from the catheters and the
implant is subsequently optimized. On rare occasions
(e.g., retropharyngeal nodes) extra dose points can be
positioned at specified locations. Tumors are treated by
either fractionated HDR or PDR. (For the total number
of fractions, see Table 21.5).
Figure 21.10 Anteroposterior X-ray film of an interstitial
implant in the tonsillar fossa and soft palate.
213.7 Clinical results: tumor control of
tonsillar fossa and soft palate
From November 1990 until December 1994, 40 patients
with primary squamous cell carcinoma originating from
the tonsillar and fossa soft palate were treated by inter-
stitial radiation therapy with or without external radio-
therapy to the primary. Eighteen patients were NO, 22
had neck nodes at admission (N+). Of the implanted
primary tumors, five were staged as Tl (13%), 22 as T2
(55%), 11 as T3 (28%) and 1 as T4 (3%). The neck was
treated either by elective neck irradiation or functional
neck dissection only (NO; =18), or by a therapeutic neck
dissection combined with external radiotherapy (N+;
n=22). The functional results and local-regional control
rates so far are excellent, in particular given the fact that
13 out of 40 (33%) patients had very advanced (T3/T4)
tumors. Only four patients experienced a local relapse
(one T2, NO [soft palate], one T3, NO [tonsillar fossa];
one T3, N3 [tonsillar fossa]; one T2, N2a [tonsillar
fossa), one of which (T2, N2a [tonsillar fossa]) was sal-
vaged. Three relapses in the neck occurred. The actuarial
local control rate after brachytherapy at 4 years for all
Tl-4, NO, + tumors was 89% (Figure 21.11), whereas an
overall survival of 69% was observed. No difference was
found for tonsillar fossa and soft palate (Figure 21.12) or
fractionated HDR (n=21) versus PDR (n=19) (Figure
21.13). For a recent and more detailed analysis of
local-regional control rates, the reader is referred to ref-
erence 25.
As of January 2001, the treatment schedule has been
slightly modified. For all T-stages (Tl-4), a dose of
4-6 Gy by external radiotherapy is used. The surdosage
by brachytherapy for the primary consists of fraction-
ated HDR 4 Gy + 4 times 3 Gy + 4 Gy (total dose 20 Gy;
2 fractions per day). Or, in the case of PDR, 2 Gy + 10
times 1 Gy + 2 Gy (total dose 22 Gy; 8 fractions per day).
Figure 21.11 Actuarial local control rate for patients with
carcinoma of the tonsillar fossa and soft palate, treated
between 1990 and 1994 with either fractionated HDR or PDR.

Figure 21.12 Actuarial local control rate for patients with
carcinoma of the tonsiliar fossa versus tumors of the soft palate,
treated between 1990 and 1994 with either fractionated HDR or PDR.
Figure 21.13 Actuarial local control rate for patients with
carcinoma of the tonsi liar fossa and/or soft palate, treated
between 1990 and 1994 with fractionated HDR versus PDR
brachytherapy.
213*8 Clinical results: early and late side-
effects for tonsillar fossa and soft palate
With regard to acute and late side-effects, all patients were
(prospectively) scored using a modified RTOG scoring
system regarding skin, subcutaneous tissue, mucosa, dys-
phagia, salivary gland function (xerostomia), spinal cord,
and pain. In summary, no significant lasting untoward
acute and late side-effects were observed to be different
from those of the LDR treatment era. Figure 21.14
demonstrates, as an example, the actuarial late complica-
tion-free probability of mucosal reactions grade 3 and 4
for fractionated HDR and PDR. Again, for a recent
update of side-effects using this technique for tonsillar
fossa and soft palate tumors, see reference 25.
213*9 Nasopharynx: technique of
endocavitary brachytherapy
As reported previously, in the case of cancer of the
nasopharynx we treat the primary cancer by external
Brachytherapy techniques and preliminary clinical results 307
Figure 21.14 Actuarial late complication-free probability of
mucosal reactions grade 3 and 4 for carcinoma of the tonsillar
fossa and soft palate, treated by fractionated HDR and PDR
between 1990 and 1994.
radiotherapy to a dose of 60 Gy (Tl-3) or 70 Gy (T4
and/or parapharyngeal space extension). Neck nodes are
generally boosted to a dose of 70 Gy [26,27]. After comple-
tion of the external radiotherapy part of the treatment, a
booster dose is applied by brachytherapy. With regard to
the endocavitary brachytherapy, a silicone mould, the
Rotterdam Nasopharyngeal Applicator (Figure 21.15), is
used for the treatment of the nasopharynx. Figure 21.16
shows schematically how this applicator is positioned.
Planning of the brachytherapy treatment of the nasophar-
ynx using the intracavitary mould is based on orthogonal
radiographs. Patient points, representing tumor points
and normal-tissue points, which will be used for dose opti-
mization, are indicated on the lateral radiograph as indi-
cated in Figure 21.17. Following our protocol, the points
are transferred to the anteroposterior (AP) radiograph at a
prescribed distance from the midline.
Points are selected which should receive the reference
dose. Usually, these are the nasopharynx points (Na) and
the Rouviere node (R). The dose distribution is opti-
mized such that these points receive the prescribed dose,
Figure 21.15 The silicone Rotterdam Nasopharynx Applicator:
outer diameter 5.5 mm and inner diameter 3.5 mm.
308 HDR interstitial and endocavitary brachytherapy in cancer of head and neck

Figure 21.16 After

decongestion (R/xylometazoline
HC11%) and topical anesthesia
(R/Concaine hydrochloride 7%)
of the nasal mucosa and
nasopharynx, guide tubes (outer
diameter 2 mm) are introduced
through the nose and exit
through the mouth. The
Rotterdam Nasopharynx
Applicator (RNA) is guided
intraorally over the guide tubes
(GT) by pulling on the nasal part
of the guide tubes. The
applicator is finally placed in
situ into the nasopharynx and
nose. To facilitate positioning of
the applicator into the
nasopharynx, gently pushing the
oral parts of the guide tubes
intraorally using some standard
type of forceps can sometimes
be of additional help, as in C.
By using a silicone flange, the
Rotterdam Nasopharynx
Applicator is secured in the
correct position for the duration
of the treatment, for example
3-4 days.

Figure 21.17 Schematic diagram

of a lateral X-ray film of a patient
with cancer of the nasopharynx and
of the Rotterdam Nasopharyngeal
Applicator in situ. Patient points -
that is, normal tissue points (CC, Pi,
OC, Re, BOS, N, Pa) as well as tumor
tissue points (Na, R) - are indicated.
For explanation see also Table 21.6.
 Brachytherapy techniques and preliminary clinical results 309

Table 21.6 Example of the planning of an endocavitary treatment of the

nasopharynx

Na-r 104 100 101

Na-1 96 100 99
C 30 26 27
R 117 100 102
Pi 22 23 19
OC 15 15 12
Re-r 18 18 13
Re-1 19 20 13
BOS-r 43 42 40
BOS-1 41 41 39
N-r 140 142 102
N-1 151 168 103
Pa-r 86 84 75
Pa-1 83 85 73
The second column shows the non-optimized situation. In the third column, the dose
has been optimized taking into account both nasopharynx points and the node of
Rouviere. In the last column, the dose has been optimized such that both nasophar-
ynx points, both nose points, and the node of Rouviere receive the reference dose. Na:
nasopharynx; C: cord; R: Rouviere node; Pi: pituitary gland, OC: optic chiasm; Re:
retina; BOS: base of skull, N: nose; Pa: palate.

i.e., an optimization on patient points [20]. If, during nal radiotherapy only, 65 patients treated with a mini-
evaluation, the dose in specific points seems unsatisfac- mum dose of 60 Gy were recruited and analyzed for
tory, these points can be included in the optimization comparison purposes. Figures 21.18 and 21.19 depict the
procedure as well. In that case, each patient point can be local relapse-free survival and overall survival, respec-
assigned a weighting factor for dose requirements (Table tively, for both patient groups. It seems that boosting the
21.6). The planning procedure is illustrated by the exam- primary tumor to a high dose is of benefit. However,
ple mentioned in Table 21.4 [27]. there is a significant excess death rate due to intercurrent
Brachytherapy can be given on an outpatient basis in disease and/or second primaries. Moreover, comparing
fractions of 3 Gy each, twice a day, with an interval of at Figure 21.20 and Figure 21.21, we can observe that the
least 6 h, using the HDR afterloader (see also Table 21.5). gain in local control is mainly confined to the Tl-3
Currently, as of 2001, using the UICC/AJCC 1997 classifi- patient category. Figure 21.22 shows the overall survival
cation system, the protocol for the brachytherapy boost
has been slightly modified. For Tl-2a tumors after exter-
nal radiotherapy 60 Gy a booster dose of 4 Gy + 3 times
3 Gy + 4 Gy is given (total brachytherapy dose 17 Gy;
2 fractions per day). For good responding T2b tumors, a
dose of 4 Gy + 3 Gy + 4 Gy (total dose 11 Gy; 2 fractions
per day). Poorly responding T2b tumors and T3, 4
cancers are preferentially treated by Stereotactic Radiation.

213*10 Nasopharynx: clinical results

From March 1991 until December 1994,49 patients with

primary squamous cell carcinoma of the nasopharynx
were treated according to the protocol combining exter-
nal radiotherapy and fractionated HDR. Out of those 49
patients, ten were excluded because of re-radiation
(n=5), distant metastasis at presentation (n=l), and his-
tology other than squamous cell carcinoma (n=4).
Subsequently, from a database of cancers of the head and
neck treated in the DDHCC from 1978 to 1988 by exter-
Figure 21.18 Local relapse-free survival for patients treated for
Tl-4 carcinoma of the nasopharynx by ERT only (between 1978
and 1988) to a minimum dose of 60 Gy, as opposed to patients
treated by ERT plus endocavitary brachytherapy (between 7997
and 1994).
310 HDR interstitial and endocavitary brachytherapy in cancer of head and neck
Figure 21.19 Overall survival for patients with Tl-4 cancers of
the nasopharynx. (See also the legend to Figure 21.18.)
Figure 21.20 Local relapse-free survival for Tl-3 tumors
originating in the nasopharynx. (See also the legend to Figure 21.18.)
Figure 21.21 Local relapse-free survival for T4 cancers in the
nasopharynx. (See also the legend to Figure 21.18.)
rate comparing Tl-3 patients treated by external radio-
therapy alone with those treated by external radio-
therapy and endocavitary brachytherapy. Except for a
few patients developing synechiae, no significant differ-
ence in morbidity was observed for patients treated by
external radiotherapy only compared with those treated
by external radiotherapy plus brachytherapy. For a more
elaborate, recent analysis of local-regional control rates
Figure 21.22 Overall survival for T1-3 cancers in the
nasopharynx. (See also the legend to Figure 21.18.)
and side-effects using external radiotherapy in conjunc-
tion with the Rotterdam Nasopharynx Applicator, the
reader is referred to reference 28.
21,4 INTEGRATED BRACHYTHERAPY UNIT
(IBU): THE FUTURE
A new development in brachytherapy is the concentra-
tion of implantation, implant reconstruction, dose plan-
ning, and irradiation in a shielded operating room, i.e., an
IBU. In this way one can achieve an improvement of the
implant quality and a shortening of the overall procedure
as reconstruction and planning are performed immedi-
ately. Finally, it offers the possibility of applying intraop-
erative brachytherapy. An IBU should be equipped with
an HDR afterloader and a dedicated brachytherapy local-
izer, consisting of an L-arm in combination with a C-arm
(Figure 21.23), which is on-line connected to a treatment
planning system. The design of the localizer enables one
to view the implant from any chosen direction.
The main features of the IBU are:
1. on-line filmless planning enabling real-time
feedback of the dose distribution of the implant
during the implantation procedure;
2. intraoperative irradiation using the HDR afterloader.
The procedure in an IBU is summarized in Figure
21.24 (taken from reference 29). After implantation of
the catheters or applicators, reconstruction images are
made using fluoroscopy. Both the video images from the
image intensifier and the settings of the localizer, i.e.,
L-arm angle, C-arm angle, and the isocenter image
intensifier distance, are on-line transferred to the treat-
ment planning computer. After correction of the geo-
metric distortions present in fluoroscopy images and, if
necessary, some image processing, the geometry of the
implant is reconstructed followed by dose planning and
dwell-time optimization. The resulting dose distribution

Figure 21.24 Intraoperativefilmless planning procedure in an
IBU. (For explanation, see text.)
is presented on a monitor in the operating room for
evaluation. In the case of an unsatisfactory dose distrib-
ution, one has the ability technically to optimize the
implant. In other words, this real-time feedback of the
resulting dose distribution during implantation allows
dose optimization not only by dwell-time optimization,
but also by modification of the implant geometry.
Concerning the irradiation, the patient can either receive
a high, single intraoperative fraction in the IBU, e.g.,
using a flexible intraoperative template (see next sec-
tion), or a relatively small fraction (e.g., 4 Gy), to be fol-
lowed postoperatively by fractionated HDR or PDR
treatment, e.g. for a volume implant of the base of
tongue. In some cases, the IBU system is only used for
verification of the position of catheters or applicators
and/or for on-line reconstruction and dose planning.
Integrated brachytherapy unit: the future 311
Figure 21.23 The isocentric
IBU localize? consisting of an
L-arm in combination with a
C-arm. The localize? is in the
'parkingposition,' i.e., rotated
over 40 , enabling maximum
access to the operating table
during implantation.
21*4*1 Brachytherapy of the neck in an IBU
using a flexible intraoperative template
In October 1994, an IBU was installed in the DDHCC.
To date, the IBU has been mainly used in attempts to
improve on the quality of standard brachytherapy proce-
dures; that is, the implant geometry is visualized (and/or
changed) intraoperatively using fluoroscopy (see, for
example nasal vestibule), and X-ray films for planning
purposes are taken with the patient still under general
anesthesia, thus reducing the 'time to start' of the actual
irradiation. The next step will be research and develop-
ment of routine filmless planning (see above). The intra-
operative brachytherapy procedure is illustrated by the
following case report.
CASE REPORT: RE-IRRADIATION OF THE NECK
Our experience with re-irradiation in cancer of the head
and neck has been previously reported [30]. A variety of
tumor sites, including the neck, appeared to have been re-
irradiated by means of brachytherapy external radio-
therapy surgery; 55% of the patients obtained tumor
control of the re-irradiated site. It was concluded that re-
irradiation can be of benefit when pursuing long-lasting
local-regional control and, in particular, the use of
brachytherapy (albeit LDR at the time) was advocated.
Regarding specifically the technique of implantation of
the neck, after dissection the tumor bed was implanted
using a variable number of catheters (usually six to nine)
sutured onto the soft tissues in the neck (Figures 21.25 and
21.26). As of 1990, similar techniques have been used for
recurrent (after previous external radiotherapy and/or
surgery) tumors in the neck in combination with fraction-
ated HDR brachytherapy (total dose of fractionated HDR
312 HDR interstitial and endocavitary brachytherapy in cancer of head and neck
Figure 21.26 X-ray film of a single-plane implant tumor bed in
the neck for re-irradiation by LDR brachytherapy in a patient
with recurrent tumor after previous surgery and/or ERT. (See also
the legend to Figure 21.25.)
54-60 Gy). In a preliminary analysis, only four out of 13
(31%) had failed at the site of the fractionated HDR
implant (data not published). Although these control
rates seem satisfactory given the poor population subset,
the procedure is laborious and, for the reconstructive sur-
geon, not particularly gratifying. This is partly due to the
Figure 21.25 Schematic diagram of a single-plane
implant in the neck using standard afterloading catheters
(outer diameter 2 mm) sutured onto the soft tissues in the
neck (tumor bed). The defect in the neck is reconstructed as
a one-step procedure at the time of implantation.
Catheters remain in situ for a number of days (3-10),
depending on factors such as the condition of the patient,
fractionation schedule, and total dose.
impediment of the implant per se at the time of the recon-
structive procedure, to the catheters having to remain in
situ for quite a number of days, with the potential risk for
infections in the area of the newly reconstructed defect in
the neck, as well as the risk of wound breakdown if, for
technical reasons, the catheters have to be positioned (too)
close to the covering skin (high skin dose; this, by the way,
might also have implications regarding the type of recon-
structive procedure chosen).
21.4.2 Technical aspects of brachytherapy
of the neck using a flexible intraoperative
template
To eliminate the disadvantages of conventional implants
of the neck by individual catheters (see Figure 21.25), a
novel technique was developed in our institution. In prin-
ciple, it consists of a flexible silicone template to be used as
a temporary single-plane implant intraoperatively. This
silicone flexible intraoperative template has a thickness of
only 0.5 cm (flexible), and can be easily cut into different
shapes and sizes (custom made). In the center of the tem-
plate, catheters are positioned 1 cm apart in prefixed
channels (allowing for fixed spacing). In predetermined
pinpoint holes (1 cm apart), metallic buttons can be
introduced during the brachytherapy procedure to delin-
eate to target when using fluoroscopy (Figure 21.27).
If one combines the use of a flexible intraoperative
template technique with an IBU, some extra advantages
can be envisaged. First, the custom-made flexible intra-
operative template is, in most cases, easily positioned
(Figure 21.28) and, after on-line computer planning, a
single dose can be delivered intraoperatively using the
HDR afterloader in the IBU with the patient still under

Figure 21.27 Photograph of a flexible intmoperative template
with catheters and metallic buttons in situ, illustrating to some
extent the flexibility in curvature and shape (silicone - easy to
cut and bend) of the template. (For explanation, see text.)
general anesthesia. Second, after irradiation, the flexible
intraoperative template is removed and reconstructive
surgery can be performed without limitations due to the
brachytherapy procedure per se (i.e., no remaining in-
situ catheters). Also, the covering skin is not at risk for
too high doses of irradiation, i.e., there is less risk of
wound breakdown. Finally, optimization of the dose dis-
tribution can be performed (see below).
CASE REPORT: BRACHYTHERAPY OF THE NECK IN
AN IBU USING ON-LINE PLANNING AND A
FLEXIBLE INTRAOPERATIVE TEMPLATE
Recently, two patients presented with a recurrent sar-
coma in the neck; the head and neck tumor board
Integrated brachytherapy unit: the future 313
Figure 21.29 Photograph of neck dissection and a flexible
intraoperative template in situ (including metallic buttons to
demarcate target) in a patient with recurrent sarcoma in the
right neck. (For explanation, see text.)
decided to re-resect the remaining tumor mass and irra-
diate the tumor bed intraoperatively by means of a flex-
ible intraoperative template (delivering a single fraction
of 10 Gy at 1 cm; see also Figures 21.29 and 21.30), fol-
lowed by postoperative external radiotherapy (conven-
tional fractionation of 2 Gy/day, total dose 46 Gy).
The technique of the brachytherapy procedure has
been explained in section 21.4.1. The tailoring of the
flexible intraoperative template itself, positioning of the
template, the computer planning, and the actual irradia-
tion took approximately 3 h. To demonstrate the advan-
tage of optimized dose distributions using a flexible
intraoperative template over a classical non-optimized
LDR implant (in which catheters are sutured onto the
tumor bed; see also Figures 21.25 and 21.26), selected
Figure 21.28 Schematic diagram showing a flexible
intraoperative template for intraoperative re-irradiation
of the neck. (For explanation, see text. Compare also to
Figure 21.25.)
314 HDR interstitial and endocavitary brachytherapy in cancer of head and neck

isodose patterns are compared in Figure 21.31 (panels

A-E) for different single-plane brachytherapy tech-
niques. That is, typical examples are shown (in a central
plane, I, as well as in a plane taken more in the periphery
of the implant, II) for a non-optimized LDR implant
(see also Figure 21.31, panel A), for an implant opti-
mized on dose points positioned at 1 cm from catheters
(see also Figure 21.31, panel B), for a dose calculation of
('standard') flexible intraoperative template (thus disre-
garding the possibly severe curvatures of a template in a
real anatomical situation) optimized on dose points at
1 cm from the catheters with the dwell times transferred
to the actual flexible intraoperative template (Figure
21.31, panel C), for an optimized flexible intraoperative
template used in the actual patient with dose points at
1 cm from catheters (Figure 21.31, panel D), and, finally,
for an optimized flexible intraoperative template as used
for a typical situation with dose points at 1 cm in region
1 (e.g., at 'shallow depth') and dose points at 2 cm in
region 2 (e.g., dose prescription to 'deeply located' dose
points, for example due to anatomical constraints)
(Figure 21.31, panel E).
In conclusion, in general, better dose distributions can
Figure 21.30 X-ray film of an implant in the neck using a
be obtained with flexible intraoperative template as
flexible intraoperative template in an IBU. (See also text and the
opposed to classical LDR catheter implants (compare
legend to Figure 21.29.)

Figure 2131 Comparison of

different dose distributions for
implant of the neck. Examples
of isodose patterns are shown
for a central plane (plane I) as
well as for a plane taken more
in the periphery of the implant
(plane II). These dose distri-
butions were calculated for a
typical case of an LDR non-
optimized implant (panel A);
optimized catheter implant
with dose points at 7 cm from
catheters (panel B); optimized
standard flexible intraoperative
template with dose points at
1 cm from the center of the
implant (panel C); optimized
flexible intraoperative template
used in the patient in Figure
21.30, with dose points at 1 cm
from catheters (panel D); and
optimized flexible intra-
operative implant to be used for
situations with dose points at
different depths, that is, with
dose points at 1 cm (region 1;
R-1) and 2 cm (region 2; R-2)
(panel E). (For detailed
explanation, see text.)

panels A and B to C in Figure 21.31). Also, a dose calcu-
lation using a standard flexible intraoperative template
generates sufficiently adequate dose distributions as long
as the curvature of the actual template is not too strong
(compare also panel C to D in Figure 21.31). In some
instances, with a flexible intraoperative template one can
even divert to dose points at different levels, thereby
arbitrarily dividing the implant into different 'dose point
regions' (panel E). As with data concerning other appli-
cations of intraoperative irradiation such as those gener-
ated by linear accelerators, we have to await and see
whether, with the use of large, single fractions of
brachytherapy, we will run into severe late side-effects.
21.5 THE FUTURE OF BRACHYTHERAPY: A
ROTTERDAM VIEWPOINT
It is not within the scope of this chapter to elaborate on
the future of brachytherapy. In fact, this chapter repre-
sents a comprehensive departmental Vision.' That is,
given the technical means and infrastructure of the
department, the authors have tried to present a 'how I do
it' type of overview. Needless to say, there are many other
ways to go about brachytherapy. Recently, the depart-
ment expanded by purchasing a brachytherapy-
dedicated CT scanner. With regard to head and neck
cancer, in the next few years major efforts will be made
to define the role of brachytherapy planning and to
implement it as a routine procedure. Another interesting
subject is the further extension of radiobiological models
[31]. In fact, as of 1997, we routinely use fractionation
schedules in head and neck brachytherapy, with the first
as well as the last fraction size topped up by 1 Gy [32].
This way we hope to shorten the overall treatment time
as well as to make the schedule more 'effective' [33].
21.6 SUMMARY
Single stepping-source, computer-controlled afterload-
ing devices have changed classical low dose-rate radio-
biological thinking as well as the application techniques
per se in brachytherapy considerably. In the Head & Neck
Cancer Cooperative Group of the University Hospital
Rotterdam/Daniel den Hoed Cancer Center, fractionated
HDR or PDR brachytherapy schedules have been initi-
ated and clinically tested since August, 1990. In total,
from August 1990 until December 1994, 176 patients
were treated by either fractionated HDR or PDR. This
chapter reviews our brachytherapy rationale, techniques,
and dose specification methods as well as the clinical
(brachytherapy) protocols in use. The first clinical results
in terms of local tumor control and complications (acute
and late side-effects) are reported for cancer of the
nasopharynx (endocavitary brachytherapy), nasal
References 315
vestibule (mould and interstitial brachytherapy) and
tonsil and soft palate (interstitial brachytherapy).
Although base of tongue and mobile tongue cancers are
routinely treated in our institution by external radio-
therapy in combination with fractionated HDR or PDR
interstitial brachytherapy, clinical outcome has not been
analyzed in detail to date. For this reason, we elected not
to digress on base of tongue in this chapter, except for
referring to papers and preliminary outcome data.
Finally, some aspects regarding the way we are presently
implementing (fractionated) HDR brachytherapy using
an integrated brachytherapy unit are discussed.
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1. Armour, E., Wang, Z., Corry, P. and Martinez, A. (1990)
Equivalence of continuous and pulse simulated low dose
rate irradiation in 9Lgliosarcoma cells at 37 and 41 C.
InLJ. Radiat. Oncol. Biol. Phys., 22,109-14.
2. Brenner, D.J.and Hall, E.J. (1991) Conditions for the
equivalence of continuous to pulsed low dose rate
brachytherapy. IntJ. Radiat. Oncol. Biol. Phys., 20,181-90.
3. Lea, D.E. and Catcheside, D.G. (1942) The mechanism of
the induction by radiation of chromosome aberrations in
tradescantia.y. Genet, 44,216-45.
4. Barendsen, G.W. (1982) Dose fractionation, dose rate and
iso-effect relationships for normal tissue responses. IntJ.
Radiat. Oncol. Biol. Phys., 8,1981-97.
5. Thames, H.D. (1985) An 'incomplete-repair' model for
survival after fractionated and continuous irradiations.
IntJ. Radiat. Oncol. Biol. Phys., 47,319-39.
6. Dale, R.G. (1985) The application of the linear-quadratic
dose-effect equation to fractionated and protracted
radiotherapy. Br.J. Radio!., 58, 515-28.
7. Thames, H.D., Bentzen, S.M., Turesson, I., Overgaard, M.
and Van den Bogaert, W. (1990) Time-dose factors in
radiotherapy: a review of the human data. Radiother.
On<:o/.,19,219-35.
8. Fowler, J.F. (1989) The linear-quadratic formula and
progress in fractionated radiotherapy. Br.J. Radiol., 62,
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9. Pop, L.A.M., van den Broek, J.F.C.M. and van der Kogel A.J.
(1994) Clinical considerations in the design of new
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an alternative for LDR-brachytherapy. Radiother. Oncol.,
31,(Suppl.1),S38.
10. de Boer, R.W. and LebesqueJ.V. (1991) Equivalent doses
of low-dose-rate brachytherapy and pulsed-dose-rate
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11. Ang, K.K., Guttenberger, R., Thames, H.D., Stephens, L.C.,
Smith, C.D. and Feng, Y. (1992) Impact of spinal cord
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schedules. Radiother. Oncol., 25,287-94.
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12. Turesson, I. and Thames, H.D. (1989) Repair capacity and
kinetics of human skin during fractionated radiotherapy:
erythema, desquamation and telangiectasia after 3 and 5
years' follow-up. Radiother. Oncol., 15,169-88.
13. van Rongen, E., Thames, H.D. and Travis, E.L (1993)
Recovery from radiation damage in mouse lung:
interpretations in terms of two rates of repair. Radial
Res., 133,225-33.
14. Fowler, J.F. (1993) Why shorter half-times of repair lead to
greater damage in pulsed brachytherapy. Int.}. Radiat.
Oncol. Biol. Phys., 26,353-56.
15. Turesson, I. (1990) Radiobiological aspects of continuous
low-dose-rate irradiation and fractionated high-dose-rate
irradiation. Radiother. Oncol., 19,1-16.
16. van den Aardweg, G.J.M.J. and Hopewell, J.W. (1992) The
kinetics of repair for sublethal radiation-induced damage
in the pig epidermis: an interpretation based on a fast
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94-104.
17. Levendag, P.C., Meeuwis, C.A., Wijthoff, S.J.M. and Visser,
A.G. (1992) Reirradiation of recurrent head and neck
cancers: external versus interstitial radiation therapy.
Activity, 3,32-9.
18. Kolkman-Deurloo, I.K.K., Visser, A.G., Niel, C.G.J.H.,
Driver, N. and Levendag, P.C. (1994) Optimization of
interstitial volume implants. Radiother. Oncol., 31,
229-39.
19. Thomadsen, B.R., Houdek, P.V., van der Laarse, R.,
Edmundson, G.K., Kolkman-Deurloo, I.K.K. and Visser,
A.G. (1994) Treatment planningand optimization. In HDR
Brachytherapy: A textbook, ed. S. Nag. Amonk, NY, Futura
Publishing Company, 79-145.
20. van der Laarse, R., Edmundson, G.K., Luthmann, R.W. and
Prins, T.P.E. (1991) Optimization of HDR brachytherapy
dose distributions. Activity, Selectron Brachyther.J., 5(2),
94-101.
21. Edmundson, G.K. (1991) Geometry based optimization for
stepping source \mp\ants.Activity, Selectron Brachyther.J.,
5(4), 22-6.
22. Edmundson, G.K. (1994) Volume optimization: an
American viewpoint. In Brachytherapy from Radium to
Optimization, ed. R.F. Mould, J.J. Battermann, A.A.
Martinez and B.L. Speiser. Veenendaal, The Netherlands,
Nucletron International BV, 314-18.
23. Levendag, P.C. and van Putten, W.LJ. (1990)
Brachytherapy in head and neck cancer: Rotterdam low
dose rate experience. In Brachytherapy HDR and LDR,
ed. A.A., Martinez, C.G. Orton and R.F. Mould.
Veenendaal, The Netherlands, Nucletron International
BV, 325-44.
24. Levendag, P.C., Vikram, B., Flores, A.D. and Yin, W.B.
(1994) High dose rate brachytherapy for cancer of the
head and neck. In High Dose Rate Brachytherapy: a
Textbook, ed. S. Nag. Amonk, NY, Futura Publishing
Company, 237-73.
25. Levendag, PC., Schmitz, P.I.M.Jansen, P.P.etal. (1997)
Fractionated high-dose-rate brachytherapy: first clinical
experience in squamous cell carcinoma of the tonsillar
fossa and soft palate. Int.J. Radiat. Oncol. Biol. Phys.,
38(3), 497-506.
26. Levendag, P.C., Visser, A.G., Kolkman-Deurloo, I.K.K.,
Eijkenboom, W.M.H. and Meeuwis, C.A. (1994) HDR
brachytherapy with special reference to cancer of the
nasopharynx. In Brachytherapy from Radium to
Optimization, ed. R.F. Mould, J.J. Battermann, A.A.
Martinez and B.L. Speiser. Veenendaal, The Netherlands,
Nucletron International BV, 121-31.
27. Levendag, P.C., Peter, R., Meeuwis, C.A., Visch, L.L.,
Sipkema, D., de Pan, C. and Schmitz, P.I.M. (1997) A new
applicator design for endocavitary brachytherapy of
cancer in the nasopharynx. Radiother. Oncol., 45,95-8.
28. Levendag, P.C., Schmitz, P.I., Jansen, P.P. etal. (1998)
Fractionated high-dose-rate brachytherapy in primary
carcinoma of the nasopharynx./ Clin. Oncol., 16(6),
2213-20.
29. Kolkman-Deurloo, I.K.K., Visser, A.G., Idzes, M.H.A. and
Levendag, P.C. (1997) Reconstruction accuracy of a
dedicated localiser for filmless planning in intra-
operative brachytherapy. Radiother. Oncol., 44,73-81.
30. Levendag, PC., Meeuwis, C.A. and Visser, A.G. (1992)
Reirradiation of recurrent head and neck cancers:
external and/or interstitial radiation therapy. Radiother.
Oncol., 23,6^5.
31. Visser, A.G., van den Aardweg, G.J.M.J. and Levendag, P.C.
(1996) Pulsed-dose-rate and fractionated high-dose-rate
brachytherapy: choice of brachytherapy schedules to
replace LDR treatments. Int.J. Radiat. Oncol. Biol. Phys.,
34(2), 497-505.
32. Levendag, P.C. and Jansen, P.P. (1997) Fractionated high-
dose rate brachytherapy in cancer of the head and neck.
9th International Brachytherapy Conference, Palm
Springs, USA, September 3-6,1997.
33. Brenner, D.J., Hall, E.J., Huang, Y. and Sachs, R.K. (1994)
Optimizing the time course of brachytherapy and other
accelerated radiotherapeutic protocols. Int.J. Radiat.
Oncol. Biol. Phys., 29(4), 893-901.

Brachytherapy in the treatment of pancreas and
bile duct cancer
DATTATREYUDU NORI, SUHRID PARIKH, SRINATH SUNDARARAMAN AND MARGOT HEFFERNAN
22.1 INTRODUCTION
Although radical surgery can cure patients with pancre-
atic or biliary tract carcinoma, few patients present with
resectable disease. The majority of patients with pancre-
atic carcinoma have lesions in the head of the pancreas that
are locally advanced at the time of diagnosis or are techni-
cally unresectable because of local extension to adjacent
structures. Surgical options for patients with unresectable
lesions are limited to palliative biliary bypass alone or in
combination with elective gastroenterostomy. Similarly,
surgical resection in the very small minority of resectable
candidates and palliative stenting in unresectable cases
have been the only treatment considerations for bile duct
carcinoma. However, over the past decade, radiation ther-
apy has been used more frequently in locally advanced
pancreatic and biliary carcinomas. While the initial intent
of radiotherapy was palliative in most cases, there is grow-
ing evidence that dose escalation - using a combined
approach of external-beam radiation plus conformal
brachytherapy - can actually improve survival in a select
group of these inoperable patients. This chapter highlights
the role of brachytherapy in the treatment of (a) pancre-
atic carcinoma, and; (b) bile duct carcinoma.
22.2 PANCREATIC CANCER
The incidence of pancreatic carcinoma appears to be
increasing, though it is unknown whether this is an out-
22
come of poor previous reporting or new influences
related to the environment or genetic predisposition [ 1 ].
Today, carcinoma of the pancreas accounts for 3% of the
annual cancer incidence in the USA and 5% of cancer
deaths. This translates into 27000 new cases (13000
males and 14000 females) each year. However, despite
the advances in diagnosis, staging, and therapy, more
than 90% of these patients die within a year, with an
annual mortality of 25900 cases (12400 males and
13 500 females). Less than 2% of the patients are alive at
5 years [2,3].
22.2.1 Pretreatment assessment
At the time of diagnosis, more than 60% of the tumors
have extended beyond the pancreas, with at least 20% of
patients having clinically evident distant metastases
[4,5]. A significant number of patients do exhibit the
classic triad of symptoms associated with cancer of the
pancreas - pain, weight loss, and progressive jaundice -
but these usually imply advanced disease. Back pain is a
particularly ominous sign because it signifies infiltration
of the celiac plexus - these patients are usually unre-
sectable. It is unfortunate that, early in the course of the
disease, when it is more likely to be resectable, the clini-
cal picture is generally ill-defined and vague [6-8]. The
traditional approach to the patient with non-metastatic
pancreatic carcinoma was a surgical exploration.
Preoperative staging was of limited importance because
surgery provided the opportunity to obtain a
318 Brachytherapy in the treatment of pancreas and bile duct cancer

pathological diagnosis, assess resectability, and offer pre- 22*2.2 General management (treatment
emptive surgical palliation (4). However, a relatively methods)
small number of patients are truly resectable (< 20%),
and palliation can often be easily achieved by endoscopic SURGERY
or other non-operative approaches. Also, a multimodal-
ity approach is playing a greater role in the treatment of Although surgical resection employing a Whipple's pro-
these patients. Thus, a proper staging of the disease cedure (pancreatico-duodenectomy) is the standard
extent prior to laparotomy is essential, not only to spare treatment for patients with pancreatic carcinoma, 5-year
a large number of patients a needless exploration, but survival rates have remained dismal (5-year survival
also to identify patients suitable for these multidiscipli- rates are rarely consistently more than 5%); morbidity
nary approaches. and mortality also remain high [10-17]. Furthermore,
Imaging tests of the pancreas are considered the cor- even in the resected cases, up to 85% fail locally [18,19],
nerstone of the diagnosis of pancreatic carcinoma to and local recurrence is the ultimate cause of death in
assess operability and resectability [2,9]. A high-resolu- almost 50% of patients [13,20,21,86]. Because less than
tion, spiral, computerized tomography (CT) with intra- 20% of all patients have resectable disease, the majority
venous contrast, employing a 'pancreatic protocol', is of patients who are explored may not be candidates for
usually adequate in delineating the loco-regional resection. On the other hand, almost 40% of patients
anatomy to allow a preoperative selection of potentially have locally advanced disease, in the absence of obvious
resectable patients. CT-portography may be added if distant metastases. Standard postoperative regimens
there are doubts about the invasion of the major vascu- have done little to improve the outcome for these
lar structures around the pancreas. A pre-laparotomy patients. Thus, these patients with potentially limited
laparoscopy (with a peritoneal lavage) is very useful in disease merit consideration for innovative approaches,
diagnosing peritoneal/omental seeding below the resolu- including intraoperative brachytherapy.
tion of the CT scan. Selected cases may also require one
or more of the following: ultrasonography, endoscopic CHEMOTHERAPY
retrograde pancreatography, endoscopic ultrasonogra- 5-Fluorouracil (5-FU) used to be the only agent with any
phy, or celiac angiography. The current staging system is demonstrated responses in pancreatic cancer, but it does
based on the AJCC staging classification (Table 22.1). not confer any survival benefit. Combination chemo-
therapy may produce more objective tumor responses,
Table 22.1 AJCC staging classification for cancer of the exocrine but does not appear to prolong median survival beyond
pancreas that expected with single-agent regimens [22]. The
T Primary tumor arrival of gemcytabine on the chemotherapy scene has
TX Primary tumor cannot be assessed raised new hopes for these patients. In one randomized
TO No evidence of primary tumor study comparing 5-FU with gemcytabine in previously
T1 Tumor limited to pancreas untreated patients, gemcytabine was associated with a
T1a Tumor 2 cm or less in greatest dimension significantly better response rate and median survival as
T1 b Tumor more than 2 cm in greatest dimension well as palliation of disease-related symptoms (pain,
T2 Tumor extends directly to any of the following: weight loss, performance status) [23].
duodenum, bile duct, peri pancreatic tissues
T3 Tumor extends directly to any of the following:
RADIATION THERAPY
stomach, spleen, colon, adjacent large vessels
Attempts at definitive external-beam radiotherapy have
N Regional lymph nodes met with little success. Due to the high incidence of local
NX Regional lymph nodes cannot be assessed failure in these patients, attempts have been made to esca-
NO No regional lymph node metastases
late the radiation dose. A major deterrent to this is the close
N1 Regional lymph node metastases
proximity of dose-limiting structures such as the liver,
M Distant metastases duodenum, stomach, kidney, and spinal cord. Although
MX Presence of distant metastases cannot be assessed recent developments in three-dimensional radiation ther-
MO No distant metastases apy allow the delivery of higher doses to the tumor volume
M1 Distant metastases while minimizing radiation damage to the surrounding
structures [24], local control is still a major problem and
Stage grouping the survival benefit is uncertain. The role of conventional
Stage 1 T1 NO MO external-beam radiation therapy in pancreatic carcinoma
T2 NO MO is essentially limited to palliation of pain; an occasional
Stage II T3 NO MO patient with localized, but unresectable, disease may
Stage III AnyT N1 MO
obtain a survival benefit. Combined modality treatment
Stage IV AnyT AnyN M1
using external radiation therapy and 5-FU has been

demonstrated to increase median survival rates in patients
with locally unresectable disease. The Gastrointestinal
Tumor Study Group (GITSG) randomized trial, which
treated inoperable patients with a curative intent, pro-
vided the first definite evidence that chemoradiation
could actually prolong survival in this otherwise fatal dis-
ease. However, even in that trial, the median survival was
only 35 weeks with combined chemoradiation [25]. There
were no long-term survivors. Local failure still remains a
major problem [26].
INTRAOPERATIVE RADIATION THERAPY
Several institutions have studied the role of intraopera-
tive electrons to boost the dose to the tumor bed; in this
setting, a single large fraction of radiation can be deliv-
ered in the operating room, while retracting all the vital
structures away from the radiation field [26-28]. The
results suggest a definite impact on local control, but
overall survival is not affected. Because of the wide range
of intraoperative radiation therapy (IORT) doses and
the adjuvant therapies that have been given with it, inter-
pretation of results is difficult [28].
Thus, for patients with resectable disease and espe-
cially those with unresectable disease, the current meth-
ods of treatment have had little impact on median
survival in the last 15 years. However, the available infor-
mation from external-beam dose escalation protocols
and the experience with IORT suggest that pancreatic
cancer does exhibit a dose-response relationship with
radiation. Administration of higher doses can improve
local control, and this may translate into better survival.
Data also suggest that the concomitant administration of
chemotherapy and high-dose radiation increases median
survival. Interstitial brachytherapy offers us the ideal
avenue for maximal dose escalation.
The concept of brachytherapy in pancreatic cancer is
not new. Handley first performed an interstitial pancre-
atic implant back in 1934 [29] and is quoted as having
said'. .. a surgeon who, on opening the abdomen, finds
an irremovable cancer is not doing his duty to the patient
unless he subjects the growth to interstitial irradiation'
[30]. One of the major advantages of brachytherapy is the
Table 22.2 Brachytherapy approaches employed in pancreatic cancer
Intraoperative external- Via naso-pancreatictube
beam therapy for selected cases of
Orthovoltage ampullary cancers
Electron beam
Intraoperative high dose-rate
brachytherapy
HAM applicator
Catheter based
HAM = Harrison-Anderson-Mick; USG = ultrasound.
Pancreatic cancer 319
ability to conform and sharply limit the radiation dose to
the implanted area, thus allowing delivery of a very large
radiation boost to the site of gross disease. Brachytherapy
in pancreatic cancer has been implemented using several
different approaches (Table 22.2). This chapter focuses
exclusively on intraoperative interstitial implants. This
approach can be utilized both in unresectable and in
resected carcinomas of the pancreas and these intraoper-
ative implants can be combined with postoperative stan-
dard external-beam radiation and/or chemotherapy.
INTRAOPERATIVE BRACHYTHERAPY
Intraoperative brachytherapy is a radiation technique
that delivers a high local dose to the tumor volume while
sparing normal surrounding tissue. Theoretically, the
application of interstitial brachytherapy to pancreatic
cancer should offer a better chance for loco-regional
control [31] because: (1) the physical dose distribution
favors a higher total dose delivered at a higher dose rate
to the tumor than to the adjacent normal tissues; (2) bio-
logically, the delivery of a continuous therapeutic dose
over a defined interval of time may offer a therapeutic
advantage [32]; (3) it allows for the delivery of a rela-
tively higher dose to the center of the implant where
more resistant hypoxic tumor cells may exist; and (4)
brachytherapy can be combined with external radiation
with no additional morbidity.
Indications for intraoperative brachytherapy
Basic radiotherapeutic principles dictate that candidates
for intraoperative brachytherapy have pancreatic tumors
that are unresectable but localized, with no evidence of
metastatic liver, omental or peritoneal disease. The pri-
mary tumor should have minimal, if any, peripancreatic
extension, to allow for the inclusion of all the known
tumor volume within the implant. If regional nodal
metastases are present and an implant is feasible, an
interstitial implant may be done in order to relieve pain,
but the intent would clearly be palliative. A histologic
diagnosis by frozen section should be available. Patients
with portal hypertension and tumors larger than 6 cm.
are not candidates for intraoperative brachytherapy.
Interstitial
Intraoperative
lodine-125
Palladium-103
Percutaneous
CT guided
USG guided
Infusional
320 Brachytherapy in the treatment of pancreas and bile duct cancer

Available isotopes 22*23 Treatment planning and technique

The suitability of a radionuclide for interstitial
brachytherapy depends on its half-life, its photon energy Intraoperative permanent interstitial implants, in which
spectrum, and the number of photons it produces per radioactive sources are permanently placed in the tissue,
decay (Table 22.3). Radionuclides with short half-lives are the preferred approach because of the relative sim-
are advantageous for permanent brachytherapy applica- plicity and easy applicability to deep-seated tumors such
tions in pancreatic tumors because the rapid dose deliv- as pancreatic cancers. Temporary implantation in this
ery will aid in controlling fast-growing tumors. The location is associated with a number of technical diffi-
radiation hazard from the patient will also decrease more culties related to proper catheter placement and subse-
rapidly [33]. Choice of photon energy determines the quent removal, and is not recommended in this setting.
penetrating ability of radiation in tissue [34]. Photon The successful outcome of a brachytherapy treatment
energies from isotope sources have a wide range, from 20 depends upon careful preoperative planning and a pre-
to 1060 KeV (Table 22.3). cise implementation of the technique. An accurate delin-
Gold-198 was one of the earlier isotopes used, as a eation of the tumor volume and proper spacing of
substitute for radon [35]. Its short half-life and higher sources are essential to avoid overdosage and necrosis
photon energy increase the radiation exposure to hospi- within the tumor volume or 'cold spots' and consequent
tal personnel and result in excessive radiation doses to underdosage of the tumor.
the surrounding normal structures. We do not consider The basic permanent interstitial technique is used for
this as a suitable radionuclide for pancreatic implants tumors of the pancreas (Figure 22. la-f) [45]. It consists of
today. two steps: the insertion of unloaded needles and the sub-
Iodine-125 was the preferred isotope for several years
[36-42]. This was primarily because of its low photon
energy, ranging from 27 to 35 KeV [36], which mini-
mizes the radiation to any of the surrounding vital struc-
tures. The major disadvantage of iodine-125 as a
permanent implant isotope is the low dose rate, of about
7-8 cGy tf1 (as a result of a long half-life of 60 days cou-
pled with sources of low specific activity). This is obvi-
ously a disadvantage when dealing with aggressive,
rapidly growing tumors wherein tumor proliferation can
easily outstrip radiation-induced cell kill.
Palladium-103 is a new isotope developed specifically
to address this issue. Its half-life of 17 days with a high
specific activity yields dose rates of 18-20 cGy h~'. At the
same time, the energy spectrum from palladium-103, of
20-35 KeV [43,44], is low enough to spare the sur- Figure 22.1 a A CTscan of the abdomen in a patient with
rounding sensitive and dose-limiting structures, like the localized unresectable carcinoma in the head of the pancreas.
stomach, small bowel, anastamotic sites, etc. These prop- This tumor was unresectable because of superior mesenteric
erties make it more favorable in the treatment of rapidly artery invasion.
growing tumors such as pancreatic carcinoma because
most of the dose radiation is delivered over a short
period (8 weeks) and prolonged radiation exposure of
adjacent normal tissue is minimized. We have employed
palladium-103 as a substitute for iodine-125 in intraop-
erative brachytherapy of pancreatic carcinoma in a phase
I-II study [44]. The findings of this study are discussed
under the results section.

Table 22.3 Isotopes for permanent implants in pancreas

rnrrinnmn

Gold-198 2.7 0.412 2.5 Figure 22.1 b Mobilization of the pancreas and bimanual
lodine-125 60.2 0.028 average 0.025
examination. Also shown is retraction of stomach by the metal
Palladium-103 17.0 0.021 average 0.008
retractor.

Figure 22.1 c Insertion of a 75 cm long afterloading needle
into the head of the pancreas.
Figure 22.1 d Measuring the depth-wise dimensions of the
tumor with the help of a metal ruler.
sequent afterloading with radioactive isotope. An
exploratory laparotomy allows an accurate determination
of the extent of disease, making possible a decision as to
resectability or the alternative option of permanent inter-
stitial implant with iodine-125 or palladium sources.
Satisfactory tumor exposure is essential to a good
implant. Mobilization of the stomach and upward retrac-
tion will expose the anterior surface of the pancreas, allow-
ing the proper insertion of the unloaded needles. In lesions
of the pancreatic head, mobilization of the duodenum
(Kocher's maneuver) will aid in the determination of the
posterior extent of the tumor. The tumor dimensions are
measured in X, Y, and Z directions - the length and width
are measured using caliper, while the anteroposterior
dimension is estimated by carefully placing a 15 cm long, 17
gauge needle into the tumor and seeing how much of the
needle still protrudes above the pancreas. The total activity
to be implanted is based on the average dimension (X+Y +
Z -5- 3) of the region to be treated. A minimum peripheral
dose of 160 Gy is prescribed using iodine-125 sources,
while 110 Gy is prescribed for palladium-103 (because of
its shorter half-life, and higher dose rate). The total activity
Pancreatic cancer 321
Figure 22.1 e Mobilization of the head of the pancreas with
insertion of afterloading 16-gauge needles for insertion of
radioactive pellets.
Figure 22.1f A postoperative CT scan showing optimal
placement of radioactive pellets into the head of the pancreas.
and number of radioactive sources required to deliver this
dose are determined from a nomograph (Figures 22.2 and
22.3), based on the estimated average dimension of the
tumor. The nomograph also gives information on the total
number of afterloading needles required to place the
required number of sources and, thus, the source spacing.
The predetermined number of needles are inserted into the
pancreatic tumor as parallel to each other as possible, usu-
ally with an interneedle spacing of 1.0-1.5 cm, and the
sources are introduced into the needles with the help of a
permanent implantation applicator.
The radioactive seeds should be placed at least 0.5-1.0
cm distant from the surface of the pancreas in order to
avoid radiation damage to the adjacent stomach and
duodenum. A segment of omentum should be posi-
tioned over the implanted tumor to increase the distance
between the implanted seeds and the bowel and to pre-
vent leakage of pancreatic fluid. Small surgical hemoclips
should be placed on the anterior surface of the pancre-
atic tumor to define the region on future localization
films for dosimetry evaluation, as well as to help delin-
eate the target volume for any planned external-beam
322 Brachytherapy in the treatment of pancreas and bile duct cancer

therapy. Stereo shift or orthogonal films are taken when
the patient becomes ambulatory, usually on postopera-
tive day 3 or 4 (Figures 22.Ig and 22.4), isodose contours
are generated, and the minimum and maximum tumor
doses can be estimated.
Postoperative external-beam radiotherapy to the pri-
mary and regional lymphatics may be added, with or
without chemotherapy. This is usually instituted 3-6
weeks following surgery, to allow for complete recovery
from the operation. External-beam therapy is usually

Figure 22.1 g A postoperative

CT scan showing the combined
dose distribution from
permanent implant and
external-beam radiation to 4500
Gy in 5 weeks. In this example
the head of the pancreas and
peripancreatic areas received a
combination dose (external
beam and implant) between
9000 and 10 000 cGy, with a
significantly lower dose given to
the adjacent normal structures.

Figure 22.2 Nomograph for palladium-103.


Figure 22.3 Nomograph for iodine-125.
delivered through a three-field or four-field plan, deliv-
ering a dose of 4500-5040 cGy in 180 cGy fractions, and
5-FU mitomycin-C may be added in the first and last
week of radiotherapy.
RESULTS
Borgelt reported on the experience at the M.D.
Anderson Cancer Center using gold grain implants for
Figure 22.4 Complications as a function of isotope used. The
complications are significantly higher for gold-198 (Au-198)
compared with iodine-125 (1-125), and least with palladium-103
(Pd-103).
Pancreatic cancer 323
unresectable pancreatic cancer [46]. A median survival
of 8 months was reported. Major morbidity (26%) and
mortality (13%) were very high. The author ascribed
the high incidence of complications to the dosimetric
characteristics of gold-198, with the higher photon
energy and excessive radiation dose to adjacent normal
tissues being the main causes of the postoperative
complications.
In an earlier study, Peretz et al. reported on 98 patients
with biopsy-proven unresectable adenocarcinoma of the
pancreas treated with intraoperative iodine-125
implants [37]. Thirty patients had Tl NO MO disease, 47
patients had T2-3 NO MO disease, and 21 patients had
significant regional lymph node involvement (Tl-3 Nl
MO). Of the 57 patients who presented with pain, 37
(65%) were free of pain following the implant. Sixty-two
patients had one or more follow-up localization films to
assess tumor response; a 30% or greater reduction in the
tumor size was seen in 28 (45%). A multivariate analysis
showed that four factors significantly affected survival: T
stage (p = 0.002), N stage (p = 0.017), administration of
chemotherapy (p = 0.002), and greater than 30% reduc-
tion in the size of the implant volume on follow-up films
(p = 0.03). Whereas the median survival for the entire
324 Brachytherapy in the treatment of pancreas and bile duct cancer
group was 7 months, a subgroup of patients with Tl NO
stage disease who received postoperative chemotherapy
survived 18.5 months. This advantage of post-implant
chemotherapy has also been reported by other groups
[47].
Thus, the cumulative experience with pancreatic
implants using iodine-125 sources for unresectable pan-
creatic tumors demonstrates a significant palliation of
symptoms, with circumstantial evidence of local control
of the primary tumor in a high proportion of the
patients (as evidenced by a reduction in the implant vol-
ume on follow-up CT scans). Post-implant chemother-
apy enhances the final outcomes and, in a select subset of
patients, this multimodality approach may even prolong
survival (the 18.5 months' median survival compares
favorably to several surgical series with little of the atten-
dant morbidity).
As discussed above, one of the disadvantages of
iodine-125 is its long half-life time and the consequent
very low dose rate of radiation. Palladium-103 over-
comes this major disadvantage by virtue of its short
half-life (17 days); this permits the use of higher total
activities, with higher dose rates for a given total dose.
To evaluate this clinically, we implemented a phase I/II
trial to study the feasibility, toxicity, and palliative effi-
cacy of palladium-103 as an intraoperative, interstitial
isotope for localized but unresectable pancreatic ade-
nocarcinoma [44]. Fifteen patients with biopsy-proven
unresectable adenocarcinoma of the pancreas were
implanted with interstitial palladium-103 during
laparotomy. The technique of implantation and the
instrumentation are the same as with iodine-125. The
palladium-103 nomograph assures the minimum
peripheral dose of 11 000 cGy. In addition, all patients
underwent biliary and gastric bypass. A mean of 45
palladium-103 sources was implanted; the mean total
activity (to obtain a minimum peripheral dose of
11000 cGy) was 68.9 mCi. All patients received post-
operative external-beam radiation (4500 cGy in 5
weeks).
This combined treatment, consisting of intraoperative
brachytherapy using palladium-103 and postoperative
external-beam radiation, was well tolerated in all
patients. There was no treatment-related mortality, and
no serious complications such as bleeding or fistula for-
mation. Pain relief was obtained within 3-6 weeks in ten
out of 12 patients presenting with pain. Survival ranged
from 6 to 24 months, with a median survival of 10
months. The absence of complications is particularly
gratifying considering other reports in the literature
[48]; we believe that appropriate patient selection and
meticulous attention to technical details can help mini-
mize the complication rate in this rather challenging
anatomic site.
This study suggests that palladium-103 can be consid-
ered an alternative source to iodine-125 for interstitial
brachytherapy for unresectable carcinoma of the pan-
creas. Because of its shorter half-life, palladium-103 can
be implanted at higher total activities. The surrounding
normal tissue, such as the stomach, small bowel, and
anastamotic sites, is spared from radiation reactions
more effectively because of the low gamma ray energy
spectrum of palladium-103 as compared to that of
iodine-125. This study also suggests a faster rate of pain
palliation compared to the iodine-125 series, although
median survival rates are similar to those observed in
patients implanted with iodine-125. Because of the
phase I/II nature of the study, a particularly unfavorable
group was selected for this protocol (Figure 22.5), mak-
ing interpretation of survival data difficult. However, one
patient with biopsy-proven unresectable pancreatic ade-
nocarcinoma did survive almost 5 years; at 3.5 years
post-implant, he had a second laparotomy for adhesive
small bowel obstruction, and biopsies of his primary site
were completely free of disease [49]. The patient eventu-
ally succumbed to disseminated intra-abdominal
disease.
Figure 22.5 Comparative median survival data shown in bar
graphs for different isotopes used for unresectable carcinoma
compared with surgical results for resectable carcinoma of the
pancreas.
22.2A Summary/conclusions
It is apparent that standard therapies fail to control the
local progression of disease in patients with unresectable
pancreatic carcinoma; this may be a significant factor in
their ultimate death. Intraoperative brachytherapy offers
the potential of maximal dose escalation in these
patients; significant tumor responses have been reported
in a number of clinical series to date [37,40,47]. Current
data indicate that this procedure is most effective in a
subgroup of patients with early-stage, unresectable dis-
ease, especially when coupled with postoperative sys-
temic chemotherapy.
Thus, intraoperative brachytherapy, when properly
implemented, can deliver a high radiation dose and
achieve faster pain palliation and better local control
without significantly increasing complications or opera-
tive mortality.
 Bile duct carcinoma 325

223 BILE DUCT CARCINOMA Table 22.4 AJCC staging classification for cancer of the
extra hepatic biliary duct cancers

Biliary duct carcinoma is a relatively rare disease in the T Primary Tumor

TX Primary tumor cannot be assessed
USA and the Western hemisphere. Approximately 4000
Tis Carcinoma in situ
new cases are reported in the USA each year and less
Tl Tumor invades mucosa or muscle layer
than 10% of these achieve a prolonged 'cure' [50]. T2 Tumor invades perimuscular connective tissue
T3 Tumor invades adjacent structures: liver, pancreas,
duodenum, gallbladder, colon, stomach
223.1 Pretreatment assessment
N Regional lymph nodes
Patients present with painless obstructive jaundice, NX Regional lymph nodes cannot be assessed
weight loss, pruritus, and a Courvoisier gallbladder. NO No regional lymph node metastasis
Positive physical findings are few in the early stages of N1 Regional lymph node metastasis
the disease, and a palpable right upper quadrant mass, a N1A Metastasis in cystic duct, pericholedochal, and/or
periumbilical mass, or a rectal shelf usually indicate late- hilar lymph nodes (i.e., in the hepatoduodenal
stage disease [51]. The majority of patients with bile duct ligament)
carcinoma will have elevations of bilirubin and alkaline N1B Metastasis in peripancreatic (head only),
phosphatase. Although many diseases can mimic bile periduodenal, periportal, celiac, and/or superior
mesenteric lymph nodes
duct carcinoma, the distinction between bile duct carci-
noma and another process can be made on the basis of
M Metastasis
clinical presentation and results of imaging studies such MX Metastasis cannot be assessed
as ultrasonography, high-resolution spiral CT, magnetic MO No metastasis
resonance imaging (MRI), percutaneous transhepatic M1 Metastasis present
cholangiography (PTCA), and endoscopic retrograde
cholangiopancreaticography (ERCP) [52]. Stage grouping
Stage I T1 NO MO
STAGING Stage 1 1 T2 NO MO
Stage I II T3 NO MO
These tumors pose a therapeutic challenge, because they Stage IVA AnyT N1 MO
are often multicentric, or can spread extensively along Stage IVB AnyT Any N M1
the ductal system by contiguity, placing the entire biliary
tree at risk. The walls of the biliary tree are very thin, and
the outer layers have a rich lymphatic system. This prob-
ably accounts for the fact that the majority of the from 7% to 44%, especially with extended hepatic resec-
patients present with locally advanced disease, with tions (54). Hence, most of the patients are managed with
adherence to, or encasement of, the periductal vascular palliative procedures, such as stenting, with an occa-
structures, and/or regional lymphadenopathy [53]; less sional patient undergoing a palliative local or limited
than 20% of patients with bile duct carcinoma are can- resection [54]. Even after curative resection, the local
didates for a potentially curative resection [54]. recurrence rate is high and the mean survival is 16-20
However, hematogenous dissemination with distant months [56]. The majority of patients die from uncon-
metastases is uncommon, at least at presentation. The trolled loco-regional disease [57] with biliary obstruc-
staging is based on the AJCC/UICC classification system tion, sepsis, and liver failure.
(Table 22.4).
CHEMOTHERAPY

Few chemotherapeutic agents show significant activity

223.2 General management
SURGERY
A complete surgical resection with pathologically nega-
tive margins probably offers the only hope for cure in
these patients. However, only about 10-20% of the
patients are operable at presentation and, of these,
40-50% cannot undergo a curative resection at the time
of laparotomy, due to invasion of adjacent major blood
vessels, the presence of extensive intraductal involve-
ment, peritoneal seeding, or regional lymph node spread
[51,53,55]. Operative mortality is high; reports range
against biliary carcinomas. Although the reason for this
lack of sensitivity is unknown, it may be due to inherent
cellular resistance to the available drugs or poor delivery
of the chemotherapeutic agent to the tumor due to
intense peritumoral fibrosis [57].
The relatively small patient population may also
account for the paucity of chemotherapeutic protocols in
biliary cancer, when compared to other more common
gastrointestinal malignancies [54]. Investigators have had
the broadest experience with 5-FU, which has response
rates of approximately 14% [58-60]. Single-agent activity
has been noted with other drugs, such as adriamycin, but
326 Brachytherapy in the treatment of pancreas and bile duct cancer
clinical results have been disappointing [54]. Currently,
no combination regimen has proven sufficiently encour-
aging to become established therapy [57].
RADIATION THERAPY
Given the overwhelming problem of loco-regional dis-
ease, radiation therapy would be the logical modality for
these patients. However, despite lack of good supporting
data, bile duct carcinomas have been traditionally con-
sidered radioresistant. It is only since the mid 1970s that
a number of reports have appeared in the literature indi-
cating that radiotherapy has a useful palliative role and
may even prolong survival in selected patients with
unresectable disease [57]. As with pancreatic cancer,
however, the proximity of the liver, duodenum, stomach,
spinal cord, and kidney limit the dose that can be safely
delivered using conventional approaches.
INTRAOPERATIVE RADIATION THERAPY
The application of IORT, which allows a substantive,
single dose of radiation to be delivered to the tumor
exposed at laparotomy, has been used alone and in com-
bination with external-beam radiation therapy in the
treatment of bile duct tumors [61], Damage to the small
bowel is minimized by the strategic use of retractors,
while the dose profile of the electron beam spares the
deeper tissues such as the kidneys and spinal cord.
Various doses of IORT have been employed in different
series [61-65]. There is a suggestion of slight survival
benefit in some series [63]; clinical estimates of tumor
control may, however, be overestimated [51], as there is
no pathological confirmation of local disease eradication,
and the majority of the patients still succumb to loco-
regional disease. The other major limitation of this
technique lies in the radiobiology of large-fraction radio-
therapy. The single large dose of radiation is associated
with a high risk of late normal-tissue damage; fibrosis of
the biliary duct can occur after single doses of 15 Gy and
doses greater than 30-40 Gy can cause secondary biliary
stenosis. Major mucosal edema followed by stenosis and
even perforation will occur at 30 Gy after 6 weeks [57]. A
variety of other severe side-effects, such as duodenal
ulceration and hemorrhage, have also been described.
Iwasaki et al. reported four fatal complications in a series
of 19 patients as a result of this treatment [62].
MULTIMODALITY TREATMENT
Progress in the treatment of bile duct carcinomas is
anticipated from a multimodality approach. Because
loco-regional disease seems to dominate the clinical pic-
ture, advances in optimizing radiation therapy offer the
potential for the greatest clinical gains. This could be
achieved by the combination of external-beam therapy
with a local boost from either intraluminal sources or
intraoperative external-beam radiation. The use of 5-FU
as a radio-sensitizing agent may further improve results.
In 1990, we reported our experience with 5-FU
chemotherapy in combination with radiation therapy
(50 Gy to the tumor bed and lymph nodes); most
patients received a low dose-rate intraluminal boost of
15-20 Gy. This treatment was well tolerated and the
overall 3-year actuarial survival was 50% [55]. However,
the use of low dose-rate (LDR) brachytherapy was asso-
ciated with logistical, technical, and significant radiation
exposure problems.
The feasibility and morbidity of external-beam radio-
therapy with or without intraluminal irradiation have
been reported in a series of 38 patients [83]. It was con-
cluded that accelerated external-beam radiotherapy with
or without intraluminal treatment was feasible and asso-
ciated with acceptable toxicity.
BRACHYTHERAPY
Intraluminal brachytherapy is an important component
in the multimodality approach to bile duct carcinomas.
The objective of this treatment is to deliver a high local
dose of radiation to the tumor while sparing surround-
ing normal tissues. The treatment can be safely adapted
for right and left hepatic duct as well as for common bile
duct lesions. Several different techniques have been
described; most of these are variants on one of two
themes, employing either conventional strength iridium-
192 sources at a low dose rate (LDR) or the high dose-
rate (HDR) remote afterloading technique. It has been
reported that there does not appear to be any difference
in survival or complications between low dose-rate and
high dose-rate brachytherapy after biliary drainage,
although local failure was a continuing problem [84].
The approach to source placement is where these tech-
niques differ - thus, the plastic catheters (through which
the radiation sources are loaded) can be placed at the
time of the radiological studies (PTCA), or at laparo-
tomy, or via an endoscope during an ERCP.
The transhepatic catheter placement (during PTCA)
has the advantage of providing both internal drainage
across the tumor and external drainage via the proximal
end of the catheter. Occasionally, peritumoral edema
may block the passage of the tube into the duodenum; a
few days of external decompression of the biliary tree
allows the edema to resolve and a second attempt is usu-
ally successful in passing the tube into the duodenum. In
the face of a refractory obstruction, intraluminal
brachytherapy to the proximal tumor may further help
open up the channel to the duodenum [66]. This is
probably the preferred approach in most cases.
Intraoperative catheter placement (T-tubes and sev-
eral other variants) can be performed by the surgeon
after biopsy, bypass, or resection. It is very important to
coordinate the procedure with the radiation oncologist
to ensure an appropriate location of the catheters in rela-
tion to the tumor, tumor margins, and bowel segments,

as well as to ensure that the lie of the catheter has no
acute angulations which can preclude successful after-
loading [67,68].
Catheter insertion can also be accomplished by the
gastroenterologist at the time of the ERCP [69,70]. This
technique has the advantages of avoiding a percutaneous
liver puncture and a laparotomy. It is essential that the
gastroenterologist avoid the creation of a redundant
loop in the duodenum which is difficult for the HDR
source to negotiate [71,72]. The necessity for multiple
ERCPs, difficulty in anchoring the catheter in the biliary
tree, accidental irradiation of the duodenum, in-transit
irradiation of the upper gastrointestinal structures,
problems with the source negotiating the long path cre-
ated by the transnasal catheter all the way to the bile
duct, and the need to remove, and then replace, the bil-
iary endoprosthesis are all problems with this approach.
TREATMENT PLANNING AND TECHNIQUE
The following general principles are applicable for per-
cutaneous biliary irradiation regardless of the specific
technique employed.
1. The site and length of the malignant stricture are
identified by review of the cholangiograms (Figure
22.6).
2. Biliary drainage is established with an adequate-
sized catheter (10 French for LDR techniques, and
12-14 French for HDR techniques).
3. The patient is pretreated with antibiotics (usually
ciprofloxacin) the day before the procedure, and the
antibiotics are usually continued for a day following
the procedure.
4. The outer end of the biliary drain is opened, cleaned
well with Betadine, and flushed with 50 ml of
normal saline.
5. The sterile, blind-ended brachytherapy applicator
catheter is passed through the biliary drainage
catheter; this passage may be eased by keeping a
Figure 22.6 Cholangiogmm of a 60-year-old white male
showing obstruction of common hepatic duct.
Bile duct carcinoma 327
guide wire within the brachytherapy catheter to
'stiffen' it and help negotiate any curves or bends.
However, it should be remembered that the
transhepatic drain has numerous side-holes, both
proximal and distal to the stricture, and the
brachytherapy catheter may be 'deflected' out
through one of these holes, especially if it encounters
resistance to smooth passage along the biliary drain.
This could result in penetration of the liver
parenchyma by the catheter, and should be
suspected any time the patient complains of
discomfort or pain during the negotiation of the
catheter. The use of fluoroscopy with or without
biliary contrast injection can help in such situations.
6. A dummy source is then passed into the
brachytherapy catheter and orthogonal radiographs
are obtained for computerized dosimetry (Figure
22.7).
7. The target volume is carefully delineated on the
simulation films, using the original cholangiograms
as a guide.
8. Following the generation of a computer-assisted
plan, the patient is treated to the prescribed dose.
9. With continued aseptic precautions, the
brachytherapy catheter is withdrawn, the biliary tree
is flushed again with 50 ml of sterile normal saline,
and external biliary drainage is reinstituted.
TARGET VOLUME
Given the multicentric nature of the tumor, the propen-
sity for submucosal or intraluminal spread, and reports
of marginal failures in the early literature, a wide variety
of margins have been employed proximal and distal to
the cholangiographic abnormality, while defining the
target length. Herskovic et al. [73] even recommended
irradiating a length extending from the ampulla to at
least 5 cm proximal to the hepatic bifurcation. Levitt et
al. [72] recommend a source length 1.5 times the length
of the stricture. We recommend a margin of 2-3 cm on
either side of the cholangiographic abnormality and
have not noted any marginal failures with this approach.
DOSE SPECIFICATION
The diameter of the extrahepatic biliary tree can vary
from 3 mm to 25 mm [73]. Traditional cholangiographic
imaging is barely adequate in defining the presumed
proximal and distal extent of disease; it gives no indica-
tion as to the lateral extent of the tumor. Various pre-
scription points have been employed - distances of
0.5-1.5 cm with the reference being either the source
train or the exterior catheter wall, or even the bile duct
surface; sometimes, the reference point is not even spec-
ified. This results in a great variation in reported deliv-
ered doses and dose rates. It also makes it difficult to
compare results from different series; an analysis of
complications and derivation of a dose-response
328 Brachytherapy in the treatment of pancreas and bile duct cancer
relationship are a real challenge, given the heterogeneity
of data. In order to standardize dose prescription and
make inter-institutional comparisons meaningful, it is
recommended that the dose be prescribed at 1 cm from
the central axis of the source.
DOSE-FRACTIONATION SCHEMES
Traditionally, a 2-4-week gap has been allowed between
the completion of the external-beam radiotherapy and
the institution of brachytherapy, although there are no
hard data to support the use of any break at all. While the
doses reported in the literature vary widely, a single frac-
tion of 2000 cGy, prescribed at 1 cm from the source axis,
is usually employed with LDR brachytherapy, when it is
used as a boost following external-beam radiotherapy.
Similarly, for HDR brachytherapy, we currently employ
four weekly fractions of 500 cGy, at a distance of 1 cm
from the source axis, as a boost following 45-50 Gy
external-beam therapy. In palliative settings, the therapy
obviously needs to be tailored to the individual patient.
RESULTS OF LOW DOSE-RATE THERAPY
Although several series have reported results of LDR intra-
luminal brachytherapy [69,70], none has conclusively
shown a survival advantage. Using the percutaneous
approach, Molt et al. [69] reported a median survival of
4.5 months amongst 15 patients undergoing treatment
with intraluminal brachytherapy. Similarly, Johnson et al.
(70) combined external-beam radiation and intraluminal
brachytherapy in the treatment of bile duct cancer and
reported a median survival of 5.5 months.
Results with endoscopic management of inoperable
cholangiocarcinoma using the LDR iridium-192 source
technique were reported by Ede et al. [71]. The authors
Figure 22.7 The right and left
transhepatic drainage catheter
and a dummy source ribbon in
the left catheter.
justified their endoscopic approach by the high rate of
morbidity and mortality associated with percutaneous
stent insertion in malignant obstructive jaundice. This
approach necessitated hospitalization and two ERCPs for
visualization of the biliary tree, localization of the tumor,
insertion of a stent, and administration of brachyther-
apy. Complete obstruction or strictures interfered with
this treatment in three out of 14 patients, necessitating a
percutaneous transhepatic drainage. A dose of 6000 cGy
was prescribed to 0.5 cm from the axis of the source. The
indwelling time ranged from 77 to 116 h (median 85 h),
depending on the length and activity of the available
source. No deaths were reported within the first 30 days
following the treatment. The complications related to
this treatment included transient increase in bilirubin
level noted in four patients due to interference with bile
drainage during the procedure, and ascending cholangi-
tis in 3/14 cases (21.4%) within 4 days following the
treatment. The rate of ascending cholangitis was 30%,
according to authors using a similar procedure [58]. The
patients in Ede's series were discharged from the hospi-
tal 2.5 days on average (range 0-28) following the proce-
dure. The overall median survival was 10.5 months.
The combination of external-beam radiation with
LDR internal irradiation via an indwelling biliary
catheter, reported by Herskovic et al., resulted in a very
high complication rate [73]. Seven out of 16 patients
(44%) experienced severe life-threatening complications
within 1-9 months following the procedure, such as sep-
tic shock, septicemia, abscesses, endocarditis, cholangi-
tis, hemobilia, duodenal and gastric ulcers. The median
survival in this series was 9 months.
One of the major problems inherent in the LDR
approach is the prolonged interference with biliary
drainage, resulting in a high risk for cholangitis and
 Conclusion 329

other septic complications. There is also the problem of patients reported mild to moderate gastrointestinal
radiation exposure to the treating personnel; the need symptoms, due to the external-beam radiation therapy,
for hospitalization is another issue in today's cost- which were treated symptomatically. None of the
conscious environment. All these issues are easily patients had any severe treatment-related complications
addressed by an HDR approach, as described below. necessitating admission. The median survival for the
entire group was 19 months. Decrease in jaundice was
reported by all patients. Symptomatic improvement,
RESULTS OF HIGH DOSE-RATE TREATMENT
such as increase in appetite and weight gain, was
We reported the results on a total of 46 HDR brachyther- reported by nine patients.
apy sessions in 14 patients with inoperable bile duct car-
cinomas [74,75]. The combined treatment, consisting of
EBRT and 5-FU and a boost given by conformal HDR 22.4 CONCLUSION
percutaneous transhepatic intraluminal cholangio-
irradiation (PTICI) was well tolerated by all 14 patients.
High dose-rate percutaneous transhepatic intraluminal
The general principles of transhepatic intraluminal
cholangio-irradiation, when combined with external-
brachytherapy, as described earlier, were implemented.
beam radiation and administration of 5-FU chemother-
12-French gauge hepatic drainage catheters were inserted
apy, is a well-tolerated procedure that may prolong the
in the right and in the left hepatic ducts. Following simu-
median survival of selected patients with unresectable
lation, and definition of the target length, the number of
bile duct carcinoma. This technique is simple, safe,
dwell positions, their optimal separations from each
reproducible, and is associated with a significantly lower
other, and the length of time the sources should remain in
complication rate and no exposure to personnel. The
each of the dwell positions to deliver a dose of 500 cGy to
entire procedure is done on an outpatient basis. Also, in
a depth of 1 cm from the catheter are determined with the
selected cases with complex tumor anatomy, the tech-
aid of a computer. A total of 2000 cGy is delivered in four
nique allows for a more versatile optimization of the
weekly fractions. The computerized optimization pro-
dose distribution, as well as offering the option to vary
gram is very useful in treating complex lesions involving
the dose prescription as the tumor regresses between
the right, left, and common hepatic ducts, as the dosime-
fractions (Table 22.5). As with any other brachytherapy
try at the bifurcation is quite complex. One month after
the last treatment, the patients were evaluated by the
interventional radiologist for placement of an internal
stent and removal of the biliary drainage catheter.
Kamada and colleagues analyzed the treatment of 145
consecutive patients treated by intraluminal iridium-192
irradiation either alone or in combination with external-
beam therapy (mean dose 83 Gy) with an expandable
metallic biliary endoprosthesis to establish an internal
bile passage. Median survival for patients for whom an
endoprosthesis was used was 14.9 months, compared to
9.3 months when no endoprosthesis was used. The over-
all results indicated a survival advantage for patients not
suited to surgical resection [81]. j-A-HDR PTICI [36] -a-LDR PTICI [59] --Conformal RT [6I]|
Conformal HDR brachytherapy, combined with
external-beam radiation therapy and 5-FU, appears to be Figure 22.8 Computerized disease-related survival with LDR
a safe, well-tolerated and efficient treatment for unre- and HDR brachytherapy compared with high dose conformal
sectable cholangiocarcinoma (Figure 22.8). Eight external-beam radiation.

Table 22.5 Comparison of LDR and HDR brachytherapy for bile duct carcinoma

Treatment duration 5-10min 24^8 h

Ability to optimize Very versatile Little, if any
Complications Few (little interruption of biliary drainage) High (prolonged interruption of biliary drainage)
Prescribed dose SOOcGyxS 2000cGyx1
Dose prescription point 1.0 cm from source axis 1.0 cm from source axis
Median survival 19 months 13 months
Cost Low (outpatient procedure) High (inpatient procedure)
330 Brachytherapy in the treatment of pancreas and bile duct cancer
procedure, good collaboration with the surgeon/radiolo-
gist and meticulous attention to detail are essential for a
safe and successful outcome. Further advances, including
a better definition of the target volume, and innovative
adjuncts like hyperthermia, may improve on these
results [76-87].
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 23
Brachytherapy for treating endometrial cancer

H. A. LADNER, A. PFLEIDERER, S. LADNER, AND U. KARCK

23,1 CLINICAL ASPECTS a 5-year survival rate of about 20%. In 1995, Weiss et al.
[8] reported only 21 patients who had undergone pri-
mary irradiation during the preceding 6 years. The
During the last 30 years, technical advances as well as
changes in therapy, as described above, have developed
clinical developments have produced a significant
slowly over the last 20 years. According to other authors
change in the diagnosis and therapy of endometrial can-
[9,10], the difference in survival rate between surgical
cer. The increase in absolute numbers of endometrial
and radiotherapy treatment was, in the decade until
cancers [1,2] and the increase of patients over 65 years of
1985, of the order of 20% (i.e., 80% survival versus
age cause a number of problems, including accompany-
60%), and it is difficult to evaluate the optimal indica-
ing illness, appropriate radiation fractionation schedules
tions for irradiation. Some of the management aspects
and techniques [3,4]. Progress in anesthesiology and
are now described, together with the technical progress
postoperative care now allows surgery in nearly all cases
that has been made. In this context, it appears important
of endometrial carcinoma. As a result of these develop-
to outline the best technical application of afterloading
ments, staging can now be based on postoperative
therapy in the future on the basis of the interesting
histopathological assessment. Relevant prognostic fac-
review by Joslin [11].
tors of endometrial cancer include stage (FIGO), depth
of myometrial invasion, extrauterine extension, histolog-
ical subtype, grade, ploidy, and levels of progesterone 23*1*1 Brachytherapy
receptors. Pathogenetically, two different types are
described [5,6]. The estrogen-dependent type A is char- There are three main requirements for the best appro-
acterized by a low histologic grade 1, high progesterone priate use of brachytherapy:
receptor value, endometrioid cancer in obese patients,
1. Spatial dose distribution must be adapted to the
and has an excellent prognosis. Type B cancers show no
individual anatomical situation.
hormonal stimulation, are high-grade cancers [3] with-
2. Temporal dose distribution should be short enough
out progesterone receptor activity, and have a poor prog-
to avoid clinical complications without reducing the
nosis.
therapeutic ratio.
A review of the recent literature shows almost general
3. The technique should be simple to apply and allow
agreement that the cornerstone of curative treatment for
for reproducible source positioning. It should also be
endometrial carcinoma is abdominal hysterectomy,
safe to use and allow for adequate radiation
bilateral oophorectomy, and facultative lymphadenec-
protection of staff.
tomy [7]. Modern facilities now provide for surgery in
obese, elderly women with vascular illness, which has In the past, these requirements were not always satisfac-
dramatically reduced the number of 'inoperable' torily met.
patients. Only a few patients with inoperable endome- The classic radium methods such as the Paris System,
trial carcinoma now receive primary radiotherapy, with the Manchester System, and the method of Fletcher et al.
334 Brachytherapy for treating endometrial cancer
(1980) [12] involved protocols similar to those used for
cervical carcinoma, with some degree of individualiza-
tion. The Stockholm technique used flexible applicators
which formed the basis of the classical Heyman packing
technique of the uterine cavity with radium sources. It
allowed the dose distribution to be adapted to the vari-
ous shapes and sizes of uterine cavity in an optimal way,
especially in cases with exophytic tumors. Furthermore,
a relatively uniform dose distribution was delivered to
the entire myometrium.
High dose-rate (HDR) afterloading and its develop-
ment for irradiation of endometrial carcinoma are asso-
ciated with the name of Ulrich Henschke [ 13]. Following
his guidelines for remote HDR treatment of gynecologic
carcinomas, a variety of techniques in brachytherapy of
uterine cancer was established in the following years
[14-21,82].
Due to the use of combined treatments (brachyther-
apy and external-beam radiation therapy, EBRT), the sit-
uation was and still is complicated when looked at from
the radiobiology viewpoint [11]. This is due to the fact
that intracavitary irradiation is not delivered homo-
geneously throughout the treated volume. Further, in
consequence of the steep dose gradient from the brachy-
therapy, the normal tissues outside the brachytherapy
target volume receive relatively low doses of irradiation
and the brachytherapy target volume is small in compar-
ison to the external-beam target volume [11].
23.1.2 Dose rates and the choice of
nuclide
The reference dose rate according to the International
Commission on Radiation Units (1985) is defined as fol-
lows: HDR treatment with more than 12 Gy h'1, medium
dose-rate (MDR) treatment with 2-12 Gy h"1, and low
dose-rate (LDR) treatment with less than 2 Gy h"1.
There are different spatial arrangements of sources in
use, such as a single oscillating source, a single source
moving in steps (so-called train of different weighted
pellets), or a train containing active sources and spacers.
Simon and Silverstone [22] recommended a modified
Heyman packing technique using hollow capsules, after-
loaded by low-activity cesium-137 sources. However,
they were confronted with the clinical consequences of a
relatively long treatment time and lack of radiation pro-
tection for staff and visitors.
A prerequisite for the achievement of optimal spatial
and temporal dose distribution in combination with
radiation protection and the advantages of Heyman-
style packing with remote HDR afterloading is the avail-
ability of small sources and computerized treatment
planning. One good example seems to be the Wurzburg
system, with small iridium-192 sources (diameter 1 mm)
in conjunction with a MicroSelectron HDR afterloading
machine, which allows for different kinds of dose opti-
mization when carrying out treatment planning (for
technical details, see Herbolsheimer et al. [23]).
Optimization according to the individual case can be
performed by altering the dwell times of the six to 18 dif-
ferent capsules.
When comparing the advantages of cesium-13 7,
cobalt-60 and iridium-192 in regard to size, specific
activity, and gamma energy, cesium-137 meets the spe-
cial requirements best. This was reported in 1977 by
Walstam [24], who suggested cesium-137 as the most
suitable nuclide for brachytherapy in general.
23.2 MANAGEMENT AND CLINICAL
PRACTICE
The technique used by M. Herbolsheimer and K. Rotte
in the U K F Wurzburg (Germany) is one which we
advocate and now describe. One of the most important
requirements for optimal brachytherapy is to be able to
provide an individual dose distribution according to the
size and share of the uterine cavity. A modified packing
system such as the classical Heyman packing system
using HDR afterloading can only be used when a suffi-
cient number of small sources is available. This modified
method was introduced by Herbolsheimer and Rotte
(Wurzburg, Germany) in 1988. The use of small irid-
ium-192 sources (diameter 1 mm) allows the uterine
cavity to be packed with up to a maximum of 18 hollow
plastic capsules, each capsule having a diameter of 4 mm.
Following the placing of the capsules in the uterine
cavity, orthogonal pelvic radiographs showing the distri-
bution of the capsules, the measuring probes in the
organs at risk and the bony structures are taken and dig-
itized. A computer-controlled planning system provides
the dose distribution in three dimensions and calculates
the doses to the reference points of the organs at risk. In
order to adapt the reference isodose to the uterine sur-
face, the doses were prescribed to the so-called point
'MY' (myometrium) during the early years following the
introduction of the system. 'MY' is situated 2 cm lateral
to the central uterine axis and 2 cm below the most prox-
imal capsule, which means 2 cm below the uterine fun-
dus. Because the uterine shape is not visible on
conventional radiographs and due to the fact that the
point 'MY' is only an approximation, magnetic reso-
nance tomography has been introduced into the plan-
ning procedure since 1993. Double-angulated slices
(Figures 23.la and 23.Ib) are digitized and several refer-
ence points on the uterine surface are defined individu-
ally. In order to combine these points located on the
serosa of the uterus by the reference isodose, it is neces-
sary to distinguish each capsule from another and to
assess them separately. A binary code of the dummies
allows one to perform an optimization of the dose dis-
tribution. Five treatment fractions are given, each of 10

Gy separated by 10 days. These treatments are scheduled
within a course of megavoltage external-beam treatment
to the pelvic lymphatics using bisegmental-biaxial arc
rotation. Twenty-five fractions, each of 2.0 Gy, are deliv-
ered to the maximum dose point according to a three-
dimensional plan based on computer tomography. The
80% isodose should at least enclose the target volume.
The total dose to the center of the pelvis, that is to say to
the uterus, is delivered by brachytherapy alone, thus
external-beam treatment is restricted to the lateral pelvic
lymphatics. As a consequence, the mean dose to the
tumor will be considerably higher in comparison to a
treatment strategy using brachytherapy only as a boost
after homogeneous irradiation of the whole pelvis.
Moreover, the exposure of the organs at risk is lower.
This has been shown by analysis of more than 200
patients [23]. The new Wurzburg results (1988-1994)
demonstrate a 3-year actuarial survival rate of 82% in
Management and clinical practice 335
Figure 23.1 Digitized slices
from a scan illustrating the
isodose distribution in relation
to various reference points.
Isodoses are in centigrays and
axis scale dimensions are in
centimeters.
FIGO stage I-III patients (n=68, 9% recurrence rate). In
bulky tumors, which may be expected to contain a large
fraction of hypoxic cells, non-restricted brachytherapy is
used only as a boost. Compared with other afterloading
methods, the advantage of this technique is that it pro-
vides for individual planning of doses.
23.2.1 Forms of applicator
Techniques based on the use of rigid applicators do not
allow sufficient adaptation to individual anatomical sit-
uations. Only the applicators using iridium developed by
Bauer et al. [25], the cobalt bulb techniques of Bjornsson
and Sorbe [26], the flexible tube combined with vaginal
ovoids [27], and the endouterine'umbrella' [21] provide
a reasonable compromise with individual dose distribu-
tion because they use semi-flexible applicators. Other
336 Brachytherapy for treating endometrial cancer
authors perform uterine packing [17,28], sometimes
combined with ovoids in the vaginal vault [29].
23*2.2 Remarks about dose rate
There is no general agreement about what provides the
best remote-control brachytherapy method (low,
medium, or high dose rate). An important advantage of
LDR techniques remains the greater therapeutic ratio in
comparison to HDR regimes based on the repair capac-
ity of the tissues involved. Sublethal radiation damage
recovery of normal-tissue damage may occur during the
exposure time if the dose rate to any tissue or organ at
risk is similar to classic radium therapy [30]. The
reduced therapeutic ratio of HDR treatment in com-
parison with LDR brachytherapy requires adequate frac-
tionation based on mathematical models which relate to
time-dose relationships and take into account the time
factors for repair of normal tissue [31,32].
The question of which treatment method is the most
preferable, HDR or LDR afterloading, cannot be
answered [33]. Both strategies have their specific advan-
tages. In general, clinical studies comparing HDR and
LDR treatments confirm that there is no significant dif-
ference between the two modalities of brachytherapy
[10,28,34,35]. At present, there is a clear tendency in favor
of HDR brachytherapy. However, LDR techniques still
retain their place, which is not confined only to gyneco-
logic tumors. It seems to be a question of habituation or
availability of the afterloading machines. In Germany,
many radiotherapy institutions prefer HDR brachyther-
apy because it is also possible to use the machine for non-
gynecological patients requiring HDR. There is no
agreement in regard to the optimal dose rates.
23.23 Preoperative and postoperative
irradiation
Preoperative radiotherapy, partly combined with addi-
tional postoperative irradiation, has been used at several
institutions [12,21,35,36]. The value of preoperative
radiotherapy is discussed controversially [36,37]. Others,
such as de Waal and Lochmuller [38] and Calais et al.
[39], saw no improvement in the results after preopera-
tive radium or brachytherapy of endometrial carcinoma
compared to postoperative application. The timing of
radiotherapy (brachytherapy and EBRT), i.e., preopera-
tive versus postoperative, was not a significant factor in
univariate or multivariate analysis [40,41].
The important question remains: for which group of
patients will afterloading therapy lead to an improve-
ment in overall survival? Several studies suggest that in
some cases the application of adjuvant afterloading ther-
apy in combination with EBRT will improve survival in
patients exhibiting unfavorable prognostic factors such
as low differentiation (grade 2), stage III disease, certain
histologic subtypes (e.g., clear cell adenosquamous and
serous-papillary carcinoma), lymph node metastases,
peritoneal spread, etc. However, controlled studies are
missing. Further, it remains unclear whether adjuvant
radiotherapy is helpful in cases of incomplete surgery.
The results of therapy can only be evaluated by an
exact analysis of recurrences and all forms of relapsing
disease and metastases, including cases of complete fail-
ure. Recurrences in FIGO stage I or II disease are of par-
ticular interest. Following a review of a large number of
recent publications, it is apparent that several reports
suggest and discuss the benefits of adjuvant irradiation
in endometrial cancer.
23.2.4 Postoperative brachytherapy of the
vagina
The incidence of vaginal recurrences after primary hys-
terectomy and bilateral salpingo-oophorectomy ranges
from 5% to 20% if no postoperative radiation is per-
formed [18,42]; the median rate is about 10% [43].
Many authors have reported a considerable reduction
of this rate by including vaginal irradiation in the pri-
mary management using iridium, cesium, or cobalt
[15,17-19,28,39,44-52), but there are also controversial
opinions as to whether vaginal irradiation should be
done. Sometimes its value is questioned: Malkasian et al.
[53] reported 10% recurrences (stage I, EBRT for high-
risk patients); Hording and Hansen (54) reported 19%
recurrences (stage I, surgery without irradiation).
Recurrences occur not only in the vaginal cuff, but also
in the lower vagina, particularly in the suburethral area.
Therefore, we also irradiate the lower vagina to the
hymenal ring. A similar procedure is reported by others
[42-44,52]. In contrast, Pipard et al. [55] and Pernot et al
[21] do not recommend including the entire length of
vagina because they foresee a potential risk to healthy tis-
sues. Randall etal. [56] described the role of an intravagi-
nal cuff boost of 30-50 Gy surface dose after adjuvant
external-beam irradiation in early-stage disease treated
from 1971 to 1983 with reduction of recurrence rates from
23% to 13% in those cases receiving a vaginal cuff boost.
23.2.5 Fractionation schemes and
different dose rates
Kob et al, using iridium, discuss fractionation regimes
of: 4 x 10 Gy, 5 x 8 Gy, and 8 x 5 Gy at reference point A
[34]. Sorbe and Smeds refer to 4 x 9 Gy, 5 x 6 Gy, 6 x 5
Gy, and 6 x 4.5 Gy [18]. Pettersson et al used cesium.
Their reference dose to the rectum was 17 Gy or more,
and since 1981 has been less than 17 Gy [49]. Kucera
used iridium, giving a 10 Gy single dose since 1983: 3 x
7 Gy total dose to the surface of the vagina, and 2 x 7 Gy
(at 2 cm distance from the applicator axis) in combina-
tion with EBRT [19]. Different LDRs are discussed by
Haie-Meder et al [57].

23.2*6 Disease recurrence rates after
surgery and irradiation
Table 23.1 demonstrates the recurrence rates after 5 years
as published in the current literature. The differences in
the quoted rates appear to originate from the fact that in
some cases all stages were analyzed together, whereas
in other reports only the early stages were included, i.e.,
only stage I [18]. Other confounding factors are differ-
ences in age structure of the patients and the incidence
of accompanying illnesses. When looking at all stages
together in an unselected population, a recurrence rate
of about 10% appears to be achievable. Figures substan-
tially higher than 10% ought to stimulate a re-evaluation
of the therapeutic regimen used.
Table 23.1 Frequency of recurrences following surgery and
irradiation, as published in the current literature
Reference 5-year recurrence rate (%)
Poulsen and Roberts [62] 14
Lancia no etal. [40] 10
Kuceraeffl/. [19] 2.2
SorbeandSmeds[18] 4 These report results similar to our own.
Randal I era/. [56] 16
Kleineefo/. [63] 8 vaginal surgery has been individualized [45,51,52,60].
Petterssonefo/. [49] 10
Calais efo/. [39]
23.2.7 Therapy and outcome of recurrent
disease in Freiburg, Germany
DEFINITIONS
An isolated vaginal recurrence is a tumor up to 20 mm
in size, limited to the vagina, occurring later than 6
months after primary therapy. The definition of isolated
vaginal recurrences was adopted from Perez et al. [58]
and slightly modified in later publications [46,52,59,60].
Table 23.2 Published 5-year survival rates after radiotherapy of isolated vaginal recurrence and mean follow-up time
M\dersetal. [46] (1984), 1960-1976, all stages
Mandell etal. [43] (1985), 1969-1980, stage I
Nori [17] (1987), 1969-1979, stage I
Greven and Olds [66] (1987), 1970-1982, stages I and II
Curran et.al. [59] (1988),* 1970-1985, all stages
Kuten etal. [61] (1989),* 1959-1986, all stages
Vavra etal. [51] (1993), 1973-1987, stage l-lll
Elliott etal. [52] (1994),* 1964-1985, stages I and II
Searsetal. [60] (1994),* 1973-1991, all stages
Ladner, UHW Freiburg (1995),* 1969-1990, all stages
Weighted mean, publications with * only
Management and clinical practice 337
In the Freiburg data, vaginal recurrence was distin-
guished from the combination of vaginal and pelvic
recurrence and from primary vaginal involvement, stage
III or IV (FIGO, 1988). Recurrences within 6 months or
failure of therapy was classified as progressive disease.
Pelvic recurrence is defined as tumor growth limited to
the pelvis, not involving the vagina, and occurring later
than 6 months after primary treatment.
The definition of distant metastasis is that of proven
distant disease. The 5-year and 10-year survival rates use
the data of Kaplan and Meier (SPSS program).
FREIBURG RESULTS
The prognosis of recurrent disease depends on the tissue
site involved. Isolated vaginal recurrence (n=52) has a
favorable prognosis, with a 5-year survival rate of 56.5%
and at 10 years of 40%, whereas for patients who in addi-
tion had pelvic recurrence (=65), only 29% survived 5
years, which at 10 years was reduced to 17%. Similar
results were obtained from cases with primary involve-
ment, with a 5-year survival of 29% (n=67). Other
5-year survival results following radiotherapy for iso-
lated vaginal recurrence have been reported (Table 23.2).
The application of brachytherapy, teletherapy, and
Thus, results can be compared in order to assess the pos-
sible effects of differing therapeutic approaches which
might become apparent. The Freiburg data suggest that
the combination of hysterectomy and postoperative irra-
diation of the entire vagina (done in 925 patients, 76% of
1215 outpatients, 1969-1990) as primary management
lowers the frequency of all types of recurrence (vagina:
1.5%, pelvis: 2%, distant: 5.4%) for all stages.
In patients demonstrated to have distant metastases
(=103) after the completion of primary therapy, there
was a 5-year survival rate of 44.3% (at 10 years, 20%).
This relatively high survival rate may be caused by the
delay in the progression of distant metastasis following
42 3-19 24
12 4 40
18 4 50
18 3-10 33
55 5 31
17 4.8 40
40 3(0 54 (3a)
27 10 23
10(10a)
45 7 44
52 11 56
40(10a)
226 5 41
338 Brachytherapy for treating endometrial cancer

primary therapy because, when looking at the 5-year sur- Table 233 The published 5-year survival rates following
vival rate after the diagnosis of distant metastasis, it goes primary radiotherapy for stage I and stage II disease and for all
down to 21% (at 10 years, 15%). These results also indi- stages
cate that, in the majority of isolated vaginal recurrence
cases, cure can be achieved by consequent brachytherapy
and/or surgery. There is no reason for fatalism for Stage I
patients suffering recurrent endometrial cancer. Varietal. [71] Iridium 57
Sorbertfl/. [73] Cobalt 47
Kucera ero/. [19,75] 67
23.2*8 Primary irradiation Rouaneteffl/. [69] 58
Kupelianeffl/. [68] 87(stagel-ll)
For patients who are inoperable, for whatever reason, Petereiteffl/. [77] 69 (3 years)
radiotherapy should be individualized. However, there are, Ladnerefo/. (1996) 71 (see Table 23.4)
today, few patients, whether due to age or to medical disor-
der, who should be considered inoperable. The mean ages Stage II
of patients in various publications addressing this problem Grigsby et al. [72] Radium 71
were68.5years [68],68years [69] and70years [70]. Taghianeffl/. [74] 56
A comparison of 5-year survival data reported in the Booth by efo/. [76] 36
Kucera [19,75] Iridium 47
literature is difficult, because of patient selection, differ-
Ladnerefo/. (1996) Iridium 58 (see Table 23.4)
ences in technique and dosage, and inexact staging. In
women who undergo combined brachytherapy and All stages
external-beam irradiation, the 5-year survival rates are Taghianefo/. [74] Cesium 52
now reported to range from 50% to 88% for stage I Onnlsetal. [78] 57
tumors and between 35% and 60% for stage II tumors; Pernot etal. [21] 55
when all stages are combined, the 5-year survival rate Vahrson[10] Iridium 62
averages about 55% (Table 23.3). A breakdown of the Rouanetefo/. [69] 58
Freiburg results is given in Table 23.4. Rotte [79] 72
For patients undergoing primary irradiation, mortal- Lad neretal. (1996) Iridium 55 (see Table 23.4)
ity rates after therapy due to intercurrent disease range
between 36% and 60% [8,21,29,71,80,82]. These reports
demonstrate the need to evaluate correct survival data
relapses ranged from 8% to 25% for stage I and II dis-
[10,21,29,82].
ease: Boothby etal. [76], 19%, stage II; Kucera etal. [75],
12%; Huguenin etal [4], 19%; Kupelian etal. [68], 14%;
23*2.9 Recurrent disease Rouanet et al. [69] (for all stages), 31%. The rate of dis-
tant metastases was about 30-35%. Because of the high
The published rates of pelvic recurrences and distant frequency of recurrent disease, several authors consider a
metastases after primary irradiation cover a wide range. higher total dose of irradiation or a higher number of
According to Glassburn et al. [36], de Vita et al. [42], and fractions should be considered in an attempt to improve
Pernot et al. [21], who summarized the literature, disease the outcome [19,75].

Table 23.4 Five-year and 10-year survival rates after primary irradiation with high voltage (HV) irradiation and/or
brachytherapy (BT) in the FIGO Stages I-IV. UHW Freiburg, Germany, 1969-1990 (15% of all patients, 392/2530)

I BT + HV 47 71.4 66.4
BTonly 202 55.8 31.2

II BT + HV 12 58.3 38.9
BTonly 60 51.2 31.6
III BT + HV 38 21.1 14.0
BTonly 7 0 0

IV BT+HV 10 30.0 30
BTonly 5 0 0

I-IV BT+HV 82 55.1 45.4

BTonly 312 49.5 28.9
 Conclusion 339

23.2*10 Complications Table 23.6 Frequency of recurrences and prognostic factors in

2533 patients with endometrial carcinoma treated at Freiburg
Fistulas involving the rectum or bladder, ureteric stric- University Hospital, Germany, between 1969 and 1990
ture, vaginal necrosis or stenosis, and contracted bladder
are reported to affect from 3% to 19% of patients (Table
23.5). VR 2.7% (41) 1.2% (12)
VPR 3.4% (51) 1.3% (13)
PR 1.7% (26) 1.5% (16)
23.2.11 Prognostic factors DM 5.3% (80) 2.1% (22)
All recurrences 13.1% (198) 6.1% (63)
Recently, we performed a retrospective analysis of all 2533
"n = 1500.
patients treated for endometrial carcinoma at the "n = 1033.
Freiburg University Hospital from 1969 until 1990 in VR-vaginal recurrence, VPR-combined vaginal-pelvic recurrence,
order to identify risk factors for survival, recurrence, and PR = isolated pelvic wall recurrence, DM = distant metastasis.
adjuvant radiotherapy. Based on a profile of risk factors,
patients were classified as either low risk (adenocarcino-
mas in FIGO stage la with grading 1 or 2, stage Ib only
Further analysis of the data indicates that, in patients
with grading 1) or high risk (all tumors with grading 3 or
with stage I disease, postoperative radiotherapy
higher than Ib G2 and all non-adenocarcinomas) in an
improved the 5-year survival independently of histolog-
approach similar to that of the study of Shumsky et al
ical grading (SPSS program, COX-regression). However,
(1997) [86]. The median follow-up for our patients was
this might be due to patient selection and requires fur-
12 years. In the Freiburg patients, we found surgical stage,
ther analysis. Postoperative brachytherapy alone had the
grade, and patient age to be significant predictors
same effect.
(p<0.001) for 5-year survival and recurrence (Table 23.6).
The recurrence rates were 6.1% for low-risk and 13.1%
for high-risk patients, as defined above. Shumsky et al.
23.3 CONCLUSION
[86] found in their 435 patients a recurrence rate of 4.1%
in low-risk and of 23.4% in high-risk patients. Therefore,
we propose, together with Greven et al. [84], Shumsky et In conclusion, we believe the therapeutic challenge in
al. [86], Garcia-Domenech et al. [83] and Rakowsky et al. endometrial cancer continues to be the careful identifi-
[85], that low-risk patients do not need to be maintained cation of high-risk prognostic features [81] and the indi-
on a close, routine follow-up and that an intensified vidualized use of the respective therapeutic modalities,
schedule ought to be used for high-risk patients. in particular adjuvant postoperative radiotherapy.

Table 23.5 Published results of the different complication rates following radiotherapy

Variaefo/. [71] Iridium 10

Booth by efo/. [76] 19
Kupelianeffl/. [68] 8
Roseetal. [29] 11
Petereitrtfl/. [77] Iridium 11
Taghianefo/. [74] 15
Kuceraefo/. [75] Iridium 7
Rouanetefo/. [69] Cesium 12 (3% grade 3 and 4)
Remoteo/. [21] Cesium 9
Rauthetfo/. [81] 3 Severe
Hugueninefo/. [4] 11
Chaorto/.[70] 4
Rotte [79] Iridium 7 (No fistula)
MurrellandOrton [64] 13
Pettersonefo/. [49] 3
Calais etal. [39] 14 Preoperative
8 Postoperative
Norirto/. [65] 9
Onsrudefo/. [6] Cobalt 12
Chen etal. [67] 1.3 1 fistula
340 Brachytherapy for treating endometrial cancer
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51. Vavra, N., Denson, U., Kucera, \\.etal. (1993) Prognostic
factors related to recurrent endometrial carcinoma
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54. Hording, U. and Hansen, U. (1985) Stage I endometrial
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55. Pipard, G., Milsztajn, M., Jaquet, P. and Sentenac, I. (1985)
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56. Randall, M.E., Wilder, J., Greven, K. and Raben, M. (1990)
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57. Haie-Meder, C, Kramar, A., Castaigne, D.etal. (1995)
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58. Perez, C.A. and Camel, H.M. (1982) Long term follow-up in
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59. Curran,W.J.,Whittington, R., Peters, A.J. and Fanning,].
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61. Kuten, A., Grigsby, P.W., Perez, C.A., Fineberg, B., Garcia,
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64. Murrell, D.S. and Orton, C.G. (1988) Survival and
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Postoperative high dose-rate intravaginal brachytherapy
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66. Greven, K. and Olds, W. (1987) Isolated vaginal recurrence
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Cancer 60, 419-21,
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Exclusive radiation therapy in endometrial carcinoma.
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Medically inoperable stage I adenocarcinoma of the
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75. Kucera, H., Vavra, N. and Weghaupt, K. (1990) Zum Wert
deralleinigen Bestrahlungdesallgemein inoperablen
Endometriumkarzinoms mittels high-dose rate-iridium-
192. Geburtsh. Frauenheilk., 50,610-13.
76. Boothby, R.A., Carlson, J.A., Neiman, W. etal. (1989)
Treatment of stage II endometrial carcinoma. Gynecol.
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endometrial cancer. InlJ. Radial Oncol. Biol. Phys., 32,
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78. Onnis, A., Marchetti, M. and Maggino, T. (1993)
Endometrial cancer treatment today. Eur.J. Gynaec.
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(\98Q)Am.J. Obstel Gynecol., 136,885-6.
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and Llixiona,J.(1997) Prognostic factors in endometrial
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Sulkes, A. (1997) Prognostic factors in stage 1 and stage 11
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 24
Low dose-rate brachytherapy for treating cervix
cancer: changing dose rate

R.D. HUNTER AND S.E. DAVIDSON

24.1 HISTORICAL BACKGROUND

Gynecological radium techniques were developed

empirically initially in Paris and Stockholm. The
Manchester Radium System was an important and pop-
ular development of those systems and the last major
revision of this system using radium was described by
Tod and Meredith in 1953 [1]. The Manchester System
was designed to deliver a constant dose rate to defined
points in the paracervical tissues near the cervix, irre-
spective of variation in the dimensions of the uterus and
vagina, and achieved this by differential loading of two
standard-sized intrauterine tubes and three intravaginal
'ovoid' sources to allow for normal variations in uterine
and vaginal size. In this system, an application was spec-
ified in terms of the 'dose' in roentgens delivered at a
specified ideal geometry point, which was called Point 'A'
(Figure 24.1.) The paracervical tissue lateral to the cervix
was considered to be of prime importance in the radia-
tion tolerance of the central pelvic gynecological tissues
and, because the dose distribution was inhomogeneous
and the gradients steep, a point rather than a volume was
defined. Point A is defined as being 2 cm lateral to
the central canal of the uterus and 2 cm superior to the Figure 24.1 The Manchester System. Definition of point A, a
mucous membrane of the lateral vaginal fornix, in the point 2 cm lateral to the central canal of the uterus and 2 cm
axis of the uterus. A second dosage reference point, point superior to the mucous membrane of the lateral fornix, in the
B, was denned as being 3 cm lateral to point A and at the axis of the uterus. Point B is defined as being in the transverse
same level 5 cm from the midline and was used when axis through point A, 5 cm from the midline.
344 Low dose-rate brachytherapy for treating cervix cancer: changing dose rate
X-ray therapy was combined with intracavitary therapy
(see Figure 24.1). The dose received at point A is there-
fore a measure of the dose in the paracervical tissue. The
cervix, upper vagina, and uterus are remarkably tolerant
to radiation, but the tissues in the paracervical region,
which include the uterine artery and the ureters, are
more vulnerable.
It was demonstrated that the expression of radium
dosage as a dose at point A showed a correlation with
failure of local control and the incidence of late normal-
tissue damage in the pelvis, thus justifying the choice of
this particular reference point for intracavitary dosime-
try [ 1 ]. The Manchester System is based on a strict set of
rules concerning the intracavitary applicators (in partic-
ular, the choice and positioning of the vaginal ovoids,
their separation, and the relative strengths of the
intrauterine and intravaginal sources). The differential
loading patterns ensured that, irrespective of the use of
different lengths of intrauterine tubes and of the size of
the vaginal ovoids, a constant dose rate is achieved at
point A in ideal geometry and, therefore, provided the
applicators were placed correctly, in the patient. There
was an acceptance that, in practice, the dose rates would
vary by up to 10% of that prescribed in individual
patients, but clinical studies on control and morbidity
have always used this philosophy.
Radium was far from the ideal material for intracavi-
tary therapy. The ideal radionuclide should produce only
a single gamma ray spectrum with an energy of around
0.5 MeV. Below this level, attenuation, rather than the
inverse square law, dictates tissue absorption and conse-
quently influences dose distribution. At energies above
0.5 MeV, radiation protection becomes increasingly diffi-
cult and expensive. The nuclide should have a long half-
life, be cheap and easily produced, preferably solid, and
with stable solid decay products and, in particular, have a
high specific activity. The closest to the ideal radionuclide
for low-dose intracavitary therapy at the present time is
radioactive cesium-137. It remains the best radionuclide
for remote after-loading systems operating at dose rates up
to eight times those of the old radium system.
In intracavitary brachytherapy, the dose rate is defined
by ICRU 38 as 'at the point or surface where the dose is
prescribed.' In the classical radium systems, this was typ-
ically at Point A and lay between 0.4 (Paris), 0.53
(Manchester) and 1.0 Gy h'1 (Stockholm). ICRU 38 [2]
chose to include dose rates up to 2 Gyh-1in low dose rate
(LDR) and the studies in changing dose rate described in
this chapter involve, therefore, a change from one LDR to
a higher LDR and do not quite reach medium dose rate
(MDR). In Manchester, dose rates of 1.4-1.8 Gy h'-1 have
been used and, by definition, this constitutes LDR treat-
ment.
Preloaded applicators gave rise to significant levels of
radiation exposure to the radiotherapist, the technicians
who prepared the sources, and nursing staff in the
theater and the wards. These sources had to be placed in
the uterus and vagina as swiftly as possible and, occa-
sionally, due to disturbed geometry, had to be removed
and re-introduced on another day. Alternatively,
although the applicator's position was less than perfect,
the radiotherapist might have decided to accept a com-
promise in the treatment rather than repeat the proce-
dure. This requires experience and judgment and
sometimes the radiotherapist accepted a less than satis-
factory technical insertion for other clinical reasons.
This solution to the problem gave rise to the concept
of afterloading, in which empty applicators are intro-
duced initially without the need for undue hurry and/or
compromise. Only when the geometric relationship of
these applicators is known to be ideal are the radioactive
sources inserted into the applicators. These small-caliber
tubes must be lightweight for the patient's comfort and
capable of easy sterilization. They should not be
adversely affected by exposure to gamma radiation, and
there should be minimal attenuation of gamma rays by
the walls of the applicators.
Many afterloading techniques have been devised and,
in general, they are described as manual or remote after-
loading. As the term implies, manual afterloading
involves the manual insertion of radioactive sources into
suitably placed applicators, after verification of the
geometry of the applicators. This is an advantage to the
patient and to the radiotherapist, but does very little to
reduce the radiation exposure to the nursing staff. This
problem can be overcome by remote afterloading, for
which the empty applicators have been placed in posi-
tion and the radioactive sources are remotely introduced
from a protective safe. A variety of sophisticated remote
afterloading machines have been developed, each offer-
ing a range of dosimetric options.
In Manchester, an LDR remote afterloading system
has been preferred in which the source strengths and
geometry allow radium-like fractionation and dose dis-
tributions to be maintained. In this system, the applica-
tors (Figure 24.2) are inserted under a general anesthetic
in theater and the conscious patient is then transferred
to the shielded treatment room. The empty applicators
are then attached to the afterloading machine. Sources
can be transferred between the safe and the applicators
appropriately by remote control from outside the room
by trained nursing staff.
24.2 PRETREATMENT ASSESSMENT AND
INVESTIGATIONS
Radiotherapy plays a significant role in the management
of patients with all stages of carcinoma of the cervix. The
results of radiotherapy in early-stage cervical carcinoma
have always been considered comparable to those of
Wertheim's hysterectomy. In practice, radiotherapy can
be available for almost all patients, whereas surgical

Figure 24.2 Remote afterloading applicators: (a) standard
applicators, central tube with fixed flange and small avoids
arranged as in treatment; (b) central tube with vaginal cylinder
to replace avoids in tandem; (c) manual insert to check the
position of individual sources after insertion of applicators.
treatment necessitates selection of patients, even in those
with early disease. Close collaboration with gynecolo-
gists is essential to ensure the optimum approach for
each patient.
Probably the most important aspect of the treatment
is accurate staging to determine whether the primary
tumor is limited to the cervix or whether it has spread
beyond the cervix, particularly into the parametrium or
toward the bladder or rectum. It is also important to
know whether the pelvic lymph nodes are involved, as
this determines the overall approach to management. In
general clinical practice, FIGO tumor stage remains the
most important prognostic factor for disease outcome,
closely followed by tumor volume and lymph node sta-
tus [3-8]. At examination under anesthetic, inguinal,
vaginal, and rectal examination should be performed.
This will allow the extent of involvement of the cervix,
fornices, and vagina to be determined. The uterus is also
assessed for size and mobility. Rectal examination gives a
more accurate assessment of the parametrial tissues,
especially with regard to the extension of disease into the
lateral pelvis. Rarely, rectal infiltration of the mucosa
may be noted. Direct visual inspection and palpation of
Pretreatment assessment and investigations 345
the vaginal walls are superior to any imaging modality in
determining the presence of vaginal extension. General
clinical examination should assess the patient's suitabil-
ity for general anesthesia and for fractionated external-
beam radiotherapy.
24.2.1 Imaging
A chest X-ray should always be done. It is unlikely to
reveal metastatic disease, but may help in pulmonary
and cardiac assessment for anesthesia and may be useful
long term in the assessment of any changes that appear.
Magnetic resonance imaging (MRI) or computerized
axial tomography (CAT) is not indicated for FIGO stag-
ing of carcinoma of the cervix [9], but one of them will
often give useful information for planning purposes.
MRI scanning, and particularly T2-weighted images,
gives better demonstration of the tumor and its local
extension in the pelvis than CAT scanning, though there
remains a difficulty in demonstrating early parametrial
or vaginal involvement [10]. It is also better for demon-
strating intrapelvic nodes. Both techniques give similar
results for detecting enlarged lymph nodes outside the
true pelvis. MRI scanning gives a larger field of view and
has the advantage of multiplanar imaging. The disad-
vantages are that MRI scanning is time consuming and
some patients cannot tolerate this examination due to
claustrophobia. Whatever the final choice of investiga-
tion, the para-aortic nodes, kidneys, and ureters must
also be examined.
24.2.2 Biopsy
Usually the diagnosis is obvious, but a simple punch
biopsy will provide histological proof of malignant dis-
ease. Biopsy proof should be considered mandatory in
any patient fit for radical therapy.
24*2*3 Full blood count
Because of the regularity of bleeding, anemia is often
present. The hemoglobin of patients on treatment
should be maintained above 10.5 g dl-' and should, if
necessary, be corrected by blood transfusion prior to
commencing radical radiotherapy. A significantly raised
white blood count may indicate a pyometrium, pelvic
abscess, or large infected primary tumor. Drainage of
pelvic infection and treatment with broad-spectrum
antibiotics may be necessary prior to treatment.
24*2*4 Biochemical profile
A biochemical profile may give early indication of or
confirm impaired renal function.
346 Low dose-rate brachytherapy for treating cervix cancer: changing dose rate
24.2.5 Cystoscopy
Cystoscopy is carried out for patients with locally
advanced disease, particularly that involving the anterior
fornix or the anterior vagina, if any urinary symptoms
are present and if MRI scanning suggests bladder wall
involvement.
243 TREATMENT METHODS
Over the past 10 years, and especially in the last 5
years, there has been a decline in the numbers of patients
referred to the Christie Hospital, Manchester, for pri-
mary radical radiotherapy. This has been due, in part, to
the decline in the incidence of invasive cervical carci-
noma within the region (as in the whole of the UK) and
also to a change in gynecological practice. Fewer patients
are referred with FIGO stage IB and IIA disease as these
patients are being treated by primary surgery. The
majority of patients referred for consideration of radio-
therapy now have locally advanced disease. This means
that, in contrast to the situation 20 years ago, only a
small number of patients are treatable with brachyther-
apy alone. The majority are treated with external-beam
radiotherapy followed as quickly as possible by a single
intracavitary treatment.
The anatomy of the cervix, the ease with which appli-
cators can be placed in the uterus and vagina, and the
high tolerance of the vagina, cervix, and uterus to radia-
tion make this an ideal site for intracavitary therapy.
Because of the rapidly falling gradient of radiation dose
laterally towards the pelvic side wall from the central
radiation source, it is necessary to supplement the lateral
pelvic dose in any patient whose primary disease is more
than 4 cm diameter (stage IB2 [ 11 ]) or involves the para-
metrium by external-beam radiation. Carcinoma of the
cervix regularly metastasi/es to the pelvic lymph nodes
(parametrial, obturator, hypogastric, external iliac, com-
mon iliac, and presacral nodes) and then in a sequential
manner to the para-aortic nodes. The potential lymph
node drainage areas present a considerable volume of
tissue and the dose which can be given is limited by the
many normal tissues involved, particularly the tissues of
the gastrointestinal tract.
In a series of prospective clinical trials between 1949
and 1980 [12,13] at the Christie Hospital, it was demon-
strated that, unless there are problems with severe hem-
orrhage from the tumor when an initial hemostatic
limited intracavitary treatment should be carried out,
external-beam radiotherapy should be given first. This
approach allows all tumors time to regress and improves
the geometry of the insertions in the majority of
patients. External-beam radiotherapy can be homoge-
neous or the central pelvis can be shielded for part or all
of the treatment, but if shielding is used, it should be
designed carefully to try to achieve some matching with
the intracavitary dosimetry [14]. The acute reactions of
smaller-volume external-beam treatments, e.g., true
pelvis, are better tolerated and are therefore easier to
integrate with intracavitary techniques while maintain-
ing overall treatment times.
Overall treatment time has recently been shown to be
of importance in the treatment of carcinoma of the
cervix by radiotherapy. Treatment prolongation results
in an approximately 1% loss of disease control per day
beyond 30 days [15]. As a consequence, it is recom-
mended, in recently published UK guidelines, that
patients with carcinoma of the cervix do not have their
treatment prolonged unless there are good clinical rea-
sons [16] for doing so.
The dose to points A and B from both treatment
modalities can be used as a general guide to matching
the different treatment schedules, though simple addi-
tion of intracavitary and external-beam dosages is not
reliable in the assessment of tolerance, particularly
when different (non-classical) dose rates are being
employed.
243*1 External-beam techniques
In Manchester for four decades a technique was
employed for patients with small-volume disease and
parametrial involvement which used a parallel antero-
posterior (AP) pair of megavoltage fields in which a spe-
cial, graduated, vertical central wedge was placed in the
beam. This wedge allowed 50% of the prescribed dose to
point A and 100% to the pelvic side wall (point B). The
dose given was 3250 cGy in 16 fractions over 21 days.
This was then followed by two insertions 7-10 days
apart, giving 6000 cGy to point A. In a trial of this treat-
ment versus a homogeneous pelvic external-beam tech-
nique with no central shielding, no significant difference
was seen in survival, pelvic disease control, or morbidity
between the two different philosophies [13].
Nowadays, for patients in whom enlarged pelvic
lymph nodes are demonstrated by MRI or CT, an exter-
nal-beam technique is used which treats the whole pelvis
and its lymph node drainage areas from below the low-
est extent of the disease in the vagina to the top of the
fifth lumbar vertebra. It is a four-field technique and the
AP fields are rectangular or hexagonal in shape. It can be
designed to cover the primary tumor and nodes whilst
reducing, where possible, the total volume of tissue to be
irradiated. The lateral fields in the four-field box tech-
nique are the same length as the AP fields and are 10-11
cm in width. An 8-20 MeV linear accelerator is used for
this treatment and no pelvic shielding is employed. The
dose given to the pelvis is 4000 cGy in 20 fractions over
28 days, giving equal contributions from the AP and lat-
eral fields. The intracavitary dose used is 3250 cGy, with
a single remote afterloaded cesium insertion (formerly

3750 cGy with radium) to point A as soon as possible
after the external-beam treatment.
For patients with bulky central disease and no evi-
dence of nodes on scanning, an alternative, smaller four-
field box is used to treat the pelvis homogeneously. This
treatment is set up isocentrically to cover the true pelvis
with a 14-15 x 10-12 cm AP parallel pair and with a
9-10 x 10-12 cm lateral parallel pair. The size of the
fields depends upon the extent of the primary tumor and
the size of the pelvis. The dose given is 4000-4500 cGy,
depending on the volume employed, and it is given in 20
fractions over 28 days. This is followed by a single intra-
cavitary insertion giving 2000-2250 cGy to point A (pre-
viously 2500 cGy using radium). There is no proven
advantage to any particular one of these treatment tech-
niques, but the choice is made according to the age of the
patient, size of the tumor and evidence of nodal disease,
fitness for anesthesia, and suitability for intracavitary
treatment.
24.3.2 The intracavitary technique
Utilizing lightweight metal applicators mimicking the
size and shape of the radium applicators, the distribu-
tion of 40 mCi cesium-137 pellets in the afterloaded
applicators of the new afterloading system has been
arranged so that the resulting isodose patterns are as
near identical as possible to those of the standard
Manchester Radium System. This LDR system has been
giving a dose rate of 1.4-1.8 Gy h-1, i.e., 2.9-3.5 times the
dose rate of the radium treatment, depending on the
decay in the activity of the sources. In order to prevent
increased morbidity with this increased dose rate, it is
now known, on the basis of clinical trials, that the actual
dose must be decreased [17]. The trials in the 1980s were
set up as randomized prospective trials with the princi-
pal aim of isolating the dose rate factor as an indepen-
dent variable. The doses now employed in Manchester
(2000), are those which have been shown to give the best
disease control with acceptable treatment morbidity and
these generally employ a dose reduction of 10-17% (see
below).
24.33 Low dose-rate remote afterloading
The main advantage of remote afterloading LDR tech-
niques for intracavitary treatment, compared to using
radium or cesium-137 preloaded sources, is the reduc-
tion of exposure to the medical and nursing staff in
theaters and the nursing staff on the wards.
Using a remote afterloading LDR system such as that
described above also shortens the treatment time signif-
icantly for the patients in comparison with the times for
treating patients with conventional radium or cesium-
137. Another advantage is that it is easier with rigid
applicators to attain and hold better geometry of the
Treatment methods 347
insertions compared to preloaded sources. It is easier,
however, to cause physical damage to the patient using
rigid applicators by stretching the uterine and vaginal
tissues or to produce vaginal mucosal tears when insert-
ing gauze packing around the applicators.
Compared with high dose-rate (HDR) intracavitary
brachytherapy, LDR patients, who are now treated in one
insertion, do not have the repeated procedures including
sedation/anesthesia when treatments are given in multi-
ple fractions, in practice often three to 12 times the num-
ber of classical LDR fractions.
243.4 Treatment planning
Treatment must be planned according to the extent of
the disease because this determines the minimum vol-
ume of tissue to be irradiated. The presence of any illness
which may impair the patient's tolerance to radiation,
e.g., diabetes, hypertension, or previous major pelvic
surgery, may influence the decision regarding radiother-
apy technique and dosage.
In the planning of this treatment, the two most
important factors are the volume of the tumor and the
tolerance of the normal tissue in the radiation field. As
stated above, small-volume disease - stage I and small-
volume stage IIA - can be treated with intracavitary
therapy alone in two insertions 7-10 days apart. The
dose given is 6500 cGy (formerly 7500 cGy with radium).
This dose should be reduced to, for example, 6250 cGy or
6000 cGy in those patients who have undergone a recent
cone biopsy as the particular susceptibility of this group
to late morbidity was confirmed in the afterloading trials
(see below). For more advanced disease, a combination
of external-beam and intracavitary treatments is used, as
outlined in the preceding section.
243.5 Treatment
The afterloaded applicators are inserted in theater with
the patient under general anesthetic, or spinal anesthetic
if the patient's medical condition makes general anesthe-
sia inadvisable. A self-retaining catheter is placed into
the bladder after drainage of urine. An equal volume of
Urografin 150 (30%) is diluted with sterile water and the
urinary catheter balloon is inflated with 7 ml of the 1:2
diluted Urografin. The cervical canal is found by gentle
probing and dilated to Hagar dilator Number 6 or 7 to
allow the insertion of the uterine applicator tube. An
inert gold seed marker is placed into healthy tissue in the
cervix or upper vagina, which allows the position of the
applicators relative to the cervix to be checked radi-
ographically at any time during the subsequent treat-
ment. The uterine canal length is measured with the
uterine sound and the appropriate intrauterine tube
(4 cm or 6 cm with a flange) is inserted. The majority of
patients are treated using an intrauterine tube angled at
348 Low dose-rate brachytherapy for treating cervix cancer: changing dose rate
40 to the vagina and fitted with a fixed flange which can
sit at the cervix without obscuring the view of the vagi-
nal vault (see Figure 24.2). The deliberate angle in the
tube draws the uterus, in most patients, into a central
position in the pelvis away from the pouch of Douglas,
the sigmoid colon, and the anterior rectal wall. The uter-
ine tubes initially employed (Fletcher type) had varying
degrees of curvature of the intrauterine section. If the
curvature is small, the uterus is forced by the applicator
to become partially retroverted and the fundus comes in
close proximity to the sigmoid colon. Such tubes may
have contributed to bowel damage by bringing the
sources closer to the large bowel [18].
The vaginal source tubes are mounted into ovoids of
dimensions similar to those of the rubber preloaded
applicators (small, medium, and large) or 'long small'
ovoids, which have an extra 0.5 cm of packing built into
the ovoid. If these 'long small' ovoids do not fit comfort-
ably, this means that there is not enough room for the
normal small ovoid and satisfactory packing at the vault.
The Manchester afterloading applicator includes a
screw clamp on the intrauterine tube which, when tight-
ened, draws the three applicators into an ideal physical
position. It is possible to use this applicator in about 95%
of patients. For patients with a fixed retroverted uterus,
this applicator can be replaced with one with a moveable
clamp which allows the uterine tube to be rotated
through 180 and also allows the intrauterine length to
vary. The use of this flexible applicator requires consid-
erably more skill and can create difficult decisions about
dosage and dose distribution.
Gauze packing is placed firmly and carefully behind
the ovoids, anteriorly between the ovoids and the base of
the bladder, and around the applicator tubes down to the
level of the introitus. In most patients, this packing will
keep the applicators in position.
For those patients with a small vaginal vault or exten-
sion of disease down the vagina, a single-line source is
used. The intrauterine tube is loaded below the cervix
and down to the introitus if required, to give isodoses
which approximate to those of small radium sources in
tandem. The vaginal walls are distanced from the tube by
plastic cylinders, with a choice of diameter, including
cylinders with extra in-built packing of 0.5 cm both
anteriorly and posteriorly, which ensure that the vaginal
mucosa does not come in contact with the applicator
tube itself. To prevent displacement of the applicator
during the treatment, a suture is normally placed at the
introitus when a single in-line source is used.
At the end of positioning the applicators, a measure-
ment is made of the dose coming through to the anterior
rectal wall. An insert mounted with cesium-137 pellets
and simulating the treatment positions is placed in the
applicators and a reading is made of the anterior rectal
dose by exploring the lower rectum with an ionization
chamber. The dose rate, as measured by the chamber in
contact with the anterior rectal wall, is kept below two-
thirds of the dose rate to point A. If the reading is higher
than two-thirds of the point A dose rate, then the gauze
packing is removed and replaced and a further assess-
ment of the anterior rectal dose is made. If the readings
remain high despite repacking, an adjustment to the
treatment may be necessary.
The urinary catheter is drawn down and secured
against the applicator stems to ensure that the balloon of
the catheter is located at the bladder neck. Urine is
drained and 120 ml of air is inserted into the bladder.
AP and lateral radiographs are taken to check the
position of the applicators with dummy trains of sources
and markers in place, before the patient returns to the
ward. Direct measurements of bladder dose have never
established a place in Manchester. A study of bladder
base dose was carried out on a series of 20 patients
undergoing intracavitary treatment using CAT scanning
and this scan information was transferred to a treatment
planning computer [19]. The ICRU bladder reference
dose was calculated from the radiographs. This study
showed that the ratio of the maximum bladder base dose
to the ICRU reference dose rate varied considerably,
from 1.01 to 3.59. In half the patients, the maximum
bladder dose was not in the midline. The variation in the
size and position of the bladder relative to the applica-
tors in the uterus and the vagina is very considerable, due
to different lengths of vagina, vault capacity, and tumor
bulk. The ICRU reference dose never represented the
maximum bladder dose in this study and no other single
fixed point within the bladder could be identified.
All patients treated with radical intracavitary treat-
ments alone, and certainly any patient for whom the
treating doctor had difficulty with the placement of the
uterine applicators, have a CAT scan carried out to check
the position of the applicators. This principally looks at
the intrauterine tube to see its position within the uterus
and to ensure that no perforation has taken place. It is
also possible to determine if the tube is eccentrically
placed within the uterus and if the uterine wall is
thinned over the tip of the applicator tube. If a perfora-
tion is seen, the applicators are removed immediately,
the patient is commenced on antibiotics, and a further
attempt at intracavitary treatment is carried out after
7-10 days. If the tip of the uterine tube appears to thin
the uterine wall, the active pellet loading can be altered
and sources removed from the upper uterus.
In a series of 650 patients scanned after an apparently
straightforward insertion, unexpected uterine perfora-
tion was seen in 3% of patients on CAT scan [20].
In the treatment room, when the patient has fully
recovered from the anesthetic and the CAT scans show
satisfactory positioning of the applicators, the intracavi-
tary applicator tubes are linked to the cesium-137 line
sources in the protective safe by transfer tubes. The
remote afterloading system used at present utilizes
cesium-137 as 1.5 mm glass spheres incorporated in
stainless-steel spheres of 2.5 mm diameter. The maxi-

mum strength is 150 mBq. The actual treatment 'sources'
are made from a combination of active and dummy
spheres arranged in a line (see Figure 24.2) and there is
no difficulty in producing applicator loading patterns
that will reproduce the dose distributions of the
Manchester Radium System. The source pattern con-
struction takes place within the protected machine and
the selected source 'lines' are transferred to the intrauter-
ine and vaginal applicators by compressed air. The relia-
bility of this two-way transfer system is very important.
In practice, angulations up to 90 can be negotiated
effectively by the pellets.
The patient is nursed on her back or side during the
treatment and, while attached to the machine, move-
ment is permitted under supervision. Traction on the
treatment lines has to be prevented as this could displace
the applicators. A marker system to identify the treat-
ment applicator position relative to the patient's thigh is
used as an extra safeguard (Figure 24.3).
During treatment, which may last for 24 h, trained
nursing staff supervise the equipment. This system
allows regular treatment interruptions for nursing care.
The movement of the radioactive sources is controlled
completely from outside the treatment room once the
Figure 24.3 Afterloading applicators in position. The position
of the flange relative to the patient is drawn on the thighs as
illustrated.
Treatment results 349
computer has been programmed and set. A record of the
treatment interruptions is made by the machine to
ensure that the patient has the correct treatment time
before it is terminated.
Present clinical experience has shown that preloaded
radium and cesium-137 insertions can be safely replaced
by remote afterloaded cesium-137. This eliminates all
the hazards of preloaded sources and, using higher dose
rates than those of the Manchester Radium System, has
practical advantages for the patient and the hospital.
From the randomized prospective trials carried out in
Manchester, the intracavitary dose must be reduced to
allow for the increased biological effectiveness of the
higher dose rate treatments when dose rates three to four
times that of the radium treatments are employed. The
correction factor used is a minimum of 10%, but may be
as much as 20%, depending on the clinical situation.
This is based on the treatment results from the Selectron
trials (see next section).
24,4 TREATMENT RESULTS
Acute radiation reactions (within 2 months of treat-
ment) and late pelvic changes are inevitable with radical
radiotherapy to the pelvis. In general, the likelihood of
complications increases with large treatment volumes
and high-dose treatments, but some changes of bowel
and bladder function are seen in all patients.
Bowel symptoms depend on which area of bowel is
affected; the terminal small bowel, sigmoid colon, rec-
tum, or all levels may be affected. During the second half
of treatment and for 6 weeks following treatment,
patients experience frequency and irritability of the
bowel, which may produce varying severities of diarrhea,
tenesmus and, very rarely, acute perforation. The major-
ity of patients can control these symptoms with bulk
aperients and antidiarrhea therapy, but occasionally
patients' treatment may need to be halted. Mild cystitis
producing dysuria and frequency may occur and this
usually settles by 6 weeks following treatment.
All patients who are premenopausal will have an
induced menopause because of the radiation dose to the
ovaries. Hormonal replacement therapy can be given
safely to premenopausal patients following radiotherapy
to the pelvis. Acute radiation reactions may involve only
the upper vagina or may involve the whole length if this
has to be treated. Adhesions will form in the acute phase
if these are not prevented. Our patients are advised to use
a vaginal dilator daily for the first 6 weeks after treatment
and then two to three times a week over the next 3
months to avoid permanent vaginal fusion. Local estro-
gen cream may be used to help delayed healing at the
vaginal vault.
All normal tissues included in the high-dose pelvic
treatment volume may show late effects. The rectum,
350 Low dose-rate brachytherapy for treating cervix cancer: changing dose rate

sigmoid colon, and bladder are most commonly affected.
Bowel complications may appear from 6 months to 10
years after treatment and bladder complications from 18
months to 7 years. The effects that appear earlier are usu-
ally hemorrhagic and necrotic and the later effects are
fibrotic and hence stenotic. Much of the morbidity
changes and symptoms can be controlled conservatively,
but symptoms that do not resolve or are sufficiently
severe require surgery. Late complications are sometimes
also seen on the anterior rectal wall close to the vaginal
source position. Bleeding per rectum may settle with
topical steroids and laxatives, but heavier or chronic
bleeding may be a problem and may even require surgi-
cal resection. Sigmoid colon injury may give rise to lower
abdominal or left iliac fossa pain and intermittent con-
stipation, and increasing stenosis may lead to obstruc-
tion and thus surgery. Bladder injury is usually seen on
the posterior wall in the midline close to where the vagi-
nal and uterine sources were placed. A few patients may
have generalized changes in the bladder leading to con-
traction of the bladder or hemorrhagic changes. Chronic
bleeding may require cautery, but if the fibrotic process
is severe, reducing the bladder volume to less than 200
ml, surgery may be required to augment or remove the
bladder [14].
24.5 CLINICAL TRIALS OF DOSE-RATE
CORRECTION FACTORS IN CARCINOMA OF
CERVIX
24.5.1 Intracavitary therapy alone
A total of 563 patients with stage I and small-volume Ha
disease were entered into randomized prospective trials
in Manchester comparing manually preloaded radium/
cesium (dose rate 0.53 Gy h"1) with afterloaded cesium-
137 using the Selectron LDR after-loading system, as
described above (dose rates 140-180 cGy h"1) from 1980
to 1988. The actual corrections employed were 0%,
6.5%, 13%, 20%, and 10%. All other treatment parame-
ters were controlled between the groups.
When considering randomized dose, the mature over-
all survival at 5 years for all patients shows no significant
difference between groups (p = 0.56).
From Figure 24.4 it can be seen that the 5-year pri-
mary disease-free survival of the group of patients with
small-volume disease ranges from 96% to 84% across all
the four phases of the trial, with the results showing a
significant fall in primary disease-free survival only with
the 20% reduction in dose (6000 cGy to point A).

Figure 24.4 Graph of primary disease-free survival for 564 patients treated with Intracavitary sources In the trials of remote
afterloading versus preloaded sources in Manchester. The significance of the dose received in all the trials is due to the significant
decrease in survival in the group who received 6000 cGy. Each dose group is indicated by the different lines, as shown in the key, with
numbers of patients in parentheses. (With permission of all the consultants in the Clinical Oncology Department, Christie Hospital,
Manchester, and those involved with the treatment of the gynecology patients: Dr R.D. Hunter, Dr R. Stout, Dr E. Sherrah Davies,
Dr M.L Button, Dr R. Gattamaneni, and Dr B. Hancock.)
 Clinical trials of dose-rate correction factors in carcinoma of cervix 351
Morbidity for the different dose-rate correction arms
is shown in Figure 24.5. These results were updated in
1993, with minimum follow-up of 5 years, and graded
using the Franco-Italian Glossary, which is now used in
many European centers to record morbidity for all
patients receiving radiotherapy for cervical carcinoma
[21]. The randomized dose was the major factor in the
morbidity experienced by these patients. The morbidity
can be seen to be ranked by dose as expressed at point A
utilizing the Manchester philosophy (see above). The
majority of morbidity was evident by 2 years post-
treatment, though some further bladder morbidity was
seen beyond 5 years post-treatment.
Modeling the relationships between dose and (a) pri-
mary control of tumor, and (b) grades 2, 3 and 4 mor-
bidity has allowed an estimate of the optimum dose-rate
correction factor to be made from the clinical data. The
optimum estimated dose is close to 6500 cGy, a dose-rate
correction of 13.3%. This dose, in the trials, gave 5%
serious (grade 3/4) late morbidity with no significant
decrease in overall and disease-free survival. This level of
serious morbidity is not significantly different from that
experienced by the patients treated with classical dose-
rate cesium-13 7/radium at the same time.
24.5.2 External-beam (wedged) and
intracavitary therapy
In parallel with these very pure intracavitary therapy tri-
als in which primary control and morbidity can only be
a consequence of the single treatment modality, the
Christie department also conducted a study of dose-rate
correction in patients being treated for more advanced
disease with external-beam therapy followed by intra-
cavitary therapy. This trial of megavoltage parametrial
radiotherapy given with two intracavitary insertions was
carried out between 1983 and 1989. Patients with bulky
stage IB, stage IIB, or stage III disease received parame-
trial radiotherapy using a graduated wedge in the beam
(as described in section 24.3.1, 'External-beam tech-
niques') giving 3250 cGy in 16 fractions over 21 days.
A total of 596 patients were randomly allocated to
three treatment schedules: classical radium/cesium-137
(6000 cGy H-1), Selectron 5.5 (5500 cGy h-1) and
Selectron 5.0 (5500 cGy H-1). The dose-rate corrections
are therefore 8.5% and 17%. The mature 5-year results
showed no difference in overall survival (p 0.35) or
pelvic disease-free survival (p - 0.35) between the three
groups. Morbidity graded prospectively by the FI glos-
sary is shown in Table 24.1. This shows no difference
between the three different groups for any level of mor-
bidity. The overall 5-year survival in this study was 65%
for stage II and 38% for stage III. The grade 3/4 morbid-
ity in this group of 596 patients was 6.5%. An optimum
dose-rate correction factor cannot, therefore, be calcu-
lated for this study. A compromise of a value in the range
10-15% is the safest conclusion from these data.
25*53 External-beam (unwedged, pelvic
box type) and intracavitary therapy
No formal trials have been conducted in this situation,
which is unfortunate because the use of intracavitary
therapy alone and wedged external-beam therapy is now
unusual both in Manchester and internationally. The
only contemporary data that we have, come from a
Figure 24.5 Graph of time to
complication for all trials
treated by randomized dose.
The different dose groups are
shown as in the key, with
patient numbers in
parentheses. There is a highly
significant association with
dose received and
complications, p = 0.00005.
352 Low dose-rate brachytherapy for treating cervix cancer: changing dose rate
Table 24.1 The number of patients allocated to each treatment group and the 5-year mature
prospective grade 2, grade 3/4, and grade 4 morbidity
Radium/cesium-137 Classical 6.0 201
Selectron 5.5 193
Selectron 5.0 202
retrospective audit in 1997 of 123 sequential patients
treated between 1982 and 1992 by a pelvic box technique
(4000-4500 cGy in 16-20 fractions in 21-28 days) and
followed by a single intracavitary afterloaded 'high LDR'
cesium-137 insertion and a 10-20% dose-rate correc-
tion. The majority of the patients had stage III disease
and were unsuitable for the wedged field approach. This
group of patients had a 5-year survival of 37% and a
grade 3/4 morbidity rate of 3.2%.
24.5.4 Since 1988
Following the completion of the formal trials, the
department has replaced preloaded radium therapy with
afterloaded cesium-137 at the higher dose rates
described above. Dose-rate correction factors have var-
ied slightly, depending on the technique employed, but
they have consistently been maintained in the range
10-20%.
The most recent data that we have available were
obtained in 1999 and included all cases with cervical car-
cinoma treated radically at the Christie Hospital in 1993.
This analysis is part of a UK national audit of treatment
results and morbidity of patients treated in 53 radiother-
apy centers in the UK (in press). One hundred and
eighty-three patients were identified and clinical out-
come data were available for 181 patients. Five-year sur-
vival for stage IB disease (n = 45) was 71% (72%), for
stage IIB (n = 70) 52% (63%), and for stage III (n = 50)
34% (41%). The numbers in parentheses are the FIGO
5-year survival figures for 1990-1992. The complication
rate, grade 3/4 morbidity (all sites), in the patients
included in this audit was 3.4%.
24.6 INTERNATIONAL EXPERIENCE
Other series reported in the literature show the possibil-
ity of an increase in late radiation damage in groups of
patients treated at the higher low and medium dose rates
possible with the new afterloading systems when com-
pared with retrospective series [22-24]. The only other
randomized prospective trial exploring this particular
issue employed a higher dose rate (220 10 cGy h-1) and
concluded that, while the different levels of correction
factor did not influence pelvic control, a dose-rate cor-
7 13(2)
12 13(2)
8 14(0)
rection of 12.5% was insufficient when moving from
classical dose rates to this level, and that a correction fac-
tor of 'around 30%' was associated with an acceptable
level of morbidity [25]. Dose-rate correction factors
between these values were not explored.
In practice, the majority of users of high LDR and
MDR brachytherapy have evolved their own schedules to
compensate for the dose-rate effect. In many situations
this has involved changes in dose distributions and frac-
tionation as well as in dose rate [26]. These experiences
have led some authors to suggest that the linear-
quadratic (LQ) model can now be used to predict the
optimum dose and schedules that may be employed
[27]. This remains to be proven in clinical practice.
One hundred years after the discovery of radium,
gynecological intracavitary radiotherapy systems have
contributed to the cure of many patients. The modern
systems are more controlled, precise, and safer, particu-
larly from the point of view of the staff treating the
patient, than the original techniques, but evidence of
therapeutic gain is not clearly identifiable. However,
internationally there continues to be an enormous range
of systems, modifications of systems, and personal prej-
udice dictating treatment, with no real evidence of spe-
cific benefits from one as compared to another.
Treatment in many centers is 'custom and practice' mod-
ified with experience and amended by Ionizing
Radiation Legislation.
The Manchester System of the early twenty-first cen-
tury is a direct descendant of the original radium system
and can be tracked back to it through the successful
completion of the series of trials and studies over that
period. One direct consequence of moving from the
radium system of the 1940s to the present high 'LDR'
remote afterloading cesium-137 system has been the
demonstration of the importance of carefully controlled
dose-rate correction factors. Morbidity continues to dog
the new systems, as it did the old ones, and is a conse-
quence of primary tumor damage, the proximity of
uninvolved normal tissues, particularly in early disease,
radiation dose, and individual radiosensitivity. The
modern systems are not worse than their predecessors,
but they are also not significantly better than them.
Everyone would wish to see total control without mor-
bidity, but realistically that is not achievable, given the
starting position with the majority of patients, but tech-
nical means to optimize treatment and biological means

to increase the efficacy on the tumor and decrease the
efficacy on normal tissue need urgent exploring.
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High dose-rate brachytherapy for treating
cervix cancer
C.A.JOSLIN
25.1 HISTORICAL BACKGROUND
Among those who introduced high dose-rate (HDR)
intracavitary afterloading for the treatment of cancer of
the cervix were O'Connell et al. in 1965. They used dose
escalation studies followed by surgery to carry out an
assessment of the histological and acute clinical effects of
treatment compared with established radium treatment
[1-4]. Others were also developing remotely controlled
afterloading techniques from the 1960s using either
HDR or dose rates in line with conventional low dose-
rate (LDR) radium, following the introduction of the
concept of afterloading by Henschke in 1960 [5-8].
The author's experience of using HDR remote after-
loaded source applicators for treating cervix cancer
began during the 1960s [1-4] and this treatment was
developed in combination with external-beam irradia-
tion for the radical treatment of cervix cancer from 1967
onwards [9,10].
During the 1970s the use of dose rates above those for
radium but much lower than those for HDR were intro-
duced and are discussed in Chapter 24. A significant dif-
ference between those techniques and HDR was that
LDR intracavitary irradiation was not necessarily com-
25
bined with external-beam irradiation, particularly for
early-stage disease, whereas HDR intracavitary irradia-
tion was. The principal reason for this was that to use
HDR alone entailed using an impractical number of
fractions. Various combined fractionation regimes have
been introduced since the 1970s and the treatment
results published. Strongly held views regarding the
advantages and disadvantages of HDR versus LDR ther-
apies have been expressed. A review in 1990 concluded
that the optimal technique and dose fractionation
scheme had yet to be established through systematic tri-
als [11].
From 1967, the author used HDR in conjunction with
external-beam irradiation on a radical treatment basis to
treat patients with early and advanced cancer [9]. The
method used followed the established Manchester
System, which included a central intrauterine tandem
and two small vaginal ovoids. The external-beam irradi-
ation was given using parallel opposed fields and a cen-
tral wedge, which was tapered to compensate for the
fall-off in dose from the intracavitary treatment. The
experience gained from treating a large elective group
was published in 1972 and with extended follow-up in
1991 [9,10]. Others have reported the results of compar-
ative studies and a few controlled clinical trials

[12-20,59,61,91]. Among one of the early reported series
was that of Shigematsu et al., who compared HDR with
manual LDR treatment for treating advanced cervical
cancer. They reported higher local disease control rates,
but also a higher rate of complications for the HDR
group when compared to historical LDR treatment [12].
The various publications identified minor differences in
results, but no significant major differences were
reported.
A general review of the published data by Fu and
Phillips in 1990 reported that most non-randomized
studies showed similar survival, local control, and com-
plication rates using fractionated HDR remote after-
loaded intracavitary irradiation combined with
external-beam irradiation compared with historical or
concurrent LDR controls. It was pointed out that the
techniques as well as the dose fractionation schedules
used in the different institutions were variable and that
the optimal technique and dose fractionation regime
had yet to be established through systematic clinical tri-
als. The conclusion drawn was that much clinical
research effort was needed to establish the optimal tech-
nique for the delivery of HDR afterloaded intracavitary
brachytherapy for treating carcinoma of the cervix [11].
That situation remains largely unchanged and is likely to
remain so in the immediate future.
The purpose of this chapter is initially to consider
those aspects of cervix cancer that affect management by
radiotherapy and then the application of HDR remotely
controlled brachytherapy in combination with external-
beam irradiation for treating early-stage and late-stage
disease. It also compares some of the reported results of
HDR with LDR treatment.
25.2 AGE GROUPS AFFECTED
Cancer of the cervix in the UK has increasingly become
a disease of young and old women. The biphasic age
incidence and frequency of the disease have affected
management mainly because, in general, the younger
woman presents with early-stage disease and the older
woman with advanced disease. Whereas both age groups
were extensively treated by radiotherapy until the late
1980s, since that time patients with early disease are
increasingly receiving surgical treatment.
253 TUMOR SIZE
Patients with squamous cell cancer of the uterine cervix
present with a primary tumor that may vary in size from
microscopic subclinical disease to an enlarged tumor
that may extend into the parametrium, reach the pelvic
side wall(s), invade the lower vaginal tissues, and infil-
trate the body of the uterus. Invasion of adjacent organs
Lymph node status 355
or tissues such as rectum and bladder may also occur.
This wide range of primary tumor extent means that to
deliver a curative dose at the periphery of the primary
tumor may require external-beam irradiation in addi-
tion to intracavitary irradiation.
In order to study the effects of treatment and give a
prognosis, it is important to classify patients according
to the disease extent. In clinical practice, the FIGO sys-
tem has proven to be of great practical value and
remains the most common method of staging. The
FIGO staging system involves clinically assessing the
extent of the primary tumor with the aid of an
intravenous pyelogram, and cystoscopy. However, in
addition to these standard assessment procedures, com-
puterized tomography (CT) and magnetic resonance
imaging (MRI) scans, transrectal ultrasound (TRUS),
and surgical staging are increasingly being used to assess
the disease extent.
Computerized tomography is now routinely used by
some for tumor localization and to assess parametrial
infiltration. It can be used to detect hydronephrosis and
enlarged lymph nodes. When compared with CT, MRI
has been reported to be more accurate for assessing the
primary tumor, but comparable for assessing lymph
nodes. TRUS has limitations when assessing advanced
cancer [21-24,70,72].
These additional assessment aids raise the important
question of how best to provide appropriate reporting
procedures for staging, especially if used to optimize
treatment on an individual patient basis.
The size of the primary tumor, including the extent of
any local invasive component, determines the type of
treatment. Views differ regarding the efficacy of intra-
cavitary irradiation alone to cure tumors more than 3 or
4 cm in diameter and of external-beam irradiation to
cure patients with extensive lymph node spread of dis-
ease. In general, some form of combined intracavitary
and external-beam irradiation has become the treatment
of choice.
25.4 LYMPH NODE STATUS
The size of the primary tumor and the incidence of
spread to pelvic lymph nodes are related- When the pri-
mary tumor is less than 2.0 cm in diameter, lymph node
involvement occurs in about 6% of cases, increasing to
18% for tumors greater than 2.0 cm in size. For tumors
greater than 3.0 cm in diameter, over 30% of patients
have lymph node involvement. A review of the published
data of lymph node involvement against clinical stage of
disease reported a rate of 19.8% for stage Ib, 36.1% for
stage lib, and 42.7% for stage Illb [25].
The lymph node groups most commonly affected are
the obturator, internal iliac, external iliac, and common
iliac nodes, with the risk of involvement being least for
356 High dose-rate brachytherapy for treating cervix cancer
the last group. The position of these lymph node groups
within the pelvis extends from about the lower border of
the fourth lumbar vertebra to the lower border of the
obturator foramen and laterally to between 1 and 2 cm
wide of the inner pelvic brim.
Bipedal lymphangiography can distinguish nodes
with filling defects and CT can detect enlarged nodes.
Neither of these investigations will clearly distinguish
enlargement specifically due to cancer, nor will they
identify microscopic disease. However, it has been
reported that CT scans are of prognostic value for assess-
ing outcome and that the cause-specific disease-free
survival is related to lymph node size [26-28,70].
25.5 EARLY-STAGE DISEASE
The alternative treatments, in which HDR brachyther-
apy may form part, include the following.
25.5.1 Intracavitary irradiation alone
Despite the fact that pelvic lymph nodes may be involved
by cancer, LDR intracavitary therapy alone has been an
established method of treatment for well over 60 years.
Such treatment ignores lymph node status, yet is
reported to produce results that are comparable to those
of other reported treatments. HDR brachytherapy alone
has not become an established alternative method of
treatment, mainly due to the practical problem of the
number of treatment fractions required in order to
restrict the risks of late reacting tissue damage. However,
the use of HDR brachytherapy alone has been reported
for treating cervical intraepithelial neoplasia (GIN III)
lesions [32], and Newman et al. reported treating stage la
cervical cancer by HDR brachytherapy alone [74].
25.5.2 Intracavitary irradiation followed
by Wertheim hysterectomy
The usual technique is to treat the primary tumor giv-
ing a dose less than radical followed by surgery. This
form of management was in use for many years with
radium and LDR afterloading and some would still
advocate it. The reason for mentioning it in this chapter
is that some of the earliest work using HDR brachyther-
apy involved efficacy studies by histological assessment
of surgical specimens following a few HDR fractions
[3,19].
25.5.3 Combined intracavitary and
external-beam irradiation
When compared with Wertheim's operation, there are
advantages but also some disadvantages. Although the
overall survival and morbid effects are comparable to
those of surgery alone, many gynecological surgeons
now favor surgery alone for the younger woman, and
that is a view also supported by many clinical oncolo-
gists. However, radiotherapy is still in use as the princi-
pal method of treating early-stage disease and a
considerable amount of HDR experience has now been
reported.
25.6 LATE-STAGE DISEASE
The risk of lymph node involvement in late-stage dis-
ease, i.e., stages lib and Illb, has been reported to exceed
30%. Also, depending upon the extent of spread of dis-
ease into the parametrial tissues, the outer limits of the
primary tumor may receive insufficient irradiation from
intracavitary treatment alone to be cured. In general,
therefore, treatment is given using a combination of
external-beam and intracavitary irradiation. The precise
combination will differ from one center to another, but
the reported results are similar [11].
The manner of combining the two treatment modali-
ties includes:
1. external-beam irradiation to the pelvis to deliver a
homogeneous dose followed by one or more boost
doses of HDR intracavitary irradiation to the cervix.
2. external-beam irradiation to the pelvis to deliver
treatment designed to compensate for the fall-off in
dose from the HDR intracavitary treatment. The
external-beam irradiation is delivered through a
beam-shaping wedge in order to modify the mid-
pelvic dose distribution to partly compensate for the
rapid fall-off in dose from the intracavitary
irradiation. The alternative is to use a simple lead
block to overlie the position of the intracavitary
treatment. This will partially protect the bladder,
rectum, and lower vagina from the external-beam
effects. Treatment is usually given daily for 4 days
each week, and intracavitary irradiation is given
once weekly for several weeks [9,10].
It is not recommended that combined treatment should
be given on the same day unless there is a minimum gap
of 6-8 h between treatments, principally because the
total radiobiological equivalent dose may increase the
risk of late normal tissue damage.
25.6.1 The case for external-beam
irradiation
The external iliac nodes are the most laterally placed
group, being situated at about 5-6 cm from the pelvic
midline. The dose received at this distance from the
intracavitary treatment will depend upon the system
used, and for a Manchester System would be from 25%

to 30% of the point A dose. That order of dose is unlikely
to be sufficient to cure lymph node disease except in
some cases of microscopic disease. Therefore, additional
external-beam irradiation is necessary to boost the dose
to the external and common iliac nodes to a curative
level.
Whether external-beam irradiation will effectively
control lymph node disease remains an important ques-
tion. Rutledge and Fletcher reported that, in a lym-
phadenectomy series, a high percentage of disease
control was obtained in external iliac and obturator
nodes with doses ranging from 50 to 60 Gy in 5-7 weeks
[98]. Others have reported that external-beam irradia-
tion before surgery can effectively reduce the expected
number of involved nodes. Lagasse et a/., in a random-
ized study, found that patients receiving preoperative
irradiation had nodal involvement in 12% of cases, com-
pared with 22% who received surgery alone. The latter
then had postoperative irradiation, producing a 5-year
survival of 74%, compared with 88% in the former
group [99]. The published reports of pelvic recurrence
rates following external-beam irradiation for the differ-
ent stages of disease have been less than the expected
lymph node involvement rate, and that evidence is the
substantial argument made to support external-beam
irradiation.
Also, in the case of a primary tumor exceeding 5 cm in
size, a curative dose at the tumor periphery from intra-
cavitary radiation alone is difficult to achieve without
putting the central pelvic organs at high risk of radiation
damage. As a consequence, shrinkage of the primary
tumor by external-beam irradiation before intracavitary
irradiation is indicated [47].
The claimed advantages and disadvantages from using
remote afterloaded HDR intracavitary irradiation
include:
1. no radiation exposure to staff during the setting up
and delivery of treatment;
2. the ability easily to retain treatment applicators in
position during the short treatment time;
3. delivering treatment in minutes as opposed to hours
or days: this is to the patient's advantage as well as
making it easier to deliver treatment in a consistent
manner;
4. delivering treatment at dose rates comparable to
external-beam irradiation so that the radiobiological
effects are dependent on dose per fraction, number
of fractions, and treatment volume;
5. no need for an indwelling bladder catheter;
6. minimal risk of ischemia of vaginal vault
epithelium due to prolonged pressure from ovoids
and packing;
7. a high throughput of patients who, in some
situations, can be treated on a daycare basis;
8. it has been reported by some that they find no need
to treat patients under general anesthesia.
Intracavitary treatment 357
The disadvantages include:
1. an increased number of treatment fractions and
anesthetics;
2. an increase in theater work load;
3. the need to combine external-beam with intracavitary
irradiation for early-stage disease. This argument is
based on only 20% of stage Ib cases having lymph
node involvement and external-beam irradiation
being unnecessary in 80%. However, similar
arguments can be claimed against lymphadenectomy.
On balance, it has been the author's experience that
the advantages outweigh the disadvantages.
25.7 INTRACAVITARY TREATMENT
The uterine cervix is ideally suited for intracavitary irra-
diation because:
1. the endocervical canal and vaginal vault form a
suitable vehicle to carry radioactive sources;
2. the normal cervical tissues and vaginal vault
epithelium are relatively radioresistant and tolerate
high doses of irradiation;
3. the intensity of irradiation rapidly falls off with
distance from the intracavitary sources. This restricts
the amount of irradiation received by normal tissues
beyond the cervix region.
The majority of preloaded systems (classically,
Stockholm, Paris, and Manchester) are adaptable for
afterloading. In particular, the Manchester System has
been developed to provide for afterloading with low,
medium, and high strength sources. High strength
sources involve several hundred giga-becquerels of activ-
ity in total. The applicator system should be sufficiently
rigid to prevent distortion when inserted. The range of
source lengths and ovoid applicators should provide a
number of predetermined treatment options.
In terms of dose distribution, most afterloaded sys-
tems are designed to be compatible with conventional
manual systems, although there may be differences
between systems in the definition of prescriptive refer-
ence point(s) and, in turn, dose delivered. Related to this
is the sensitivity of the position of reference points close
to the sources and disposition of those sources in regions
of HDR gradient [33-35].
However, the advent of independent control of each
source position and dwell time provides for a consider-
able variation in dose distribution and specification that
can be important when combining intracavitary and
external-beam therapy, particularly when optimized
treatment is planned [33]. Treatment optimization may
be indicated on the basis of the extent of local disease or
the proximity of normal tissues to one or more sources.
Optimization can be achieved by the use of CT or MRI
358 High dose-rate brachytherapy for treating cervix cancer
scans in conjunction with a computer planning system
[31,34,36]. For further discussion, the reader is referred
to the physics section of this book.
25.8 SOURCE POSITION RELATIONSHIPS
When intracavitary source applicators are independently
positioned, the geometrical relationship between them
will depend on the size and shape of the tumor. This may
result in a portion of the primary tumor being under-
dosed and normal tissue overdosed. The later effect may
be further increased by the addition of external-beam
irradiation. Alternatively, one may use a system in which
the individual source carriers are fixed in a predetermined
fashion to provide a standard-shaped isodose volume. If
necessary, the shape of the isodose volume can be modi-
fied by altering the source dwell times and altering the rel-
ative position of the applicators to each other [33,40,41 ].
25.9 DOSE DISTRIBUTION
In order that the intracavitary dose distribution may
match the classical Manchester Radium System, the size
of the intrauterine tube and vaginal ovoids should be as
per the Manchester System. This means that for HDR
treatment the sources need to be small and of high spe-
cific activity, such as cobalt-60 or iridium-192. Our ini-
tial experience was gained from using cobalt-60 sources
that were too large to pass through a tight radius of
curvature and the ovoids were placed in line with the
vaginal axis. The introduction of iridium-192 sources
meant that their relatively small size permitted a relative
tight radius of curvature of the carrier tubes and, for
some systems, to have the vaginal ovoids at an angle to
the vaginal axis. The bladder and rectal doses have been
measured and calculated at an ovoid angle of 18 and
60 and calculated for 0 [37]. It was found that altering
the ovoid angle from 60 to 18 resulted in a reduction
of the dose rate at point A and no significant difference
in the bladder or rectal dose. The calculated dose to the
bladder with the vaginal ovoids at 0 was found to be
reduced at the expense of an increased dose to the rec-
tal wall. Resulting from this work, and because using
ovoid sources in line with the vaginal axis did not pro-
duce any excess major rectal or bladder problems using
cobalt-60, we elected to continue with a similar source
configuration following the introduction of iridium-
192 sources.
The size of ovoid and uterine tandems used has been
shown for LDR systems to affect dose distribution, and
large ovoids result in a lower bladder and rectal dose but
higher point B dose. Also, longer uterine tandems pro-
duce a lower rectal dose and higher point B dose [86].
Increases in age and stage of disease have been
reported to result in less use of large ovoids and long
tandems and consequent higher dose to the rectum and
bladder and lower dose at point B. Starting with large
ovoids may result in small ovoids becoming neccessary
as treatment progresses. The regular use of small ovoids
throughout all applications overcomes the majority of
these changes in dose distribution that may occur.
Geometric variation may occur between HDR treat-
ments. This has been reported more commonly to occur
when colpostats rather than tandems are used. Also,
vaginal packing was shown to have a consistent effect on
dose distribution [87].
In the case of a small vagina, Sherrah-Davies reported
that LDR treatment could be effected using small ovoids
mounted on straight tubes. This meant that the long axis
of the ovoids was in line with the vagina and vaginal
packing was easier. The geometry was less ideal, but in
practice seemed likely to replace using half-ovoids [75].
Our experience since the 1960s is that small ovoids in
line with the vaginal axis are acceptable for cases treated
with HDR brachytherapy.
An alternative system is one that uses a single-line
source. The position of the source(s) within the
intrauterine vaginal applicator is altered, either in a step-
wise or cyclical manner, in order to provide a predeter-
mined dose distribution. The advantage of a central
vaginal applicator is that, in general, an applicator of
larger diameter than an ovoid can be used. While this
will provide for a lower mucosal dose and greater depth
dose below the vaginal wall, it does not provide a higher
relative dose to the parametrial tissues. An important
advantage claimed for a single-line system is that
patients can conveniently be treated as outpatients [63].
The use of external-beam irradiation with a single-line
LDR or HDR source(s) has been reviewed and reported
to achieve good local control for non-bulky tumors [39].
Other alternatives include a modified ring-shaped
applicator [73,80,81]. Comparison of the ring applicator
and Fletcher applicator has been published, with the
caution that one cannot transfer Fletcher-recommended
loadings to the ring applicator without radically altering
the dose distribution pattern that would have been
expected with Fletcher [81]. A similar argument will
apply to high activity source loading.
The dose distribution for those systems that have pre-
determined fixed geometrical configuration will be
known. However, for systems in which individual
sources are independently positioned, the dose distribu-
tion can only be calculated from suitable radiographs
done manually or by computer. This may pose a partic-
ular problem for HDR treatment, particularly if the
patient is anesthetized, because the time taken to carry
out the dose calculations and modify the treatment
time(s) may greatly exceed the treatment time itself. The
ideal situation is one where the source configuration is
fixed and the dose distribution known and supported by
a dose atlas for reference purposes [33,85].
 Special considerations 359

25.10 TARGET VOLUME not necessarily having a similar shape. For intracavitary
therapy it is usual to prescribe treatment at either a dose
point (point A) or isodose (reference isodose surface),
The regional extent of cervical cancer can be separated
usually taken as 60 Gy for LDR or its considered radio-
into two components: (1) the primary tumor, and (2)
biological equivalent for HDR. A volumetric description,
the pelvic lymph nodes. These are essentially two
in three-dimensional terms, of the reference isodose sur-
separate but interrelated clinical tumor volumes. The
face should approximate to the planned treatment vol-
two clinical tumor volumes can be superimposed within
ume and for fixed source systems will remain constant.
a common planning target volume, one being large and
This is discussed in Chapter 6 and elsewhere [40].
the other relatively small. The different normal tissues
In a reported study for LDR, the 60 Gy reference iso-
within each target volume will, because of their different
dose volume for a constant point A dose prescription
radiobiological factors and volume of tissue irradiated,
increased with ovoid size, but showed no consistent vari-
require different dose fractionation restrictions to pro-
ation with length of uterine tube. Applicator geometry
vide the best therapeutic ratio. To deliver a maximum
affected the isodose volume, which could also change
tumor dose, consistent with a high chance of effective
during treatment. The 60 Gy isodose volume was con-
tumor control and minimum risk of late normal-tissue
sidered potentially useful for dosimetric comparison,
damage, will entail using a carefully designed combina-
but had a limited role in predicting clinical response
tion of intracavitary and external-beam irradiation. In
[41].
particular, a combination of the two modalities should
The majority of HDR systems use small ovoids and
optimize the dose distribution for treating either early or
this has been our treatment policy since the 1960s. Also,
late disease.
when a fixed source configuration and loading pattern
Determining the extent of the clinical tumor volume
are used, the isodose reference volume, when combined
is at best a combination of objective and subjective
with external-beam irradiation, will provide a consistent
assessment. An improved assessment can be achieved by
and reproducible system for carrying out dosimetric
using conventional lymphography, ultrasonography, CT
comparison.
and MRI scans [22-24,27-30,72,101]. The relative mer-
its and limitations have been covered in various publica-
tions, but currently the most accurate single imaging
process is MRI [30,31,100,101]. This has the additional 25.12 SPECIAL CONSIDERATIONS
advantage that it can also be used to monitor tumor
shrinkage during treatment [30].
For LDR systems it is possible, using radiographic
A detailed study of the value of individualizing the
images, to calculate the dose at a prescriptive point
volume required to cover pelvic lymph nodes by using
before treatment is completed and, if indicated, to mod-
lymphography has reported that a change of 1.0 cm in
ify the treatment time to deliver the prescribed dose. As
width of the treatment fields can determine whether
previously discussed, this is not practical when high
lymph nodes are optimally covered or not. A change of
activity source treatments are used that last only a few
1.0 cm in width of the treatment volume represented an
minutes. As a result, unless a fixed source configuration
average change in target volume of 340 cm3.. This could
is used, treatment is effectively being prescribed in terms
increase morbidity risks for those likely to benefit from
of time and quantity (i.e., milligram-hours).
smaller fields. Similarly, for those needing wider fields,
Also, when using orthogonal or stereoshift radi-
there would be a greater chance of recurrent nodal dis-
ographs to calculate the dose to the Manchester point A,
ease [29]. CT and sagittal MRI also provide the means of
the calculated dose will be dependent upon the way in
geographically identifying the position of the pelvic
which point A is defined. If the usual current method of
lymph node groups in order to determine the outer lim-
relating point A to the flange of the uterine tube is used,
its of the planning target volume.
as opposed to the vault surface of the vaginal ovoid, a
This is not only important laterally, but also posteri-
considerable difference in dose rate at point A may occur
orly at the S2-S3 interspace and anteriorly at the anterior
[33]. Any change of distance between the ovoids and
edge of the pubic symphysis [101]. These levels have
flange from one treatment to another will have a greater
been identified as a potential problem in four-field treat-
effect on the point A dose when referenced from the
ment systems and both CT [22,57] and sagittal MRI
flange. The difference between the two alternative dose
[31,101] offer a more accurate method of planning.
calculation systems, for a patient prescribed to receive a
dose of 8.5 Gy once weekly for 4 weeks, is illustrated in
Figure 25.1. The prescribed treatment was based on a
25.11 DOSE-VOLUME SPECIFICATION
previous standard calibration. It can be seen that the cal-
culated dose varied greatly from the prescribed dose,
The planning target volume to be treated to a specified irrespective of the system used, being more consistent
dose should contain the clinical tumor volume, although when the ovoid surface was used. Such problems will, of
360 High dose-rate brachytherapy for treating cervix cancer
Figure 25.1 Values of point A dose using two alternative
definitions for five separate insertions in a single patient.
course, not apply to a fixed source configuration, which
was a major reason for us introducing a rigid source car-
rier system (see Figure 7.3, p. 109).
The method of specifying absorbed dose to organs at
risk is important when comparing different methods of
management. The biological effects are known to
depend upon total dose, dose rate, and dose per fraction,
which will change with distance from the sources.
Attempts should, therefore, be made to determine the
dose per fraction when reporting the maximum dose
received by a particular tissue. The volume of tissue
receiving the maximum dose is also important, and
planning systems in future may need to provide routine
dose-volume histograms (see Chapter 5) [42,79].
25.13 TREATMENT PLANNING
25*13*1 Combined intracavitary and
external-beam irradiation
For the reasons already outlined, HDR intracavitary irra-
diation is usually combined with external-beam irradia-
tion. For the treatment of early disease, the emphasis is
usually on intracavitary irradiation, with external-beam
irradiation being used to boost the dose to the pelvic
lymph nodes to what is considered to be a maximum tol-
erance level.
For advanced and bulky stage Ib disease, external-beam
irradiation is usually intended to shrink the primary
tumor to a size that can adequately be encompassed with
a boost volume of intracavitary irradiation. This partic-
ularly applies to late stage lib and Illb cancers of the
cervix. Also, such cases will have a 30-50% risk of
lymph node involvement, being largely dependent upon
external-beam irradiation to deliver a radical dose.
To encompass the pelvic lymph nodes adequately, the
width of the pelvic template used is typically 15 cm wide.
This will mean that, for the average patient, the planned
target volume will extend 1-2 cm lateral to the pelvic
brim. The height of the template will depend upon the
disease extent and was historically based on anatomical
levels, but a typical height is 14 cm. This may be
extended to 18-20 cm when the lower vagina and lower
para-aortic nodes are included. Normally, the lower edge
of the planned volume should be just above the lower
border of the obturator foramen and the upper edge at
the lower border of the fourth lumbar vertebra.
Posteriorly, the treatment volume should be 3 cm ante-
rior to the posterior point of the hollow of the sacrum
and, anteriorly, 2 cm anterior to the surface of the lum-
bar vertebrae for early disease, but may require modify-
ing in advanced disease. However, as previously
discussed and especially in advanced disease, patients
may be inaccurately planned unless aided by CT or MRI
[22,29,100,101].
Despite the complexity of some of the treatment sys-
tems used, irradiation of the pelvis may be adequately
achieved in most patients using two parallel opposed
fields, provided the energy used is 4-10 MV. In situations
in which pelvic separation exceeds 20 cm, it is often
preferable to treat the pelvis with a four-field 'brick' tech-
nique. If the latter is used, consideration should be given
to CT or, preferably, sagittal MRI planning to reduce the
risk of treating with inadequate anterior and posterior
margins [31,57,101].
25*13*2 Homogeneous external-beam
irradiation with high dose-rate intracavitary
boost irradiation
Although this technique may be used for treating all
stages of disease, the major use is for treating bulky stage
Ib and stage lib and Illb cases. External-beam irradia-
tion is delivered to the pelvis without central shielding,
to deliver a homogeneous dose distribution. The
reported dose fractionation schedules vary, but in gen-
eral the schedule is from 45 to 50.4 Gy in 20 to 28 frac-
tions, respectively, treatment being given daily for 5 days
each week. Intracavitary therapy follows within 1-2
weeks from completion of intracavitary irradiation. A
dose of 7.5 Gy to the Manchester point A is delivered on
two occasions, one week apart; alternatively, a dose of 7.0
Gy on three occasions is given. (The reader is referred to
section 25.13.11, 'Optimal dose regime').
25.13*3 Intracavitary high dose-rate
irradiation with shielded external-beam
boost irradiation
When the emphasis of treatment is on intracavitary irra-
diation with external-beam irradiation to boost the dose
to the pelvic lymph node areas, some form of shielding
to reduce the dose to normal tissues and organs receiv-
ing intracavitary irradiation is necessary. This treatment
schedule is usually restricted to patients with early dis-

ease, and this has been our practice since 1974. However,
our best results for treating advanced disease were
obtained using this treatment method from 1967 to 1974
[9,10].
The most critical part of the combined treatment vol-
ume will occur in the region where the steep dose gradi-
ent from the intracavitary irradiation combines with the
external-beam irradiation. This occurs particularly in
the region of points such as Manchester point A and
especially if a centrally positioned lead block is used for
screening, as opposed to a wedge that has been designed
partially to compensate for the fall-off in dose from the
intracavitary sources. One advantage of an HDR intra-
cavitary system is that the dose per fraction is similar to
that for external-beam irradiation. This does not resolve
the radiobiological problems of determining the effec-
tive dose for the two treatment modalities, but does
restrict the radiobiological problem to dose per fraction
and total dose. (The reader is referred to the radio-
biology section of this book for further reading.)
The various dose combinations of external-beam and
intracavitary irradiation for treating cervical cancer have
been largely developed as a result of clinical experience
gained from using external-beam irradiation with
radium intracavitary systems. In the latter situation, it
has generally been accepted that the intracavitary dose at
a specific point, e.g., point A, can be added to the dose of
external-beam irradiation at the same point. This is irre-
spective of the fact that adding doses for different dose-
rate and dose per fraction schedules may result in
different radiobiological effects for the same total dose.
Considerable care should therefore be given to applying
this approach when comparing HDR with LDR systems.
The author has used a combined treatment regime in
which the external-beam irradiation is given through
parallel opposed fields with a centrally placed beam-
shaping wedge. The wedge was designed to compensate
partly for the fall-off in dose from the intracavitary treat-
ment in both lateral and longitudinal directions. Various
modifications have been made since it was first intro-
duced in 1971, but the basic principle has remained
unchanged. The design was based on matching the aver-
age radiation distribution from the intracavitary sources,
obtained from a computer program to produce isodose
plots, carried out on several patients. One treatment
aspect that has always been considered to be extremely
important has been to restrict the overall volume of nor-
mal tissues included in the external-beam irradiation in
order to restrict the risk of bowel injury. For the regime
used, this has involved screening off the corners of the
fields to provide irregular octagonal fields [9].
25*13*4 Wedge position
The position of the treatment wedge will normally be
dependent upon the position of the intracavitary source
Treatment planning 361
system. Its position is usually centered over the
Manchester A-B line, 2.0 cm above the cervix marker or
applicator flange, as determined by check X-rays. With
most intracavitary carrier systems, the position of the
sources and uterus can be brought to within 1.0 cm of
the central sagittal plane of the pelvis. One exception to
this is when the uterus is fixed to other structures, either
due to tumor or some other pathology. For stage I and II
cases, lateral displacement due to cancer is not usually a
problem.
25*13.5 Treatment procedure
The procedure follows a relatively standard approach,
with patients being set up in the lithotomy position on a
mobile treatment table. Patients are usually anesthetized,
although some described methods do not use anesthet-
ics but sedation. When anesthetized, setting up is nor-
mally carried out on a treatment trolley in an operating
theater and, following completion of the setting-up pro-
cedure, the patient can be moved on the trolley to the
radiation treatment room. Where indicated, and
depending upon the treatment protocol, check radi-
ographs may be done for dose calculation purposes.
The procedure for insertion of the afterloaded appli-
cators will normally follow a similar pattern to that for
LDR systems. There are, however, some essential differ-
ences in that treatment only lasts for a few minutes and
an indwelling bladder catheter is not necessary; although
some catheterize the bladder as part of the initial theater
procedure, others consider a full bladder is preferable.
Also, pyometra is not, generally, a contraindication to
continue with HDR irradiation that only lasts from 5 to
20 min. Following treatment, antibiotics are given and, if
indicated, a suitable intrauterine drain may be inserted.
Clearly, care is necessary against perforating the uterus in
the presence of pyometra, particularly as the uterine wall
may be thin. By carefully taking this approach, the
author has not experienced any radiation or medical
problems.
The use of a rectal retractor eliminates the need for
vaginal packing and reduces the risk of disturbing the
anatomical relationship of the uterus to other pelvic
structures. Also, clamping volsella forceps to the cervix
and attaching the forceps to the applicator system exter-
nal to the introitus using a spring under slight tension
allow the uterus to be positioned at a low level in the
pelvis. This provides a means of similar positional place-
ment on further intracavitary treatment occasions.
The insertion of an inert metallic 'seed' in the anterior
lip of the cervix will, on X-ray, identify the relative posi-
tion of the cervix to the applicator flange. Depending on
the treatment schedule, this can also be used to check
any change in position of the uterus between receiving
intracavitary treatment and external-beam irradiation.
Difficulties may arise toward the completion of a
362 High dose-rate brachytherapy for treating cervix cancer
course of treatment due to tumor shrinkage and fibrosis,
but this has not proven to be a major dosimetry prob-
lem. Also, the position of the applicators can, unless the
uterus is fixed or tethered to the pelvic wall, be posi-
tioned in the midline of the pelvis.
A common method of checking rectal dose is by using
a suitable rectal dose measuring probe. This is not a
practical proposition for HDR treatment unless equiva-
lent low-activity monitor sources are used which allow
manual loading of the treatment applicators. When mea-
surements are made, the distance of the maximum dose
from the anal verge should be recorded. This will provide
a check for the position of treatment applicators within
the pelvis and should be a similar location on each treat-
ment occasion [3,9].
The clinical value of bladder dose measurement and
calculation is contentious. A major reason for question-
ing the value of bladder dose measurement is discussed
in the previous chapter, and the topic is discussed further
below.
For patients who receive external-beam irradiation in
conjunction with a beam wedge or screening block, the
position of the treatment wedge or screening block is
normally centered over the site of the inert metallic cer-
vical marker, overlying the position of the high-dose
intracavitary treatment.
Before the initial intracavitary treatment commences,
check radiographs can be done, usually in the treatment
room. Depending on the treatment schedule, these can
be used for planning external-beam irradiation. For
most applications, patients are lightly anesthetized dur-
ing treatment delivery and a patient-monitoring system
is essential. This will include cardiovascular, respiratory
function, and closed circuit television monitoring. Also,
a two-way speech system allows communication with
the patient in order to provide reassurance as necessary.
Once irradiation is completed, the treatment applicators
are removed. The entire procedure normally takes less
than 30 min.
25.13.6 Rectal dose
Rectal dose measurement carried out before treatment
will normally follow one of the established methods as
Table 25.1 Using a Joslin-Flynn applicator and rectal retractor (see Figure 7.3) to limit the
rectal dose. The dose 5 mm below the surface of the retractor is expressed as a percentage of
the point A dose. Values are approximate and are averaged for ovoid positions 1 and 2
45 65
65 65
used for LDR systems, whereas dose calculation before
treatment is not practical [9]. In general, we have fol-
lowed a relatively standard procedure for restricting the
maximum measured rectal dose as for low-activity man-
ually loaded systems. This has meant restricting the dose
to no more than 60% of the prescribed point A dose for
any individual treatment fraction.
For those systems that have a fixed source configura-
tion with standard source loading and the rectal tissues
are separated from the ovoids by a rigid fixed retractor of
known thickness, which forms part of the treatment
applicator, the rectal dose can be predetermined (see
Figure 7.3, p. 109). We use rectal retractors of 10 mm,
12.5 mm, and 15 mm thickness and the dose received by
the rectal wall will vary from 50% to 65% of the pre-
scribed point A dose (Table 25.1). As a result, it is not our
routine practice to measure rectal dose. However, it
needs to be stressed that for systems that do not ensure a
predetermined known dose to the rectum, dose mea-
surements are essential. Those dose measurements are
made immediately before treatment using appropriate
manually loaded low-activity sources.
An alternative to dose measurement is to carry out
dose calculations using orthogonal or stereoshift X-rays
at one or more rectal points. However, as previously dis-
cussed, this is not a practical routine procedure for
HDR intracavitary irradiation. Also, modification of the
source loading may alter the dose distribution and rec-
tal dose. This needs to be taken into account if the dose
distribution is to not exceed normal-tissue tolerance
[86].
Transverse CT images can be used to estimate a three-
dimensional dose distribution for critical structures and
other points of interest [36]. Using this approach for
LDR treatment, it was shown that the maximum rectal
dose value obtained from a transverse CT slice near the
top of the vagina was representative of the rectal dose
burden and offered a means of correlating with rectal
complications. Future developments are likely to involve
applicator systems specifically designed to be CT and
MRI compatible [34]. Commercial planning systems are
available that provide for the calculation of pretreatment
doses to point A, rectum, and bladder wall. It is possible
that, in future, this sophisticated system will be practical
for HDR intracavitary therapy.
55 50
55 50

25.13.7 Bladder dose
As for the rectum, it is not possible effectively to spare the
bladder from receiving a significant dose of irradiation,
but it should be minimized. The early afterloaded appli-
cators did not routinely provide ovoid screens, but, dur-
ing the early 1980s, screens were introduced for the LDR
Selectron applicator. Using screens, the bladder dose was
reduced by 15%, being similar to a distance increase of
5 mm between ovoid and bladder wall [45]. Using small
ovoids in which the long axis is in line with the vaginal
axis makes the use of ovoid screens impractical.
The routine measurement of bladder dose is normally
advocated and is included in the ICRU 38 recommenda-
tions, as discussed in Chapter 6 [40]. Crook et al. have
reported finding that, using LDR brachytherapy, the
dose-injury relationship is less reliable then for rectum
because of the smaller number of complications, and the
bladder reference point is less reliable. They also advised
that pelvic floor laxity, due to age and multiparity, leads
to considerable variation in the orientation of the blad-
der in the pelvis, with a consequent effect in the rela-
tionship of the maximum mucosal dose and the
standard reference point [42]. In a comparison of calcu-
lating the bladder dose by balloon or chain for an HDR
system, Kuipers and Visser found that the dose predicted
with the aid of a chain was 11% higher than that deter-
mined by balloon. They considered alternative points to
correct for that deficit [43].
Hunter et al. carried out CT scans on patients receiv-
ing LDR brachytherapy. They found that the ratio of the
maximum bladder dose compared with the ICRU blad-
der reference point varied by a factor of 1.01 to 3.59.
They advised that the inhomogeneous distribution of
bladder dose depended upon the anatomy, disease
extent, applicator design, and technical details of the
insertion. The important factor was to identify the
patient at risk of major injury [44] (see also Chapter 24).
The procedure of bladder dose measurement is not
made more difficult by the use of HDR techniques.
However, because of the short treatment times for HDR,
it is not practical to carry out routine CT scans in order to
calculate bladder dose distribution at the time of treat-
ment. Also, sectional CT images taken as part of a treat-
ment planning procedure for external and combined
brachytherapy, i.e., with or without treatment applicators
in position, do offer some way forward for determining
dose distribution to the bladder and other pelvic organs.
A major problem is that of possible changes in bladder
shape and position between fractional treatments, and
between CT position and treatment position.
25.13.8 Factors affecting pelvic disease
control
Kapp and colleagues [65] found few studies that had
analyzed prognostic factors in patients treated with HDR
Treatment planning 363
regimes, whereas this had been done for LDR regimes.
They confirmed that prognostic factors for 181 patients
treated with HDR brachytherapy compared with a pre-
viously treated LDR brachytherapy group were similar.
The significance of pretreatment hemoglobin level, of
tumor size, pelvic and para-aortic lymph nodes as
assessed by CT scan in contrast to clinical staging
(FIGO) has also been demonstrated [26,70].
A relationship between outcome, tumor bulk, stage,
lymph node status and overall treatment time in patients
treated by a combination of external-beam with LDR or
HDR intracavitary treatment has been reported
[39,70,93]. For patients treated by a combination of
external-beam irradiation and LDR brachytherapy, Perez
et al. reported on the 10-year actuarial pelvic failure rate.
It was 5% for stage Ib tumors less than 2.0 cm in size and
34% for unilateral or bilateral bulky tumors greater than
5 cm in size. Also, for a given stage and size of tumor, the
pelvic failure rate decreased with increasing dose. For
stage lib cancer, with total doses of 70 Gy to point A, the
pelvic failure rate was about 50%, whereas for doses over
80 Gy it was 30% for bulky and 20% for non-bulky
tumors [46].
In a retrospective analysis of 659 patients treated by
external-beam irradiation (50 Gy) and HDR brachyther-
apy (20-34 Gy), Ito et al. reported no correlation
between radiation dose and pelvic failure except in
advanced stage III cases. In these cases, an HDR dose of
24 Gy or less to point A correlated with a higher pelvic
failure and lower survival [47].
Computed tomography has been used to visualize the
volume and shape of deep-seated cervix tumors as a pre-
dictive test of treatment outcome in a quantitative man-
ner [70,71]. The initial volume, measured at the
beginning of radiation therapy, was not a significant
prognostic guide for local tumor control, but the volume
measured immediately following completion of external
irradiation was. Of patients whose second volume was
less than 38 cm3, 90% were locally controlled 3 years
later, whereas for those with volumes larger than 38 cm3,
local control was 74%. Five-year actuarial survivals were
53% and 26%, respectively [71].
Using HDR intracavitary treatment, our experience of
stage I cases is that for tumors less than 2 cm in size it is
unusual to fail to control local disease. It has also been
our experience that control of the primary tumor is
related to its size.
Table 25.2 gives the pelvic disease control rates for var-
ious LDR and HDR regimes. There are no significant dif-
ferences to note, and this also applied to the comparative
and prospective studies carried out.
Our experience, from using two different dose frac-
tionation regimes in which the biologically equivalent
dose (BED) values, both acute (GylO) and late (Gy3),
were similar and overall treatment time was 21 or 29
days, was that for stage I cases pelvic disease control was
achieved in 96% and 81% of cases, respectively. Others
Table 25.2 Published reports of 5-year survival and pelvic disease control rates for carcinoma of the cervix treated by combined external-beam and HDR or LDR intracavitary
irradiation

Joslin(1972) HDR 94 62 37
[9]
Khoury (1991) 1 5 year results [10] 93 54 34
Kuipers(1984) [59] HDR 80 71 43
[60] HDR 71 76 62 90 85 70
Vahrson(1988)
Comparative study LDR 74 53 24
Cikaric(1988) [61] HDR - 54 37
- 70 43
Comparative study LDR
Khoury (1991) [10] HDR 86 66 46
(Literature review mean %) (855 cases) (1830 cases) (1841 cases)
85 70 49 53
Chen (1991) [64] HDR
Arai (1992) [69] HDR 88 77 67 52 24
Hammer (1993) [88] HDR 79 63 41 92 60 53
85 53 43 43
Comparative study LDR
Teshima(1993) [20] HDR 85 73 53
Randomized study LDR 93 78 47
[68] HDR 72 65 66 66 45 66 83 78 88 40
Selke(1993)
Sarkaria(1994) HDR 77 stages I to III 77 overall
*[15]
Comparative study LDR 66 stages I to III 80 overall
[16] HDR 78 64 50 75.8 overall
Patel(1994)
Randomized study LDR 73 62 43 79.7 overall
MacLeod (1997) [62] HDR 78 72 42 29
el-Baradie(1997) *[17] HDR 62 All stages combined 67 overall
MDR 68 74 overall
Prospective study
Tan (1997) [39] HDR 79 61 31 88 69 45
Kapp(1997) [65] HDR 93 57 46
[67] HDR 79 59 41 94 87 72
Wang (1997)
[66] HDR - - 51 71
Takeshi (1998)
[63] HDR - 77 50 87 64
Kagei (1998)
Single-line source
*[18] HDR 86 65 33 85 80 44
Petereit(1999)
Prospective study LDR 82 58 58 91 78 75

*3-year study.

have reported that prolongation of treatment time is
associated with decreased local disease control and sur-
vival in stage lib and Illb patients treated with HDR and
external-beam irradiation. This constituted the most sig-
nificant prognostic factor, staging being second.
However, there was no correlation between late compli-
cations and prolongation of treatment time [48].
25.13.9 Pelvic failure and distant
metastasis
Our first radical dose fractionation regime failed to con-
trol pelvic disease in 26% of stage II cases, of whom 18%
developed metastasis, as did 22% of those with a clear
pelvis. For stage III cases, pelvic recurrence occurred in
44% of cases, of whom 27% developed metastasis and
25% of those with a clear pelvis. From this it would
appear that failure to control pelvic disease is not neces-
sarily associated with an increased risk of metastatic dis-
ease. Toita et al. found that distant metastases-free rate
was strongly correlated with nodal status as a suitable
independent predictor [70].
25.13.10 Survival rates
The 5-year survival rates of patients who received HDR
intracavitary brachytherapy combined with external-
beam irradiation have been variously reported, but all
reports indicate similar results [11-13,17,18,88-90]
(Table 25.2). Overall, the HDR results are similar, stage
for stage, for the different dose fractionation regimes
used. Table 25.2 also includes the results for a few LDR
series, some of which were historical controls and others
either concurrent or controlled studies.
Information on the long-term actuarial survival is
important and, for our series of stage I-II and III cases
treated from 1967 to 1974, at 5, 10, and 15 years it was
63.4%, 58.8%, and 57.9% respectively. When separated
into stage I, II, and III, the 5-year survivals were 94.5%,
62.6%, and 37.3%, and at 15 years were 92%, 53%, and
33%, respectively. Clearly, survival to 5 years is an indi-
cation of a high probability of cure. A review by Khoury
et al. of several thousand cases reported 5-year survival
rates of 86%, 66%, and 46% for stages I, II, and III,
respectively [10].
25.13.11 Optimal dose regime
An American survey of radiotherapy regimes for cervical
cancer reported a wide variation in doses used. Of 315
responders reporting on 4892 cases, 24% used HDR
brachytherapy. The median external-beam doses were 48
Gy and 50 Gy and the median intracavitary dose 6 Gy
on five occasions. This compared with LDR median
external-beam doses of 45 Gy and 50 Gy; the LDR doses
Normal-tissue effects 365
were 42 Gy and 45 Gy for early and advanced cancer,
respectively. These dose regimes represent what might be
described as an 'optimal' reference regime on which to
base further dose fractionation studies [84].
Petereit and Pearcey reviewed the literature in order to
determine if there was an optimal fractionation sched-
ule. They used the linear quadratic equation to deter-
mine the biologically effective tumor dose for an
alpha/beta ratio of 10, at point A. The median external-
beam fractionation schedule was 40 Gy in 20 fractions
and the HDR schedule was 28 Gy in four fractions. For
stages Ib, lib, and Illb, the BED values at point A were 96,
96, and 100 Gy, respectively. They advised that the opti-
mal fractionation regime was still unknown and cur-
rently can only be based on the recommendations of
single institutions with significant experience [55].
25.14 NORMAL-TISSUE EFFECTS
The price of failure to completely control pelvic disease
is usually fatal. As a result, the major treatment emphasis
has been on cure. With a shift of public concern to mor-
bidity issues and the technical advancements that have
taken place, including attention to quality control and
assurance, the price of cure is also receiving greater
attention. The addition of external-beam to intracavi-
tary irradiation has increased the incidence of small
bowel injury and this has become a major risk for
normal-tissue injury.
The commonly recognized morbidities are well docu-
mented in the literature. They include parametrial fibro-
sis, which may be associated with obstruction to a lower
ureter, extrinsic rectal fibrosis causing rectal stenosis,
vaginal stenosis, or occlusion. A localized high dose
may cause rectovaginal and vesicovaginal fistulae.
Occasionally, a stricture may occur in the sigmoid colon,
particularly in the terminal ilium, and, less commonly,
perforation or fistula.
The dose delivered from intracavitary irradiation to
the above-mentioned structures will depend, for a par-
ticular system, on the disposition of the sources and their
geometrical relationship to the structures in question.
The only situation in which control of dose can be accu-
rately achieved and maintained is for rectal tissues.
Because of the difficulty of dose calculation to critical
tissues, the present practice of dose checking by mea-
surement for those tissues that are accessible has much to
commend it. However, where both calculation and mea-
surement can be done, they should complement each
other.
The last two decades have seen increased attention
being given to these problems [10,11,14,26,42,46,53,54,
58,67,76,77,80,88,89,97]. Unfortunately, one of the
major issues of recording and reporting morbidity has
been the lack of an internationally accepted and applied
366 High dose-rate brachytherapy for treating cervix cancer
system of morbidity grading. This has made it extremely
difficult to compare data from different centers. A review
by Sismondi et al. of 96 articles reported no classification
in 59, and the remainder used different criteria [49]. A
French-Italian glossary for reporting complications,
suitable for a computerized format, was published in
1993. This basically followed a standard approach of
mild (Gl), moderate (G2), severe (G3), fatal (G4) com-
plications, extended to include, for each grade, a series of
subdivisions based on signs and symptoms [50,51]. The
system was independently assessed in 1996 and reported
as useful [52]. Reference is made to this glossary because
of its specific application to gynecological cancer.
25*14.1 Early tissue damage
Early reactions commonly affect patients receiving a rad-
ical course of pelvic irradiation. In particular, diarrhea
affects up to 50% of patients receiving external-beam
irradiation in addition to intracavitary irradiation. In
some cases, this may be associated with small bowel
colic. The onset often occurs during the second week of
treatment and generally settles within 1-2 weeks follow-
ing completion of treatment. Conservative treatment
usually produces an easing of symptoms. Our policy has
been to rest the older patient if symptoms do not settle
within 1 or 2 days. Patients with severe proctitis or
abdominal colic should be rested from treatment until
symptoms settle. If the symptoms return on resuming
radiotherapy, the management policy should be
reviewed, including possible surgery.
Urinary symptoms are, in our experience, less com-
mon and when they occur may be due to infection and
accordingly investigated and treated.
Early reactions were fully recorded in our first series
of 144 cases treated by HDR and external-beam irradia-
tion from 1967 and published in 1972 [9]. Acute effects
following HDR intracavitary therapy are not generally
dealt with in detail in the literature and it is not possible
to provide any meaningful comparison with LDR
regimes. However, it has been suggested that the criteria
for producing an equivalent HDR to LDR dose protocol
should be based on matching early rather than late
effects [95].
25.14.2 Delayed tissue damage
Delayed normal-tissue damage may involve any tissue or
organ within the irradiated volume, but is usually
restricted to tissues within the planned treatment vol-
ume. The major tissues and organs at risk include rec-
tum, sigmoid colon, small bowel, bladder, and vagina.
Fractionation of the HDR brachytherapy is essential
and at least single weekly fractions are normally given.
Twice-weekly brachytherapy with a consequent reduc-
tion in dose per fraction has been reported to reduce the
risk of normal-tissue injury [12,74,90,94]. Twice-daily
HDR fractions have been reported to show similar com-
plications to LDR when made biologically equivalent,
the major advantage being a shortened hospital stay
[91]. Others have reported on the giving of concomitant
HDR with daily external-beam irradiation on three
occasions each week for 3-4 weeks. On the concomitant
treatment days, a stepped wedge was used in conjunction
with external-beam irradiation. The complication rates
were reported to compare favorably with LDR experi-
ence [92]. Again, the importance of a time gap to allow
for sublethal damage tissue recovery between fractions
should be stressed.
Patient follow-up for at least 5 years is important, dur-
ing which time 80% of patients suffering symptoms and
signs of moderate/severe morbidity will have come to
light (Table 25.3). Also, patients may die without pre-
senting with late tissue injuries and it is important to
provide data on an actuarial basis [9,51].
25.14.3 Rectum and sigmoid colon
Although the reporting of rectal complications has
become more prevalent in recent publications, many of
those reports relate complications to total dose rather
than to the dose fractionation schedule received by the
rectal tissues. This approach would appear to be based
on external-beam studies of tolerance for a fraction size
of 1.8 Gy and 2.0 Gy [76]. Calculating and reporting the
BED, using the ICRU rectal reference point, for com-
bined external-beam and HDR intracavitary treatment,
may overcome some of the difficulties of correlation of
dose fractionation to morbidity. However, the rectal dose
as calculated at a defined point may not be the point of
maximum dose as determined by CT [36].
Correlation between rectal complication and calcu-
lated rectal dose has been reported [53,54,90]. Using the
ICRU criteria, Ogino et al. advised that the incidence of
rectal complications was from 5% to 10% at time-dose
fractionation (TDF) values from 104 to 124 and BED
(Gy3) values from 119 to 146. Grade 4 complications
were not observed with a TDF below 130 or BED below
147 [53].
Petereit and Pearcey reported no correlation between
point A BED (Gy3) and risk of late rectal and bladder
complications. They questioned the quality of the cur-
rent HDR brachytherapy literature in providing details
of dose fractionation schedules rather than the
linear-quadratic (LQ) model [55]. Le Pechoux et al.
reported that no factor was predictive of local control,
but the dose of external-beam irradiation significantly
influenced the risk of complication [56].
Some of the reported results of severe rectal morbid-
ity, mostly graded as 2 or 3, are shown in Table 25.3.
These results are for different HDR and LDR regimes,
including comparative studies in the same centers. It can
 Normal-tissue effects 367

Table 25.3 Complication rates reported by various centers using HDR and LDR brachytherapyfor cervix cancer. The grading criteria
are not standardized to a particular system

Reference First author Date Treatment type Stages Small bowel Rectum Bladder

[96] Sato (1984) HDR I-IV 14.9% 9.2%

LDR 13.6% 7.5%

[59] Kuipers (1984) HDR 7% 3.5%

Comparative study LDR 6% 3.3%

[61] Cikaric (1988) HDR II and III N.R. G3 3% G2 4% G3 0.7%

LDR II and III G3 6% G2 6% G3 2%

[80] Rotte (1989) HDR l-lll G3 1.4 1.1

Comparative study LDR G3 6.2 2.2

[10] Khoury (1991) HDR l-lll G3 4.0% G2 3% G, 0.5% G2 4.0% G3 0%

[68] Selke (1993) HDR l-lll 7.6%G 3 andG 4
[69] Arai (1992) HDR I-IV 1.1% 4.1% 1.4%

[20] *Teshima (1993) HDR l-lll 10% of patients

Randomized study LDR l-lll 4% of patients
[16] Patel (1994) HDR l-lll 6% G 3 andG 4 0.4%
Randomized study LDR l-lll 20% G 3 andG 4 2.4%
[67] Wang (1997) HDR l-lll G 3 andG 4 6% G 3 andG 4 9%
[62] MacLeod (1997) HDR l-lll 5% overall late severe morbidity
[39] Tan (1997) LDR l-lll G2 4.3% G3 1.4% G2 2.7% G3 0.6%
Single-line source
[65] Kapp (1997) HDR I-IV 2% severe 8%
[66] Takeshi (1998) HDR III 8.3% (major) 2.6% (major)
[63] Kagei (1998) HDR II and III 1% 2% 1%
Linear source arrangement G3 + G4

*3-year study.
N.R. = not recorded; G = grade.

be seen that the results appear to favor HDR in some
cases and LDR in others. Among the reasons that the
results from the various centers may not be intercompa-
rable are differences in dose specification and systems, of
follow-up [ 11 ]. As so often occurs when reviewing vari-
ous reports, without having the necessary information
accurately to equate all the various parameters affecting
outcome, no significant differences between the morbid-
ity outcome of treatment for LDR and HDR systems are
likely to be identified.
Sigmoid colon narrowing has been reported as a com-
plication following HDR and LDR treatments. In the
case of HDR, it is usually in association with external-
beam irradiation. A long intrauterine tandem loaded to
the tip may result in a high dose to the sigmoid colon
[38,75]. Our experience does not support this view,
except possibly when long tubes are used throughout
treatment (Table 25.4). In the mixed situation, a long
tube was used for the first two insertions and a medium-
length tube for the remaining three insertions. As a
result, the author has made it a policy to restrict the use
of long tubes to two insertions.
Also, the tendency to push the flange of the central
tube against the cervix and inadvertently move the
uterus deep into the pelvis should, as previously dis-
cussed, be counterbalanced.

Table 25.4 Morbid effects using a long intrauterine tube when treating stage I and II cancers of the cervix, Leeds series 1974-1983

Long 6 2(33.3)
Medium 148 10(6.7) 9(6.1) 7(4.7)
Mixed 167 13(7.8) 4(2.4) 11(6.6)
368 High dose-rate brachytherapy for treating cervix cancer
25.14.4 Bladder
The reported symptoms include urinary frequency,
dysuria, and hematuria. Late radiation changes may
cause varying amounts of atrophy of the bladder mucosa,
often associated with telangiectasia. Occasionally, a
vesicovaginal fistula will occur. In a total of 187 stage Ib
cases treated with HDR intracavitary irradiation, we saw
one case of vesicovaginal fistula. Although most cases will
present with bladder symptoms within 2 years, cases can
first present at up to 10 years or later.
The risk of hematuria recurring is relatively low and
affects up to 5% of patients. Our experience has been that
only rarely are patients so severely affected that urinary
diversion is necessary. Similarly, a constricted bladder suf-
ficiently severe to warrant an ileal loop bladder is unusual.
Because of the problems of accurately determining
bladder dose, comparison of the late effects for the dif-
ferent techniques used is difficult. Most reported series
of complication rates only provide details of dose frac-
tionation at a specific point, e.g., point A. The value of
the ICRU bladder reference point being the point of
maximum bladder dose has not been supported by
Hunter et al. [44], whereas Pourquier et al. found that
the maximum dose to the trigone showed a significant
difference in patients with or without complications
[77]. Specific details of the dose fractionation break-
down of the maximal dose (either measured or calcu-
lated) to the bladder are rarely reported. The majority of
calculations relate to the trigone area that is fixed relative
to the lower gynecological tract, whereas the maximum
dose may be at some other point [43,44]. In general, the
various studies that have reported bladder injuries show
no significant difference between rates for LDR and
HDR techniques either between or within institutions
(see Table 25.3). Future developments based on dose
area plots of the bladder mucosa or dose-volume plots
may provide a better dose-injury risk correlation [42].
25.14.5 Small bowel
The overall reported rates of small bowel injury are var-
iously reported as affecting 25% and more of patients.
However, when restricted to moderate and severe mor-
bidity, the rate falls to 5-15%. These rates apply
whether LDR or HDR treatment in conjunction with
external-beam irradiation is given. The risks of devel-
oping small bowel injury have been reported to be
dependent on total dose, dose per fraction, dose rate,
and the size of the planned treatment volume. A history
of previous laparotomies and pelvic inflammatory dis-
ease increases the risk of small bowel injury [58], The
volume effect on clinical tolerance has also been
demonstrated. An analysis of radiation-related small
bowel complications indicated that, if the volume of
irradiated small bowel was increased by a factor of 2,
the total dose had to be reduced by 17% for the same
complication risk [79].
The major contributing cause of small bowel injury is
external-beam irradiation, although intracavitary irradi-
ation will contribute from 20% to 30% of the point A dose
at the level of the pelvic brim. This will mean that an HDR
fraction of 6-7 Gy at point A will be approximately 2.0 Gy
at the pelvic brim. This dose per fraction is of a similar
order to that from external-beam irradiation. Thus, the
terminal ilium may receive a similar dose per fraction
from combined treatment. However, small bowel may lie
within the pouch of Douglas or be stuck to the surface of
the uterus. In these situations, the affected portion of
bowel may receive a high dose with each fraction of HDR
brachytherapy. Mobile small bowel may alter in position
between fractional doses of HDR brachytherapy, and the
risk of repetitive significant doses of irradiation to a par-
ticular segment of bowel will be reduced.
In our experience, more than 60% of late large and
small bowel complications occur within 2 years of treat-
ment, with a median time of 14 months, being similar to
other reports [10]. However, patients may initially pre-
sent with small bowel morbidity at up to 10 years from
treatment and, if previously discharged from follow-up
at 5 years, these may not be recorded [10].
Various treatment techniques have been studied in
order to minimize the volume of small bowel included in
the external-beam volume. We have applied radiation
shields to shape the anterior and posterior pelvic fields to
the perimeter of the pelvic lymph node groups. This
entails screening off all corners of the standard treat-
ment field to produce an octagonal shape. Also, we nor-
mally treat patients in a prone position in an attempt to
reduce the volume of irradiated small bowel.
A prospective study of different treatment techniques
has identified compression in the prone position com-
bined with bladder distension as a single reproducible
procedure. It was found that the irradiated volume of
small bowel, especially following pelvic surgery, corre-
lated with acute gastrointestinal effects. Late effects also
correlated with prior pelvic surgery and volume of small
bowel receiving more than 45 Gy [82].
Radiation enteritis is invariably progressive and fur-
ther complications often occur following initial symp-
toms and signs. Prevention is virtually impossible for the
range of dose fractionation schedules used for treating
cervical cancer, but steps should be taken to minimize
the risk [78]. The subject of radiation morbidity to the
gastrointestinal tract following radiation has been exten-
sively covered elsewhere [83].
25.15 CONCLUSION
An attempt has been made to discuss, in outline, some of
the important issues that apply when treating cervix

cancer by HDR brachytherapy and external-beam irradi-
ation.
The various published reports of pelvic disease con-
trol rates, cure rates, and morbidity reveal a lack of stan-
dardization of several aspects of management, although
these problems are being steadily overcome with
improved imaging, treatment planning, accuracy of
treatment delivery, and clinical management. However,
in clinical practice, anatomical variation, size, and shape
of tumor will mean that standard treatment will be inad-
equate for some patients.
How to overcome some of the physical problems is
compounded by the relationship between physical dose
parameters and radiobiological effects [102]. Whether
HDR or LDR is the better treatment remains an open
issue and is likely to remain so for the foreseeable future.
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90. Utley, J.F., van Essen, C.F., Horn, R.A. and Moeller, J.H.
(1984) High dose rate afterloading brachytherapy in
carcinoma of the uterine cervix. Int. J. Radial Oncol.
Biol. Phys., 10,225-6.
91. Hsu, W.L, Wu, C.J., Jen, Y.M. et al. (1995) Twice per day
fractionated high versus continuous low dose rate
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cancer: a non-randomised comparison of treatment
results. InlJ. Radial Oncol. Biol. Phys., 32(5), 1425-31.
92. Han, I., Malviya, V., Chuba, P. et al. (1996)
Multifractionated high-dose-rate brachytherapy with
concomitant daily teletherapy for cervical cancer.
Gynecol. Onto/., 63(1), 71-7.
93. Garipagaoglu, M., Yalvac, S., Kose, M.F. et al. (1999)
Treatment results and prognostic factors in inoperable
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dose brachytherapy. Cancer Lett., 136(1), 17-26.
94. Stitt, J.A. (1999) High dose rate brachytherapy in the
treatment of cervical carcinoma. Hematol. Oncol. Clin.
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95. Brenner, D.J., Huang, Y., Hall, E.J. (1991) Fractionated high
dose-rate versus low dose rate regimens for intracavitary
brachytherapy of the cervix. Equivalent regimens for
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96. Sato, S., Yajima, A. and Suzuki, M. (1984) Therapeutic
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97. Akine, Y., Tokita, N., Ogino, T. et al. (1990) Dose
equivalence for high-dose-rate to low-dose-rate
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98. Rutledge, F.N. and Fletcher, G.H. (1958) Transperitoneal
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99. Lagasse, L.D., Smith, M.L, Moore,J.G.etal.(1974) The
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100. Khoo, V.S. (2000) MRI-'Magic radiotherapy imaging'for
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101. Zunino, S., Rosato, 0., Lucino, S. et al. (1999) Anatomic
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102. Joslin, C.A. (1996) Commentary: Brachytherapy-clinical
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Brachytherapy for brain tumors
MAARTENC.CM.HULSHOFANDJANJ. BATTERMANN
26.1 INTRODUCTION
Primary tumors of the central nervous system comprise
1.5% of all malignant disease. Astrocytomas represent
about 40% of all brain tumors of which the majority
(75%) are malignant (anaplastic astrocytoma and
glioblastoma multiforme) [1]. For patients with a
glioblastoma multiforme, which compromise 75% of the
malignant astrocytomas, surgery alone results in a sur-
vival of approximately 4-6 months and, in combination
with conventional external irradiation, survival is about
6-9 months [2]. Combinations with chemotherapy or
radiosensitizers for patients with a glioblastoma multi-
forme did not result in a prolonged survival. For
anaplastic astrocytomas, the median survival is some-
what better, but still less than 10% survive 5 years. There
is a good rationale for increasing the radiation dose with
brachytherapy in malignant gliomas: radiation therapy is
so far the most effective treatment and a dose-effect rela-
tionship up to 60-70 Gy has been demonstrated [2,3].
However, more than 90% of malignant astrocytomas fail
treatment within 2 cm from the original tumor site, and
distant metastases are hardly ever seen [4]. Further con-
trol by local treatment failed when the external dose was
raised to 75 Gy [5] and this increased dose exposes the
patient to a significant risk of normal-brain necrosis [6].
The radiation dose in brachytherapy has a rapid dose
fall-off, thereby sparing normal surrounding brain tis-
sue. In addition, the use of external heavy particle ther-
apy has failed to improve the treatment results, mainly
because of the toxicity to normal brain tissue [7]. With
the development of accurate stereotactic techniques, the
26
principles of interstitial radiotherapy became available
for brain tumor patients.
In Europe, a long tradition of brachytherapy exists for
high-grade as well as low-grade gliomas [8]. In the last
two decades, the use of brachytherapy for brain tumors
increased all over the western world, and nowadays most
publications and studies come from the USA and
Canada.
26.2 TREATMENT TECHNIQUE
Both computerized tomography (CT) and magnetic res-
onance imaging (MRI) scans are used to define the
tumor localization, although it is generally accepted that
MRI better outlines the tumor contour. Under local or
general anesthesia, a stereotactic head frame is fixed at
four points to the patient's skull and a contrast-
enhanced scan is obtained, with images every 3 or 5 mm
(Figure 26.1). The target volume is outlined on each
individual image and generally includes the contrast-
enhancing area with or without a margin of 5 mm. After
digitizing the target geometry using three-dimensional
software, the most suitable catheter trajectory and num-
ber and length of catheters are determined with a three-
dimensional preplanning. The preplanning will try to
optimize the dose distribution, aiming at a dose rate of
40-100 cGy h-1 at the reference points, with as small a
number of catheters as possible and without unaccept-
able overdosage in the tumor center. These calculations
and preplanning procedure take about 1-1.5 h. For that
reason, local rather than general anesthesia for fixation
374 Brachytherapy for brain tumors
Figure 26.1 CT image of cerebrum with Leksell base ring
during the calculation of target points.
of the base ring is preferred, both by physicists and clin-
icians. In the operation room, catheters are introduced
percutaneously and parallel to each other at the calcu-
lated positions using burr or twist drill holes (Figure
26.2). Catheters are directly fixed to the skin or via a tem-
plate, which is sutured to the skin. Usually within 24 h
after implantation, a contrast-enhanced scan is obtained
for analysis of the catheter configuration (Figure 26.3).
The accuracy of these stereotactic techniques is stated to
be within 1-2 mm [9,10]. Actual length of sources is
determined for each catheter on this scan. After recon-
struction of catheter position and determination of
source position by X-ray film in two directions, a three-
dimensional dosimetric plan is made. Most institutes use
temporary sources of high-activity iodine-125 seeds or
iridium-192 wires. Final loading can be done manually
or with a remote afterloading system.
The advantage of remote afterloading is the better
radiation protection for personnel, but the disadvantage
is the greater immobility of the patient.
Another treatment technique is the permanent implant
of low-activity iodine-125 seeds. This can be done during
open brain surgery, whereby source carriers are implanted
in the margins of the tumor after debulking of the tumor,
or stereotactically, whereby seeds are implanted after
three-dimensional preplanning of seed positions.
Prophylactic antibiotics and corticosteroids are mostly
given as a routine measure. Removal of the catheters can
be done without anesthetic and is never described as a
clinical problem.
There is good general agreement on the eligibility cri-
teria for brachytherapy in the different reported series.
Tumors should be unifocal, supratentorial, not larger
than 5 cm (in largest diameter), and without ventricular,
corpus callosum, or brainstem infiltration. Patients
should have a good performance status.
263 RESULTS
263.1 Recurrent malignant gliomas
The first reported results of brachytherapy in malignant
glioma concerned recurrences after surgery and external
Figure 26.2 Leksell stereotactic
system and intracerebral
catheters during implantation.
 Results 375

anaplastic glioma treated with brachytherapy had equal

survival results to recurrence of a glioblastoma multi-
forme [15]. There is little known about the effect of
brachytherapy on the quality of life of these patients.
Leibel et al. showed that there was no significant reduction
in deterioration during the 6 months after implantation
[14]. However, symptomatic radiation necrosis needing
re-operation occurred in 40-50% of cases [14,17]. These
series used high dose-rate (HDR) brachytherapy with
temporary implants. Studies involving resection of the
recurrent tumor followed by permanent low dose-rate
(LDR) implants suggest that this approach decreases the
incidence of symptomatic necrosis [15,18,19].

263.2 Newly diagnosed malignant

Figure 26.3 CT scan of cerebrum for analysis of catheter
position. Note the catheter positions at the periphery and center
of the tumor.
irradiation. It has been estimated that median survival
after recurrence of a malignant glioma without further
treatment is 3.2 months [11]. Re-operation can be effec-
tive in selected patients (performance status, tumor size,
and age), but the beneficial effect in terms of survival is
disappointing, with median survival after re-operation
ranging between 19 and 36 weeks [12,13]. Results from
series of patients treated for a recurrent malignant glioma
with brachytherapy at median doses of 50-70 Gy range
between 47 and 64 weeks [14-16], and they all claim
improved survival compared to historical data. However,
after 2 years almost all patients have died. Recurrence of
gliomas
The longer than expected survival results for recurrent
tumors have led to the use of brachytherapy as an adju-
vant treatment in newly diagnosed gliomas. Initial
results of brachytherapy as a boost after external irradia-
tion for newly diagnosed malignant gliomas showed
encouraging survival rates in non-randomized trials
(Table 26.1) [19-23]. Loeffler et at showed a very
promising result of 27 months' median survival after
brachytherapy in 35 patients with a glioblastoma multi-
forme compared to 11 months for a matched control
group [22]. The Northern California Oncology Group
(NCOG) study 6G-82-2 demonstrated an improved
median survival of 88 weeks for patients with a glioblas-
toma multiforme. Patients with non-glioblastoma
multiforme anaplastic gliomas, however, had a median
survival of 155 weeks, which was not different from
other reported series without brachytherapy [21].
Selection criteria will have a significant influence on sur-
vival results and thus it is difficult to draw conclusions
from non-randomized studies. Florell et al. studied the
influence of selection by retrospectively identifying
patients as either eligible or ineligible for brachytherapy.
Eligible glioblastoma multiforme patients lived much
longer than the ineligible patients (13.9 versus 5.8
months) and they concluded that the improved survival
is at least partly the result of patient selection [24].

Table 26.1 Results of brachytherapy after external irradiation for newly diagnosed glioblastoma multiforme

Laperriere et al. [26]* 71 50 60 42 + 31 13.8

wen et al. [33] 56 59 50 22 - 64 18
Sneedefo/. [28] 159 59 55 26 + 51 18
Voges et al. [20] 27 10-40 60 25 - 0 15.6
Malkin [23] 20 60 59 37 - 43 22
Kootetal. [30] 21 60 40 48 - 33 17

* Randomized trial.
376 Brachytherapy for brain tumors
In 1986 and 1987, two randomized studies were con-
ducted in the USA and Canada. The first results of Trial
8701 of the Brain Tumor Cooperative Group (=272)
have only been published in an abstract form so far [25].
Patients randomized to brachytherapy received a tempo-
rary implant delivering a total dose of 6000 cGy at the
tumor periphery with a mean dose rate of 40 cGy h-1,
after a mean external dose of 6020 cGy. Preliminary
comparison has shown a significant survival advantage
of 3.5 months for the implant group for patients with a
glioblastoma multiforme [25]. The Canadian trial ran-
domized 140 selected patients to external-beam therapy
of 50 Gy only or external-beam plus a minimal intersti-
tial boost of 60 Gy with a median dose rate of 70 cGy h-1.
Inclusion criteria were as follows: supratentorial malig-
nant astrocytoma, age 18-70 years, Karnofsky
Performance Status (KPS) > 70, no involvement of cor-
pus callosum, and maximum tumor diameter < 6 cm.
Brachytherapy was given with one or more parallel
catheters of temporary high-activity iodine-125 seeds.
Median survival for the implant group was 13.8 months,
compared to 13.2 for the no-implant group, which was
not a significant improvement [26]. Re-operation was
performed in 31% of the implant group and in 33% of
the no-implant group. In both randomized studies, as in
most retrospective series, patients who underwent a re-
operation for a recurrence and/or necrosis after
brachytherapy did significantly better than those with-
out re-operation [15,21,22,25,26]. Other factors that
improved survival were young age, high performance
status, and smaller tumor size. Patients under the age of
30 particularly had an improved survival [22,27].
The pattern of recurrence and toxicity after interstitial
boost treatment is an interesting secondary endpoint.
Even after a combined interstitial and external dose of 100
Gy or more, recurrences after brachytherapy occurred in
about 90% at the primary site [26,28-30]. A few studies
reported lower local recurrence rates, but still about 70%
[31,32]. However, the pattern of recurrence has changed.
Distant relapses within the central nervous system are
described in 22-28% of interstitially treated patients with
a glioblastoma multiforme [28,32,33] compared to about
10% after external irradiation only [4]. In the randomized
study there was a higher incidence of multifocal recur-
rences in the implant arm [26]. Studies from the Boston
group described a higher incidence of marginal recur-
rences (37%), with only 35% failing within the
brachytherapy volume [33]. However, it remains difficult
to distinguish radiologically between marginal and local
treatment failures. Smaller tumors (< 25 cm3) and 'ade-
quate' implants were shown to have a higher local control
rate [28,31,32]. The higher rate of marginal and distant
relapses that occur when local treatment is improved con-
firms the fact that glioblastomas have a diffuse and wide-
spread growth pattern. A dose-response relationship was
demonstrated by Sneed et al., but interstitial doses of more
than 50 Gy were also related to increased risk of life-threat-
ening necrosis [34]. Sneed recommended a conformal
interstitial dose of 45-50 Gy in conjunction with conven-
tional external-beam radiotherapy.
The acute toxicity of brachytherapy in brain tumors
is low. Overall toxicity of stereotactic management in
midline brain lesions was found to be 4.2% [35]. The
risk of arterial bleeding caused by the implantation of
catheters is 0-2% [20,21,26,30] and infections are also
rare. Late toxicity, however, is a clinical problem.
Necrosis leading to a re-operation is a major problem in
all series. We think that after doses of more than 100 Gy,
with much higher doses in the center of the implant
volume, necrosis can be viewed as integral to this proce-
dure and not as a complication. The described inci-
dences of re-operations of 35-64% [26,28,33] can be
considered as an underestimation of the risk for brain
necrosis because some of the patients do not live long
enough to develop necrosis and others are in too bad a
condition for re-operation. Median time to re-operation
was about 40-50 weeks [21,28]. Apart from necrosis,
histology after re-operation also showed, in most cases,
vital tumor cells [28,31], confirming the fact that
glioblastoma cells are highly radioresistant. Bernstein et
al. reported severe vascular occlusion in 4% of their
implant group [36]. In our series in the Academisch
Medisch Centrum, Amsterdam (AMC), three out of 21
patients developed a sudden palsy 6-12 months after
brachytherapy, mimicking a cerebrovascular accident
within the implant volume [30]. The overall complica-
tion rate, excluding re-operation for necrosis, was about
25% in the randomized series, which is in the range of
other series [10,24,30].
The effect of brachytherapy on quality of life should
be an important endpoint. Gutin et al. described a con-
tinuing dependency on corticosteroids to combat the
edema of focal radiation necrosis, which caused the
reduction in mean KPS in their series [21]. In 13 patients
from the same group who survived more than 3 years,
mean Karnofsky had decreased from 95 at the time of
brachytherapy to 75 at the time of last follow-up [28]. In
the only published randomized trial, there was a signifi-
cant increase in dexamethasone dosage for the implant
group, but performance status did not differ between the
implant and no-implant groups [26].
2633 Low-grade tumors
There are no randomized trials of brachytherapy for
low-grade or benign brain tumors. The largest retro-
spective series comes from Freiburg in Germany,
describing 455 patients with inoperable (often deep-
seated) low-grade tumors treated with temporary or
permanent interstitial iodine-125 [37]. Selection criteria
were signs of tumor progression, circumscribed tumors
not exceeding 5 cm, KPS > 70, and no corpus callosum
infiltration. Dose rates of preferably < 10 cGy h-1 were

given up to reference doses of 60-100 Gy to the outer
rim of the tumor. The 5-years survival rates for pilocytic
astrocytomas, grade II astrocytomas, oligoastrocytomas,
oligodendrogliomas, and gemistocytic astrocytomas
were, respectively, 85%, 61%, 49%, 50%, and 32%. These
results are comparable with the survival data of the
European Organization for Research and Treatment of
Cancer (EORTC) study [38], taking into account the
more favorable prognostic factors of the implanted
group (smaller tumors, good performance). Radiogenic
complications were observed in 39 out of 515 patients at
the same institute. The most important risk factor was
the volume of the 200 cGy isodose [39]. Good local
responses were described with LDR implants in inoper-
able brainstem gliomas [40]. Brachytherapy can be con-
sidered as a treatment option for progressive, small, and
inoperable low-grade gliomas.
26.4 FURTHER DEVELOPMENTS
To further improve local tumor control in glioblastoma
multiforme, some centers started to combine interstitial
radiation with interstitial hyperthermia, using the same
catheters. A randomized trial comparing brachytherapy
boost alone versus brachytherapy boost plus interstitial
hyperthermia in patients with newly diagnosed glioblas-
toma multiforme demonstrated a small but significant
improvement in median survival of 9 weeks for the
hyperthermia group [41]. Further technical develop-
ments can improve the level, homogeneity, volume, and
control of the temperature in the target volume and thus
could improve the clinical results [42]. A phase I-II
study is ongoing in the AMC, Amsterdam, with this new
technique for newly diagnosed glioblastoma multiforme
patients.
Dose escalation by focused stereotactic external radia-
tion (radiosurgery) has become available and the advan-
tages in dose distribution with this technique can be
compared with brachytherapy. The first clinical compar-
isons between radiosurgery and brachytherapy in newly
diagnosed and recurrent brain tumors resulted in a sim-
ilar survival for both treatment options [43,44].
Radiosurgery has the advantage of being an outpatient,
non-invasive therapy, with the possibility of fractiona-
tion. A phase III trial is being conducted in Europe ran-
domizing between conventional radiotherapy with or
without a stereotactic external boost in newly diagnosed,
selected glioblastoma multiforme patients.
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and Ostertag, C.B. (1995) Interstitial radiosurgery of low-
grade gliomas. J. Neurosurg., 82,418-29.
38. Karim, A.B.M.F., Maat, B., Hatlevoll, R. et al. (1996) A
randomised trial on dose-response in radiation therapy
of low-grade cerebral glioma: European Organization for
Research and Treatment of Cancer (EORTC) Study 22844.
IntJ. Radiat. Oncol. Biol. Phys., 36, 549-56.
39. Kreth, F.W., Faist, M., Rossner, R., Birg, W., Volk, B. and
Ostertag, C.B. (1997) The risk of interstitial radiotherapy
of low-grade gliomas. Radiother. Oncol., 43,253-60.
40. Mundinger, F., Braus, D.F., Krauss, J.K. and Birg, W. (1991)
Long-term outcome of 89 low-grade brain-stem gliomas
after interstitial radiation therapy./ Neurosurgery, 75,
740-6.
41. Sneed, P.K.,Stauffer, PR., McDermott, M.W.etal.(1998)
Survival benefit of hyperthermia in a prospective
randomised trial of brachytherapy boost hyperthermia
for glioblastoma multiforme. IntJ. Radiat Oncol. Biol.
Phys., 40,287-95.
42. Crezee, J., Kaatee, R.S.J.P., van der Koijk, J.F. and
LagendijkJ.J.W. (1999) Spatial steering with quadruple
electrodes in 27 MHz capacitively coupled interstitial
hyperthermia. IntJ. Hyperthermia, 15,145-56.
43. Stea, B., Rossman, K., KittelsonJ. et al.(1994) A
comparison of survival between radiosurgery and
stereotactic implants for malignant astrocytomas. Acta
Neurochir., 62,47-54.
44. Shrieve, D.C., Alexander, E., Wen, P.Y. et al. (1995)
Comparison of stereotactic radiosurgery and
brachytherapy in the treatment of recurrent glioblastoma
multiforme. Neurosurgery, 36,275-82.

Interstitial brachytherapy in the treatment of
carcinoma of the cervix
A.M.NISARSYEDANDAJMELA. PUTHAWALA
27.1 INTRODUCTION
It is estimated that approximately 16000 new cases of
invasive carcinoma of the cervix were being diagnosed in
the United States in 1996, with an estimated 4900 deaths
as a result of cervical cancer. The death rate per 100 000
population due to cervical cancer decreased by almost
50% from 1960 to 1990. The relative 5-year survival
improved from 58% in 1960 to 69% in 1989 among
whites, and from 47% in 1960 to 57% in 1989 among
blacks [ 1 ]. The prognosis for patients with cervical can-
cer mainly depends upon their age, the clinical stage,
nodal status, tumor volume, and lymphovascular inva-
sion [2-5].
The overall 5-year survival in patients with stage I and
IIA disease is 85-90% [6-9], but only 30-50% with
stage III disease. As the tumor volume increases, so does
the risk of nodal metastases with poor prognosis. The
risk of pelvic recurrence is 8-10% in patients with stage
I and IIA disease, as compared to 45-50% in patients
with stage III disease [10,11]. Lociano et al [12]
reported, from the Patterns of Care Study, an increased
risk of in-field failure and poor survival with increasing
tumor bulk within stage. Among 1558 patients treated
between 1973 and 1978, Perez et al. [13] reported that
the tumor size as a single variable was directly related to
pelvic failure rate and inversely related to disease-free
survival. Lowrey et al. [14] found that tumor size was a
27
strong independent predictor of pelvic control, distant
relapse, and disease-free survival. Although surgery or
primary irradiation, or a combination of both, yields
70-90% cure rates in patients with stage I and IIA dis-
ease; in locally advanced stage IIB, III, and IVA carcino-
mas, which are surgically unrespectable, external
irradiation with conventional intracavitary application
fails to provide an adequate dose to the target volume
without extensive bladder and rectal doses. Waterman et
al [15] in 1947 and Prempree and Scott [16] in 1978,
reported transvaginal interstitial radium needle implant
technique in the treatment of cancer of the cervix stage
IIIB, with 31% 5-year survival and 78% loco-regional
control, respectively. This technique had the disadvan-
tage of excessive exposure to personnel and higher com-
plication rates. We have reported an afterloading
technique of interstitial-intracavitary implants using the
'Syed-Neblett' template in the treatment of carcinoma of
the cervix [17-20]
27.2 PRETREATMENT WORK-UP
The following is an optimal work-up to determine the
histology, tumor grading, volume, local tumor invasion,
lymphovascular invasion, staging, etc., for designing
appropriate treatment.
1. History and physical examination.
380 Interstitial brachytherapy in the treatment of carcinoma of the cervix
2. Pelvic examination, cystoscopic and procto-
sigmoidoscopic examination, preferably under
anesthesia.
3. Complete blood count (CBC), liver function tests,
and serum electrolytes; additionally, a human
immunodeficiency virus (HIV) test for patients
younger than 25 years of age.
4. Chest X-ray.
5. Intravenous pyelogram and/or computed
tomographic (CT) scan of the abdomen and pelvis.
6. Biopsy of cervical tumor.
7. Bipedal lymphangiography and/or retroperitoneal
pelvic and para-aortic lymph adenectomy, only for
patients on specific protocols.
273 TECHNIQUE
The interstitial-intracavitary implant technique utilizes
an intracavitary tandem (whenever possible), as in con-
ventional intracavitary applications, but the conven-
tional intravaginal ovoids have been replaced with
interstitial ovoids, i.e., transperineally implanted multi-
ple guide needles through the paravaginal and parame-
trial tissues [17-20]. The interstitial-intracavitary
Syed-Neblett applicator consists of a perineal template,
vaginal obturator, 17-gauge hollow guide needles, and a
tandem (Figure 27.1). The template is made of silicone
and has a 2-cm diameter central hole to accommodate
the vaginal obturator, and 34 holes drilled 1 cm apart in
concentric circles to accommodate the guide needles.
The vaginal obturators are 2 cm in diameter and have
three different lengths, 12, 15, and 18 cm. The vaginal
obturator has a central tunnel to accommodate a tandem
and six longitudinal grooves on the surface for guide
needles, and an embedded screw at its distal end to
secure the tandem. The guide needles are 17 gauge and
20 cm in length. Each needle has the proximal end
tapered and closed for easy penetration of the skin and
tissues, and a met al ring close to the distal end to prevent
Figure 27.1 Assembled Syed-Neblett applicator.
it from sliding through the template and being left in the
tissues when the implant is removed.
The pre-implant preparation of the patient is the
same as for the conventional intracavitary procedures,
i.e., nothing by mouth after midnight and a Fleet's
enema on the morning of the procedure. The procedure
is performed either under general anesthesia or, more
frequently and preferably, under epidural block so that
the patients can control the pain following the proce-
dure themselves. The patient is placed in the lithotomy
position and an abdominal-pelvic examination is per-
formed to determine the size and extent of the residual
tumor and/or metastases, and any anatomical distor-
tions. A proctosigmoidoscopic examination is per-
formed to evaluate any abnormalities and radiation
reaction, and also to clean out the feces from the rec-
tum. The perineum and vagina are prepped with
Betadine solution and the area is draped as for any sur-
gical procedure. A Foley catheter is inserted into the
bladder and the balloon is filled with 7 ml of Hypaque
for X-ray localization films. The cervix and vagina are
visualized with a vaginal speculum and two gold marker
seeds are implanted into the cervix at the two and eight
o'clock positions, and another at the lower end of the
vaginal extension of the tumor, using an MD Anderson
marker applicator.
The endometrial canal is sounded and the length mea-
sured. The endocervical and endometrial canals are then
dilated using Hank or Hegar dilators. A Fletcher or
Henschke tandem is inserted into the endometrial canal
with the met al flange fixed at the appropriate level
according to the length of the endometrial canal.
First, a guide needle (which has no guard ring at the
distal end) is inserted into the remains of the anterior or
posterior lip of the cervix to a depth of 3.5-4 cm. The
distance between the distal end of the tandem and the
first guide needle is measured, as this distance has to be
maintained at the completion of the procedure. The
vaginal obturator is inserted into the vagina while the
tandem is threaded through its central canal. The tem-
plate is held against the perineum and the vaginal obtu-
rator with the tandem, and the guide needle is threaded
through its central hole. A rubber O-ring 2 cm in diam-
eter is threaded over the vaginal obturator and placed
into the groove on the template to secure the obturator
and the first needle into position. An appropriate num-
ber of needles are implanted through the perineal tem-
plate transperineally on both sides to encompass the
initial extent of the tumor, i.e., 20 to 36 needles. The
depth of insertion of these guide needles is the same as
that of the first guide needle [20] (Figure 27.2).
Lateral pressure is exerted on the needles between the
perineum and the template while the needles are
implanted to prevent central coning of the needles. The
needles are dipped in alcohol for easy insertion through
the template as alcohol acts as a lubricant for the tem-
plate material.

Figure 27.2 Tandem, vaginal obturator, and perineal template
are positioned (a), and guide needles are implanted (b).
The tandem is now pushed into the uterus and
secured in position by tightening the screw at the distal
end of the vaginal obturator with an Allen wrench. The
template is secured in position by 2-0 silk sutures
through the perineal skin and anterior two corners of the
template. The space between the perineum and the tem-
plate is filled with vaginal gauze, usually soaked in
antibiotic cream or saline. A piece of vaginal gauze
soaked in barium paste, or a rectal marker, is then
inserted into the rectum for X-ray localization films
(Figure 27.3).
27.4 LOCALIZATION FILMS
The tandem and the guide needles are loaded with
inactive dummy sources, and anteroposterior and lat-
eral orthogonal X-rays are obtained for computerized
dose distribution plotting and volume analysis (Figure
27.4).
Loading and unloading of radioactive sources 381
Figure 27.3 Implant completed for carcinoma of the cervix,
stage IVA.
27.5 LOADING AND UNLOADING OF
RADIOACTIVE SOURCES
The tandem is loaded with radioactive cesium-137 and
the parametrial guide needles with iridium-192 sources
in the patient's room, with usual radiation precautions.
The tandem is usually loaded with three sources of
cesium-137 of 10 mg Ra-eq at the tip, and two sources of
approximately 5 mg Ra-eq each distally, with appropri-
ate spacers according to the length of the endometrial
canal. Each of the guide needles is usually loaded with a
plastic ribbon containing seven seeds of iridium-192
sources spaced 1 cm apart, having an activity of
0.3-0.45 mg Ra-eq each.
The dose to the parametria can be optimized either by
differential unloading of tandem and central guide
needles or by using a higher activity of iridium-192
sources in the lateral guide needles. The dose can be
optimized by utilizing 'remote afterloads' with a single
iridium-192 source with their software and computer
treatment planning systems for continuous low dose rate
(LDR), pulse low dose rate (PDR), medium dose rate
(MDR), or high dose rate (HDR).
It is desirable to keep the dose rate to the medial para-
metria, ie, Point A, under 80 cGy h-1 in LDR treatment
protocols to minimize complications.
The radioactive cesium-137 and iridium-192 source
ribbons are unloaded from the tandem and parametrial
guide needles after the desired dose is delivered. The
radioactive sources are placed in an appropriate lead
container, or withdrawn by the remote afterloader, and
taken to the isotope storage room.
382 Interstitial brachytherapy in the treatment of carcinoma of the cervix
The patient and the room are surveyed with the
Victoreen survey meter for any radioactivity and the
implant is then removed. The patient receives morphine
sulfate 10 mg intramuscularly 15 min before removal of
the implant.
The packing and the perineal sutures are removed.
The screw holding the tandem to the vaginal obturator is
withdrawn. The guide needles and tandem are removed
in one motion by pulling the template from the per-
ineum. The minimal bleeding from the perineum usu-
ally stops with the use of gentle pressure with gauze. The
Foley catheter is removed and the patient is ambulatory
within an hour.
27.6 TREATMENT PROTOCOL
Patients receive external irradiation to the pelvic nodes,
cervix, and vagina to 5040 cGy in 28 fractions, or
5000 cGy in 25 fractions, 180 or 200 cGy per fraction
and five fractions per week, usually with the four-field
technique. The rectum and bladder are shielded after
4000 cGy or 3960 cGy, using a midline block.
The first interstitial-intracavitary implant is usually
performed 1 week following completion of the external
irradiation. The second application is performed 2 weeks
following the first implant.
27.7 DISCUSSION
In cervical cancer, the tumor size, even in the early stages
of disease, has been found to be the most significant
independent prognostic factor in multivariate analysis in
several series [3,5,11].
Figure 27.4 (a) Anteroposterior
X-ray localization film with
isodose distribution plot
overlaid, (b) Lateral X-ray
localization film with isodose
distribution plot overlaid.

The treatment of choice for patients with locally
advanced cervical cancer, i.e., stages IIB, III, and IVA, is
radiation therapy with or without systemic chemother-
apy and possible pelvic exenteration for patients with
stage IVA disease. However, a combination of external
and conventional intracavitary irradiation results in
40-50% pelvic failures, with significant complications.
However, in most series, pelvic failures increased pro-
portionately, i.e., 40-60%, with advanced stages of dis-
ease treatment with a combination of external and
conventional intracavitary irradiation [11,21-23].
These treatment failures have essentially been due to
large tumor volume and inadequate doses delivered by
the intracavitary applicators. The radioactive sources in
the tandem and ovoid could not deliver high enough
doses to the target volume without excessive doses to the
rectum and bladder. Anatomical distortions, even in
early disease, i.e., narrowing of vagina, obliterated for-
nices, or inability to use tandem, can also cause failure to
deliver adequate doses to the tumor volume.
Waterman et al. [13,24] reported a 31% 5-year sur-
vival for patients with stage IIIB carcinoma of the cervix
using a transvaginal interstitial radium needle implant
technique. Prempree and Scott [16] reported 78% local
tumor control using a similar technique in 1978 in stage
IIIB carcinoma of the cervix. This technique of intersti-
tial implant has several inherent technical and radiation-
exposure problems.
We reported the technique of interstitial-intracavitary
applicators using the 'Syed-Neblett' template with pre-
liminary results in advanced carcinoma of the cervix in
1978 [17-20]. This technique involves the use of an
intracavitary tandem and interstitial ovoids, i.e., multi-
ple guide needles inserted into the parametria transper-
ineally through the template. The technique is easily
reproducible and provides excellent dose distribution to
the tumor volume with relative sparing of critical struc-
tures, i.e., rectum and bladder.
Table 27.1 Interstitial irradiation (afterloading technique) for carcinoma of the cervix
Pitts and Waterman, 1940 IIIB
Prempree and Scott (1978) [16] IIIB
Feder, Syed and Neblett (1978) [18] IIIB
Geddisrto/. (1983) [25] I, II, III, and IV
Aristizabal et al. (1983) Advanced Hand IIII
Ampuero et al. (1983) [27] IIBandlllB
Aristizabaltfo/. (1985) [26] Advanced Hand IIII
Syed et al. (1986) [20] I, II, III, and IV
' Severe complications include severe proctitis, cystitis, rectovaginal fistula and/or vesicovaginal fistula.
Discussion 383
The technique lends itself to HDR treatments utilizing
commercially available remote afterloaders. Table 27.1
reflects the results during the evolution of the technique
by several authors. Geddis et al. [25] reported, in 1983, a
14% rate of severe complications. These higher compli-
cations occurred during the evolution of the technique
and have been mainly due to: (1) extensive necrotic
tumors; (2) lack of availability of computer dosimetry, so
the dose was based on milligram-hours, thus delivering
much higher doses; (3) high dose rates, i.e., 120-200 cGy
h~', to point A; and (4) point A received a total of
10000-14000 cGy by a combination of external and
interstitial irradiation with higher doses to the rectum
and bladder. Aristizabal et al. [26] reported 76% and
74% pelvic control in stages IIB and IIIB, respectively,
and reduced the complication rate from 33% to 6% by
modification in implant geometry and reduction of total
milligram-hours. Ampuero et al. [27] reported 38% local
recurrence and 29% complications in 24 patients with
stage IIB and IIIB cervical cancer.
Martinez et al [28] published results of 70 patients
with locally advanced cervical carcinoma treated by
transperineal implants using the Martinez Universal
Perineal Implant Template (MUPIT) and achieved 66%
local control and 14% severe complications.
We reduced the dose rates and also the doses to the
rectum and bladder by dose optimization and by differ-
ential unloading or using higher activity sources in the
lateral parametrial needles (0.4-0.5 mg Ra-eq) and
lower activity sources (0.2-0.3 mg Ra-eq) in the medial
parametrial needles. The complication rate in subse-
quent series of patients has been reduced to 3% while
maintaining the loco-regional control at 78% in stage
IIB, III, and IVA carcinomas of the cervix (Tables 27.2
and 27.3). This finding is supported by others [33] who
report that grade IV complication rates can be reduced
from 14% to 3% when dose rates are reduced to below
70% cGy h~' without jeopardizing disease control rates.
110 31 (5-year) 13
49 78
Syed-Neblett 38 60 (median 8
24 months)
Syed-Neblett 84 71 14
Syed-Neblett 21 85 58 35
Syed-Neblett 24 72 29
Syed-Neblett 118 75 21
Syed-Neblett 60 78 58 3
384 Interstitial brachytherapy in the treatment of carcinoma of the cervix

Table 27.2 Carcinoma of the cervix, Syed-Neblett template: cumulative dose of 7706 cGy at point A using a standard
complications Fletcher-Suit technique. The interstitial group received a
mean external dose of 5050 cGy and two interstitial
implants using a transperitoneal Syed-Neblet template
with a mean tumor dose of 2239 cGy and 1942 cGy for
IB 6 0 0 0 0 each application, respectively. No statistical difference
IIAandllB 23 2 2 0 0 could be detected in survival for stage III and IVA
IIIAandlllB 26 1 1 2 0 patients, but for stage II patients the intracavitary results
IVA 0 0 0 0 0 were better, with more relapses in the interstitial group.
All 60 3(5%) 3(5%) 2(3%) 0 However, the intracavitary group received a larger dose
than the interstitial group (4608 versus 3504 radium
RV, rectovaginal; W, vesicovaginal.
milligram-hours equivalent) because a tandem was only
used in 24% of the interstitial implants. Complications
Table 27.3 Carcinoma of the cervix, Syed-Neblett template:
occurred in 21% of patients in each group.
patterns of failure
We have published the guidelines to be followed while
employing the Syed-Neblett template technique to min-
imize the complications and maximize the local tumor
control [20]. Bloss et al. [31] reported improvement in
IB 6 0 0 0 local control by utilizing the interstitial-intracavitary
IIAandllB 23 2(+2Y 2 5
applicator with radiofrequency hyperthermia for radio-
IIIAandlllB 26 4 4 5
potentiation in patients with locally advanced and
IVA 5 1 0 3
necrotic cervical cancers.
All 60 9 (1 5%) 6(10%) 13(22%) The following are our conclusions and current indica-
'Two patients had only central recurrence; the other two failed only tions for the use of interstitial-intracavitary applica-
in the parametria. tions:
1. Interstitial-intracavitary application using the Syed-
Neblett technique is safe and easily reproducible.
The clinical outcome for HDR interstitial brachyther-
2. Loco-regional control of 70-77% can be achieved in
apy in combination with external-beam irradiation [34]
stage IIB and III cancers, with less than 4% severe
has also reported satisfactory local and regional control
complications.
results. Six fractions were used of 5.5-6.0 Gy interstitial
3. This technique lends itself to manual, continuous
therapy in combination with external-beam irradiation,
LDR, pulse LDR, MDR, and HDR utilizing remote
with central shielding, to a dose of 50 Gy to the pelvic
afterloaders.
side walls. The patients chosen had locally advanced dis-
4. Interstitial hyperthermia, i.e., radiofrequency or
ease which precluded satisfactory tandem and ovoid
microwave, can be utilized with the template
insertion. This is perhaps an indication for interstitial
technique for radiopotentiation.
treatment that requires further consideration.
5. It is preferrable to use this technique in patients
Hockel and Muller [29] modified the Syed-Neblett
with: (a) cervical cancer stages IIB, III A, IIIB, and
template for HDR brachytherapy of gynecological
IVA, and in patients with stage IB and IIA with
malignancies to reduce the rectal and bladder doses. The
distorted anatomy, i.e., narrow vagina and
template's assembly allows cystoscopic and rectoscopic
obliterated fornices; (b) inability to use tandem in all
control of needle positions. Wolkov et al. [30] con-
stages; (c) carcinoma of the cervical stump; and (d)
cluded, from the results of 14 patients with locally
recurrent carcinoma of the cervix who have not
advanced cervical cancer and review of the literature,
been properly selected.
that the loco-regional recurrence rate utilizing a
transperineal template technique is approximately 50%
less than the traditional intracavitary irradiation, with an
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25. Geddis, D., Morrow, C.P., Klement, V., Schlaerth, J. and
Nalick, R.H. (1983) Treatment of cervical carcinoma
employing a template for transperineal interstitia!192lr
brachytherapy. Int.J. Radial Oncol. Biol. Phys., 9,
819-27.
26. Aristizabal, S.A., Valencia, A., Ocampo, G. and Surwit, E.A.
(1985) Interstitial parametrial irradiation in cancer of the
cervix stage MB and 1MB: analysis of pelvic control and
complications.Endocuriether./Hypertherm. Oncol.,'1,
41-8.
27. Ampuero, F., Doss, L.L, Khan, M., Skipper, B. and Hilgers,
R.D. (1983) The Syed-Neblett interstitial template in
locally advanced gynecological malignancies. InlJ.
Radial Oncol. Biol. Phys., 9,1897-903.
28. Martinez, A., Cox, R.S. and Edmundson, G.K. (1984) A
multiple site perineal applicator (MUPIT) for treatment of
prostate, anorectal and gynecologic malignancies. Int.J.
Radial Oncol. Biol. Phys., 10,297-305.
29. Hockel, M. and Muller, T. (1994) A new perineal template
assembly for high-dose rate interstitial brachytherapy of
gynecologic malignancies. Radial Oncol., 31,262-4.
30. Wolkov, H.B., Manjat, J., Ordoridca, E. and Trelford, J.
(1987) Interstitial templates for locally advanced cervix
cancer. Med. Dosimetry, 12(1), 21-4.
386 Interstitial brachytherapy in the treatment of carcinoma of the cervix

31. Bloss, J.D., German, M.L, Syed, A.M.N. et al. (1992)
Treatment of advanced carcinoma of the uterine cervix
with interstitial radiotherapy and hyperthermia.
Endocuriether./Hypertherm. Oncol., 8,145-50.
32. Monk, B.J., Tewari, K., Burger, R.A., Johnson, M.T., Montz,
F.J. and Berman, M.L (1997) A comparison of intracavitary
versus interstitial irradiation in the treatment of cervical
cancer. Gynecol. Oncol., 67(3), 241-7.
33. Gupta, A.K., Vicini, F.A., Frazier, A.J. et al. (1999) Iridium-
192transperineal interstitial brachytherapy for locally
advanced or recurrent gynaecological malignancies. Int.
J. Radial Oncol. Biol. Phys., 43(5), 1055-60.
34. Demanes, D.J., Rodriguez, R.R. and Ewing, T.L (1999) High
dose ratetransperineal interstitial brachytherapy for
cervical cancer: high pelvic control and low complication
rates: Int.J. Radial Oncol. Biol. Phys., 45(1), 105-12.
 28
Interstitial brachytherapy in the treatment of
carcinoma of the anorectum

AJMELA. PUTHAWALAANDA.M. NISARSYED

28.1 INTRODUCTION tion therapy with a combination of external-beam irradi-

ation and interstitial iridium-192 afterloading implants
in the treatment of carcinoma of the anus and lower rec-
Surgery has played a dominant role in the definitive
tum in lieu of surgery [ 17,18]. Our experience is based on
treatment of carcinoma of the lower rectum and anus,
treating most of the patients with large bulky disease who
which has typically required abdominoperineal resec-
were considered unresectable and/or inoperable because
tion with permanent colostomy. However, over the past
of advanced age and medical problems. We reported in
two decades a more conservative approach has been
1982 the treatment results of 40 such individuals who
sought in an attempt to preserve the organ and its func-
underwent a combination of external-beam irradiation
tion. This is especially true for carcinoma of the anus, for
and interstitial iridium-192 implant [19]. Seventy percent
which a combined modality, i.e., radiation therapy and
of the patients achieved local tumor control with median
systemic chemotherapy, has yielded up to 85% local con-
follow-up of 36 months. Since then, at our institution, we
trol and preservation of the sphincter function in 65% of
have extended the use of definitive radiation therapy to
patients [1-5,22,23]. Newer surgical techniques, i.e.,
include patients with relatively early stages of cancer as an
using an endorectal staple gun or pull-through proce-
alternative treatment to abdominoperineal resection. In
dure, as well as laser fulguration of the lower rectal can-
1987, Papillon and Montbarbon [20] reported a 3-year
cers allow the preservation of the sphincter function
local control rate of 80% among 276 patients with epider-
[6-10]. The use of preoperative radiation therapy as well
moid carcinoma of the anal canal treated by a combina-
as chemotherapy has also facilitated organ preservation
tion of external-beam and interstitial iridium-192
for borderline cases which would otherwise require
implant radiation. Ninety percent of these patients had
abdominoperineal resection and permanent colostomy
retained normal anal function.
[11-13]. As early as 1915 Cade [14] reported the use of
an intracavitary radium applicator for lower rectal can-
cers. In 1975, Papillon [15] reported a large series of 28.2 PRETREATM ENT ASSESSM ENT AN D
patients who were treated successfully using endocavi- INVESTIGATIONS
tary radiation for early-stage cancer of the lower rectum.
In 1982, his updated results were published in the book The pretreatment work-up should include complete his-
entitled Rectal and Anal Cancers. Conservative Treatment tory and physical examination, assessment of the
by Irradiation: an Alternative to Radical Surgery [16]. regional lymph nodes, proctosigmoidoscopy, biopsy, as
For the past two decades we have used definitive radia- well as metastatic work-up including chest X-ray, liver
388 Interstitial brachytherapy in the treatment of carcinoma of the anorectum
function studies, complete blood count, urinalysis, coag-
ulation profile, and serum human immunovirus. Trans-
anorectal ultrasonography may be useful to evaluate the
thickness of the lesion and penetration of any pelvic
organs. Computer tomographic (CT) and magnetic res-
onance imaging (MRI) may be useful in some cases.
283 TREATMENT PROTOCOL
For epidermoid carcinoma of the anal canal, if there is no
contraindication for systemic chemotherapy, these
patients should first be treated with a combination of
external-beam irradiation and continuous 5-fluorouracil
intravenous infusion for 3-5 days, starting with the first
day of external irradiation, with or without mitomycin-C
or Cisplatin. All patients, except patients with early stage
Tl tumors of the anorectum, receive a minimum dose of
4500 cGy delivered on megavoltage unit using anteropos-
terior (AP) and posteroanterior (PA) parallel opposing
ports to encompass the primary disease and the draining
lymphatics, using 1.8-2 Gy per fraction, five fractions
per week. Patients with recurrent tumors after definitive
surgery who have not received either preoperative or
postoperative adjuvant radiation therapy should also be
treated with external irradiation as above.
28.4 INTERSTITIAL BRACHYTHERAPY
The patient should have at least a 2-3-week rest period
after completion of external-beam irradiation. One or
two applications of interstitial brachytherapy may be
required, depending upon the bulk of the original lesion.
Each implant application may deliver a total tumor dose
of 15-25 Gy over 30-60 h. Preferable dose rate for the
anorectal implant is 0.4-0.5 Gy h'1. If two implants are
planned, then the interval between implants should be at
least 3-4 weeks. The implants are usually performed
under general anesthesia; however, epidural or spinal
anesthesia is preferable and the indwelling epidural
catheter could also be left in for the duration of the
implant for pain management.
28.5 EQUIPMENT
The equipment includes the following: Syed-Neblett dis-
posable rectal template (Figure 28.1), a set of 15-20 cm
long 17-gauge, hollow, stainless-steel needle guides,
number 36 rectal tube or, preferably, plastic chest tube,
marking pen, ruler, non-radioactive gold marker seeds,
wire stylette, one 20 cm long 17-gauge open needle for
marking seed insertion, 1-0 silk suture with non-cutting
Gl needle, 2-inch roller gauze, 5 ml of Hypaque, triple
sulfa cream, and Foley catheter 16 French, as well as alco-
hol to soak the template and to lubricate the guide
Figure 28.1 Syed-Neblett disposable rectal template (right) and
classic (multiple use) rectal template (left).
needles so they can be easily inserted through the tem-
plate (the needles are locked into position in the tem-
plate after complete evaporation of alcohol). If the
non-disposable template is used, then Allen-head screws
should be loosened to allow the needles to pass through
the template. After insertion of all the needles, screws
should be tightened to fix the needles in place [13].
28.6 INTERSTITIAL BRACHYTHERAPY
TECHNIQUE
After induction of satisfactory anesthesia, the patient is
placed in the lithotomy position. The abdomen and per-
ineum are prepped and draped in the usual fashion. The
patient is then catheterized with a Foley catheter with the
bulb inflated with 5 ml of Hypaque for localization of
the bladder. The Foley catheter should be attached to the
drainage tube and to the collecting bag. For male patients,
the scrotum and penis should be pulled up with gauze and
should be held by the abdominal drape with an Alice
clamp. Prior to prepping and draping of the patient, a
proctosigmoidoscopy should be carried out to ensure the
satisfactory evacuation of the rectosigmoid colon and,
more importantly, to register any undue reactions to the
previously given radiation, as well as to locate the tumor
and to take the measurements, i.e., extent of the tumor
along the longitudinal axis in relation to the anal verge as
well as circumferential involvement along the lumen. A
bimanual examination should also be carried out and the
tumor location should be marked on the perianal skin in
relation to its circumferencial involvement (Figure 28.2).
Gold marker seeds are then inserted transperineally with
the finger in the rectum to define the superior-most and
inferior-most extent of the palpable tumor as well as the
lateral-most extent of the tumor. Usually, four marker
seeds are implanted to help define the tumor volume on
the radiographs. The first guide needle is then inserted
transperineally through the perianal skin, guiding it with
the finger in the rectum, keeping the needle just under the
mucosa. The first needle should be placed approximately

Figure 28.2 Tumor location is marked on the perineal skin.
The first guide needle is placed with the finger in the anorectum.
Total depth of insertion is measured from the anal verge.
at the center of the tumor on the longest extension of its
vertical axis. The tip of the needle should be advanced at
least 2-3 cm beyond the palpable lesion. The depth of
insertion of this needle should then be measured from the
perineal skin (Figure 28.2) and a Kelly clamp should be
placed on the needle near the skin. The rectal tube or,
preferably, a number 36 French plastic chest tube, is then
Figure 28.3 Plastic tube (No. 36 French) in rectum, and first
guide needle through the template which is held against the
perineum.
Interstitial brachytherapy technique 389
inserted in the rectum to a depth of at least 10-12 cm.
A1 -0 silk suture should then be taken through the perianal
skin and through the tube to secure the implant in place.
The sutures should be placed opposite to the implant area
so the suture will not be cut off while the needles are being
inserted. A disposable Syed-Neblett rectal template is then
placed against the perineum, letting the first guide needle
pass through the appropriate hole in the innermost circle
and the rectal tube pass through its large central hole
(Figure 28.3). The template is then held against the per-
ineum in a fixed position, and two or three more needles
are inserted to a similar depth on the side of the perineal
area where the tumor extension was marked on the skin
earlier. In the second circle encompassing the circumfer-
ence with a 1-cm margin on either side should be com-
pleted, i.e., six to nine guide needles, and in the third circle,
again, six to eight needles are inserted to a similar depth
through alternate holes. The needles should be dripping
wet with alcohol to facilitate their passage through the
template. 1-0 silk sutures are then taken through the per-
ineal skin and the upper outer corner holes on the tem-
plate to keep it in position. Two-inch roller gauze
impregnated with triple sulfa cream is then applied lightly
between the template and the perineal skin (Figure 28.4).
The patient is then sent to the recovery room.
Figure 28.4 Template is sutured to the perineal skin after
insertion of all required afterloading guide needles.
390 Interstitial brachytherapy in the treatment of carcinoma of the anorectum
Prior to starting the interstitial implant, it is recom-
mended that the patient receives 1 or 2 g of a broad-
spectrum antibiotic intravenously, and antibiotics
should be continued for the duration of the implant. AP
and lateral orthogonal X-rays with dummy sources in all
guide needles are taken for computer dosimetry. The
number of iridium-192 seeds to be loaded in each guide
needle is decided in the operating room after taking the
measurements, with usually a 2-3 cm margin given
superiorly and inferiorly. If the tumor extends through
the perianal skin, the sources are usually brought down
beyond the skin; otherwise, the sources should be kept
under the skin to avoid a brisk, moist skin reaction. The
implant is then loaded with iridium-192 ribbons, either
manually or using the remote afterloading device. The
computerized isodose distribution on both the X and Z
axes at 5-mm intervals is obtained. The X and Z axes are
usually placed through the center of the implant. The
isodose planes at X = 0 and Z - 0 are then directly over-
laid on the AP and lateral orthogonal radiographs
(Figure 28.5). The isodose line encompassing the tumor
volume adequately is chosen as minimum dose rate [21].
The dose-volume histograms are also obtained (Figure
28.6). The duration of the implant is then calculated by
dividing the total dose to be delivered by dose rate.
At the completion of interstitial irradiation, the
radioactive sources are removed, again either manually or
by remote afterloading device. The sutures are removed
from the perineal skin and the template is removed by
pulling it away from the perineum so all the needles will
be removed at once. Betadine solution is then applied to
the skin and light pressure is exerted with dry gauze for a
few minutes to stop the bleeding. The applicator, the
patient, and the room should be checked with a Geiger
counter to ensure that all sources have been removed and
placed in the lead container. If the patient has no contin-
uous epidural pain medication, intramuscular Demerol
(meperidine hydrochloride), 50-100mg, should be
given at least 10-15 min prior to removal of the implant.
Figure 28.5 Anteroposterior (a)
and lateral (b) orthogonal
radiographs with computer-
generated isodose distribution
overlaid for dose calculation.
 Results 391

tion of this treatment had extensive tumors (T3 or T4)

or they were treated for recurrent cancer (Table 28.2).
Local tumor response has been assessed on clinical
examinations, including proctosigmoidoscopy and
repeat biopsies, if indicated. Most lesions resolved 2-3
months after completion of this treatment. Occasionally,
induration or mucosal thickening may persist for a long
time at the site of the original tumor secondary to fibro-
sis. In the past, some of these patients had undergone
repeated biopsies because of concern about persistent or
recurrent tumor and had developed ulceration and
necrosis. Most recurrences or persistent disease are clin-
ically manifested by 12-18 months and, rarely, after 24
months following this treatment.
Histologic grade and type had no significant impact
on the rate of local tumor control. The overall complica-
tion rate has been 19.6% (Table 28.3). The most com-
mon complication of this treatment is rectal ulceration
or necrosis. Tumor-associated necrosis usually resolves
Figure 28.6 Dose-volume histogram.
on conservative management if treatment is successful.
Hyperbaric oxygen therapy is usually successful in
patients who develop persistent ulceration and necrosis.
28.7 AFTERCARE It is advisable for these patients to undergo temporary

The patient should be advised to take sitz baths once or Table 28.1 Anorectal carcinoma stage distribution
twice a day for the first week to 10 days. The patient may
also need steroid cream or Cortifoam enema to help alle-
viate the pain and discomfort from ensuing proctitis. T1 15
Usually, acute proctitis subsides in 2-3 weeks on conser- T2 50
vative management. T3-4 38
Recurrent 60
Total 163
28.8 RESULTS

Table 28.2 Anorectal carcinoma local control at 3 years

One hundred and sixty-three patients with a diagnosis of
carcinoma of the anorectum were treated between 1974
and 1992: 103 patients were treated for primary cancer
n 15/15(100%)
and 60 patients were treated for recurrent cancer (Table
T2 46/50 (92%)
28.1); 132 patients had adenocarcinoma and 31 patients T3-4 30/38 (79%)
had squamous cell carcinoma. A cumulative local tumor Recurrent 39/60 (65%)
control was achieved in 130 (80%) of 163 patients at 130/163(80%)
Total
3 years of follow-up (Figure 28.7). Most patients who
had either persistent or recurrent disease after comple-
Table 28.3 Anorectal carcinoma complications

Rectal ulceration and necrosis 19/163(11.7%)

Anal stricture and fibrosis (with 7/163(4.3%)
or without incontinence)
Hemorrhage 2/163(1.2%)
Perianal infection or ischio-rectal 3/163(1.8%)
abscess
RectovaginaI fistula 1/163(0.6%)
Total 32/163(19.6%)a

'24/163 (14.7%) patients required colostomy because of complica-

Figure 28.7 Cumulative local control. REC, recurrent. tions.
392 Interstitial brachytherapy in the treatment of carcinoma of the anorectum
colostomy, and they should also have no evidence of per-
sistent or recurrent disease proven on biopsy. Anal stric-
ture and fibrosis with incontinence are rare
complications and are often associated with circumfer-
ential implants. Twenty-four (14.7%) out of 163 patients
required palliative colostomies following treatment
because of persistent ulceration, necrosis, or anal stric-
ture and tenesmus. Most of these patients had already
been treated for extensive disease. This treatment-related
complication rate can be minimized if patients are
selected carefully who have limited disease which does
not require more than half the circumference implant
and active length of more than 7 cm. Salvage surgery is
feasible for a substantial number of patients who may
fail this treatment regimen. It often requires
abdominoperineal resection with permanent colostomy.
In our series, five (42%) out of 12 patients who failed
this regimen were salvaged by abdominoperineal resec-
tion. The ideal lesions to be treated with definitive radi-
ation therapy using a combination of external-beam
irradiation and interstitial brachytherapy: (1) are located
within 8 cm from the anal verge; (2) involve less than
half the circumference of the lumen; (3) measure less
than 3 cm in thickness and less than 6 cm in length; (4)
have no complete fixation to the pelvic bones or visceral
invasion; and (5) have no extensive ulceration.
REFERENCES
1. Cummings, B.J., Harwood, A.R., Kean, T.J., Thomas, G.M.
and Rider, W.D. (1980) Combined treatment of squamous
cell carcinoma of the anal canal: radical radiation
therapy with 5-fluorouracil and mitomycin-C: a
preliminary report. Dis. Colon Rectum, 23,389-91.
2. Cummings, B.J., Thomas, G.M., Kean,T.J.ef al. (1982)
Primary radiation therapy in the treatment of anal canal
carcinoma. Dis. Colon Rectum, 15,778-82.
3. Nigro, N.D. (1984) An evaluation of combined therapy for
squamous cell cancer of the anal canal. Dis. Colon
Rectum, 27,763-6.
4. Sischy, B. (1985) The use of radiation therapy combined
with chemotherapy in the management of squamous cell
carcinoma of the anus and marginally resectable
adenocarcinoma of the rectum. Int.J. Radial Oncol. Biol.
Phys.,! 1,1587-93.
5. John, M.J., Flam, M., Lovalvol, L.J.etal.(1987) Feasibility
of non-surgical definitive management of anal canal
carcinoma. Int.J. Radial Oncol. Biol. Phys., 13,299-303.
6. Bacon, H.E. (1956) Abdominoperineal procto-
sigmoidectomy with sphincter preservation: Sand 10
years after 'pull through' operation for cancer of the
rectum.JAMA, 160,628-34.
7. Rich, T.A., Weiss, D.R., Mies, C. et al. (1985) Sphincter
preservation in patients with low rectal cancer treated
with radiation therapy with or without local excision or
fulguration. Radiology, 156, 527-31.
8. Wolmark, N. and Fisher, B. (1986) An analysis of survival
and treatment failure following abdominoperineal and
sphincter-saving resection in Dukes' B and C rectal
carcinoma: a report of the NSABP clinical trials. Ann.
Surg., 204,480-9.
9. Saadia, R. and Schein, M. (1988) Local treatment of
carcinoma of the rectum. Surg. Gynecol. Obstel, 166,
481-6.
10. Yeatman,T.J.and Bland, K.I. (1989) Sphincter-saving
procedures for distal carcinoma of the rectum. Ann. Surg.,
209,1-18.
11. Kligerman, M.M. and Urdanetta-Lafec, N. (1974)
Observation on 15 operable/nonresectable cases of rectal
cancers given preoperative irradiation. Am. J. Roentgenol.
Radium Ther. Nucl. Med., 120,624-6.
12. Roswit, B., Higgins, G.A. and Kahn, R.J. (1975)
Preoperative irradiation for carcinoma of the rectum and
rectosigmoid colon: report of a national Veterans
Administration study. Cancer, 35,1597-602.
13. JessupJ.M., Bleday, R., Busse, P.et al. (1993) Conservative
management of rectal carcinoma: the efficacy of a
multimodality approach. Semin. Surg. Oncol., 9,39-45.
14. Cade, S. (1950) Malignant Disease of the Rectum and Anus,
Vol 3: Textbook on Malignant Disease and its Treatment by
Radium. Baltimore, Williams and Wilkins.
15. Papillon, J. (1975) Intracavitary irradiation of early rectal
cancers for cure: a series of 186 cases. Cancer, 36,696-701.
16. Papillon, J. (1982) Recta I and Ana I Cancers. Conservative
Treatment by Irradiation: an Alternative to Radical
Surgery. New York. Springer-Verlag.
17. Syed, A.M.N., Puthawala, A.A., Neblett, D.L. et al. (1978)
Primary treatment of carcinoma of the lower rectum and
anal canal by a combination of external irradiation and
interstitial implant. Radiology, 128,199-203.
18. Syed, A.M.N. and Feder, B.H. (1977) Technique of
afterloading interstitial implants. Radiol. Clin., 46,
458-75.
19. Puthawala, A.A., Syed, A.M.N., Gates, T.C. and McNamara,
C. (1982) Definitive treatment of extensive anorectal
carcinoma by external and interstitial irradiation. Cancer,
50,1746-50.
20. Papillon, J. and Montbarbon, J.F. (1987) Epidermoid
carcinoma of the anal canal: a series of 276 cases. Dis.
Colon Rectum, 30,324-33.
21. Neblett, D.L, Syed, A.M.N., Puthawala, A.A., Harrop, R.,
Frey, H.S. and Hogan, S.E. (1985) An interstitial implant
technique evaluated by contiguous volume analysis.
Endocuriether./Hypertherm. Oncol., 1,213-22.
22. Sandhu, A.P., Symonds, R.P., Robertson, A.G., Reed, N.S.,
McNee, S.G. and Paul, J. (1998) Interstitial iridium-192
implantation combined with external radiotherapy in
anal cancer: ten years experience. Int.J. Radial Oncol.
Biol. Phys., 40(3), 575-81.
23. Broens, P., Van Limbergen, E., Penninckx, F. and
Kerremans, R. (1998) Clinical and manometric effects of
combined external beam irradiation and brachytherapy
for anal cancer. Int.J. Colorectal Dis., 13(2), 68-72.

High dose-rate brachytherapy in the treatment of
skin tumors
CAJOSLINANDA. FLYNN
29.1 INTRODUCTION
Epidermal skin in fair-skinned people is particularly at
risk of developing skin cancer. In recent times, the risk
has greatly increased with changes in social habits such
as increased exposure to sunlight [ 1,2]. The frequency of
skin cancer approaches 10% of all cancers, depending
upon the country and its ethnic population. The risk
increases as age increases [3], the commonest age group
affected being 60 years and older. The site and extent of
the disease, the histology, and the medical fitness of the
patient can determine the type of treatment used. Basal
cell carcinomas (or rodent ulcers) most commonly affect
the skin of the head and neck regions, remain localized,
and require local radical treatment. Less commonly,
rodent ulcers occur in sites other than around the head.
Squamous cell carcinoma may also involve the skin of
the head and neck region, but more commonly involve
the skin over the dorsum of the hand, particularly when
these areas are exposed to ultraviolet light over long
periods [1,2].
Radiation therapy can be an effective and satisfactory
treatment for the majority of cases of non-melanoma
skin cancer. In a review of the literature, Halpern advised
that, with efficient methods of dose fractionation and
delivery of radiotherapy, skin cancers could be con-
trolled in over 90% of cases treated [4]. He also advised
that, in general, the cosmetic appearance and function
are better preserved under most circumstances. How-
29
ever, other forms of treatment such as curettage and
cautery are effective against small rodent ulcers in the
majority of patients. Surgery may also be used, but this
can cause disfigurement in larger lesions, although
sometimes a combination of surgery and radiotherapy is
indicated.
The type of radiotherapy and method of application
are often determined by their practicability and the risk
of exposure to staff and other people. One method in use
for many years involved surface treatment moulds
loaded with radium-226 as the active material [5]. More
recently, radium-226 has been replaced by cesium-127 or
iridium-192. However, there remains the potential radi-
ation hazard arising from preparation of the sources, the
loading of the mould, and also from nursing the patient
during treatment. Because of this, the use of manually
preloaded surface moulds went out of fashion, and
nowadays most treatment is given using either superfi-
cial X-rays or low-energy electrons [4]. However, when
the treatment volume includes cartilage and tendons,
where the superficial tissues are thin and overlie bone, or
the treatment area is large, a case for using surface mould
therapy can be made. This will particularly apply when
the only alternative treatment is to use superficial X-ray
therapy when the absorbed dose to bone will be greater
than in muscle.
With the advent of remotely controlled afterloading
equipment, the potential radiation hazard can be virtu-
ally eliminated and the place for using a surface treat-
ment mould needs further consideration. The purpose
394 High dose-rate brachytherapy in the treatment of skin tumors

of this chapter is to discuss the use of afterloaded treat-

ment moulds rather than superficial X-rays or electrons
for treating skin cancer, particularly with regard to high
dose-rate (HDR) remotely afterloaded surface moulds.
However, when indicated and for completeness, refer-
ence will be made to other brachytherapy systems.
The authors' experience was originally gained with the
use of surface mould therapy using sources of radium-
226, gold-198, cesium-127 or iridium-192 placed on
individually made shells or wax blocks. The spatial dis-
tribution and quantity of the radioactive sources were
determined by the Paterson-Parker Rules [5-7]. The
amount of radioactive material depended on the size of
the treatment area and the distance between the plane of
the sources and the treated surface. For large treatment
areas, considerable amounts of source activity were
needed, with consequent restriction on the amount of
time that could be spent positioning the device on the
patient and on nursing and visitors' time spent with the
patient. In particular, the technical staff who prepared
the mould before application, and dismantled it after
use, could be exposed to a significant radiation hazard.
The use of a remote afterloading machine offered a pos- Figure 29.1 Percentage depth dose characteristics of a 40 mm
sible solution to those difficulties [8], and subsequently diameter surface mould (SM) at 10 mm and 30 mm treating
other reports of this technique were published [9-11]. A distances (TD): curves SM 10 mm TD and SM 30 mm TD. For
recent literature search has shown that there continues to comparison, superficial X-rays of 2 mm aluminum half value
be an interest in the technique [13-20]. layer (Al HVL) and 8 mm Al HVL at a focus-to-skin distance (FSD)
of 150 mm are also shown: curves X-ray 80 kV and X-ray
140 kV. (Data from references [7] and [12].;
29.2 HIGH DOSE-RATE AFTERLOADING
SYSTEMS

dose data for 150 mm focus-to-skin distance (FSD)

One author (CAJ) described a suitable remotely con-
trolled system in 1969 [9], which was also being devel-
oped by the second author (AF), in conjunction with Dr
A.J. Ward, in another center (Cookridge Hospital, Leeds)
at about this time. Both these treatment systems used an
HDR cobalt-60 unit, the Cathetron, previously described
[8]. However, the methods used are adaptable to any
afterloading machine with suitable small sources and
source delivery system. More recently, Selectron-LDR
(low dose-rate), microSelectron-HDR, and pulsed dose-
rate (PDR) machines have been adopted for use in after-
loading surface moulds [13-15,17-20].
293 ABSORBED DOSE DISTRIBUTION
Due to the short source to skin distance, which is typi-
cally between 5 mm and 30 mm, a rapid fall-off in dose
with depth from the skin surface of the applicator
occurs. Figure 29.1 shows a typical depth dose profile for
a source to skin distance of 10 mm and 30 mm, for a
40 mm diameter applicator. The curves shown are for
radium-226, but are not substantially different for other
isotopes in common use. Also, for comparison, depth
superficial X-rays at 80 kV and 140 kV are shown, the
data being taken from the British Journal of Radiology,
Supplement 26 [12]. In the case of a surface mould, the
reduction in dose with depth within the irradiated tis-
sues is principally due to the increase in distance from
the radiation source(s), and the relative effect of tissue
attenuation and scatter is small. In contrast, absorption
and scatter, depending upon the quality of the beam, will
be more important for superficial X-rays. The net result
is that for water (or muscle tissue) the depth dose char-
acteristics of the two modalities are similar, despite the
differences of photon energy and source to skin dis-
tance/FSD.
However, for tissues of higher atomic number, such as
cartilage and bone, the photoelectric effect will dominate
in the case of superficial X-ray therapy, but not in the
case of a surface mould when using an isotope emitting
high-energy photons. When these tissues are included in
the treatment volume, there will be a relatively greater
absorption of energy for superficial X-rays than for a
surface mould, which may lead to a greater absorbed
dose than that prescribed. This, in turn, will increase the
risk of severe late normal-tissue injury, which the higher
energy radiation from a surface mould will largely avoid.

29,4 SELECTION OF TREATMENT DISTANCE
As shown in Figure 29.1, the depth dose characteristics
of a surface mould depend strongly on the treatment
distance, a greater distance giving a higher relative depth
dose. Before any part of the mould device is actually con-
structed, it is necessary to decide on the appropriate
treating distance. This will depend mainly on the thick-
ness of the tumor to be treated and the dose required at
the deepest part of the target volume. Whilst it would
normally be necessary to construct a full treatment plan
for the mould when all of the parameters have been
decided, it is useful initially to choose a treatment dis-
tance based on the information contained in the
Paterson-Parker tables [7]. Although these tables are cal-
culated for radium-226 sources, the depth doses that
may be obtained from them are sufficiently accurate for
this purpose when using other nuclides such as cobalt-
60, cesium-137, or iridium-192.
The choice of treatment distance is a compromise
between conflicting requirements, and usually a dis-
tance of 10 mm or 20 mm is chosen. A treatment dis-
tance of less than 10 mm may produce unacceptable
dose variation on the skin surface if the latter has undu-
lations that cannot be accurately followed by the source
applicators. A treating distance greater than 20 mm may
lead to long exposure times and to a wide penumbra
effect outside the edges of the intended treatment area.
This may result in a clinically meaningful dose to criti-
cal organs such as the eye. To some extent these effects
can be overcome by suitable shielding at the edges of the
mould, as illustrated in Figure 29.2 and discussed in ref-
erences 9-11.
An additional consideration is the thickness of the
tumor. There is an approximate relationship between the
diameter of a skin cancer and its thickness. Lesions that
are up to 25 mm diameter are, in general, no more than
5-6 mm thick. This is an important relationship because
a cancericidal dose will be necessary at the maximum
Figure 29.2 Cathetron HDR afterloading surface mould,
showing lead shielding around the irradiated area.
Mould production 395
depth of the tumor. The fall-off in dose from the skin
surface is greatly affected by the treatment distance.
Figure 29.1 shows that, for a treating distance of 10 mm,
using cobalt-60, the percentage depth dose falls to 20%
at 30 mm beneath the skin surface. This needs to be
taken into consideration when prescribing treatment
which, for skin tumors, has historically been prescribed
to the skin surface.
With the elimination of exposure risks to staff, it may
be tempting to improve the dose homogeneity by
increasing the treating distance to 20 mm or 30 mm.
Care should be taken if this is intended, because the
usual method of treatment delivery does not normally
provide any form of collimation. While improved colli-
mation can be achieved to some extent by surrounding
the treatment area with appropriate lead shielding, this
may produce practical problems because of the weight of
lead required and the need to provide some sort of sup-
porting structure.
29.5 MOULD PRODUCTION
29.5*1 Providing a cast
The first step in the production of a mould is to take a
cast of the affected area. If a flat area is involved, the
traditional plaster of Paris can be used. However, for
more detail on an undulating surface it may be better
to use one of the modern alginate impression materi-
als. A close-fitting, transparent plastic shell is made
from the cast, usually by vacuum forming. If the area
to be treated is on a limb extremity, such as the dor-
sum of the hand, the shell can be attached to a base-
plate to provide stability; otherwise, straps can be used
to attach it to the patient. The area to be treated is
marked on the skin and superimposed on the shell
(Figure 29.3).
Figure 29.3 HDR afterloading surface mould, with the area to
be treated marked on the skin.
396 High dose-rate brachytherapy in the treatment of skin tumors
29.5.2 Disposition of sources
The proposed arrangement of the sources and dwell posi-
tions should be determined. Our usual procedure is to
use the Paterson-Parker distribution rules as a guide to
the arrangement of the source positions around the
periphery of the treated area and, when necessary, in a
line or series of parallel lines over the area itself. For some
afterloading machines, the number and configuration of
the source trains available are restricted. These may be
used if the source train length matches the required treat-
ment length; otherwise, a single active source can be step-
wise positioned along the line of the treatment. With
some current afterloading machines, the stepping source
arrangement offers greater flexibility, providing for any
active length that may be required, and allows the dose
distribution to be optimized if required. This can be of
particular value when irradiating an irregular surface or
where the treatment area is not flat (Figure 29.4).
29.5.3 Applicator supports
Having decided on a provisional source(s) arrangement,
the construction of the mould may be completed. On
Figure 29.4 MicroSelectron HDR afterloading surface mould,
showing the source catheters (applicators) in parallel lines over
the irradiated area. (Courtesy of Nucletron BV.)
our early moulds using the Cathetron machine, we used
a Perspex frame to support the (then rigid) treatment
catheters (Figure 29.5), but later we developed flexible
catheters. These are now superseded by using 6-French
bronchus-type catheters with the microSelectron, or
similar. The catheters are supported by Perspex catheter
supports of the appropriate height, attached to the sur-
face of the shell. These supports have a hole drilled in
them to accommodate the flexible catheters, as appropri-
ate. They are of the correct height to provide the
required treatment distance, allowing for the thickness
of the shell material. The supports at the end of each
catheter position contain a recess rather than a complete
hole. This provides an end-stop to define the longitudi-
nal position of the catheter and to prevent any catheter
movement. It also ensures that the catheters are inserted
in the correct position for treatment. In some cases, lead
shielding is placed around the treated area to help to
protect nearby critical organs, as already mentioned and
illustrated in Figure 29.2. There are, of course, alternative
methods of supporting the applicators, such as embed-
ding them in a wax or acrylic sheet of the appropriate
thickness.
29*5*4 Provisional treatment times
A provisional set of treatment times for the various
source positions is then drawn up. This should be done
by referring to appropriate data on the dose rate(s) and
distribution(s) for the available source trains. For the
microSelectron-HDR and other similar afterloaders, the
calculation can be performed on the brachytherapy
treatment planning system. The use of a dwell time opti-
mization program may be considered to improve the
dose homogeneity on the treated surface, but in practice
we found this difficult to use as the position of the dose
calculation points cannot easily be defined, particularly
for a curved surface. For a small mould with only a few
treatment applicators, we found it just as easy to adjust
Figure 29.5 Cathetron HDR afterloading mould, showing the
catheter support Perspex frame.

the dwell times empirically, in conjunction with dosime-
try measurements, as described below.
29.5.5 Dosimetry measurement
The dosimetry should be checked before treatment is
started by thermoluminescence dosimetry (TLD) or
other suitable dosimetry system. Our own experience is
with TLD. A number of thin sachets containing lithium
fluoride crystals are taped to the underside of the shell
on the treated surface, and the space beneath this is filled
with a tissue-equivalent material. The mould is exposed
according to the provisional treatment times, and the
dose to the treated area is determined. A correction to
the dose measured is made to allow for the thickness of
the sachet, based on the depth dose characteristics as
previously calculated. The treatment times are then
adjusted as necessary. The dose distribution is regarded
as being satisfactory if the range of doses measured is
within 10% of the mean. This is the range suggested in
the Paterson-Parker Rules, which can often be improved
on in practice.
29.6 CLINICAL PRACTICE
Most of our experience has been gained from treating
patients who were diagnosed with basal cell carcinoma,
squamous cell carcinoma, or intraepidermal carcinoma.
However, a few cases of less common soft tissue sarcoma
have been treated postoperatively, including a case of
recurrent malignant melanoma in a young man and a
primary malignant melanoma of the pinna in a geriatric
patient. A variety of body sites were treated, including
the scalp, dorsum of hand, chest, abdominal wall, and
lower leg. The main constraint from a technical point of
view has been that the treated area should not be so
curved as to restrict the movement of the source train
through the catheters. This restriction is less critical for
current machines which use small stepping iridium-192
sources, such as the microSelectron-HDR; whereas, for
machines for which the size of the radioactive source(s)
is relatively large, the minimum radius of curvature will
be restricted. One other constraint has been the need to
restrict the radiation dose received by any critical normal
tissue(s) adjacent to the target volume.
29.6.1 Dose fractionation schedules
For soft tissues, the fall-off in dose with distance below
the skin surface is similar whether superficial X-rays or
cobalt-60 treatment moulds are used. If a similar dose
fractionation regime is used for HDR treatment moulds
as for superficial X-rays, any difference in tissue effect(s)
will be principally dependent on the radiation quality
Clinical practice 397
alone. This is of particular importance where bone or
cartilage underlies a tumor, when it is clearly advanta-
geous to use high-quality radiation. In order to achieve a
radiobiological effect in muscle similar to that used in
time-established superficial X-ray treatment, the dose
per fraction for cobalt-60 will need to be increased by
about 10%. Compared to muscle, bone will absorb about
four to five times more energy per gram from superficial
X-rays as compared with cobalt-60, with obvious advan-
tages in favor of cobalt-60.
For many treatment situations, small treatment areas
less than 3.0 cm in diameter should be restricted to a
dose of 45 Gy in ten fractions. When treating areas larger
than 3.0 cm diameter, increased fractionation is neces-
sary if the risk of late normal-tissue damage is to be min-
imized. Among the situations in which careful
consideration of the dose fractionation regime used is
necessary, is treatment to areas with minimal subcuta-
neous thickness such as skin overlying the shin bone.
29.6.2 Dorsum of the hand and lower arm
The commonest tumor is an invasive squamous cell car-
cinoma. These tumors are more often seen in older
patients who have already suffered skin changes due to
chronic exposure to sunlight. The majority of lesions are
flat and do not exceed 20 mm in diameter at presenta-
tion. Typical dose regimes are 45 Gy in ten fractions and
50 Gy in 15 fractions. Usually, a source to skin treating
distance of 10 mm or 15 mm is suitable. Others have
reported using a short-distance cobalt unit to give 55 Gy
in 15 fractions over 3 weeks to fields less than 3.0 cm in
diameter. They referred to lesions on the dorsum of the
hand being radioresistant, with a higher recurrence rate
compared to other sites.
The skin overlying the treated area may become thin
and atrophic. Such changes can be aggravated in a situa-
tion where skin damage is already present due to previ-
ous chronic exposure to sunlight. Problems may also
arise in a patient who, following treatment, is exposed to
a risk of traumatic skin injury. We have seen such a case
in a sailor who suffered a skin laceration through the
treated area 2-3 years following radiation which
required plastic surgery. In the older patient with thin
atrophic skin, increased fractionation is advisable and
the alternative treatment by plastic surgery should be
carefully considered.
Occasionally, multiple lesions may be unsuitable for
surgery or small-field radiotherapy. A technique using a
large treatment field to deliver 60 Gy in 2.0-Gy fractions
to an area covering more than half the circumference of
the forearm has been described by Rudoltz and others
[20]. They used a thermoplastic mould 5.0 mm thick
with 22 silicone-rubber catheters longitudinally placed
20 mm apart. The given dose was prescribed to 8 mm
depth in tissue, treatment being delivered using source
398 High dose-rate brachytherapy in the treatment of skin tumors
dwell positions at 1-cm intervals and the mould covered
with a lead shield. The results were reported as satisfac-
tory, the disadvantage being the extended treatment time
and concern about radiation exposure to staff. This lat-
ter problem emphasizes the need to deliver treatment
within a radiation-protected room, the purpose of lead
shielding being to reduce whole-body irradiation to the
patient.
29.63 Face and scalp
When treating sites in this area, it is important to pay
particular attention to appropriate shielding of sur-
rounding normal tissues. Treatment distances should be
short in order to reduce the exposure time of the
radioactive sources. If shielding cannot be easily pro-
vided, it is preferable to consider using electron-beam or
photon-beam therapy. The areas most applicable to sur-
face mould therapy are the forehead and temporal areas.
Where areas are situated close to the hairline and
because of the wide penumbra, the risk of alopecia is
high and appropriate shielding should be used where
possible.
29*6.4 Pinna
Carcinoma of the skin of the pinna will overlie cartilage
and the benefits of high-energy photon radiation will
particularly apply for the reasons discussed earlier. HDR
afterloading using cesium-137, cobalt-60, or iridium-
192 is especially suitable. Treatment can be given using a
single-plane applicator at a treatment distance of 10-20
mm (although the authors have found 15 mm to be the
most practical distance) to a prescribed dose of 45-50 Gy
in eight to ten fractions. The pinna is amenable to the
protection of adjacent structures, which is important if
hair loss is to be minimized. However, the use of radia-
tion shielding of adjacent tissues may involve the practi-
cal problems of physically supporting a lead shielding
block [10]. For thick lesions of the helix, a double-plane
applicator can be used and planned according to the
Parker-Paterson Rules, but the practicalities of protect-
ing surrounding tissues may prove difficult.
29.6.5 Legs
In general, skin healing following radiation, particularly
overlying the anterior tibia, is poor. Of 20 cases treated
with 45-47.5 Gy in 10 or 11 fractions, poor healing
affected three cases, with superficial necrosis affecting
three other cases (one following injury). Considerable
care is therefore necessary when considering dose frac-
tionation regimes for this site, and increased fractiona-
tion is advisable.
A review by Podd [21] reported an overall recurrence
rate of 4.6% and a radionecrosis rate of 9.2% when treat-
ing squamous and basal cell cancers of the lower limb in
older patients. The treatment given was to areas less than
30 cm2, which corresponded to a 6 cm diameter applica-
tor. Although either superficial or orthovoltage X-rays to
a dose of 40 Gy in ten fractions were used, allowing for
the difference in radiation quality, these reported find-
ings were similar to our own series.
The treatment of a large area carries an increased risk
of failure to obtain complete skin healing. However, in a
case report of LDR treatment in an elderly patient, a
treatment area of 8 x 8 cm, extending over half the cir-
cumference of the leg, was considered more acceptable
than either a single external-beam field or a parallel
opposed pair of fields, particularly as the latter would
have treated more than half the leg thickness [12]. We
support reserving treatment of lesions of the lower limb
using a treatment mould to situations for which alterna-
tive treatments have been carefully assessed and elimi-
nated.
29.6.6 Trunk
The skin of the lower abdominal wall is generally more
sensitive than that of the upper trunk to the effects of
radiation. However, because of the rapid fall-off in dose
beneath the skin surface, surface moulds can be
extremely useful for confining the effects of radiation to
within the abdominal wall tissues. For the treatment of
skin tumors or secondary skin nodules, this form of
therapy can be useful where the treatment of a relatively
large surface area is indicated. The technique employed
is similar to that for radium loaded chest wall moulds as
used historically. Where large areas are to be treated,
increased fractionation is necessary and, in general, this
form of treatment application has been superseded by
electron therapy. However, optimized treatment can pro-
vide better dose homogeneity over curved surfaces [10]
than from abutted electron fields [13]. When using spa-
tially positioned sources, by altering the position of the
source pencils and adjusting treatment times for differ-
ent source positions, it is possible to treat surface areas
up to 200 cm2 without loss of uniformity of dose [11].
Others have since described the use of an HDR
(iridium-192, 370 GBq) remotely loaded applicator for
treating Kaposi sarcoma lesions. This entailed using a
custom-built, ceiling-mounted immobilization device
that secures the applicator on the surface of the patient.
The applicators were made of tungsten/steel, 1, 2, or 3
cm diameter. The treatment distance was 15 mm and
treatment sites included the head and neck and extrem-
ities, as well as the torso. The applicators required a plas-
tic cap to eliminate electron contamination. For treating
Kaposi sarcoma lesions, an optimal surface dose of
10-15 Gy in a single fraction, depending on the thickness
of the lesion, was recommended [19].

29.7 CONCLUSION
The majority of skin tumors are amenable to treatment
by conventional means, including superficial X-rays,
electron therapy, and surgery. This chapter has reviewed
the literature and, coupled with our own experience, has
identified and discussed the use of afterloaded treatment
moulds in situations in which they offer potential treat-
ment advantages to the patient.
REFERENCES
1. Gloster, H.M.and Brodland, D.G. (1996) The epidemiology
of skin cancer. Dermatol. Surg., 22(3), 217-26.
2. Strom, S.S. and Yamamura, Y. (1997) Epidemiology of
nonmelanoma skin cancer. Clin. Plast. Surg., 24(4),
627-36.
3. Wei ,Q. (1998) Effect of ageing on DMA repair and skin
carcinogenesis: a mini review of population based
studies.J Investig. Dermatol. Symp. Proc., 3(1), 19-22.
4. Halpern, J.N. (1997) Radiation therapy in skin cancer. A
historical perspective and current applications. Dermatol.
Surg., 23(11), 1089-93.
5. Paterson, R.P. and Parker, H.M. (1934) Dosage system for
gamma ray therapy. Br.J Radiol., 7, 592.
6. Paterson Rand Parker H M. (1938) A dosage system for
interstitial radium therapy. Br.J. Radiol., 9,252 and 313.
7. Meredith, W.J. (ed.) (1967) Radium Dosage. The Manchester
System. ES Livingstone, Edinburgh and London.
8. O'Connell, D., Howard, N., Joslin, CAR, Ramsey, N.W. and
Liversage, W.E. (1965) A new remotely controlled unit for
the treatment of uterine cancer. Lancet, 18, 570-1.
9. Joslin, C.A.F., Liversage, W.E. and Ramsey, N.W. (1969)
High dose-rate treatment moulds by afterloading
techniques. Br.J. Radiol., 42,108-12.
10. Joslin, CAR and Smith, C.W. (1970) The use of high
activity cobalt 60 sources for intracavitary and surface
mould therapy. Proc. R. Soc. Med., 63(10), 1029-34.
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11. Joslin, C.A.F. (1972) Afterloading methods in
radiotherapy. In Recent Advances in Cancer and
Radiotherapeutics, ed. K. Hainan. Edinburgh, Churchill
Livingstone.
12. Supplement 26 BJR. (1996) Central axis depth dose data
for use in radiotherapy. Br.J. Radiol., 26.
13. Kitchen, G., Dalton, A.E., Evans, M., Pope, B. and Smith,
P.O. (1990) Selectron-LDR mould for large area basal cell
carcinoma; a case report. Activity [Selectron Activity
Journal], 4,72.
14. Kitchen, G., Dalton, A.E., Pope, B.P., Smith, P.O. and
Powner, M. (1991) Surface applicator for basal cell
carcinoma of the right pinna: a case report. Activity
[Selectron Activity Journal], 5,140.
15. Perrozzo, M., Stabile, L, Ross, R., Moorthy, C, Tchelebi, A.
and Hilaris, B.S. (1992) HDR remote afterloading as an
alternative to electrons for therapy of superficial
tumours. Activity [Selectron ActivityJournaf], 6,11.
16. Fritz, P., Hensley, F.W., Berns, C., Schraube, P. and
Wannenmacher, M.(1996) First experiences with
superfractionated skin irradiations using large
afterloading moulds. lnt.J. Radial Oncol. Biol. Phys.,
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17. Leung, J.T. (1997) Extensive basal cell carcinoma treated
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/tad/o/.,41,20-1.
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Schreiner, L.J.andSouhami, L. (1997) Surface applicators
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High-dose rate brachytherapy with custom surface mold
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4,44-5.

Hyperthermia and brachytherapy
PETER M. CORRY, ELWOOD P. ARMOUR, DAVID B. GERSTEN, MICHAEL J. BORRELLI, AND
ALVARO MARTINEZ
30.1 INTRODUCTION
Brachytherapy provides an obvious and sometimes ideal
setting for combining hyperthermia with radiation ther-
apy. Such combination therapy has been carried out in
the past primarily using microwave technology, multiple
antennae being placed intratumorally through plastic
catheters previously inserted for this purpose [1,2].
There are a number of situations, particularly in the
head and neck region, where this methodology is useful,
but it does not lend itself easily to automation and does
not adapt well to the simultaneous application of hyper-
thermia or to the use of radioactive source afterloaders.
Another situation in which hyperthermia can and has
been applied [3-5] is for implants that involve stainless-
steel needles to contain the radioactive materials. This
approach is usually done in conjunction with a cuta-
neously attached template guidance apparatus [6]. In
this case, radio-frequency (RF) power is applied directly
to the stainless-steel needles themselves. Other
approaches include needles heated with resistive electri-
cal heating elements or hot water [7,8] ferromagnetic
seeds contained within plastic catheters [9], and RF-
driven, capacitively coupled, plastic-coated catheters
[10]. Ultrasonic interstitial and intracavitary applicators
promise more functionality and versatility, but are not
yet in widespread clinical use [11].
From a clinical historical perspective, there have been
30
several randomized, prospective, clinical trials carried
out in Europe over the past few years [12] which have
demonstrated benefit associated with the addition of
hyperthermia to conventional radiation therapy. The
only similar clinical trial combining hyperthermia with
brachytherapy, conducted by the Radiation Therapy
Oncology Group (RTOG) in the USA, showed no such
benefit [13]. Unfortunately, this trial, which was fraught
with several quality assurance issues, was designed and
mostly conducted prior to the development of the qual-
ity assurance guidelines which are now known to be
essential to a positive result [14]. Only one patient of 86
in this study received what was considered an 'adequate'
hyperthermia session.
30.2 BIOLOGICAL FACTORS
Over the past 20 years, the biological effects of elevated
temperatures (40-43 C) and their implications in can-
cer therapy have been extensively investigated. The fol-
lowing points summarize these investigations and
constitute the rationale for the application of elevated
temperatures in this setting.
Hyperthermia kills tumor cells directly and
preferentially kills cells in macroscopic tumors.
If sufficient exposure is given, hyperthermia supra-
additively sensitizes cells to the action of ionizing

radiation with a thermal enhancement ratio (TER)
up to 3, and chemotherapeutic drugs with a TER up
to 10.
Hyperthermia eliminates dose-rate effects by the
inhibition of repair phenomena (Figure 30.1) [15].
This is particularly important in application with
brachytherapy because the biological effects of low
dose-rate (LDR) radiation and high dose-rate radia-
tion (HDR) should be approximately the same in
heated tumor tissues. In cooler normal tissues, how-
ever, LDR should have an advantage in terms of
lesser toxicities.
Recently, other investigators have shown that tem-
peratures in the 41-42C range, when applied to
solid tumors in rodents, can have a profound effect
on tumor oxygenation and/or reoxygenation [16,17].
This reoxygenation greatly reduces the hypoxic frac-
tion, significantly enhancing the effects of ionizing
radiation in addition to the direct hyperthermic
effects. Similar observations have been made in
human tumors [18].
Hyperthermia acts in a complementary manner to
ionizing radiation and chemotherapeutic drugs.
Those cells most resistant to radiation or drugs are
the most sensitive to hyperthermic killing and sensi-
tization.
For many years, the existence of a phenomenon
known as thermal tolerance was thought to contraindi-
cate closely spaced heat fractions and the administration
of chronic protracted heating. In fact, several publica-
Figure 30.1 Dose-rate effects in rat 9L gliosarcoma cells in
culture. (Data adapted from reference 15.)
Biological factors 401
tions (e.g., [19-21]) support the contention that few,
perhaps only 10%, of a tumor's cells are killed by hyper-
thermia and that number can be expected to vary by at
least an order of magnitude in any clinical setting. These
reports also support the notion that, while thermal tol-
erance develops, it is not a clinically limiting factor.
Furthermore, hyperthermia is rarely, if ever, used as
single-agent cancer therapy. Recent randomized clinical
trials using the combination of hyperthermia and con-
ventional fractionated radiation therapy have shown
positive benefit to the addition of hyperthermia (e.g.
[12]) demonstrate T90 values between 39C and 41C:
temperatures far too low to accomplish any significant
direct cytotoxicity. What has been shown by authors
quoted above, as well as others, is that such temperatures
for protracted periods of time continue to affect thermal
radiosensitization (TERs of 1.6-2.0) and that such sen-
sitization is essentially independent of the development
of chronic thermal tolerance. Whereas the intrinsic ther-
mal sensitivity of human cells varies over several decades
of survival from cell line to cell line at these tempera-
tures, thermal radiosensitization seems to be affected to
only a minor degree, if at all. In addition to thermal
radiosensitization, thermal intratumoral reoxygenation
and hypoxic cell fraction reduction are probably playing
an important role as well.
Irrespective of the clinical heating methodology, acute
pain associated with power application has been
reported as the primary limiting factor in achieving tem-
perature distributions with T90 greater than 41 C for
protracted periods [22-25]. This pain is often associated
with elevated temperatures themselves, as well as direct
power deposition within the involved tissues. This has
been found to be the case for tumors with nerves encom-
passed by the tumor and is a particularly significant fac-
tor for advanced malignancies in the pelvis and
abdomen. Fortunately, several publications (e.g., [15,
26-28]) have demonstrated that 41 C for long dura-
tions can yield TERs between 1.5 and 2 (Figure 30.2) as
well as the elimination of dose-rate effects. This is more
often than not the maximum temperature achievable
clinically.
All but one of the clinical brachytherapy studies to
date applied hyperthermia for 1 h at a target tempera-
ture of 43 C before beginning the LDR radiation, and
for 1 h after completion of the radiation therapy course,
usually 48-72 h. This was not done because those regi-
mens have been demonstrated to be optimal, but was
dictated solely by the practical limitations of the systems
used for tumor temperature elevation. As may be easily
seen on consideration of the data in Figure 30.3 little
added benefit in terms of antitumor effect should be
expected from this regimen.
Consideration of the above data and observations
yield several conclusions. The negative findings, relative
to the addition of hyperthermia, of the RTOG random-
ized clinical trial came about because of two factors:
402 Hyperthermia and brachytherapy
Figure 30.2 Enhancement of LDR in rat 9L cells, at a dose rate
of 50 cGy h~1, by continuous simultaneous heating at41C. The
acute X-ray dose was delivered at approximately 3 Gy min~\
(Data adapted from reference 27.)
(1) extensive thermometry was not employed and the
actual thermal distributions were not known to an ade-
quate degree of certainty, and (2) hyperthermia was
administered only for 1 h before and after the interstitial
radiation. Sparse thermometry has previously been
shown to yield a false sense of intratumoral heating ade-
quacy [22]. If the data of Figure 30.3 are representative
of what is occurring intratumorally, little or no supra-
additive enhancement of radiation cytotoxicity should
be expected.
Other important observations relative to thermal
reoxygenation are: (1) at least a 1-h exposure at
41-42C is required to optimally reduce the hypoxic
fraction; (2) reoxygenation effects disappear between 12
and 24 h after the hyperthermic exposure; and (3) at
higher temperatures, 43-44C, reoxygenation is not
observed due to intravascular coagulation. This last
observation (intravascular coagulation) might seem to
suggest that lower temperatures are better because more
reoxygenation is observed. It must be remembered, how-
ever, that for each degree increase in temperature above
42 C, direct heat killing as well as thermal radiosensiti-
zation to radiation increase by approximately a factor of
2. One scenario that would explain clinical results, where
broad temperature distributions from 39C to 44 C are
the rule rather than the exception, is that in those por-
tions of a tumor that are poorly heated (39-42 C), ther-
mal radiosensitization by reoxygenation predominates.
Figure 30.3 Effects of 1-h 43 C heat exposures both before,
after and before, and after LDR irradiation in rat 9L
gliosarcoma cells in culture at a dose rate of 50 cGy h-1 There is
no significant difference in the slopes of any of these plots. The
thermal enhancement ratio for all three hyperthermia regimens
is slightly less than 1.0, suggesting that there was no supra-
additive interaction between the heat and radiation for these
regimens.
In those portions of the tumor that are heated well
(41-44C), thermal radiosensitization by repair inhibi-
tion predominates. In the 41-42C range, both effects
are operative. This is a fortuitous situation because
tumors have proven to be remarkably refractory to uni-
form heating, even with interstitial and intracavitary
technology.
Taken together, these factors lead to the conclusion
that, for optimal antitumor effect, hyperthermia should
be administered continuously and simultaneously dur-
ing LDR irradiation. The use of pulse dose-rate (PDR)
and HDR irradiation technology requires some further
consideration. For PDR, the hyperthermia requirements
are essentially identical [28]; however, because the radia-
tion for PDR is administered in short pulses, perhaps
1 min h'1, it is not essential that hyperthermia be admin-
istered during the actual irradiation period. This factor
may be of considerable practical importance. In the case
of HDR procedures, in which radiation fractions are
spaced over days or weeks, hyperthermia should be
administered for at least a 1-3-h period immediately
prior to irradiation and, if practical, during irradiation
[29].
 A system for simultaneous hyperthermia and brachytherapy 403
303 THERMOMETRY REQUIREMENTS
Quality assurance criteria and the need to control tem-
peratures in three dimensions at some prescribed level
dictate thermometry requirements. The prescription
should be expressed in terms of the temperature distrib-
ution throughout the treatment volume and not in
terms of a given temperature at any given point within
the volume. A convenient way of describing the distrib-
ution is the percentage of intratumoral temperature
points at or above a given index temperature [22,30].
The software operating the system must have the capa-
bility of computing and displaying this type of informa-
tion in real time, providing the operator with the ability
to assess compliance with the prescription continuously.
This type of real-time analysis also permits alteration of
the power deposition pattern to comply with the pre-
scription if necessary. The RTOG in the USA has devel-
oped comprehensive quality assurance guidelines for
interstitial hyperthermia which are sufficiently extensive
to permit this type of analysis and control [14]. Table
30.1 summarizes the approximate recommended num-
ber of sensors as a function of tumor volume.
Table 30.1 Recommended implanted sensors
5 12
10 15
50 18
100 24
200 30
500 48
These publications also outline the guidelines for
placement of the sensors. Catheters containing multiple
sensors or within which a single sensor will be scanned
along its length must be placed to represent accurately
the central and peripheral aspects of the tumor as well as
sensing temperatures in tumor tissue central to the
arrays of heating entities. It must be stressed again that
these figures are recommended minima for quality
assurance purposes and for many systems additional
sensors will be necessary to achieve adequate three-
dimensional power deposition control. Clearly, systems
of the future will require expanded data acquisition
capabilities over those of the past. A 32-point measure-
ment capability appears to be the minimum required
number and, for versatility, 64 is highly desirable.
30.4 SYSTEMS CONSIDERATIONS
The primary considerations in the design of systems for
the administration of hyperthermia and brachytherapy
are based on the biological factors and thermometry
requirements discussed above, as well as on practical
considerations. The following criteria are recommended
for an ideal system:
It should be possible to deliver hyperthermia
simultaneously prior to and throughout the course of
radiation, irrespective of the brachytherapy modality
in use - LDR, PDR, or HDR.
Compatibility with LDR after-loaders as well as PDR
and HDR source loaders is required for optimal flex-
ibility in source handling and to reduce exposure to
personnel.
The thermometry system should have at least 32
temperature-measuring channels. Preferably, 64
should be available. The design should permit tem-
perature measurements in tissue between heating
elements if sensors are built into the heating ele-
ments themselves.
The system should permit dynamic alteration of the
power deposition pattern in three dimensions
throughout the course of treatment.
Power deposition control and data acquisition must
be fully automated. Because prolonged exposures of
hours to days may be required, remote monitoring
and control are highly desirable.
For practical reasons, set-up complexity should be
minimized.
For optimum utility, the system should be portable
or at least easily movable.
In practice, there are no systems that are available com-
mercially or prototype systems that have been developed
in research laboratories that can satisfy all of the above cri-
teria. It is also highly unlikely that any one system will be
appropriate for all anatomic locations. For example, while
local current flow (LCF) technology, such as that
described below, works well for tumors in the deep pelvis
with transperineal template guidance, it adapts poorly to
tumors in the head and neck. Ultrasound and microwave
systems permit wider element spacing, and as a result
fewer elements, than other technologies and provide
superior three-dimensional control, but do not adapt well
to simultaneous administration with radiation.
Capacitively driven systems are very flexible and adapt-
able to irregular shapes and to tumors in the head and
neck, but power deposition control is more difficult and
simultaneous administration is precluded for most sys-
tems. In all cases, trade-offs have been required. As a
result, there is no ideal system or method available for
hyperthermia administration at present.
30.5 A SYSTEM FOR SIMULTANEOUS
HYPERTHERMIA AND BRACHYTHERAPY
To test the hypothesis that simultaneous administra-
tion of hyperthermia throughout the course of
404 Hyperthermia and brachytherapy
brachytherapy administration should yield superior
results to protocols applying heat only before and after
radiation, a new system was designed. This first step was
the Martinez Universal Perineal Implant Template
(MUPIT) [6], used to guide implants to incorporate
printed circuit boards as integral components to effect
connections to the needles. This hyperthermic universal
perineal implant template (HUPIT) is shown in position
in Figure 30.4 after the operative procedure for a patient
under treatment.
There are 59 positions, at 11 mm separations, for
stainless-steel needles in a seven wide by nine high array,
with one needle missing at each corner. Each needle con-
nects both to the afterloader to insert/retract the
radioactive isotope, as well as to the power-generating
circuitry to induce hyperthermia. There are 48 positions
centrally located between these needles for dedicated
thermometry catheters. Connection to the power gener-
ator is via two miniature connectors, one at each end of
the template (29 wires each). The microprocessor-
controlled power generator has the capability of apply-
ing the RF power to any, all, or none of the needles
Figure 30.4 Electronic template shown fixed in position after
the operative procedure was completed on a patient being
treated for recurrent cancer of the uterine cervix. The stainless-
steel needles (N) connect to remote afterloaders to insert and
retract the radioactive sources. These needles are also connected
to the hyperthermia power source by spring-loaded collars (not
shown) that in turn connect to the 37 pin connectors (C),
mounted at each end of the template. In this instance, six
dedicated thermometry catheters (T) were implanted and a total
of 30 thermocouple sensors were inserted. V = vaginal cylinder.
simultaneously, and each needle can be connected at an
RF phase angle or either zero or 180 degrees. By varying
the pattern and phase angles of the connections, any
desired power deposition pattern can be achieved, at
least in two dimensions. As areas of the tumor warm to
the set point, the duty factor for needles in the immedi-
ate proximity to the sensors is varied to maintain the
desired temperature. The inherent flexibility of this
approach minimizes the information necessary prior to
doing the implant. Treatment planning software is used
after the implant is done to determine the initial power
deposition patterns, however. All parameters are under
operator control at all times during therapy and can be
varied to account for factors such as blood flow and
patient tolerance which cannot be accurately determined
in advance. This system satisfies all of the design criteria
outlined above except one. Because the stainless-steel
needles are not segmented, power is controlled only in
two dimensions rather than the more ideal situation in
which it would be controlled in three dimensions. To
have control in three dimensions it would be necessary
to develop needles that are segmented along their length.
This system was used to treat a variety of tumors in 19
patients to test the feasibility of the approach. The goal
was to achieve an intratumoral temperature distribution
with a T90 of 41 C and to maintain that distribution
throughout the course of treatment (continuous mild
hyperthermia, CMH). Prior to finishing the develop-
ment of the technology necessary for CMH, 14 patients
were treated with acute fractionated hyperthermia
(AFH), which consisted of hyperthermia for 1 h before
and 1 h after the interstitial irradiation. Clinical response
data for the two groups of patients were compared.
Figure 30.5 shows the therapy set-up for the patient in
Figure 30.4. The distribution of anatomic sites for the
tumor in all 34 patients is given in Table 30.2. Figure 30.6
shows a composite integral distribution of intratumoral
and normal tissue temperatures for all 19 patients
undergoing CMH. A similar distribution (not shown)
for patients who underwent AFH did not differ signifi-
cantly from that of those who underwent CMH. For
comparison, the results of a prior study, with a system
Table 30.2 Patient characteristics
Endometrium 7 -
Cervix 4 7
Colorectal 5 1
Prostate 2 1
Urethra 1 2
Vagina 2 -
Anus 1 -
Breast 1 -
Total 23 11
Females, 28; males, 6. Mean age, 64 years; age range, 34-88 years.
 A system for simultaneous hyperthermia and brachytherapy 405

that did not permit power control at the single-needle

Figure 30.5 Thermobrachytherapy set-up in the brachytherapy
treatment room for the patient shown in Figure 30.4. The box
with the connectors (copper-constantan thermocouples) at the
upper left is the thermometry system, with 32 individual
channels. Located immediately below the thermometry system is
the treatment control computer, which is connected to the
institution-wide computer network for control and monitoring
purposes. The two large tubes at the lower left are the umbilici
for two afterloaders, each of which can contain 15 iridium-192
ribbon sources. Smaller tubes (electrically non-conducting)
extend from the ends of the umbilici to the template itself. The
patient remains in this configuration for 48-72 h. On demand,
patient-controlled analgesia is used to control discomfort and
pain.
level [22] are shown. The error bars in Figure 30.6 repre-
sent one standard deviation of the 19 points for each
index temperature. Normal tissue temperatures within
1-2 cm of the tumor periphery averaged 1.5-2.5C
below those in the tumor itself.
The results of clinical follow-up, which varied in dura-
tion from 6 months to 3 years, are summarized in Tables
30.3 and 30.4, and the observed toxicities for all 33
patients are summarized in Table 30.5. The definitions
for complete response (CR), partial response (PR), and
no response (NR) are those that are conventionally used
in cancer treatment. The radiation dose for the 33
patients ranged from 15 Gy to 39 Gy and was dictated by
prior radiation exposure of the treated region. There was
no significant difference between the dose range for AFH
and for CMH. The number of implanted needles ranged
from 14 to 30, the maximum number being limited by
the aggregate number of available sources provided by
two afterloading systems (30). The number of thermom-
etry sensors inserted into the implant varied from 18 to
32 and was limited by both the number of catheters
implanted (three to six) and the number of channels
available (32).
Table 30.3 Overall response rates
CR 7/14(50%) 14/19(74%)
PR 1/14(7%) 4/19(21%)
NR 6/14(43%) 1/19(5%)
CR+PR 8/14(57%) 18/19(95%)

AFH, acute fractionated hyperthermia; CMH, continuous mild hyper-

thermia; CR, complete response; PR, partial response; NR, no
response.

Table 30.4 Responses by tumor volume

CR 88(7) 36-100 143(14) 8-450

PR 120(1) 120 138(4) 45-288
NR 254(6) 90-432 122(1) 122

* Tumor volume was computed as the product of the three measured

dimensions of the tumor multiplied by Pi/6.
For abbreviations, see Table 30.3.

Table 30.5 Toxicities

Pain during treatment 6 (22)

Pain after treatment 3(11)
Drainage 5(18.5)
Perineal reaction 4 (14.8)
Fistula 2(7.4)
Figure 30.6 Temperature distributions.
406 Hyperthermia and brachytherapy
30.6 DIRECTIONS FOR THE FUTURE
Over the past few years, LDR technology has been, for
the most part, replaced with HDR systems. These sys-
tems provide numerous benefits, which are outlined in
other chapters of this text and will not be elaborated
upon here. In practice, the adaptation of HDR to appli-
cation with hyperthermia is simpler than that for LDR
technology. Because the dose is delivered in short pulses
(a few minutes), the need for protracted hyperthermia
application is lessened. The heat dose can be delivered
prior to and after irradiation without the absolute
requirement for simultaneous delivery. Eliminating
hyperthermia for the short interval during irradiation
should have inconsequential biological effect. We have
adapted the LDR system described above to HDR appli-
cations, but insufficient clinical data and follow-up are
available to evaluate this approach objectively.
The hyperthermia/brachytherapy setting also pro-
vides an ideal scenario for the testing and application of
gene therapy in cancer treatment. Because the proce-
dures are already invasive, access to deliver the interven-
tional product is guaranteed. To assess the potential
efficacy of such an approach, a series of experiments was
initiated to mimic the use of the truncated human heat
shock promoter (designated AHSP) controlling a
reporter gene, the green fluorescent protein (enhanced
green fluorescent protein, EGFP), when delivered by a
viral vector, Adenovirus 5 (Adv), in this setting. The fol-
lowing experiments were carried out in collaboration
with Dr Mark Dewhirst and Dr Rod Braun of Duke
University, Durham, North Carolina.
Figure 30.7 shows the results of two experiments vary-
ing the effective heat dose (30, 60, 90 minutes at 42 C,
assayed 21-23 h later) and the time after heating
(0-42 h). These data clearly show a relationship between
heat dose and expression as well as time after exposure.
Quantitation of gene expression from the digitized video
frames for the Adv-AHSP-EGFP samples is expressed as
the ratio of the fluorescent signal in the sample to the
control after subtracting out baseline autofluorescence.
For the dose-response data (panels E-H: A, 0, 30, 60,
90min at 42C), the values were 3, 28, 102, and 177
respectively. For panels C and D, the values were 165 and
204 for 21 and 42 h post-heating, respectively. Other
experimental data show that, ideally, heat shock should
be delivered 12-24 h after viral administration, that the
heat-induced expression of recombinant products tapers
off over the following 24 h, and that it may be re-
expressed by heat pulses spaced at 24 h. These parame-
ters adapt admirably to a 3-4-day course of HDR with
four to six fractions of administered radiation. These
results demonstrated that gene expression could be con-
trolled over a significant range of expression and heat
doses in a predictable manner. Also of significant impor-
tance was the fact that, in the absence of heat shock, gene
product from the virally introduced recombinant DNA
was undetectable. There are few other systems available
which permit conformal control of foreign recombinant
DNA expression in such a predictable manner.
30.7 CONCLUSIONS
Whereas hard and fast conclusions are difficult with the
limited number of patients described above, we believe
that the trends in the data are encouraging. The response
data for AFH in Table 30.3 show a pattern that is consis-
tent with historical controls for brachytherapy alone.
The response rates for CMH showed an improvement
from a CR rate of 50% for AFH to 74% for CMH. The
overall objective response rate improved from 57% to
95%. Striking differences are also seen when the data are
stratified according to tumor volume for each response
category. For AFH, there is a clear dependence on tumor
volume, a characteristic of all studies that involve radia-
tion as single-agent therapy. For CMH, however, there
was no such pattern. The CR category actually was char-
acterized with a wider range of tumor volume than the
other two response categories. Statistically, no significant
differences could be determined for the ranges of tumor
volume in the various response categories; however, this
could easily be a result of the small numbers involved.
Nevertheless, the elimination of the tumor volume effect
requires a TER in the neighborhood of three. While the
numbers are small and the assumptions used to calculate
the required TER can certainly be challenged, the possi-
bility of obtaining radiation dose modification of this
magnitude encourages enthusiasm. Observed toxicities
were acceptable and did not vary significantly from what
would be expected for brachytherapy alone, with the
exception of treatment-related pain. In one case, pain
after treatment was protracted for 3 months but subse-
quently resolved without intervention. To some degree,
intra-treatment pain was noted for all patients and in six
cases (22%) this pain limited the power that could be
applied and required aggressive pain management.
The temperature distribution data shown in Figure
30.6 show an improvement in the direction of an ideal
distribution, uniform heat dose in the tumor and none
outside it. When compared to a previous study in
which dynamic control of the power deposition pattern
at the level of a single needle was not available [22],
more of the tumor is adequately heated and less is over-
heated. Unfortunately, parts of the tumor remain below
the target temperature of 41 C (10-20%) and a few
points as high as 46 C were observed. These tempera-
ture distributions probably will not improve until
three-dimensional control of the power distribution
pattern can be achieved. This shortcoming points out
the need for further instrumentation and systems
development.

As stated in the introduction, brachytherapy often
provides an ideal setting for combination with hyper-
thermia. The invasive nature of brachytherapy itself
reduces objections to the requirement for invasive ther-
mometry. In the system described above, the needles
required for introduction of the radioisotope are also
used for hyperthermia, without the need for the intro-
duction of additional invasive elements, other than for
thermometry. The ability to administer hyperthermia
simultaneously optimizes intratumoral sensitization to
radiation both for direct hyperthermic sensiti/ation and
from reoxygenation, both of which are required to opti-
mize the antitumor efficacy. While the system described
Conclusions 407
Figure 30.7 Epifluorescence
photomicrographs of rat MAC
tumors grown in a window
chamber and topically infected
with Adv-AHSP-EGFP viral
preparations. Panels A-D are for
the same tumor and track EGFP
expression and fluorescence as a
function of time after heating
for 90 min at 42 C. Panels E-F
are for three different tumors
(rats) for heat exposures of 0, 30,
60, and 90 min at 42C.
(A) Immediately prior to
infection; (B) 29 h post-infection
and immediately prior to
heating at 42Cfor 90 min;
(C) 21 h post-heating; and
(D) 42 h post-heating; (E) 28 h
post-infection, immediately prior
to heating at 42 Cfor 30 min;
(F) as in (E) but 23 h post-
heating; (G) 23 h post-heating at
42Cfor 60 min; and (H) 27 h
post-heating at 42Cfor 90 min.
The scale in the lower left
portion of panel A shows a
1-mm scale photographed
through the microscope. All
photographs are at the same
magnification and aspect ratios
are preserved. In panel D, very
intense fluorescence in the top
portion saturated the video
camera, causing underexposure
in the remainder of the
photograph. All photo-
micrographs were taken at
identical fluorescence excitation
levels and magnification.
above is effective for our purposes, particularly for
transperineal templates, it is poorly adaptable to other
anatomic areas, such as head and neck, where other
systems and principles must be employed. Although
the results described here are encouraging, multi-
institutional randomized trials with stringent quality
assurance criteria and strict patient selection criteria are
essential to accurately assess efficacy and benefit to the
patient. Finally, this combined modality may provide an
ideal setting for testing new modalities such as heat-
activated, controllable gene therapy using bacterial pro-
teotoxins and cytokines as well as hypoxic cell radiation
enhancers such as the inducible nitric oxide synthases.
408 Hyperthermia and brachytherapy
ACKNOWLEDGMENT
This work was supported in part by grant CA-44550
from the US National Cancer Institute.
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29. Armour, E.P., Wang, Z., Corry, P.M., Chen, P.Y. and
Martinez, A. (1993) Hyperthermic enhancement of high
dose-rate irradiation in 9L gliosarcoma cells. Int.J. Radial
Oncol. Biol. Phys., 28,171 -7.
30. Sapareto, S.A. and Corry, P.M. (1989) A proposed standard
format for hyperthermia treatment data. Int.J. Radial
Oncol. Biol. Phys., 16,613-27.

The costs of brachytherapy
GRAHAM READ
31.1 INTRODUCTION
Healthcare costs have shown a consistently rising trend
worldwide during the last three decades. Thus, in the
USA healthcare spending, expressed as a percentage of
the gross national product (GNP), rose from 6% in 1965
to over 14% in 1992 and to 14.9% in the year 2000 -
approximately $1.5 x 1012 [1]. There is naturally, there-
fore, an increasing interest in cost-effectiveness and cost
containment [2,3]. This will particularly focus on cancer
as, if present trends continue, cancer will soon surpass
cardiovascular disease as the leading cause of death in
the USA, with an estimated annual cost of $82 x 109,
approximately 20% of all healthcare costs [4].
In the UK, the National Health Service (NHS) reforms
of 1991 [5] were driven by a vision of a cost-efficient
healthcare system based upon an efficient contracting
and purchasing process [6]. This has subsequently been
replaced by a looser system of service and financial
frameworks (SaFFs) to be supported by clinical gover-
nance and performance indicators, with regulatory bod-
ies such as the National Institute for Clinical Excellence
(NICE) and the Commission for Health Improvement
(CHI) [7].
In Canada, the previously unchallenged healthcare
system has recently come under close evaluation and
financial scrutiny [8].
31
31.2 RADIOTHERAPY COSTS
Radiotherapy has been perceived, incorrectly as this
chapter will show, as an expensive treatment modality
[9,10]. Analyses of the costs of radiotherapy have gener-
ally been directed at treatments involving linear accelera-
tors [11,12]. Although this in itself presents considerable
difficulties, the costing of brachytherapy is even more
complex. Firstly, there is a greater variation in the modal-
ities used: some having a high capital component, such as
high dose-rate (HDR) brachytherapy, while others have a
high revenue cost, such as interstitial seed insertion.
Secondly, there has been a greater change in practice with
the abandonment of early techniques such as those
employing radium and cobalt and the adoption of newer
procedures, usually involving some form of remote after-
loading. These changes have occurred, in many cases, for
sound clinical reasons, for example the re-evaluation of
different forms of radiotherapy or a movement to other
forms of management such as surgery. Changes may also
be brought about, however, for reasons other than clini-
cal. For example, amendments and greater stringency in
protection regulations have led to a greater use of after-
loading methods as opposed to those involving the han-
dling of live sources. In some instances, certain types of
radioactive source have become unavailable. Lastly, as
with the costs of cytotoxic drugs, there have been large

changes in the costs of some sources: for example, the cost
of gold seeds rose approximately ten times between 1980
and 1990. However, the principal difficulty in assessing
the costs of brachytherapy remains the lack of published
information available.
313 PRI NCI PLES OF COSTING
313.1 Variables
Costs may be divided into those which are fixed, semi-
variable or variable. Fixed costs remain unchanged
regardless of the level of activity (Figure 31.1). These
include many aspects of the basic administration of a
hospital such as the provision of financial, catering, and
general maintenance services. Semi-variable (semi-fixed
or step) costs remain constant only for a certain level of
activity (Figure 31.2). These include most of the staffing
costs and also items of capital expenditure such as after-
loading equipment. Thus, one low dose-rate (LDR) or
HDR machine may be adequate for a certain number of
patients, above which a further unit would be required.
Variable costs vary in direct proportion to the level of
activity (Figure 31.3). These include drugs and dispos-
able sources such as iodine seeds.
Figure 31.3 Variable costs.
Principles of costing 411
313*2 Capital costs
Capital costs are the initial costs of any item of equip-
ment and those which arise subsequently, namely inter-
est and depreciation. Because costs and benefits in any
department accrue at different rates over different peri-
ods, investment appraisal is generally taken into account
by the use of investment procedures, or discounting. The
object of these procedures is to enable costs and benefits
to be evaluated as if they had occurred at the same point
in time. Thus, the initial capital costs can be converted
into a series of annual payments by using a given inter-
est or discount rate. These annual payments are referred
to as equivalent annual costs (EAC). The EAC can take
into account situations in which different components of
capital expenditure have differing lifetimes: thus, an item
of after-loading equipment may be amortised (paid off)
over a period of 15 years, whereas a building may have a
lifetime of 60 years. Since 1991, all providers in the UK
have been required to keep capital asset registers of items
valued in excess of 1000 and pay interest and deprecia-
tion charges at the recommended discount rate for pub-
lic sector projects of 6%, in accordance with UK
Treasury guidelines [13].
Frequently, an item of equipment has little alternative
use (when it could give rise to an opportunity cost) and is
then referred to as a sunk cost. Sunk costs should not be
included amongst annual capital costs.
3133 Revenue costs
Revenue or operating costs include all those costs which
recur annually. In the case of afterloading equipment,
these include maintenance on the equipment and
renewal of sources. These costs are fixed, because they
will be unchanged irrespective of the number of patients
treated. The costs of source replacement clearly relate to
the half-life of the source used and are, therefore, higher
for machines employing iridium in comparison to those
using cesium (Table 31.1). Other operating costs will be
Table 31.1 Fixed costs for LDR and HDR afterloading
equipment
Machine3 235224 299862 285077
Gynecological applicators 7191 14182 7191
First-year sources 40878 81756 20000
Total initial costs 283293 396000 312268
Sources and service" 42984 81887 223483
Total fixed costs 326277 477887 535751
"Prices relate to Nucletron equipment.
Discounted at 5% over 8 years.
Data in Canadian dollars (1992) from Jones et al. [36].
412 The costs of brachytherapy
variable, including operating room costs, admissions
costs, overheads, and consumables.
STAFF (LABOUR) COSTS
These generally account for a substantial proportion of all
costs - thus, in the UK, approximately 70% of all National
Health Service costs relate to starring and, in the USA,
Perez et al. calculated that they were 66% of their facility's
global costs [ 14]. In the UK, general management, senior
medical and nursing staff are regarded as fixed costs, and
junior medical, nursing, physics, portering, and techni-
cians are regarded as semi-fixed [15]. In contrast, in the
USA, direct labor costs are regarded as variable. Staff costs
are particularly important as brachytherapy procedures
are complex and labor intensive. Thus, Perez et al. calcu-
lated that an intracavitary insertion required an average of
195 min of medical time, and an interstitial implant 263
min, in contrast to times for external-beam treatment
planning of 23-45 min and simulation 29-45 min.
31.3.4 Marginal costs
Although estimates of average costs have frequently been
used in healthcare accounting, it may be more useful in
some circumstances to estimate the marginal costs; that is,
those costs associated with a small change in healthcare
activity [16]. The marginal costs incurred in treating, for
example, one additional patient on an HDR machine will
normally be very much smaller than those measured by
using average cost estimates. Conversely, the savings
made, for example, by reducing the number of fractions
will be much smaller than an average cost estimate.
Consequently, the amount of money saved by making
small changes in clinical practice is often overestimated.
Thus, many procedures will result in a reduction of the
length of stay for inpatients, but the savings made will only
be the marginal rather than the average costs. Substantial
savings are only made in the rare situations in which it is
possible to lay-off machines and staff and close wards.
31.3.5 Inpatient or outpatient costs
During the last decade, there has been a progressive
trend to outpatient care. It has been estimated that
Table 31.2 Costs of LDR and HDR
Staff costs 1833.73 33.1
Variable costs 383.98 6.9
Capital 3327.78 60.0
Total 5545.49 100
Costs per patient C$1997 from reference [38].
85-90% of all cancer care is now administered on an
outpatient basis [17]. This has occurred because of the
recognition of the high costs of inpatient care and, in the
USA, because of changes in healthcare legislation which
have affected patterns of reimbursement [18]. The rela-
tive costs of inpatient and outpatient treatments may
have a significant effect in cost minimization analyses,
for example when comparing HDR with LDR, as dis-
cussed below (Table 31.2). The relative benefits of out-
patient treatments are so far poorly documented. For
example, Yokes et al. found that, while outpatient
chemotherapy was 53% less expensive than inpatient
care, a significant proportion of patients refused outpa-
tient care because of fear of malfunction of the equip-
ment or inconvenience due to frequent clinic visits or
restrictions in daily home activities [19].
31.3.6 Other costs
Although the focus of costing falls naturally on those
services provided by the health service or healthcare
provider, many costs are borne by patients and their
families or carers. These include direct costs such as
travel or absence from work, which may be considerable.
Thus, in a study in the west of Scotland [20], the time
patients receiving radiotherapy spent away from home
each day varied from 35 min to 7 h, with a mean of 2 h
50 min; 16% had a relative who had to take time off
work. Indirect costs may also result from psychological
distress or the 'knock-on' consequences of loss of work
and production.
31.3.7 Costs of failure
Further considerations which are frequently ignored are
the costs evoked by either not treating the patient or by
failing to cure. It is often assumed that the costs of sup-
portive care are low in comparison with the costs of
active treatment. This has been shown not to be the case.
Perez demonstrated that the costs of curing a patient
with a stage A2 (Tib - UICC TNM stage classification)
carcinoma of the prostate with radiotherapy were
1277.38 28.1
103.42 2.3
3173.03 69.7
4553.83 100
 Charging for healthcare 413

$199320000' compared with $199347000 if the treatment Certain services, such as specialist cancer services, will
was unsuccessful [21]. It is interesting to note that the again be purchased by Regional Health Authorities
equivalent surgical costs were $199325 000 and $199349 307, (RHAs), restoring some functions which had been previ-
respectively. ously eroded - indeed they had been merged into eight
units in 1994 and complete abolition had been scheduled
for 1996. Despite these reforms, the basic purchaser/
31.4 CHARGING FOR HEALTHCARE provider division has been retained. However, without
adequate information on costs and outcomes, their abil-
ity to make informed decisions is limited.
A simple question which is often asked is, 'How much
The 1991 reforms and the creation of an internal mar-
does procedure x cost?' (Note this is not the same ques-
ket have forced a change from management accounting to
tion as 'What is the price of procedure *?') Unfortunately,
financial accounting. NHS Trusts have an obligation to:
there is rarely a simple answer. In countries such as the
(a) deliver 6% return on their capital assets; (b) balance
UK where there is state funding or insurance, the overall
their budget; and (c) live within their external spending
costs of a department will be known, but the costs of
limit. This has led to very stringent financial control.
individual procedures may be difficult to calculate.
Costs have had to be assigned to different procedures,
Where healthcare is charged directly to the patient or via
usually on the basis of inadequate data, in order to draw
an insurance company, some estimate of the costs of dif-
up contracts. Financial management was previously car-
ferent procedures will have been performed to enable a
ried out on a purely departmental basis, which meant
charge to be made. This may not necessarily represent
that the costs of any one procedure were usually
the true costs because there may be an element of profit
unknown. This sort of budgeting is known as an input
included or the charge may subsidize or be subsidized by
budget and has no regard for the level of activity, or out-
other costs. Payment patterns may have been arbitrarily
puts, in a department. In order to make an estimate of
set up over a period of years independent of cost factors.
the costs of a procedure, estimates have to made of the
Thus, Perez et al. found that brachytherapy accounted
direct operating costs, including staff and consumables,
for 10% of technical costs, but only 4% of revenue [14].
and the indirect operating costs, such as cleaning and por-
Costs for individual procedures may depend upon how
tering. The calculation of indirect costs will vary
quickly it is intended to recoup the initial capital expen-
depending upon the method of recharging used, and
diture (for an example, see Bastin et al. [22]).
capital costs will depend upon whether the procedure
uses a purpose-built protection suite or areas shared
31.4.1 UK funding with other users. Clearly, there will be considerable dif-
ferences amongst centers and countries.
In the UK, no charging existed for several decades after
the inception of the NHS and therefore costing was
31.4.2 USA funding
poorly developed and ill-understood. The 1990 National
Health Service and Community Care Act split District
In the USA, there was a progressive shift away from 'out
Health Authorities (DHAs) in the UK into purchaser
of pocket' payments to funding from Federal
units which purchase services for patients from their
Government or private insurance. The Social Security
own hospitals, from other authorities' hospitals, from
Act Amendments of 1983 shifted Medicare reimburse-
self-governing trust hospitals, or from the private sector,
ment away from retrospective payments to a prospective
and provider units, usually representing their district
payment system based upon diagnosis-related groups
general hospitals (DGHs), which provide patient ser-
(DRGs). In 1989, cost-effectiveness was proposed as a
vices. A further innovation was the creation of fund-
criterion of funding by the Health Care Financing
holding general practices which, with money top-sliced
Administration [23]. Increasingly, purchasing coopera-
from the DHAs, were able to buy services from those
tives have been formed with extensive databases on per-
provider units which in their view offered the best ser-
formance and cost. They have attempted to maintain or
vices. With a change of government in 1997, a further
lower costs by the use of clinical protocols, disease and
major revision has been initiated, with the creation of
case management, and outcomes research [24].
primary care groups (PCGs) of general practitioners serv-
ing approximately 100 000 people. Four possible levels of
function of PCGs are envisaged, with the highest being a 31.4.3 Healthcare resource groups
trust having total purchasing power for its population.
The DRG system is now being emulated in the UK with
1 the development of healthcare resource groups (HRGs)
For simplicity all monetary amounts have been left in their original
currencies with a suffix denoting either the year in which the calcula- [25]. These are intended to define patient groups which
tions were made where this is stated in the original articles or else the are both clinically relevant and consume similar levels of
year of the article. resources [26]. Provisional groupings developed for
414 The costs of brachytherapy
radiotherapy and chemotherapy were tested at three sites
in 1992 [27] and, after further piloting at eight addi-
tional sites, definitive recommendations have now been
published for use commencing April 2000 [28]. The pro-
posed groups for brachytherapy are shown in Table 31.3.
Table 31.3 UK healthcare resource groups in brachytherapy
(version 1)
Mechanical afterloading HDR
LDR
Manual afterloading
Live source
31,5 COSTS OF BRACHYTHERAPY
31.5.1 Cost areas
The principal areas are shown in Table 31.4. Capital costs
will include the costs of the afterloading equipment and
applicators. Increasing attention is being given to treat-
ment planning and optimization. As the systems used
frequently form part of a larger system for external
radiotherapy planning, the actual costs are frequently
hidden. Other important areas include operating theater
costs, hospitalization and staff costs.
Hospitalization costs are usually derived from esti-
mates of the average cost of an inpatient day. The cost
reduction from using brachytherapy, particularly HDR
therapy, will often result from the savings of such costs.
Whether these costs are actually realized will depend
upon the alternative uses to which the bed is put, and
cost savings should, therefore, be restricted to marginal
rather than average costs. These savings should include
the reduction in the number of specialized nurses neces-
sary to supervise inpatient treatments.
31.5.2 Costs of manual techniques
These include both the insertion/implantation of active
sources and the use of afterloading techniques. A
Table 31.4 Cost areas in different brachytherapy treatments
Capital ++
Isotope/source + +
Anesthetic/theater + +
Hospitalization + +
Mould room
Staff costs + +
significant feature of the cost is that of the isotope.
Unlike the older radionuclides radium and cobalt, which
could be kept in stock and used for a large number of
patients over a long period of time, newer isotopes have
relatively short half-lives and may require a new order
for each patient. The length of theater time will depend
upon the type of procedure and the experience of the
operator. An iridium implant might occupy an hour of
theatre time, whereas a prostatic iodine seed implant
may require two or three.
Telliffe [29] estimated the cost of a breast implantation
using iridium-192 wire to be 1990689. The major compo-
nent of this expenditure was the cost of the iridium wire
(1990280) and hospitalization for 2 days (1990240). One
hour of operating time was included, but this estimate
really represents only the marginal costs of the procedure
as detailed estimates of the true operating theater and
accommodation charges (which may include a purpose-
built protection suite) were not made. The duration of
stay would clearly have a significant effect on the overall
costs.
31.5.3 Costs of afterloading techniques
These differ significantly amongst LDR, medium dose-
rate (MDR), and HDR machines. This is due, firstly, to
the difference in the half-lives of the sources. Source
costs may be included as part of the initial capital cost if
the isotope is long lived. Short-lived isotopes may be
included with revenue costs. Example costs for
Nucletron HDR and LDR machines, building, and main-
tenance are shown in Tables 31.1 and 31.5. Secondly,
LDR and MDR techniques require hospitalization, with
its associated costs. Costs will also depend upon the
operating room costs and the type of anesthesia or seda-
tion employed.
Jelliffe [29] also estimated the costs of brachytherapy
using afterloading techniques in breast cancer patients
on the basis of 100 patients per annum. Again, no
allowance was made for building costs, and it is not clear
whether the annual maintenance charge included depre-
ciation of capital. He estimated the cost of an LDR
implant using cesium-137 to be 1990618, of which 1990273
was attributed to the costs of the Nucletron LDR
++
++ ++
+
++
+
+ +

Table 31.5 Fixed costs for afterloading equipment
Estimated cost
Capital investment-initial
HDR afterloading equipment 300000
Verification system options 100000
Treatment room 50000-100000
Miscellaneous 5000
Capital investment-annual
Maintenance 12000
Sources 16000
Supplies 75000
Verification system maintenance 10000
Total (7-year) 633500-798000
Data in American dollars (1993) from Bastin et al. [22].
machine based upon an initial cost of 1990180000,
including 30 cesium-137 source trains and an annual
maintenance cost 199010 340 after the first year. Two days'
hospitalization was costed at 1990240 and 1 h operating
theater time was allowed at 199080. Treatment with an
HDR unit was estimated to cost 1990435. The cost of the
HDR machine was taken as 1990280, based upon an ini-
tial cost of 1990140000, but with replacement iridium-
192 sources at 19906000 per annum. The difference in the
costs of the LDR and HDR techniques was mainly
accounted for by the lack of hospitalization with HDR.
These average costs are clearly heavily dependent upon
the number of patients treated per annum.
Benn [30] attempted to calculate and compare costs in
two hospitals with a differing workload. Again, building
and depreciation costs were not included. He estimated
the cost of a single LDR to lie between 1990510 and
1990672. He found the cost of an HDR fraction to lie
between 199049.5 and 1990117.
Bastin et al. [22] estimated that an HDR application
should be charged at $19931008, but this was dependent
upon the rate at which the initial capital costs were
recovered.
31.6 ECONOMIC EVALUATION
A number of methods of analysis seek to relate the costs
and consequences of healthcare programs. Some of these
expressions are used as 'umbrella' terms to cover any
form of cost analysis, e.g., cost-effectiveness or cost ben-
efit. However, the more precise meanings defined below
are generally accepted. Although cost analyses have been
increasingly reported in medicine, the number relating
to cancer is relatively few. Not unnaturally, because of
the high costs, procedures in medical oncology have
attracted the largest number [31] of studies, whereas
those in brachytherapy are extremely few in number at
the present time.
Economic evaluation 415
Some have argued that cost analyses are inappropriate
in medicine [32]. Indeed, in brachytherapy, one may be
faced with the situation in which, for example, the costs
of an implantation may be greater than those of an
equivalent external-beam treatment, but the benefits,
such as improved cosmesis, may be very difficult to
quantify in monetary terms.
31.6.1 Cost minimization
The method compares the total costs of two different
strategies which have the same outcome. Unfortunately,
in clinical practice it is rare to find two modalities which
differ significantly (and therefore have significantly dif-
fering costs) for which there is general agreement that
the outcomes are the same. In general, comparisons of
modalities in the literature have focused on survival and
side-effects and only in recent years has the specific issue
of cost comparison been addressed.
MANUAL VERSUS REMOTE AFTERLOADING
BRACHYTHERAPY
Jelliffe [29] estimated the cost of a manual breast
implantation using iridium-192 wire to be 1990689, com-
pared to 1990435 and 1990618 for the HDR and LDR
implants. Ostrowski [33] compared manual and remote
afterloadine techniaues.
LDR VERSUS HDR BRACHYTHERAPY
A number of studies have sought to compare LDR with
HDR brachytherapy. Leaving aside considerations as to
whether the clinical outcomes are truly similar, there
remains considerable controversy as to the optimal tech-
nique [34]. Because the numbers of applications of each
modality required to achieve the same endpoint may
vary considerably [35], this has an important conse-
quence upon the cost-minimization analysis. Thus,
Bastin et al. [22] compared LDR in gynecological cancer
consisting of two applications with 3 days' hospitaliza-
tion with an HDR of five outpatient applications. The
costs of LDR were 244% higher, primarily due to hospi-
tal and operating theater costs. The cost estimates of
Jelliffe and Benn show, however, that the comparison is
not simple. Taking only average patient costs into con-
sideration, the cost will depend upon the number of
patients treated. Furthermore, the number of fractions
used varies. Considering the marginal costs, these are
clearly smaller in the case of HDR than LDR.
In a detailed analysis, Jones et al. [36] compared the
costs of HDR and LDR machines using Nucletron
LDR-3, LDR-6, and HDR units. They found that the total
fixed cost of the HDR unit was C$1992209 474 greater than
the cost of the LDR-3 unit and C$,99257 864 more than
the LDR-6 unit (see Table 31.1). However, analysis of the
operating costs showed that, for various schedules of
416 The costs of brachytherapy
LDR and HDR, the operating costs per patient were less
for HDR than for LDR, except for the comparison of one
LDR insertion with four HDR insertions. Savings
increased in favor of HDR over LDR as the annual case
load increased (Figure 31.4). They also concluded that,
for small units treating up to 40 patients per year, the
LDR-3 unit was the most cost-effective machine. In gen-
eral, for a greater number of patients, HDR would be
recommended, but they produced algorithms allowing
more precise assessments to be made depending upon
the annual number of patients, the ratio of LDR to HDR
insertions, and other practical considerations. Their cal-
culations assumed that the machines were used only for
gynecological insertions. Cost sharing, for example for
the treatment of cancer of the esophagus, lung, or breast,
would affect the calculations significantly.
Chenery et al. estimated that HDR would lead to a cost
avoidance of C$19841700000, based upon an annual
patient load of 85 cervical and 60 endometrial cancer
patients over a period of 20 years [37]. More recently,
Pinilla [38] calculated that an HDR regimen (two frac-
tions) was 22% less expensive compared to an LDR (one
fraction) regimen amounting to C$991.66 per patient
(see Table 31.2). However, if LDR maintenance was done
in house, then the LDR cost fell to 98% of the HDR cost.
Konski et al. [39] carried out a meta-analysis of six
options in stage I endometrial cancer based upon costs
paid, and concluded that LDR was the most cost-
effective treatment, with no evidence of any difference in
disease-free survival.
Thus, a simple choice between LDR and HDR cannot
be made as it depends upon the number of fractions
used, the number of patients treated, and the mainte-
nance costs. However, there appears to be a general
agreement that, except for in the smallest centers, HDR
is likely to prove more cost-effective than LDR.
BRACHYTHERAPY AND EXTERNAL-BEAM
THERAPY
In many instances in oncology, it will be clear from the
extent or site of the tumor that external-beam radiother-
apy is the treatment of choice. In some instances, a
brachytherapy insertion may be added at the conclusion
of the external-beam treatment to supplement the radi-
ation dose to an area of special risk. Here, the issue will
be whether or not this treatment, and the implied addi-
tional cost, confers a benefit in terms of improved local
control or survival.
BRACHYTHERAPY AND ELECTRON THERAPY
Jelliffe compared the cost of a five-fraction electron
boost to that of an interstitial implant [29]. His estimate
of the cost of electron therapy was 1990200, which com-
pared favorably with costs of 1990435-1990689 for the
implants, but he noted that the poor cosmetic results
from electrons might justify the higher costs of the
implant.
BRACHYTHERAPY AND SURGERY
Comparisons between the use of brachytherapy and
surgery are often highly controversial and fraught with
difficulty. Patients treated surgically are frequently
younger and fitter. The surgical modality may, by its very
nature, provide more accurate staging information, ren-
dering stage-by-stage comparison difficult. For example,
Farndon et al. [40] reported that surgical resection in
esophageal cancer was more cost-effective than other
methods of treatment, including brachytherapy.
However, as the survival amongst surgical patients was
significantly greater, it is unlikely that the patients' stag-
ing was comparable. Although it is possible to compare
Figure 31.4 Annual cost differences
in Canadian dollars (1992) for LDR
compared with HDR for different
numbers of patients (from Jones et
al. [36]). Positive values indicate cost
balance in favor of LDR, negative in
favor of HDR.

the costs of the initial procedures, these frequently do
not take into account the costs associated with failure of
treatment or of any complications which may arise.
External-beam radiotherapy as an outpatient treat-
ment has been shown to be less expensive than compara-
ble surgical procedures for a number of common cancers
because of the avoidance of hospital, anesthetic, and
operating theater costs [41]. Hanks and Dunlap deter-
mined the costs of treating prostate cancer by radical
prostatectomy, lymph node dissection with iodine-125
implant, and external-beam radiotherapy [42]. The
median cost of radical prostatectomy was $198614000, of
lymph node dissection and iodine-125 implantation
$198612000, and of external-beam radiotherapy $6750
before 1984 and $5600 after 1984. These costs were
derived from the hospital fees, professional fees, and
other major expense items as charged and are therefore
highly influenced by the method of charging as well as by
the true costs of the procedures. Thus, the apparent
change in the cost of radiotherapy was entirely due to
changes in billing. It is interesting to note that bills for
apparently the same procedure varied by up to 82%, indi-
cating the inherent flaws in this method of determining
costs. By reviewing the current literature, they concluded
that none of the methods showed a superior outcome.
31.6.2 Cost-effectiveness
This form of analysis relates the cost of a treatment to its
outcome. Two or more treatments can be compared pro-
vided there is a common unit of outcome or effectiveness
such as 'life-years gained,' 'pain-free days,' or 'positive
cases detected.' Thus, in a cost-effectiveness analysis, a
ratio of benefit to cost is derived for each option. The
most cost-effective option, therefore, can be defined
either as that which maximizes benefits for a fixed cost or
as that which minimizes costs for a fixed benefit [43]. It
should be noted that this is not necessarily the largest net
benefit which represents the optimum choice.
In assessing the benefits of a particular treatment, the
question arises as to how to deal with costs which occur
at different points in time. This is clearly of importance
when considering the immediate benefits of a particular
treatment versus its long-term risks. Traditionally, bene-
fits have been discounted in a manner similar to that
described above for dealing with costs, which has the
effect of weighting the short-term benefits. Adopting a
zero discount rate, whilst it may be appropriate for areas
such as neonatal care, would lead in cancer to an undue
preoccupation with late effects in preference to immedi-
ate gains and may not, therefore, be appropriate.
A number of studies have shown that, in general,
radiotherapy is remarkably cost-effective. Thus,
Glazebrook was able to show that for external-beam
radiotherapy the cost of a year of life gained was
C$1992661 (C$19921.82 per day- which he compared to the
Economic evaluation 417
cost of a city bus ride!). This was one or more orders of
magnitude different from the costs of a year gained by,
for example, coronary bypass (C$19926698), renal dialysis
(C$199267345), or school testing for tuberculosis
(C$199269634) [44].
31*63 Cost utility
Although cost-effectiveness analyses may be very useful,
they are unable to compare different diseases or strate-
gies where the outcomes cannot be measured in a com-
mon unit. This may arise where, for example, a
healthcare purchaser wishes to decide between, say, allo-
cating money to cataract surgery or cancer chemother-
apy. Cost utility relates the cost of different medical
procedures to the increased utility (the amount of well-
being) they produce in terms of improved quantity and
quality of life. In order to measure utility, various
quality-of-life scales have been developed. From the
clinical point of view, quality-of-life studies are difficult
and time consuming, in contrast to more objective
measures such as response or survival. Even with
apparently 'objective' scales, assessments made by
doctors, patients, and their relatives may differ [45].
31*6*4 Cost benefit
This form of analysis, in many ways the most difficult,
seeks to determine whether the benefits of using a given
therapy outweigh its costs. A monetary value has, there-
fore, to be assigned to each strategy or treatment, which
may amount to deciding how much it costs to save a life
or to enable a person to live a pain-free one. Some people
have an ethical objection to putting a monetary value on
a human life, but such decisions are regularly made in
economic planning, even if they are not implicitly stated.
In fact, cost-benefit analysis has been regularly used in
the analysis of economic and social policy in the public
sector for many years. Roberts et al. estimated in 1985
that the NHS could not afford more than 198414000 to
save a life [46], and Rees felt that treatment costing less
than 19911000 for an improvement in benefit was excel-
lent value, whereas those costing 199110000 probably
represented an unfair distribution of resources [47].
Various approaches have been adopted in benefit eval-
uation. Initial approaches were based upon 'human cap-
ital', such as the loss of income incurred by illness.
Clearly, this does not take into account benefits for the
retired or unemployed. Another approach is to evaluate
whether we are willing to pay the stated cost for a partic-
ular procedure or service. This is often expressed as a
proportion of average income, as an alternative to a
straight monetary cost. Thus, in one study, Thompson
found that patients with rheumatoid arthritis would be
willing to pay 22% of their annual income for a hypo-
thetical cure of the disease.
418 The costs of brachytherapy
These considerations are important in brachytherapy.
Thus, supposing that brachytherapy for the treatment of
breast cancer is as effective as external-beam therapy but
is more expensive (as suggested by Jelliffe above), what
level of cost is one prepared to pay for improved cosme-
sis? Such considerations are important and are worthy of
further study.
The National Radiological Protection Board (NRPB)
has attempted to calculate the cost of the health detri-
ment caused by irradiation of the general public by tak-
ing into account the frequency of deleterious effects and
their respective costs [48]. These costs were estimated
from the loss of economic output, the costs of medical
treatment for fatal and non-fatal cancers, and the costs
for hereditary defects.
31*6*5 Radiation protection
The raison d'etre for the development of afterloading in
brachytherapy was the reduction in radiation exposure
to the various members of staff- radiotherapists, nurses,
and technicians - who were involved in the treatment of
patients with active sources, principally radium. As an
example, the treatment of patients with cancer of the
cervix using the Manchester System [49] involved the
insertion of an average of 75 mg radium, which
remained in position for approximately 3 days. Prior to
the introduction of afterloading systems, approximately
400 patients were treated per annum, totalling approxi-
mately 700 insertions carried out, at the Christie
Hospital, Manchester. Although, by adherence to all
appropriate working procedures, radiation exposure of
staff was maintained below the then annual dose limit of
Table 31.6 Annual costs of two afterloading schemes
Annual capital costs of (i) equipment
(ii) building
Annual service costs of (i) equipment
(ii) building
Net change in operating costs
Bed occupancy savings
Total net annual cost
Data in 1982 taken from Fleishman et al. [50].
Table 31.7 Recommended costs of unit collective dose for members of the public
<5x1Q- 5 <1
5xI0-5-5xI0-4 1-10
5x10-4 5x10-3 10-100
a
For explanation, see reference 51.
Data from National Radiological Protection Board [51].
50 mSv, a significant number of people received doses
within the range 30-90% of this limit. From an eco-
nomic perspective, the question arises as to whether the
reduction in radiation dosage to staff and visitors justi-
fies the increased costs of afterloading.
Fleishman et al. [50] calculated the costs of two
schemes for the introduction of LDR afterloading sys-
tems: scheme 1 involved the construction of a three
twin-bedded, purpose-built, single-storey building, and
scheme 2 the construction of two fully protected treat-
ment rooms adjacent to a ward area. The annual cost of
the first scheme was 198253000 and of the second
198230000 (Table 31.6). In order to assess the cost bene-
fit of these schemes, reference was made to work by the
NRPB, which had attempted to calculate monetary valu-
ations of radiation-induced heath detriment [51], as
shown in Table 31.7. These estimates are, of course,
highly contentious, involving judgments by the NRPB of
the value of public and occupational exposures and
other assumptions in estimating the doses received.
Using these criteria, Fleishman et al. calculated that the
total detriment cost to staff was 198258 000 and to visitors
198234 000, a total of 198292 000, and hence that the costs
of introducing afterloading could be justified.
31.7 AREAS FOR FUTURE STUDY
31.7.1 Lung cancer
An important development has been the use of intralu-
minal radiotherapy for the treatment of carcinoma of
the bronchus [52]. In order to be able to assess the cost
26000 26000
22000 13000
15000 15000
8000 2000
2000 -6000
-20000 -20000
53000 30000
2000
10000
50000

effectiveness of this treatment, the optimal scheduling,
especially in relation to external-beam radiotherapy, has
to be determined. Thus, one schedule for radical lung
treatments employed external-beam radiation to a dose
of 60 Gy in 6 weeks with brachytherapy on weeks 1, 3,
and 5, giving 7.5 Gy at 10 mm from the source on each
occasion [53]. It is difficult to extricate the value of
brachytherapy in such a complex schedule. In palliative
radiotherapy, the situation is clearer. The same author
showed that adequate relief of symptoms could be
achieved with brachytherapy alone using three applica-
tions of 10 Gy at 10 mm from the source on weeks 1, 2,
and 3. Furthermore, Collins et al. showed that a single
fraction of intraluminal radiotherapy as a primary treat-
ment was as efficient in palliating symptoms as more
prolonged courses of external-beam radiotherapy [54].
Clearly, with the recent demonstration of the effective-
ness of single fractions of external-beam radiotherapy
[55], further evaluation of the role of intraluminal
radiotherapy in lung cancer is required. Whether such
studies are evaluated as cost minimization or cost-
effectiveness will depend upon whether the evaluation is
in terms of equivalence or some other measure such as
'days free of hemoptysis.'
31.7,2 Cervical cancer
Several areas are waiting for evaluation. In non-bulky
stage I disease, both primary surgery and radiotherapy
provide equal success rates. Could one perform a cost-
minimization analysis in such a situation, and should
this then be the factor which determines the choice of
treatment? Such an analysis should go beyond the costs
of the primary procedure. It should also include the costs
of complications, whether surgical or due to late radia-
tion effect. Ovarian preservation might, for example,
obviate the need for hormone therapy. How should
patient preference be taken into account and the differ-
ences in the quality of life - if they be significant - be
evaluated? These important areas of debate require
much further work.
In higher stage disease, the importance of intracavi-
tary radiation in the treatment plan has been established.
In a review, Petereit et al. noted pelvic control rates of
52-74% with intracavitary irradiation, as compared with
33-45% without [34]. Economic considerations, there-
fore, relate to the comparison of LDR and HDR, as dis-
cussed above.
31.73 Esophageal cancer
In curative situations, the cost-effectiveness of external-
beam radiotherapy has already been demonstrated [56].
Intraluminal radiotherapy offers a promising simple
approach to address the frequent problem of palliation
in advanced tumors [57]. In evaluating palliation in
Areas for future study 419
esophageal cancer, the costs of the procedure have to be
compared with those of alternative surgical procedures,
such as insertion of a stent or laser excision, or external-
beam radiotherapy. Its effectiveness can be set against
the costs of nursing, which, in the case of a patient with
severe dysphagia, possibly requiring tube or intravenous
feeding, are likely to be very considerable. Low and
Paliero reported a small, randomized trial comparing
brachytherapy with laser photocoagulation [58]. Although
both treatments were effective, laser excision required
more expertise and was associated with higher numbers
of retreatments and complications. Further studies are
clearly needed, but evidence so far suggests that the use
of intraluminal radiotherapy in this situation is likely to
prove highly cost-effective.
31.7.4 Breast cancer
Brachytherapy in breast cancer is frequently used to
boost the site of the primary tumor. From an economic
point of view, it needs to be established, first, that the
boost dose increases local control and, second, that the
use of brachytherapy is superior to other forms of radio-
therapy such as electrons. As noted above, a short course
of electron therapy is probably less expensive than an
implant and, therefore, the difficulty of assessing the
monetary value of any improved cosmesis arises. Of
greater interest is the possibility of treating selected cases
with brachytherapy only when the possibility that
brachytherapy would prove more cost-effective than
external therapy arises.
31.7.5 Head and neck cancer
As with breast cancer, the difficulty of assessing the value
of an implant as part of an external-beam treatment
arises. However, the use of brachytherapy alone, for
example in the treatment of tongue cancer, is likely to
prove cost-effective. As with esophageal cancer, palliative
implants to improve swallowing or reduce pain are also
likely to be cost-effective.
31.7.6 Prostate cancer
There has been a major resurgence of interest in recent
years in radioactive seed implantation in prostate cancer.
This has been fueled by the increase in diagnosis of early
prostate cancer, especially in the USA, where it is the
most commonly diagnosed cancer in men. Various
methods have been used to implant patients with early
prostate cancer - principally iodine-125 seeds but also
gold-192 seeds and, more recently, iridium-192. The dif-
ficulty of obtaining a satisfactory arrangement of the
seeds has been improved by planning techniques using
transrectal ultrasound. Although it has not been shown
420 The costs of brachytherapy
in a randomized control trial that local control is equiv-
alent to or better than external-beam radiotherapy, the
procedure offers many advantages, particularly in terms
of convenience as it is may be carried out as a single out-
patient procedure, in comparison to up to 8 weeks of
daily external-beam radiotherapy. Important side-effects
such as impotence may be reduced and the patient may
rapidly return to work. Hanks and Dunlap [42] found
that iodine-125 seed insertion was more expensive than
external-beam radiotherapy, but their costs included
lymphadenectomy and were based on hospital billing.
Again, further detailed cost-based studies are required.
31*7.7 Benign conditions
A recent innovation has been the use of brachytherapy to
prevent restenosis after coronary artery angioplasty
[59,60]. Economic evaluation in this area presents par-
ticular difficulties [61].
31.8 CONCLUSION
With rising costs of healthcare, the economic analysis of
treatment modalities will be of paramount importance
in the future. Unfortunately, cost analyses of brachyther-
apy have so far attracted little interest in published
papers and are scarcely mentioned in textbooks on the
subject. As noted in this chapter, although the cost-
effectiveness of brachytherapy can often be inferred, this
is not a substitute for detailed, carefully costed, formal
analyses. It is likely that, in comparison with radical sur-
gical procedures, brachytherapy will acquit itself well in
studies of cost-effectiveness. This may also prove to be
true in comparison with radical external-beam treat-
ments. However, brachytherapy is expensive when com-
pared to a short course of external-beam radiotherapy.
In particular, the value of boost treatments, which might
replace a few additional external-beam or electron treat-
ments, should be carefully considered. A plea is therefore
made that authors include more analyses of cost-
effectiveness in future studies.
GLOSSARY
Discounting A method of evaluating costs as if they
had occurred at one point in time.
Equivalent annual cost An annual payment calculated
by a discounting method.
Financial accounting The system necessary within an
organization for transactions to take place.
Fixed costs Costs which do not vary with changes in
activity levels over a given time span.
Life year (LY) Amount of time gained by a particular
intervention. Note this applies to a cohort not an indi-
vidual patient, so that 1 LY can equal 52 weeks for one
patient or 4 weeks for 13 patients.
Management accounting Information necessary for
decision making, and the production of financial or
business plans.
Marginal costs Costs incurred by a small increase in
treatment activity such as one additional patient.
Semi-variable costs Costs which are fixed for a given
level of activity but may change if the activity rises or
falls beyond a certain threshold.
Variable costs Costs which vary in proportion to activ-
ity levels.
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Quality management: clinical aspects
CAJOSLIN
32.1 INTRODUCTION
Brachytherapy has been an established and clinically
proven method of achieving satisfactory tumor control
since the early part of the twentieth century. The pub-
lished work provides an enormous background of his-
torical data, although it is often difficult to be sure of the
precise details of the treatment given. In particular, it is
often difficult to determine the extent and histopathol-
ogy of the tumors being treated or the effectiveness of
treatment, especially in relation to normal tissue effects,
except in the most basic of details.
Professional and public demands make it important
to be able to verify that a particular mode of treatment
not only offers the greatest chance of success coupled
with the least interference in quality of life, but is also
cost-effective when compared against other treatments.
In order to meet these requirements, it is necessary to be
able to show, by means of audit, the end-results of a par-
ticular treatment. This will involve having accurate data,
which meet with universal acceptance. The collection of
such accurate data will entail having a quality assurance
program in place.
Quality assurance in radiotherapy should cover not
only the physics and technical aspects, but also the clini-
cal management aspects. This is particularly important
because radiotherapy involves a large number of
processes, all of which should be covered by an appro-
priate quality assurance procedure. It also involves a
number of different professional groups and it is
extremely important to have professional cohesion and
communication so that no shortfall exists between the
various areas of activity.
32
The International Atomic Energy Agency (IAEA) and
the International Commission on Radiological Units
and Measurements (ICRU) promoted the unification of
standards and specification of the physical, mechanical,
and clinical dosimetry in 1984 [1], In general,
brachytherapy was included with teletherapy, but more
recently it has become recognized that brachytherapy
has additional and special requirements. In particular,
radiation hazards, the use of afterloading machines, and
brachytherapy techniques differ from those of telether-
apy. However, in common with all forms of radiother-
apy, quality assurance is about reducing uncertainties of
a particular aspect of treatment to an agreed level with a
degree of confidence. This will apply whether it is a
quantity of radiation activity, rate of delivery of treat-
ment, objectively identifying the limits of a tumor, or
assessing the response to treatment.
In common with this approach, all definitions and
end-points should have international agreement. Also,
details of the assessment of response to treatment and
normal-tissue morbidity will be obtained with a greater
degree of confidence in those situations in which
patient treatment has been subject to quality assurance
criteria.
However, quality assurance is but one component part
towards establishing quality management in a treatment
program. In fact, three basic component parts can be
identified, which form the supporting structure to
achieving best practice in brachytherapy (Figure 32.1).
These are:
1. quality control,
2. quality assurance, and
3. audit.
424 Quality management: clinical aspects
Figure 32.1 Quality management as applied to a treatment
facility involves a series of interlinked processes. Q.C. = quality
control; Q.A.= quality assurance.
32.1.1 Quality control
Quality control involves those processes which regulate
the delivery of a service.
PHYSICS ASPECTS
In brachytherapy, these will involve such processes as
source specification and decay corrections, source cali-
bration, and dosimetry. Each of these processes will be
affected by various factors, e.g., source calibration proce-
dures will be dependent upon the type of source, the dis-
tance at which calibration is done, the specification
quantity (activity or air kerma rate), and other correction
factors such as half-life, attenuation, and scatter. National
and international agreements on measuring radiation
dose against a standard reference calibration have been
used in teletherapy for many years. In common with this,
brachytherapy calibration procedures should be traceable
to a national standard. These aspects are reviewed in detail
by Wilkinson and Jones, respectively, in Chapters 2 and 3.
CLINICAL ASPECTS
These involve such processes as tumor staging,
histopathological classification, tumor site, the patient's
medical condition and age. They will also involve those
processes used to assess tumor response to irradiation
and early and late normal-tissue effects.
32.1.2 Quality assurance
Quality assurance involves those processes which con-
firm the process of delivery in order to provide a high
degree of confidence that the patient received the
intended treatment. It is, in effect, the process of con-
firming that what we do is what we think we do. From
the radiotherapy context the World Health Organization
[2] has defined quality as:
'all those procedures that ensure consistency of the
medical prescription and the safe fulfilment of that pre-
scription as regards dose to the target volume, together
with minimal dose to normal tissue, minimal expense
of personnel and adequate patient monitoring aimed
at determining the end result of treatment'.
The importance of quality assurance measures has
been reported by a number of authors and in particular
the errors which may occur as a result of poor measures
of quality assurance [2]. A questioning attitude toward
the effectiveness of the procedures used and accuracy of
the equipment as it applies to a particular treatment has
been shown to be beneficial in quality assurance [3-6].
While much of this work has been done for teletherapy,
these principles also apply to brachytherapy [7-9,18].
PHYSICS ASPECTS
These should entail independent checks on all those
aspects that involve measurement(s) or calculation(s) of
matters such as source calibration, dosimetry, treatment
planning, dose calculation, and checks following servic-
ing and repair of machines. These aspects are covered in
the physics section of this book.
CLINICAL ASPECTS
These entail ensuring that the various clinical and patho-
logical investigations and other assessment parameters
have been satisfactorily carried out and recorded and
that the intended treatment plan was satisfactorily com-
pleted. They also involve ensuring that the measurement
of tumor and normal-tissue responses has been system-
atically recorded according to an established system.
32.1.3 Audit
Audit is the process of assessment of outcome resulting
from a particular treatment. It provides a means of iden-
tifying best practice when comparing one treatment
process with another and of the cost-effectiveness of
treatment [15,19]. It will require having accurate infor-
mation regarding tumor response to treatment, cancer-
free interval, and details of any recurrent disease. It is
important also to have details of all acute and late
normal-tissue responses to treatment [29]. These should
be graded according to an established system [10].
Unfortunately, there is no universal system which will
adequately apply to all sites, and various attempts have
been made to overcome this [33]. An alternative is to
provide assessment on a site-by-site basis [34].

One illustration of how to determine the impact of
research findings and evolving technology on radiother-
apy practice for cancer of the uterine cervix was initiated
by the Patterns of Care, Study Group of the American
College of Radiology in 1973. That work has continued
and various site reports of long-term management are
now being published [32].
QUALITY MANAGEMENT
Thus, quality management includes a series of interlink-
ing processes involving assurance and effectiveness of
treatment (Figure 32.1). It should be seen as a way of
providing a high quality of service for all patients having
routine treatment which will match that more generally
recognized to apply to patients being treated in a con-
trolled clinical trial. Also, the proper assessment of any
new technique can only be achieved in a quality man-
agement environment, otherwise there is the risk of it
becoming established but remaining unproven.
Brachytherapy, with its rapidly expanding technological
developments, particularly when applied to new and
innovative treatment, is but one example of a situation
in which quality management is essential.
Brachytherapy clinical trials have an important role in
establishing the best treatment for a particular situation
[7]. However, in some situations this will require
national or international cooperation. The specific aims
of such trials were considered in 1988 [7] and the vari-
ous aspects addressed under the following headings:
1. Provide for international exchange of scientific data.
2. Enhance cooperation of investigational
brachytherapy.
3. Identify the role of brachytherapy and appropriate
clinical trials.
4. Study the role of brachytherapy used alone or in
combination with other modalities.
5. Standardize the nomenclature used.
6. Standardize brachytherapy techniques, quality
control procedures, and reporting methods.
7. Develop and define specific end-point(s) to be used
to quantify tumor response and normal-tissue
effects.
8. Determine appropriate toxicity scoring methods.
9. Evaluate the clinical significance of the treatment
data (volume, dose rate, total time, total dose, and
implant techniques).
Thus, even within the ambit of a controlled clinical
trial, quality management procedures should be stan-
dardized in a manner that can also be applied as part of
everyday practice.
Quality assurance as applied to brachytherapy physics
has already been discussed in Chapters 8 and 9. Some of
the clinical aspects of quality management as it applies to
brachytherapy, either alone or in combination with
external-beam irradiation, are now discussed.
Clinical aspects of quality management 425
The major purpose of applying quality management
in the clinical context should be to reduce subjective and
increase objective assessment wherever possible. In com-
mon with this approach, the definitions and end-points
used should follow international recommendations such
as those of the ICRU-38 and ICRU-58, which deal with
specifications and measurements in treatment planning
and its delivery [8,9]. The clinical assessment of the dis-
ease being treated should be classified and staged as rec-
ommended internationally, using systems such as the
TNM or FIGO [11,12]. The assessment of response to
treatment and morbidity of normal tissues should also
follow accepted practice [10].
32.2 CLINICAL ASPECTS OF QUALITY
MANAGEMENT
32.2.1 General considerations
Whereas the treatment methods and techniques used for
teletherapy are generally more defined than those for
brachytherapy, the latter still tends to follow established
procedures, although these may be modified by the indi-
vidual beliefs and habits of the clinician, more so than
for teletherapy. The advent of optimization of treatment
planning has also brought with it treatment which can
be individualized to the patient's needs. The treatment
intent decided for a particular patient will involve a core
plan of management.
A core plan of management will normally be deter-
mined by those who are clinically responsible, but may
well involve an input from the physicist, radiographer,
and nurse specialist. The treatment objective relative to
radical (i.e., curative) intent or palliative intent needs to
be established once the full investigative procedures have
been completed.
Following this, it is necessary to provide a clear
description of the intended treatment, which would nor-
mally be followed by prescription. This includes identi-
fying the planned target volume in anatomical terms, the
treatment method in radiotherapy terms, together with
the irradiation parameters such as the intended tumor
dose either to point(s) or to a given isodose contour. The
method used should be such that a meaningful relation-
ship exists between the dose prescribed and the target
volume. The target volume, as for teletherapy, will con-
tain the tumor and should include some allowance for
the possible invasion of local surrounding tissues. Also,
the limiting dose to critical organs or tissues within or
close to the treated volume needs stipulating, and that
such doses have not been exceeded needs to be con-
firmed by either measurement or calculation. For further
information, the reader is referred to Chapter 6.
All dosimetric calculations and measurements should
be available as part of the clinical record in a summary of
426 Quality management: clinical aspects

the treatment given. Whatever particular method is used, logical and surgical staging has been carried out in addi-
it should be easy to define, easy to understand, easy to tion to clinical assessment, this should be recorded.
use, and universally acceptable. Histological assessment of the tumor type and grade is
preferably made according to the International
Classification of Diseases (ICD) system. In addition to
32.2.2 The patient
clinical assessment, surgical staging is now advocated by
many for early disease. The treatment and morbidity
A quality assurance programme starts with the identifi-
implications of this are that, when radiotherapy follows
cation of those key functions which affect the manage-
surgical staging, the risks of developing morbidity have
ment process of a patient's treatment, but it is also
been reported to be increased. It is important in this type
important to consider what the patient might expect of
of situation to determine the possible advantages of sur-
his or her management and treatment [13].
gical staging against non-surgical staging.
In particular, patients face a number of uncertainties
Special investigations appropriate to the cancer site,
relative to their treatment and outcome. Any reduction
such as cystoscopy or lung function tests, which provide
of these uncertainties could, from the patient's point of
a means of assessment of organ function should be done
view, be considered as providing a high quality of care
systematically and at set intervals during and following
and reassurance.
treatment.
From the time of diagnosis, patients require fast access
In addition to clinical assessment, radiological investi-
to the most appropriate clinician specializing in their
gations, including imaging such as computerized tomog-
type of cancer. They normally expect to be fully
raphy (CT) and magnetic resonance imaging (MRI)
informed of their condition, the treatment available, the
scans, should be carried out where indicated. Routine
side-effects, and risks of possible complications. Having
blood tests, including biochemical measurements,
agreed to a particular treatment, they should receive it
should also be done. To complete the pretreatment pro-
without delay [14]. They also expect to make a full and
file, a clinical history of any previous surgical operations
rapid recovery, with a high expectation of being cured.
or medical conditions which may affect the response
The treatment results should match those produced by
and/or outcome to irradiation should be recorded. In
leading cancer centers.
turn, this may result in a decision to modify a standard
dose prescription. Patients who come into one of these
32.23 Pretreatment assessment categories can then easily be identified for audit pur-
poses.
Pretreatment investigations should provide a clear
description of the clinical extent of the cancer and the
32.2.4 Treatment intent
anatomical structures affected. Table 32.1, lists the vari-
ous steps to carry out a pretreatment assessment. Staging
This is, in effect, a tentative management plan and
should follow either the TNM or FIGO system. In the
should provide the basis of the intended treatment. It
opinion of the author, the latter has proven the most
will include the type of brachytherapy and whether this
practical for gynecological staging, whereas for all other
is to be combined with external-beam irradiation. The
sites the TNM system should normally be applied [13].
intended dose regime, including dose rate, dose per frac-
The methodology used is important and, where radio-
tion, total number of fractions, total dose, and overall
treatment time, should follow established guidelines
when possible whether the intention is to use either
Table 32.1 Pretreatment assessment brachytherapy alone or combined with external-beam
(1) Site-specific description irradiation.
(2) Stage of disease The prescribed dose will need to be stated as applying
TNM to a specific point or points or isodose volume. This may
FIGO involve some preliminary planning in terms of opti-
(3) Histology mization of treatment. In many instances, the intention
Tumor type will be to follow a specific protocol or guidelines, and
Tumor grade
this should be stated.
(4) Mensuration
Clinical
Radiological 32.2.5 The treatment plan
(5) Patient profile
Hematological For most brachytherapy treatment, a physical outline of
Biochemical
the anatomical site is not clinically possible and is
Medical history
increasingly becoming dependent on some form of
Surgical history
imaging. However, when combined with external-beam

irradiation, a physical outline may be part of the plan-
ning procedure for the external-beam component, as for
example, when treating breast, pelvic, or head and neck
cancers. The steps involved are outlined in Table 32.2
[18,20].
Table 32,2 The treatment plan
(1) Physical outline of normal anatomy (if indicated)
(2) Physical limits of tumor (tumor volumefs])
(3) Identify critical organs
When combined brachytherapy and external-beam
irradiation are to be used, it will usually mean that there
are essentially two target volumes, one containing the
primary tumor and allowance for possible local exten-
sion, the other containing either known or suspected
secondary cancer in regional lymph nodes. The former
volume will often receive the major portion of treatment
from the intracavitary or interstitial component and the
latter from external-beam irradiation [8,9]. The reader is
referred to Chapter 6, which discusses the recommenda-
tions of ICRU reports 38 and 58.
Three-dimensional planning, conformal treatment
and its delivery require a comprehensive set of guidelines
which are directly applicable to clinical treatment plan-
ning on a site-specific basis [21,24]. One such set of
guidelines is that produced by Task Group 53 of the
Radiation Therapy Committee and the American
Association of Physics in Medicine. This report provides
a framework for radiation physicists and clinicians to
help design and perfect a comprehensive and practical
treatment planning quality assurance system [21].
In some situations, such as breast implants, there is a
high potential for a geographic miss, and a radiographic
delineation of the tumor bed by intraoperatively placed
clips has been used to enable delivery of a high dose to
zones at risk of containing a high residual tumor load
[20].
32.2*6 Tumor volume
That the physical limits of the tumor should be known is
important, and clinical and, where indicated, imaging
assessment(s) should be carried out. The different imag-
ing methods carry different advantages, and scanning for
treatment planning purposes will differ in terms of qual-
ity assurance and control compared to diagnostic appli-
cations [18]. When determining the physical limits of a
primary tumor volume, it is also important to identify,
in relation to that volume, the position of any critical
organ(s) or tissue(s) which will, by necessity, be within
or close to the target or treated volume [21].
Where secondary spread of cancer is known or sus-
pected, as for example to regional lymph nodes, the
physical limits of this 'secondary' tumour volume should
be identified [18].
Clinical aspects of quality management 427
32*2.7 Target volume
The planning target volume contains those tissues that
are to be irradiated to a specified absorbed dose accord-
ing to a specified time-dose pattern. For curative treat-
ment, the target volume consists of the demonstrated
tumor(s), if present, and any other tissue with presumed
tumor. The ICRU reports (38 and 58) advise that the tar-
get volume(s) must always be described independently
of dose distribution in terms of the patient's anatomy,
topography, and tumor volume [32].
32.2.8 The prescription and treatment
procedure
The prescription and treatment procedure will be
dependent upon the site being treated and the technique
used. In general, the prescription and treatment plan
should provide the information outlined in Table 32.3.
Treatment planning in many situations remains two
dimensional, with reconstruction in one or more planes
of the third plane. Three-dimensional reconstruction is
now in increasing use and the advantages in identifying
areas of potential underdose and overdose have been
shown when planning treatment for nasopharyngeal
cancer [24]. This has resulted in the further need to pro-
vide appropriate quality assurance guidelines [21].
Table 32.3 Provision of a prescription and treatment plan
(1) Outline of intended treatment
(2) Planned dose to point(s), or isodose level
(3) Details of actual delivery
(4) Confirmation of source position(s), (radiographic)
(5) Dosimetry assessment(s) to critical organ(s); define
method
(6) Dosimetry calculations; record method
(7) Summary of treatment delivered including modifications
(8) Confirmation of completed treatment
(9) Further treatment intention(s)
(10) Follow-up plan
The prescription should describe the technique using
simple, explicit terms. Where the prescription follows a
standard protocol, reference to the protocol is sufficient
except when departing from it. The intended total dose,
dose rate, number of treatment fractions, and total time
should be specified, relative to a reference point(s) or
isodose level at which the prescribed dose is intended.
The treatment record should also clearly identify those
patients whose prescription is modified from a standard
protocol and also the reasons, because this may affect the
treatment result [32].
Using a standard approach should provide a meaning-
ful treatment record for audit purposes. It will also help
when preparing material for publishing and make it
easier for others to follow and introduce similar
428 Quality management: clinical aspects
technique(s) and to compare their results with those
published [19].
When a non-standard approach is used, clinical dose
specification should include source geometry deviation
from a standard dose specification system [31].
32*2*9 Confirmation of delivery of
treatment
An outline of the guidelines necessary to provide a pre-
scription and treatment program is shown in Table 32.3.
Confirmation, by calculation or measurement, of the
dose received at the prescription point(s) or by critical
organs or tissues forms a vital part of any quality assur-
ance treatment program in brachytherapy. Even where
source positions are controlled by a template system to
provide a known dose distribution, variation in anatom-
ical relationships may make it important to have an
accurate assessment of the dose received by normal tis-
sues at risk. In the author's opinion, there is no place in
current brachytherapy to rely on using dose-rate tables
based on a standard treatment set-up as applied for
many years to intracavitary irradiation for treating
cervix cancer and to interstitial therapy.
The use of imaging techniques such as CT scanning
can, since the advent of afterloading, be used in many
circumstances for treatment planning and dose estima-
tions without fear of excessive radiation exposure. Such
dosimetry measurements and/or calculations, including
the method used, should be documented and form part
of the treatment record (ICRU Report No. 38,1985, and
No. 58, 1997) [8,9,32].
When external-beam irradiation is part of the treat-
ment process, it is necessary to be aware of possible geo-
metrical errors during treatment delivery. These include
errors that may produce distortion of treatment distrib-
ution. Such errors may be the result of deviation in the
treatment set-up, such as field size, gantry angle, use of
shielding blocks, couch sag, and patient movement. The
use of regular check films was reviewed by Blanco et al.
in 1987, since when, portal imaging devices now provide
for greater accuracy of treatment delivery [2527].
32.2.10 Treatment summary
A summary of the treatment delivered, including any
modification(s) to the treatment procedure, should be
recorded. Confirmation of the total prescribed dose(s),
dose rate, fractionation, and overall treatment time,
including dose(s) received by critical organs, will form
an important record of each patient's treatment. This in
turn will provide confirmation that all treatments of a
similar type are delivered to within set limits of a pre-
determined treatment plan.
32.2.11 Treatment optimization
Full details of any optimization procedure carried out
should be documented in order to be able to relate both
tumor and morbid effects of treatment to the process of
optimization. In particular, it is important to appreciate
that a poor brachytherapy technique cannot be satisfac-
torily corrected by altering source position or dwell
times under the guise of optimization. Thus, optimiza-
tion should only be used to work within restricted lim-
its, relative to a particular technique, and the
optimization procedure should be recorded. Analysis of
dose distribution using dose-volume histograms has
been reported to be useful [35,36].
32.2.12 Effectiveness of treatment
In order to carry out an assessment of the effectiveness of
treatment a number of important steps need to be taken
as part of the treatment program. Most of these steps
have already been discussed and include the important
requirement that the aim of treatment is to achieve max-
imum tumor control with the minimum risk of produc-
ing normal-tissue complications.
The process of assessment of response to and outcome
from treatment can be considered under four separate
headings:
1. local tumor control,
2. normal-tissue effects
(a) acute
(b) late,
3. time scale of follow-up,
4. further treatment.
LOCAL TUMOR CONTROL
Assessment of response should be done by objective
measurements if possible. This may be by clinical or
radiological means. It is also important that mensura-
tion should be carried out using a similar technique on
each occasion and for all similarly treated patients. Also,
measurements should be done in the same tissue planes
throughout the monitoring period and should be carried
out at similar time intervals from treatment for all
patients. Where complete tumor response occurs, fol-
lowed by local tumor recurrence, it is important to know
the period of the tumor-free interval. Such records may
prove helpful when carrying out an audit and help estab-
lish possible reasons for or better understanding of the
reasons for failing to achieve satisfactory tumor control.
NORMAL-TISSUE EFFECTS
It is important to record both the signs and symptoms
associated with and indicative of acute and late-reacting
tissue reactions. Often, the effects produced are subjective,
and appropriate methods of grading such effects are diffi-
 Administrative requirements 429

cult. Where objective clinical, radiological, or pathological time. Signs and symptoms of normal-tissue effects can
investigations are carried out, it is possible to achieve con- then be assessed in a consistent fashion, including the
sistency in terms of the reporting method used. Clearly, it use of a suitable grading system.
is preferable that, as far as objective reporting is concerned,
the person making the report should be conversant with FURTHER TREATMENT
the methodology and terminology and preferably should
Further treatment may become necessary due to recur-
be a member of the treatment team. Only by carrying out
rent disease either within or outside the original primary
careful assessment of late-reacting tissue reactions will it
target volume. Such treatment may involve further irra-
be possible to quantify dose-effect relationships in a
diation, chemotherapy, or surgery, and as such should
meaningful way. In particular, such procedure provides a
form part of the documentary record of management
means of radiobiologically estimating the a/(3 ratios for
and assessment. In particular, such treatment may affect
late-reacting tissue reactions [ 10,29,30,33,34].
normal-tissue response from previous radiotherapy or
chemotherapy.
TIME SCALE OF FOLLOW-UP

There are two major purposes for the continued follow-

323 ADMINISTRATIVE REQUIREMENTS
up of patients:
1. to provide a complete record of the effects of
Table 32.4 sets out a list of requirements which will
treatment in terms of local tumor control within the
require careful consideration if a quality management
target volume;
program is to be assured of a reasonable chance of suc-
2. to provide a complete record of the effects of
cess. Although the requirements as set out were intended
treatment on normal tissues and organs.
to apply to an external-beam radiotherapy service, they
For most normal tissues, late-reacting tissue changes are equally applicable to brachytherapy.
may take several years to become manifest. It is therefore
important to have in place a follow-up system which leads
to the identification of radiation morbidity problems and
323*1 Motivation and training
allows such events to be graded according to severity.
Motivation and training are an essential part of any
Some may question the value of regular follow-up of
quality assurance program and appropriate supportive
patients in either a radiotherapy or joint cancer clinic.
They may argue that, should patients develop signs and
symptoms of morbidity, they should be referred directly Table 32.4 Staff and administrative requirements
by the general practitioner to a consultant specializing in
(1) Motivation
the treatment of the affected organ, e.g., bladder to uro- Clear understanding of:
genital surgeon, and bowel to gastrointestinal surgeon. Objectives
Such events often occur between follow-up attendance at Individual roles
a cancer review clinic and it is, unfortunately, not stan- Working inter-relationships
dard practice for the treating clinician or the general (2) Trained staff
practitioner always to keep the clinical oncologist Clinical
informed. However, by seeing patients regularly, clinical Scientific
oncologists are more likely to learn of any treatments Nursing
carried out for normal-tissue damage from either the Paramedical
consultant concerned or directly from the patient, fol- (3) Time
Identifiable time for:
lowing which they may obtain more specific details.
Documentation
In the case of a patient developing recurrent local dis-
Check procedures
ease, referral back to the consultant who treated the Analysis
patient is often done by the general practitioner, (4) Resources
although in the case of secondary spread of cancer Therapy and simulation equipment
patients may be referred elsewhere, depending upon the Treatment planning equipment
organs affected. It is suggested, therefore, that if a full Monitoring equipment
and accurate record of a patient's history following treat- Staff availability
ment is to be maintained, the most appropriate person Record system
to do this is the clinical oncologist. This may incur car- (5) Communication
rying out an annual postal follow-up to the general prac- Documented procedures
Consistent and standardized records
titioner using a standard questionnaire.
Clear definitions of mensuration and end-points
In general, follow-up records should follow a consis-
Standard codes of practice
tent reporting pattern, carried out at set intervals of
430 Quality management: clinical aspects

training courses should be provided. An integrated inter-
disciplinary approach with full cooperation of all mem-
bers of staff, each of whom has a clearly identified role
and understands and supports the objectives of quality
assurance, is necessary. Table 32.4 identifies the individ-
ual roles of the various members of an interdisciplinary
team, each member being responsible for carrying out a
particular function. While this may provide considerable
specialized expertise relative to a specific procedure that
includes an understanding of the appropriate quality
assurance procedure, that professional knowledge needs
to be extended to being conversant with the procedural
and quality assurance aspects of the other team mem-
bers. To some extent, this can be achieved by providing
an appropriate job description for each staff member.
Included in the job description, the responsibility within
a general quality assurance program should be defined.
The precise role for each member of staff will vary, but
the composite integration of all individual roles should
be such as to provide a balanced quality assurance pro-
gram. A useful publication applicable to high dose-rate
brachytherapy is the report of the AAPM Radiation
Therapy Committee Task Group 59 [22].
The coordination of a quality assurance program may
require a designated quality assurance manager, respon-
sible to the head of department.
To provide quality assurance requires dedication and
invariably increases the workload for staff. The require-
ments outlined in Tables 32.4 and 32.5 clearly show the
diversity of responsibility necessary for individual staff

Table 32.5 Staff functions in brachytherapy

Diagnosis Site, stage, and grade of disease Surgeon

Pathologist
Radiotherapist
Treatment decision Best current management Interdisciplinary clinical team
Tumor localization (CT, radiology, Anatomical relationships Diagnostic radiologist
simulation, clinical assessment) Target volume limits Radiotherapist
Critical normal structures within treatment limits
Equipment calibration and Meeting code of practice requirements Physicist
dose monitoring Technician
Patient safety Equipment failure Physicist
Fail-safe situations Technician
Patient monitoring and communication Radiographer
Radiotherapist
Treatment plan Determine form of brachytherapy and whether Radiotherapist
with or without teletherapy Physicist
Dose-time plan
Treatment procedure Placement of source and source carrier system etc. Radiotherapist
(modifications with reasons) Simulation Physicist
Computation of dose distribution Radiographer
Dose assessments to critical organs etc.
Films for verification/dose calculation
Confirmation of dose-time prescription
Repositioning source carriers as necessary
Treatment Dose-time calculations for treatment Radiotherapist
Dosimetry checks and treatment monitoring Radiographer
Confirm completion of treatment Physicist
Personal safety Appropriate shielded room or facility Physicist
Personal monitoring Interlock systems Technician
Radiation monitoring of treatment area Radiographer
Wearing film badges when required
Effect of treatment Tumor response Radiotherapist
Acute reactions Nurses
Follow-up arrangement
Supportive care Tumor control Radiotherapist
(follow-up clinic) Late morbidity Nurses
Patient's quality of life General practitioner
Evaluation of treatment method Clinical audit Clinical team

members. The risk is that the workload may result in a
'rule of thumb' approach for expediency that is not
appropriate for quality assurance. Having the necessary
time made available in order to carry out the various
quality check procedures is essential. Unfortunately,
these requirements may be unappreciated by adminis-
trators and it is essential they have an identified and
responsible role in any quality assurance program.
Preferably, that role should include being a signatory to
the aims and objectives of the quality assurance pro-
gramme [16,17].
323.2 Resource requirements
Appropriate back-up resources are essential to apply
quality assurance. In particular, appropriate and current
state of the art equipment is essential for dose measure-
ment, calibration, and dose monitoring. An appropriate,
fully documented log for all forms of monitoring mea-
surements is essential.
An often neglected aspect of resource provision is the
increased workload placed on clerical and secretarial
staff. The amount of work entailed can be quite consid-
erable and appropriate facilities should be provided.
3233 Communications
Communications are vital and, to ensure that they are
meaningful, it is important that all documented proce-
dures are consistent and standardized. To promote a bet-
ter understanding of the recorded data, the definition of
any end-points used and of any associated measuring
methods is important. Wherever a recommended
national code of treatment practice exists, it should be
followed in order to standardize treatment and provide a
common database for cooperating centers to exchange
information.
32.4 CONCLUSIONS
The primary purpose of a quality assurance program in
brachytherapy will be similar to that for teletherapy and
medical practice in general. It should provide:
1. for maintenance of an established practice,
2. the means for assessing compliance in carrying out a
management procedure,
3. the means for monitoring and evaluation of
treatment using hard data, and
4. the means for determining weaknesses in a
treatment program to further the development of
'best current management procedures.'
A possible disadvantage is that a strictly enforced
quality assurance program may stifle initiative and the
References 431
development of new procedures and techniques. Clearly,
it is important that research and development for better
treatment should not be stifled, but should be carried
out under agreed clinical phase 1, 2, or 3 protocols [7,9].
Introducing a quality assurance system is a complex
problem because of the complexity of the various site-
specific treatment methodologies. One proposed
method of providing a national and multinational
mechanism is that of institutional certification through a
mechanism of peer review [23,28]. A summary of the
staff functions from the point of diagnosis to evaluation
of the treatment method used is provided in Table 32.5.
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6. Granville-Wright, M. (1987) Quality assurance errors in
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Brachytherapy trials. Int.J. Radial Oncol. BiolPhys., 14,
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8. ICRU (1985) Dose and Volume Specification for Reporting
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9. ICRU (1997) Dose and Volume Specification for Reporting
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(1979) Geneva, WHO.
11. Hermanek, P. and Sobin, LH. (eds.) (1987) TNM
Classification of Malignant Tumours, 4th (fully revised)
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13. Young, J. (1987) Radiotherapy, the quality assurance of
patient management. Radiography, 52, 57-63.
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14. Kovacs, G. (1998) Medical aspects of quality assurance in
brachytherapy. Strahleuther. Onkol., 174 (Suppl. 2), 47-9.
15. Farfus, B., Rons, F., S'anchez-Reyes, A., Ferrer, F., Rovirosa, A.
and Biete, A. (1996) Quality assurance of interstitial
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performance with the Paris System recommendations.
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16. Kubo, H.D., Glasgow, G.P., Pethel,T.D.,Thomadsen, B.R.
and Williamson, J.F. (1998) High dose-rate brachytherapy
treatment delivery: report of AAPM Radiation Therapy
Committee Task Group No. 59. Med. Phys., 25(4), 375-403.
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18. Smaniotto, D., Mantello, G. and Valentini, V. (1996)
Quality Assurance program in radiotherapy for carcinoma
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(1989) The recording of morbidity related to
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36. Joslin, C.A. (1996) Commentary: Brachytherapy-dinical
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Safe practice and prevention of accidents in
afterloading brachytherapy
A FLYNN, S.E. GRIFFITHS, AND C.A. JOSLIN
33.1 INTRODUCTION
In this chapter, some of the safety issues of the provision
of afterloading brachytherapy are considered. The provi-
sion of an afterloading brachytherapy service must take
full account of essential requirements for (a) the safe and
accurate delivery of the treatment as prescribed, (b) the
provision of a safe working environment for the staff of
the facility, and (c) the fulfilling of statutory and envi-
ronmental considerations relating to the receipt, safe
custody, and disposal of radioactive materials.
The requirements of both manual and remote after-
loading are considered. However, most of the chapter
deals with remote afterloading. The issues relating par-
ticularly to manual afterloading are considered in sec-
tion 33.14.
Safe practice in brachytherapy is dependent on many
factors. In particular, when using remote afterloading, it
is dependent to a large extent on safety features built into
the hardware and software associated with the installa-
tion. However, it is also especially important to have
33
highly trained specialist staff, working according to rig-
orous protocols and systems of work. These issues are
considered in detail in this chapter. Reference is made,
where appropriate, to UK, European and North
American legislation and codes on safety matters. In the
UK, the then Institute of Physical Sciences in Medicine
(now IPEM) has published a report on radiation protec-
tion in radiotherapy which includes a section on
brachytherapy afterloading [ 1 ], and an excellent review
of remote afterloading issues has been published by the
American Association of Physicists in Medicine [2].
Other countries have their own regulations and codes of
practice, but the general principles will be similar.
33.2 EQUIPMENT DESIGN
The first step in the provision of a safe installation occurs
at the pre-purchase evaluation of afterloading equip-
ment. It is at this stage that the safety features of com-
peting equipment must be evaluated, as it is difficult or
434 Safe practice and prevention of accidents in afterloading brachytherapy
impossible to rectify inherent design faults at a later
stage. There may be practical difficulties in this, as the
equipment will not be on site at this stage, but a thor-
ough examination should be made of the manufacturers'
literature, technical specifications, and operating
instructions. Other installations of a similar type should
be visited if possible, and the experience and indepen-
dent opinions of other users of the equipment should be
sought and considered.
Many design features are mandatory in many coun-
tries and, indeed, licensing by national authorities or
statutory bodies is generally a requirement. For example,
installations within the UK are required to comply with
BS 5724 Section 2.17 [3], which is identical to IEC 601-
2-17, both of which give detailed requirements regarding
the design of remotely operated afterloading equipment.
In the USA, installations have to be licensed either with
an Agreement State Agency or with the US Nuclear
Regulatory Commission, and equipment not on the
Registry of Sealed Sources and Devices cannot be
licensed [4]. In Canada, treatment programs and the use
of sealed sources have to be licensed by the Canadian
Nuclear Safety Commission. In any country, it is the
responsibility of the user to ensure that equipment com-
plies with the appropriate regulatory requirements.
The user interface should be designed so that pro-
gramming the treatment, operating the unit, and check-
ing its operation should be as simple and unambiguous
as possible. For example, there should be a display which
is operational at all times when the machine is switched
on and which shows the current status of the equipment
and its programmed treatment. This enables a compari-
son with the required treatment data from the prescrip-
tion sheet. There must also be a printout from the
machine to provide a permanent record of all data
entries and source exposures. A facility for the direct
transfer of data from the treatment planning system to
the afterloader reduces the likelihood of transcription
errors, although the data should still be manually
checked against the original prescription.
Equipment design should incorporate 'fail-safe' fea-
tures to prevent exposure of the radioactive source (or
sources) if a fault occurs with any part of the equip-
ment. These safety systems may be designed into the
hardware, software, or, more likely a combination of the
two. For example, a problem such as a disconnected or
damaged applicator or transfer tube, excessive applica-
tor curvature etc., should be detected by the equipment
before a source transfer is initiated. This is often done
by an air pressure check in the case of pneumatically
driven sources or by a check cable in the case of a
mechanically driven source. It should be made impossi-
ble to initiate an exposure unless data for a complete
treatment (or fraction of treatment if part of a fraction-
ated course or pulsed treatment) have been entered,
except under 'service mode' conditions, as described
below.
The equipment should check as far as possible that a
treatment has been given correctly. For example, the
source(s) position should be maintained within a
defined tolerance ( 2 mm is recommended in BS 5724
Section 2.17 [3]), the treatment exposure time should be
controlled by one timer and checked by an independent
back-up timer, and the return of the source(s) to the safe
at the end of a programmed exposure should be con-
firmed. Any detected malfunction during an exposure
should result in the immediate return of the source (s) to
the safe and the generation of an appropriate warning.
Preferably, the equipment should display a code to indi-
cate the nature and location of the fault. Any interrup-
tion of a treatment should be indicated: this is especially
important for low dose-rate (LDR) treatments, for
which an extended delay could affect the radiobiological
effectiveness of the treatment.
The equipment should have a back-up power supply
to provide, in the event of a power supply failure, first,
the return of the source(s) to the safe and, second, the
retention of data relevant to the treatment.
A useful feature is to have the facility to restrict certain
activities with the equipment by means of a 'service
mode' option. With this feature, procedures such as
source data entry, source removal and replacement, and
other non-'day-to-day' operations can be restricted to
certain qualified personnel. Often, a two-key arrange-
ment is used: one key enabling normal use of the
machine, and the second key being held by the person
authorized to perform these special functions.
333 ROOM DESIGN
Once the supplier and type of equipment have been
decided upon, it is necessary to consider the design of
the room in which the equipment is to be housed. The
type of room will depend on whether high dose-rate
(HDR) or low dose-rate (LDR) equipment is to be
installed. The ideal situation is one in which a treatment
room is designed specifically as a new installation for a
particular piece of equipment. Sadly, this is rarely the
case, and frequently new afterloading equipment is
installed into a pre-existing room with appropriate mod-
ifications. This may, in turn, lead to restrictions in the
manner in which the equipment may be used. For exam-
ple, sources driven out from a mobile afterloading unit
or through flexible transfer tubes may have to be kept
within a specified area within the room in order to main-
tain adequate radiation protection.
In some circumstances, it may be necessary to install
two afterloaders into one treatment room. If one or both
of these is an HDR unit, interlock systems must be
installed to prevent the use of both machines simultane-
ously. If the two afterloaders are both LDR units, it may
be desirable, for patient scheduling and logistical rea-

sons, in exceptional circumstances to treat with both
machines at the same time. If this is the case, a rigorous
system of work must be developed and adhered to in
order to minimize any radiation hazard. A.M. Bidmead
considers the design of brachytherapy rooms in detail in
Chapter 10.
33.4 INSTALLATION
The installation of complex equipment such as an after-
loading machine is normally the responsibility of the
supplier, this being part of the purchase agreement.
However, it is the responsibility of the user to:
1. agree an installation plan with the supplier;
2. arrange for appropriate utilities and services to be
provided to the treatment room;
3. perform acceptance testing on the installation prior
to a formal hand-over;
4. perform appropriate post-installation commissioning
tests, source(s) calibration, and provision of
treatment data for clinical use.
E.D. Slessinger considers these aspects in detail in
Chapter 8.
33.5 TREATMENT PROTOCOLS
When the conditions and sites to be treated have been
decided, written procedures should be documented.
These documents should describe in detail the
methodology to be used. The chance of errors occur-
ring is much reduced if 'one-off' treatments are
avoided when possible and when all treatments are
given according to a documented protocol. Each treat-
ment site and method of application should have its
own protocol. The scope of each protocol should
include localization procedures on imaging equipment,
including a description of any radiographic markers,
operating room procedures, treatment planning
method, treatment delivery, and verification and
recording procedures. The documentation should be
clear and unambiguous.
Each protocol should be written with the participa-
tion of all the staff groups concerned. The protocols
should indicate the various responsibilities of the differ-
ent staff groups. Particular care is needed to elaborate on
the interface between the various personnel, to avoid
misunderstandings, errors of omission, or errors in the
transmission of information from one person to
another. An example of a summary protocol is shown in
the Appendix (p. 441), which would be used in conjunc-
tion with detailed work instructions. The latter are not
reproduced here for reasons of space.
Treatment planning 435
33.6 TREATMENT PRESCRIPTION
The treatment prescription should be clear, complete,
and unambiguous. It should specify exactly the treat-
ment machine and technique to be used. Diagrams
should be used routinely and particularly where they aid
clarity. The type and size of applicators, radiation
sources, prescribed radiation dose and its location
should be clearly indicated. The prescription should be
clearly and legibly signed and dated by the prescribing
clinician.
The treatment prescription sheet should contain
unambiguous information regarding the treated region,
such as left or right side of the patient, and any patient
and applicator position details. For example, intralumi-
nal applicators should have their length of insertion
described, gynecological applicators should be described
to permit reproducibility for fractionated treatments
and to allow correct reconstruction for dosimetric pur-
poses. The prescription sheet should also state the dose
given to critical organs.
With HDR treatments, it is often necessary to pro-
duce a treatment prescription in a short time, as the
patient may be intubated and anesthetized whilst await-
ing the start of the treatment. This is facilitated if data
providing information on the current source strength,
radioactive decay tables, and treatment times are readily
available at the treatment machine. Errors are most
likely to occur in circumstances in which staff are work-
ing under pressure to provide treatment data and calcu-
lations quickly. It is therefore recommended that
anesthetized patients undergoing HDR brachytherapy
be treated with standard treatment plans when possible,
for which the data should be readily available. Such
standard treatments should, of course, be fully
described in the protocols.
Whereas the primary purpose of the treatment pre-
scription is to provide instructions for the person(s) giv-
ing the treatment, it is customary for it also to serve as a
permanent record of the treatment given. The
International Commission for Radiological Units
(ICRU) has published recommendations for the report-
ing of intracavitary therapy in ICRU 38 [5], and intersti-
tial therapy in ICRU 58 [6]. It is imperative that the
recommendations contained in these documents be fol-
lowed in the recording and reporting of brachytherapy
treatments. A. Wambersie and J.J. Battermann cover this
subject in detail in Chapter 6.
33.7 TREATMENT PLANNING
Once the clinician has decided on the appropriate form
of treatment for a specific patient, the planning process
may conveniently be divided into three phases.
436 Safe practice and prevention of accidents in afterloading brachytherapy
33*7.1 Transfer of information to the
planning staff
If an individualized treatment plan is required, the clin-
ical requirements of the plan (treatment volume, pre-
scribed dose, critical organ constraints, dose
fractionation, etc.) must be transmitted unambiguously
to the planning physicist or technician. A convenient and
safe way to do this is to make use of the prescription
sheet. It is worthwhile spending some time and effort on
the design of prescription sheets for the various applica-
tions so that the appropriate information may be easily
and clearly written. It is unsafe to rely on verbal infor-
mation: all information should be written and its
authorship should be clear.
33.7.2 The production of the treatment
plan
The final accuracy of the treatment plan depends on the
quality of the physical data used for its production. It is
important to ensure that the origins of the data for par-
ticular types of radiation source, individual sources, and
other physical parameters are properly researched, well
documented, and have proven accuracy. The origin of
'in-house'-produced tables and graphs should be refer-
enced and documented.
There are many software packages commercially avail-
able for the calculation of brachytherapy treatments.
Chapter 5, by R. van der Laarse and R.W. Luthmann,
considers in detail some of the computer algorithms and
software used for this purpose. Although in a busy
department it may be tempting to assume that the com-
mercial software writers have got it right, it is, of course,
ultimately the responsibility of the user to be certain that
the algorithms operate correctly and that the values of
the various physical constants and other parameters
used by the software are correct and used appropriately.
Suitable dose-checking procedures by manual calcula-
tion and measurement should be carried out to put the
computed treatment to a practical test.
It is not intended that this chapter should describe a
complete system for software evaluation, rather that it
should emphasize the importance of performing such
checks. The user should check the accuracy of the results
from a treatment planning system before putting new
software into clinical use. For simple source arrange-
ments, this may readily be done by comparison with
manual calculation and experimental data. Although
tedious, the checking of more complex treatment
arrangements should also be done.
A program of regular quality assurance checks on the
planning procedure should be devised, performed, and
recorded. This should include a daily check calculation
of a simple arrangement of sources, to check the correct-
ness of the basic source data and calculation method.
More rigorous checks, to include a test of the recon-
struction algorithm, should be done at, say, monthly
intervals. The reader is referred to reference 7 for further
guidance on this topic.
Treatment planning computers use a variety of calcula-
tion and reconstruction algorithms. It is incumbent on
those responsible for the production of treatment plans to
know and understand the computational processes
involved, particularly with respect to the various correc-
tion and conversion factors used in the software. Also,
there may be mathematical limits to some of the func-
tions, for example the Meisberger function [8] for tissue
attenuation and scatter corrections, which is only valid to
a distance of 70 mm from the source. The suppliers of
these systems must make information on such limits in
the computation algorithms available in the accompany-
ing manuals. Although systems supplied by reputable
manufacturers will have been rigorously tested before
being offered for clinical use, there may still be undetected
software 'bugs' present and the user must be alert to this. If
an anomalous result is detected at any stage in the process,
the supplier should be notified immediately so that the
software can be corrected and other users notified.
It follows from the above that treatment planning sys-
tems must always be used with caution and that the final
plan must be scrutinized for the presence of errors. Each
plan must be individually checked. Preferably, a written
checklist should be followed and a record of the check
should be filed. Where practicable, a manual calculation
of part or the entire plan should be done for comparison
with the computed version. Ideally, a second qualified
person should do the checking of a treatment plan, inde-
pendently of the original calculation.
33.7.3 Transfer of information to the
treatment unit
The completed treatment plan contains the data neces-
sary for the correct treatment of the patient. This infor-
mation must be transmitted to, and be correctly
interpreted by, the people responsible for delivering the
treatment. Conventionally, this information is trans-
ferred to the prescription sheet from the treatment plan.
Transcription errors may be reduced, particularly for
complex treatments, if the treatment planning computer
can print the information directly onto the prescription
sheet. Alternatively, the planning computer printout may
be attached to the prescription sheet: in this case, it must
be clear that the computer printout refers to the correct
patient, whose name and identification must be promi-
nently displayed. As already mentioned, care must be
taken in the design of prescription sheets and computer
printouts so that the information written thereon is clear
and unambiguous.
Some types of equipment allow direct transfer of
information from the planning computer to the treat-

ment unit. This may be either by a direct connection
between the two components, or by the use of a disk or
program card. The main advantage of this arrangement
is that it reduces the possibility of transcription errors
during programming of the treatment unit. This is par-
ticularly the case for a multichannel treatment using a
stepping source, for which manual entry of the data may
be tedious and prone to error. The correct operation of
the data transfer should be checked as part of the treat-
ment planning computer and treatment unit quality
assurance programs, and at each clinical use an appro-
priate person should check the data printout. The
remarks in section 33.7.1 also apply here: it is unwise to
rely on the verbal transmission of data, and all printouts
and written information should be signed by the person
originating them.
33.8 PRETREATMENT CHECKS
33.8.1 Equipment checks
There are certain checks that must be performed on the
treatment machine immediately prior to its use for a
patient. These form part of the wider quality assurance
program, which is alluded to in section 33.10 of this
chapter and is dealt with more fully in Chapters 8 and 9,
by E.D. Slessinger and C.H. Jones, respectively. All of
these procedures form part of the 'system of work' for
the radiotherapy department and should be written
down as part of a 'quality manual' or equivalent docu-
ment for the Radiotherapy Institute.
The exact nature of the pretreatment checks depends
on the type of equipment, but at a minimum should
include a check on the source(s) positioning accuracy in
the applicator(s) and the completion of a short simu-
lated treatment. A check of the source data activity for
the date of use should be done; this could be a mathe-
matical check of stored data, for example, rather than a
full calibration check, although the latter should also be
done at specified regular intervals. It is advisable to per-
form the machine checks before the patient undergoes
any operative procedure associated with the treatment,
so that a machine fault that could prevent treatment will
show itself before the start of anesthesia induction or
invasive procedure.
As with the rest of the quality assurance program,
appropriate documentation of the pretreatment checks
must be kept. This should include a description of the
tests and the expected results, together with acceptable
limits on accuracy. The performance of the tests should
be documented, and the record signed by the person per-
forming the test.
In a busy department performing many treatments
each day, it will be convenient to perform these checks
once daily at the beginning of the working day.
Treatment delivery 437
33.8.2 Procedural checks
The correct identification of the patient must be con-
firmed and recorded at each treatment occasion. For a
conscious outpatient, this may be done by asking the
patient to state his or her name and address. An inpatient
will have an identification tag, which must be checked. A
remote machine afterloading treatment requires the
presence of at least two radiographers (radiation tech-
nologists) to permit independent checking of the treat-
ment parameters. After one radiographer has
programmed the treatment unit, either by manual data
input or direct transfer from the planning system, the
received data must be checked by the second radiogra-
pher. The connection of the treatment applicators to the
transfer tubes may be done either by a clinician or by a
radiographer: in either case, it should be checked by the
second qualified person. Where possible, radiographic
verification of the position of the applicators in the
patient should be performed.
Particular care should be taken to ensure that the cor-
rect transfer tube is connected to each applicator. Some
machine systems have a mechanical code to ensure that
this is done correctly, but this is not always the case, par-
ticularly with interstitial implant applicators.
Use should be made, whenever possible, of standard
applicator arrangements and source loading patterns.
These standard arrangements must be documented and
copies kept available at the treatment unit control. If the
system allows, they should be stored in the equipment
memory as 'standard treatments.' If any subsequent
manipulation or recalculation of the standards is
required (for example changing the dose from the stan-
dard value to a non-standard), the second radiographer
should independently check these.
In the case of a multifraction treatment, any changes
made to the prescription as the treatment progresses
should be clearly documented, signed and dated, and
brought to the attention of all concerned.
33.9 TREATMENT DELIVERY
It is usual, in the case of machine afterloading, for the
treatment to proceed automatically under computer
control once the source(s) transfer has been initiated.
However, the progress of the treatment delivery must be
monitored. In the case of HDR treatments, the treatment
console must be monitored throughout the treatment
session so that any malfunction or interruption may be
dealt with immediately. The patient should be observed
via a closed-circuit television system. For conscious
patients, a voice intercom system should be available to
allow two-way conversation. In the case of an anes-
thetized patient, the anesthetist will require monitoring
of vital functions, and this may be achieved using remote
438 Safe practice and prevention of accidents in afterloading brachytherapy
displays and television systems. Circumstances may
necessitate the interruption of treatment, and the equip-
ment must be designed so that, in this event, it retains
appropriate information relating to the state of treat-
ment and the remaining treatment time(s). The accuracy
of the information retained under these circumstances
should be checked as part of the routine quality assur-
ance procedures. Such checks should also be done fol-
lowing a power failure to the equipment.
Similar principles apply to LDR machines, but in this
case it is not appropriate to observe the treatment
control continuously. Generally, the treatment will be
allowed to proceed to completion with appropriate
interruptions for nursing observations and care.
However, a routine check of the placement of the treat-
ment applicators should be performed at intervals
throughout the treatment: every 2 hours is suggested,
but the frequency of checks may be reduced during the
night if the patient remains asleep. The equipment
should be designed to detect and signal any malfunction
for which intervention may be required.
The situation for pulsed dose-rate (PDR) equipment
is similar to that of LDR equipment. One difference is
that, if the condition of the patient permits, he or she
may be disconnected from the treatment unit between
pulses. There should be a system for disconnecting and
reconnecting the transfer tubes in a manner which min-
imizes the possibility of reconnection errors. One suit-
able way is to use a device similar to that provided with
the Nucletron microSelectron-PDR, which permits sev-
eral transfer tubes to be disconnected or reconnected
simultaneously and ensures that transfer tubes and
applicators do not become mismatched.
Treatments on LDR and PDR systems generally take
longer than the normal working day, and arrangements
to provide 'out-of-hours' cover will be required. The
nursing staff, who will be in attendance throughout the
treatment, should be trained to provide first-line cover
for interruptions and alarms, and they should also know
how to obtain rapid help in the case of a radiation emer-
gency. However, there may be occasions when a mal-
function will require the presence of a physicist and/or
radiographer, and an 'on-call' arrangement will be
required. The staffing requirements (section 33.12)
should take into account that this cover will have to be
provided on a rota basis, and there should be sufficient
staff to provide this service. It should also be borne in
mind that, if the equipment needs to be reprogrammed
after an interruption, two qualified people will be
required so that they may check each other.
33.10 MACHINE QUALITY ASSURANCE
Each treatment unit must have a fully documented qual-
ity assurance programme, which should consist of a
series of specific tests and repetition schedules with
appropriate records. The reader is referred to Chapter 8
by E.D. Slessinger for LDR machines units and to
Chapter 9 by C.H. Jones for HDR and PDR units.
33.11 SERVICING AND MAINTENANCE
Radiotherapy equipment, in common with any other
piece of electrical and mechanical apparatus, will per-
form reliably only if it is serviced and maintained on a
regular basis. It is imperative, therefore, that appropriate
arrangements for servicing are made.
For each piece of equipment, the user has to decide
between servicing 'in-house', using the institute's own
staff, or the purchase of a service contract. The appro-
priate decision will depend on local conditions and no
specific recommendation can be made here. A service
contract from an equipment supplier entails a large
annual outlay, typically up to about 10% of the capital
cost of the equipment, but this usually has the advantage
of providing regular service visits and provision of
replacement parts when necessary. It will also usually
provide an 'on-call' service for breakdowns. Tn-house'
servicing will appear to be less expensive, but this must
be offset against the cost of the salaries and training
requirements of the staff performing the service, perhaps
the provision of extra staff to provide breakdown cover,
and the purchase of spare parts. The last mentioned may
be a particular difficulty, as parts may be expensive and
they may need to be purchased at short notice, and con-
tingency funds will have to be kept aside for this eventu-
ality.
In any event, servicing and maintenance schedules
must be drawn up and adhered to. If the servicing is to
be done 'in-house,' advice must be taken from the sup-
plier regarding the frequency of services, replacement of
certain items, and the items to be checked on a regular
basis.
For machines using short half-life radiation sources, a
regular program of source exchanges is required. For
example, iridium-192 sources (half-life 74 days) used
in afterloading machines are generally replaced at
3-monthly intervals. A source calibration by the user is
required after a source exchange; Chapter 3, by C.H.
Jones, considers this aspect in more detail.
It is recommended that quality assurance checks be
performed after a period of equipment servicing. It is
helpful to design the quality assurance program around
the servicing requirements so that the appropriate items
and operations are checked following adjustment or
replacement. This also has the advantage of reducing the
machine downtime, allowing servicing, source replace-
ments, and quality assurance sessions to be coordinated.
The importance of maintaining a service logbook that
clearly identifies all servicing and faults occurring on any

one individual machine is essential. Not only does this
provide a record of the reliability of the unit, but it
also provides information about repetitive faults and can
provide a basis for feedback to the manufacturers. It is
recommended that the logbook should contain a record
of every 'event' on the equipment, including treatment
sessions, quality assurance, servicing, calibrations,
equipment malfunctions, etc. In this way, the user has on
hand a history of the use of the equipment and any work
and modifications done to it.
33.12 STAFFING CRITERIA
There must be adequate staff of all professional groups
to allow safe provision of a brachytherapy service. For
some groups of staff, there are recommended minimum
staffing levels for certain functions. For example, Table
33.1 shows the UK IPSM (now IPEM) recommendations
for medical physicists [9], but it should be noted that
these are for the service provision only, and do not allow
for other functions such as education, training, research,
and absences due to leave. Such absences need to be
taken into account when planning a facility.
A minimum of two experienced radiographers/radia-
tion technologists is required on an afterloading treat-
ment machine in order to provide the necessary checks
of each part of the treatment process, and to be able to
manage an emergency situation. As with physicists, the
department as a whole must have more than this mini-
mum, to allow for leave absences and training.
The number of nursing and medical staff will depend
on the particular circumstances pertaining, for example
the number and type of afterloaders, the amount of
manual afterloading, working patterns, the sites treated,
the extent to which operating room procedures are used,
and whether overnight and weekend working is utilized.
There is a strong argument in favor of the concept of
a 'brachytherapy suite' in which members of staff from
each profession specialize in the practice of brachyther-
apy, preferably utilizing a specially designated geograph-
Table 33.1 Institute of Physical Sciences in Medicine minimum
physicist staffing levels for brachytherapy
Major item (e.g., HDR unit,
planning system) 0.4
Minor item (e.g., LDR unit) 0.2
Each 100 new patients per year 0.2a
3 must be defined and adhered to. There must be appro-
Should be increased if a high proportion involve complex techniques
such as iridium-192 wires or iodine-125 implants.
These are for service provision only, and do not include training,
research, etc. [9].
Manual afterloading 439
ical area within the hospital. This leads to the develop-
ment of a team approach, with each member of the team
being aware of the range of his or her responsibilities and
those of other members of the team. Many brachyther-
apy treatments are complex, and the development of an
interdisciplinary group of trained and experienced staff
will greatly reduce the risk of errors.
33.13 LOCAL RULES AND SYSTEMS OF WORK
In the UK, it is a legislative requirement [10] that each
department utilizing ionizing radiation develop 'local
rules.' These are locally written documents which
describe the key working instructions which must be
followed by people working in or otherwise entering
controlled or supervised areas of the department, the
purpose of which is to ensure that legislation is complied
with and that safe working practices are used. The regu-
lations also require employers to perform risk assess-
ments and develop contingency plans for work with
ionizing radiation. Other countries have their own legis-
lation and regulations which must be followed, but the
general principles will be similar.
The documentation should include a description of
all the procedures to be followed during normal opera-
tion of the afterloading equipment or, in the case of
manual systems, during normal calibration, manipula-
tion, usage, and cleaning of sources and appliances. It
should also include contingency plans to cover all rea-
sonably foreseeable emergency situations. A review of
safety issues in relation to remote afterloading has been
written by Glasgow [11]. Radiation protection issues are
dealt with more fully in Chapter 10 by A.M. Bidmead.
33.14 MANUAL AFTERLOADING
The same general principles apply to manual afterload-
ing as to machine afterloading. There is the same need
for the provision of unambiguous prescriptions, docu-
mentation of treatment protocols, quality assurance pro-
grams for equipment, and the provision of local rules
and systems of work. However, certain aspects of work-
ing with manual afterloading techniques require partic-
ular consideration. This section considers two areas of
manual afterloading: the use of iridium wire, and the use
of preloaded source trains for gynecological treatments.
As with the use of any type of small, sealed radioactive
source, there must be suitable arrangements for storage,
calibration, and manipulation of the radioactive mater-
ial. Controlled areas, local rules, and systems of work
priate documentation for recording the location, use,
and eventual disposal of the radioactive material.
Although the control documentation and other safety
440 Safe practice and prevention of accidents in afterloading brachytherapy
procedures should be designed to detect any misplacing,
loss, or damage to a source, a regular and frequent audit
of the source stock must be performed and documented
by the person responsible for its custody.
Iridium-192 wire poses particular difficulties in stock
control in that a single length of wire as supplied will be
cut into a number of smaller lengths for use in a treatment
application. Whereas the stock control of discrete sources,
such as gynecological cesium-137 tubes, may be simpli-
fied simply to counting the number of sources of a partic-
ular type, this is not possible with iridium wire as the
number of sources making up the stock is variable. One
method of accounting that has been used successfully is to
keep a complete record of the history of each 'delivery'
(i.e., coil or length as received) of wire, showing its initial
length and activity, then subsequently documenting the
preparation and use of each individual cut length, finally
recording the disposal of the pieces. In this case, the record
will show, at any particular time, the disposition of each
element of this particular batch, finally recording that the
length as supplied is finally disposed of.
Appropriate arrangements must be made for the tem-
porary storage of used wire prior to its disposal. Removal
of used wire from the hospital site will normally be done
by arrangement with the supplier or recognized disposal
agency. National regulations will normally limit the
activity of used wire that may be stored on site, and the
length of time for which it may be stored.
In general, sources intended for use in a patient (and
here we may include gynecological source trains) should
have some manner of coding to ensure that the appro-
priate source or train of sources is placed in the correct
applicator in the patient. For iridium wires, this will usu-
ally be done by using a source holder with labeled com-
partments or slots so that individual sources may be
identified. For gynecological source trains, it is preferable
to use a mechanical coding system on the applicator
which matches one on the source train. Also, source
trains of different configurations should be made easily
identifiable by a number system or color code.
Preferably, the color code chosen should avoid the com-
binations of colors associated with the more frequent
types of color blindness.
Procedures for the removal of sources from patients
should be laid down and followed by all personnel. In
particular, it is important that iridium wires are removed
in a manner that avoids the possibility of cutting
through the wire, as this may lead to its incomplete
removal. Also, a hand-held radiation monitor must be
used to check that all sources have been properly
removed from the patient. The correct operation of the
monitor should be checked before removal of the
sources to ensure that it is working properly. Failure to
follow these procedures may result in sources inadver-
tently remaining in the patient [12].
The ward where patients are treated with manual
brachytherapy sources should have available at all times
a shielded container which will accept the sources and
applicators in the event of their unplanned or unex-
pected removal. A useful arrangement is for this con-
tainer to be mobile, so that it may also serve as a
transport container for the routine movement of used
sources back to the sources dispensary. Clear, written
procedures and instructions must be drawn up relating
to the movement of sources to and from the dispensary
and wards. Sources that have been so returned must be
checked as soon as practicable after their return to
ensure that they are all accounted for and that they are
undamaged. It is recommended that they should be
checked, at the latest, on the next working day following
removal. They should then be cleaned and returned to
storage.
It is recommended that, at each stage of the proce-
dure, a named individual be responsible for the 'owner-
ship' of the sources, this person being responsible for
their care and custody at their stage. One way of achiev-
ing this is to make use of a 'sources receipt' document,
which accompanies the sources around the circuit from
the dispensary to the operating room, the ward, and
eventually back to the dispensary, with signatures being
given when the sources move from one area of responsi-
bility to another. In this way, control of the sources is
maintained and the movement of the sources is
recorded.
It is imperative to avoid the possibility of the uninten-
tional removal of a radioactive source from the hospital
site. There is a risk that a source, particularly a physically
small source such as a short length of iridium wire,
might be accidentally removed from (or perhaps by) the
patient and find its way into a dressing, bed linen, or
similar. In order to guard against this possibility, it is rec-
ommended that radiation detectors be placed at exits
from patient ward areas to detect any unintentional or
accidental removal from the ward area. Where practica-
ble, radiation detectors should also be placed at exits
from the hospital building(s), particularly at service exits
through which clinical waste and laundry are normally
moved.
33.15 TRAINING
The provision of training to all groups of involved staff
is essential if safe provision of the brachytherapy service
is to be maintained. The number of staff in a facility
must therefore be sufficient to allow enough time for this
training to be prepared and given. Managers of the facil-
ity should be aware of the need for training and contin-
uing education, and staff must be given time for this
important contribution to safety.
Senior professional staff should assess the training and
education needs of each discipline and ensure that the
appropriate training is provided. It is recommended
 Appendix: Example protocol for an MDR Selectron treatment 441
(indeed, a necessary requirement in some countries) that
a written record of training be kept for each person. The
training program should be tailored to the requirements
and duties of each individual; for example, the training
required by a radiographer/radiation technologist will
differ from that required by a nurse or junior clinician.
The training should include not only a broad view of the
subject, for example new developments in brachytherapy
equipment, technology, and techniques, but also practi-
cal aspects such as patient care and emergency proce-
dures.
Reference has been made earlier to the advantages of
having a dedicated team of brachytherapy specialists.
However, in many situations this is not practical and
there will be a rotation of individuals to and from the
specialty. Any person of whichever profession moving
into the specialty must be provided with adequate train-
ing before being permitted to work unsupervised. A reg-
ular, ongoing training program is vital when staff are
moved from one specialty to another. Also, as
brachytherapy is constantly undergoing development
with the consequent introduction of new concepts and
procedures, training in such new methods must be given
before they are implemented.
Training is particularly important for those groups of
staff whose professional education would not normally
include radiation physics. Physicists and radiogra-
phers/radiation technologists would normally be
expected to have gained a working knowledge of the
principles of radiation protection, for example, but this
may not necessarily be true for nurses and junior doc-
tors. LDR and PDR machines generally treat over a num-
ber of days, so there is a need for nursing and clinical
staff to have gained appropriate knowledge and experi-
ence relating to these issues in order that they may work
in a safe manner, and also operate the equipment when
necessary. In particular, they should know how to inter-
rupt and restart treatments. They must also be aware of
the limits induced by the fact that they are working in a
radiation environment. They should understand there
might be restrictions on the time that they can spend
giving nursing attention to a patient with radiation
sources in situ. They may be involved by assisting in the
procedure for the removal of sources, and they need to
know what action to take in the event of a radiation or
clinical emergency.
The added complexity of new equipment puts a fur-
ther continual training burden on radiotherapy depart-
ments. The Medical Devices Agency (MDA) safety
bulletin [13] advises that safety is dependent on training
and that, for equipment, model-specific training is
required. The Clinical Oncology Information Network
(COIN) generic radiotherapy guidelines [14] also sug-
gest training in both techniques and equipment new to
each individual. This essential training should be part of
a risk-management strategy for this potentially damag-
ing but curative modality.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Pat Earle for assist-
ing with the MDR Selectron protocol, and David
Scrimger for information regarding licensing of installa-
tions in North America.
APPENDIX: EXAMPLE PROTOCOL FOR AN
MDR SELECTRON TREATMENT
Objective To prepare and perform an MDR Selectron
treatment for individual patients in accordance with the
clinician's clinical requirements.
Scope Patients undergoing MDR Selectron treatments.
Responsibilities
Clinician
Book the patient in for the procedure with theater,
medical physics, the treatment unit Selectron, and
admissions.
Insert applicators and complete treatment card.
Approve the films and treatment calculation.
Anesthetist
Ensure patient is suitable for the proposed anesthetic
procedure.
Perform appropriate anesthesia.
Physicist/physics technician
Oversee booking arrangements.
Deliver test sources to theater.
Oversee planning films.
Calculate treatment time, and perform any other
dosimetry required, liaising with the clinician if
necessary.
Check and sign calculations and treatment card.
Record patient details in section records.
Hand over all relevant data to Selectron radiogra-
phers.
After treatment, check Selectron printout and record
relevant data in physics logbook/database.
Respond to faults/alarms, as required.
Respond to radiation emergencies, as required.
Theater nurses
Prepare instruments, applicators etc.
Identify and reassure patient.
Assist clinical medical staff, as required.
Assist with anesthetic recovery.
Hand over patient to ward nurse after procedure, with
documentation.
Radiographers
Check patient identity against prescription.
Program Selectron as required by the prescription.
Check program printout.
Reassure patient and explain procedure.
Assist clinician with connection of patient to
Selectron, checking as necessary.
442 Safe practice and prevention of accidents in afterloading brachytherapy
If clinician not available, two radiographers to perform
connections.
Advise patient and nursing staff of likely time of treat-
ment termination.
Initiate treatment.
Respond to faults/alarms, as required.
Respond to radiation emergencies, as required.
On completion, unload all channels and switch off.
Complete documentation for recording treatment.
Ward nurses
Identify and reassure patient.
Escort patient to theater, with documentation.
Escort patient from theater to simulator, then to treat-
ment room.
Prepare patient for connection to Selectron.
Attend to patient's needs throughout treatment.
Check connections to transfer tubes regularly.
Remove applicators at end of treatment.
Report faults/alarms, as instructed.
Respond to radiation emergencies, as required.
Documentation
Admissions control chart/calendar.
Prescription card.
Brachytherapy planning manual.
Selectron patient logbook/database.
Hospital patient database.
Ionising Radiation Regulations/local rules.
ICRU 38.
ICRU 58.
Radiographers' on-call rota.
Selectron manual.
Quality assurance protocol.
Selectron operations logbook.
Ward and operating theater records.
REFERENCES
1. IPSM Report No. 46 (1986) Radiation Protection in
Radiotherapy. London, The Institute of Physical Sciences
in Medicine.
2. AAPM Report No. 41 (1993) Remote Afterloading
Technology. New York, American Association of Physicists
in Medicine.
3. BS 5724 Section 2.17 (1990) Specification for Remote-
controlled Automatically Driven Gamma-ray Afterloading
Equipment. London, British Standards Institution.
4. USNRC Policy and Guidance Directive FC 86-4 (1986)
Washington DC, United States Nuclear Regulatory
Commission.
5. ICRU Report 38 (1985) Dose and Volume Specification for
Reporting Intracavitary Therapy in Gynecology. Bethesda,
Maryland, International Commission on Radiation Units
and Measurements.
6. ICRU Report 58 (1997) Dose and Volume Specification for
Reporting Interstitial Therapy. Bethesda, Maryland,
International Commission on Radiation Units and
Measurements.
7. IPEM B Report No 68 (1996) A Guide to Commissioning and
Quality Control of Treatment Planning Systems. York,
England, The Institution of Physics and Engineering in
Medicine and Biology.
8. Meisberger, LL, Keller, R.J. and Shalek, R.J. (1968) The
effective attenuation in water of the gamma rays of gold-
198, iridium-192, cesium-137, radium-226, and cobalt-
60. Radiology, 90,953-7.
9. Recommended Minimum Staffing Levels for the Medical
Physics Support of Radiotherapy (1989) York, England,
Institute of Physical Sciences in Medicine.
10. The Ionising Radiations Regulations 1999 (1999) Statutory
Instrument 1999 No. 3232. London, Her Majesty's
Stationery Office.
11. Glasgow, G.P. (1996) Radiation control, personnel
training, and emergency procedures for remote
afterloading units. Endocuriether./Hypertherm. Oncol., 12,
67-79.
12. Arnott, S.J., Law, J., Ash, D. et al. (1985) Problems
associated with iridium-192 implants. Clin. Radial., 36,
283-5.
13. Medical Devices Agency (1998) Hazard Circular, Safety
Action Bulletin Medical Device and Equipment
Management for Hospital and Community Based
Organisations, MDA DB 9801. London, Medical Devices
Agency.
14. Clinical Oncology Information Network (COIN) (1999)
Guidelines for external beam radiotherapy. Report of the
Royal College of Radiologists Generic Radiotherapy
Working Group. Clin. Oncol., 11(4), reprint.
 34
Pulsed low dose-rate brachytherapy in
clinical practice

PATRICK S.SWIFT

34.1 ADVANTAGES AND DISADVANTAGES OF
PULSED LOW DOSE-RATE APPROACH
Prior to the development of the pulsed low dose-rate
remote afterloading unit, interstitial brachytherapy for
implantable lesions required the use of manually after-
loaded strings of radioactive sources such as iridium, or
permanent implantation of sources such as iodine or
palladium, as in the case of prostate cancer. The intro-
duction of a remote afterloading unit adaptable to inter-
stitial approaches marks an important step forward in
terms of radiation safety for personnel and the applica-
tion of optimization formerly restricted to intracavitary
procedures. The pulsed low dose-rate (PDR) Selectron
uses a single iridium-192 source of 1.1 mm diameter and
2.6 mm length (Figure 34.la and b), activity generally
between 0.5-1.0 Ci, secured at the end of a cable-driven
wire. This single source is programmed to move through
a series of positions within catheters or needles placed
previously in the tumor bed, stopping for lengths of time
varying from 0 to 999.9 s per position per pulse ('dwell
times') throughout the array. The position and dwell
times are selected to deliver an average isodose distribu-
tion per pulse that most closely conforms to the geome-
try of the region to be treated. One complete movement
of the source through the entire array constitutes a sin-
gle pulse. The total duration of the pulse, the dose deliv-
ered per pulse, and the interval between pulses are all
capable of being manipulated (Table 34.1).

Table 34.1 Pulse variables

0.5 60 Hourly 30 60
0.5 60 Every 45 min 30 45
1.0 30 Hourly 30 30
1.0 30 Every 2 h 30 60
3.0 10 Hourly 30 10
3.0 10 Every 3 h 30 30
3.0 10 Every 6 h 30 60

The total duration of the pulse, the dose delivered per pulse, and the interval between pulses are all
capable of being manipulated. In all the examples, a dose of 30 Gy is delivered. The total treatment times
and the fraction sizes differ significantly, however.
444 Pulsed low dose-rate brachytherapy in clinical practice
Figure 34.1 (a) Pulsed Selection from Nucletron, with 78 channels; (b) single iridium-192 source of 1.7 mm diameter and 2.6 mm
length, with an example of the curvature of radius of a catheter negotiable by the cable-driven source.
The use of a single source of iridium reduces the need
for an extensive and expensive inventory of sources for
use in various situations. Given a half-life of 74 days, the
iridium source is replaced at 3-month intervals. Storage
of the source is simplified by its location within the
shielded unit. Because the maximum activity of the
source is 1.0 Ci, additional shielding is required to meet
governmental standards compared to that required for
standard manual afterloading.
One of the prime advantages of this remote afterload-
ing approach is the elimination of radiation exposure to
radiation oncology personnel, nursing staff, physicians
from other disciplines, or visiting family members. As
the unit is designed to allow treatment for a fraction of
each hour, the source is safely isolated for the remainder
of each hour, allowing the nursing staff to work more
extensively with the patient. This becomes particularly
important for patients with extensive medical problems.
The pulse is generally timed to end precisely at the hour
to reduce confusion as to when the nursing staff may
enter the room.
The main therapeutic advantage of pulsed
brachytherapy lies in the process of isodose optimiza-
tion. In a process identical to that used in high dose-rate
(HDR) remote afterloading units, the positions at which
the source stops and dwell time of the source at each
position are carefully manipulated. Average isodose dis-
tributions are designed to reduce 'hot spots' secondary to
decreased distances between needles or catheters in an
implant, or carefully to increase doses to areas with inad-
equate dosing ('cold spots'). Within certain limits, dose
homogeneity throughout an implant volume can be
'optimized' in pulsed brachytherapy in a fashion not
possible with static afterloading using fixed sources. It

must be pointed out, however, that even dose optimiza-
tion cannot make a poorly implanted array good. There
is no substitution for careful attention to uniform
implantation of a volume with evenly spaced needles.
Optimization also allows improved conformation of iso-
dose distribution to tumor geometry as seen on imaging
studies. In a report from Heidelberg, Berns et al. com-
pared 25 consecutive patients undergoing interstitial
breast implants as boost therapy [1]. Isodose distribu-
tions obtained with geometrical dose optimization were
compared to non-optimized distributions produced by
iridium wires. In order to compensate for the increased
reference volume irradiated due to increased dwell times
at the periphery of the implant, the active lengths of each
catheter were shortened by 5-10 mm compared to the
lengths used for static iridium wires. In all but three of
the cases, the geometrical dose optimization resulted in
distributions that were similar or superior to those
obtained with static wires, with improvement of dose
uniformity and an increase in the minimum implant
dose. A similar comparison of isodose distributions
obtained with geometric distance optimization or static
iridium wires for surface moulds showed that the PDR
approach resulted in increased dose uniformity in the
implant as well as greater conformity to the implanted
area.
When used for standard intracavitary procedures, the
pulsed low dose-rate unit has an additional advantage
over standard continuous brachytherapy using other
multisource remote afterloading continuous low dose-
rate (LDR) units. With the latter, any entry into the
patient's room, for doctors' visits or nursing attention,
necessitates a break in the treatment as the sources are
removed automatically. The overall duration of the
treatment is lengthened to account for these interrup-
tions. In the pulsed setting, such visits ideally are timed
to coincide with the breaks in treatment between pulses,
keeping the overall duration of the implant constant.
Manipulation of dwell times also provides an increased
degree of flexibility for determining the average dose per
pulse (average dose per hour) compared to that possible
with remote afterloaded fixed-position sources.
Any LDR system suffers by comparison with HDR
approaches because of the former's requirement of sev-
eral days of hospitalization to deliver the dose. Risks of
prolonged bedrest (e.g., deep venous thromboses, pul-
monary emboli, stasis ulcers, etc.) exist with PDR but
not with HDR. During the hospital stays, there also exists
the potential for movement of the instrumentation out
of the initial desired position (with tandem and ovoids,
for instance). Significant movement of the patient in the
bed may result in disruption of the unimpeded transit of
the cable-driven source, with resultant treatment inter-
ruptions, requiring intervention to untwist the cables
and catheters. Such events may occur after standard
working hours and, although not generally a danger to
the patient, may lead to prolongation of the overall treat-
Radiobiologic rationale 445
ment time. These disadvantages are weighed against the
radiobiologic benefit (see discussion below) of a low
dose-rate equivalent process over a high dose-rate
approach in terms of damage to late-reacting tissues.
Compared to continuous LDR treatments, the main
disadvantages of PDR are limited to the development of
technical difficulties that are not seen with manual after-
loading. These difficulties are decreasing with greater use
of the units, and are far outweighed by the potential
benefits.
34.2 RADIOBIOLOGIC RATIONALE
Pulsed LDR brachytherapy creates a dose-rate condition
that is different from both high dose rate and continuous
low dose rate. The first assumption which remains to be
tested is that a dose delivered to a given volume as a brief
pulse of a single stepping source, at very high instanta-
neous dose rates, is biologically equivalent to the same
average dose delivered continuously by a series of static
sources at a much lower instantaneous dose rate. The
second assumption is that the dose is relatively equiva-
lent in terms of its effect both on early-reacting tissues
(including tumor) and on late-reacting tissues. Are these
total doses (one continuous, one pulsed) equivalent over
the range of half-times of tissue repair that are clinically
relevant in the surrounding normal tissues?
Brenner and Hall [2] utilized the linear-quadratic for-
malism of Lea and Catcheside [3] in the analysis of
in-vitro dose-response data available for cell lines of
human origin in an attempt to answer these questions.
Survival (S) at a dose D is given by the following equation:
where a is the portion of cell-killing due to a single hit
(the linear component), and (3 is that portion due to
multiple hits (the exponential component). G is a func-
tion of the repair that occurs between successive hits of
radiation and is dependent on the total time of irradia-
tion, the spatial distribution of the radiation-induced
events, and the repair capabilities of the particular cell
line. Looking at experimental data from 36 human cell
lines, with their observed values for a, (3, and t0 (charac-
teristic repair time of the tissue), Brenner and Hall have
defined the conditions under which pulsed therapy
would be equivalent to continuous LDR therapy [2]. The
standard chosen for comparisons was that of a typical
continuous LDR implant delivering a total dose of 30 Gy
over 60 h. Various combinations of pulse widths and
interval durations between pulses were examined to
identify conditions under which the cell survival of
early-reacting tissues would be comparable to that seen
with a continuous regimen. In further analysis, using the
limited data available for late effects in humans, as well
as animal data on late effects (mouse lung, rat spinal
446 Pulsed low dose-rate brachytherapy in clinical practice

cord), the authors predicted the impact of a variety of

pulsed regimens on late effects. Their conclusion was
that 10-min pulses, separated by 1-h intervals, with the
overall implant duration kept constant at 60 h, would
result in a similar cell survival for early-reacting tissues
and only a 2% increase in late effects when compared to
the continuous regimen.
Although increasing dose rates result in increasing
biologic effectiveness, they are also accompanied by a
decline in the therapeutic ratio [4-7]. Two alterations
might result in an expected decrease in the therapeutic
ratio: increasing the dose delivered per pulse and
increasing the time between successive pulses. Keeping
the total duration of an implant static but increasing the
Figure 34.2 Calculated fractional change in cell survival for
interval between pulses, thereby increasing the dose per
PDR compared with LDR as a function of the assumed 7|. Both
pulse, increases the biologic effectiveness of a dose, par-
treatments consist of 30 Gy delivered in 60 h, either
ticularly in cell lines with a shorter half-time of repair
continuously (LDR) or in 60 10-min pulses of 0.5 Gy delivered
(ti). Because the amount of repair capacity is believed to
hourly (PDR). The calculated quantity is (SPDR - SLDJ/SLDR: here the
be greater in late-reacting normal tissues than in early-
survival, S, = exp(-aD - GbD2J where D is the total dose, a and
reacting tissues (including most tumors), an increase in
(3 are the linear-quadratic formalism parameters, and G is the
relative effectiveness would be expected to be more sig-
quantity describing sublethal damage repair which depends on
nificant for late-reacting tissues than for early-reacting
the half-time of sublethal damage repair [11].
tissues, resulting in a decrease in the therapeutic ratio. If
the t} for late-reacting tissues is significantly longer than
that of a particular tumor tissue, the effect of pulsed
therapy on the therapeutic ratio would be minimized. overall dose to sustain levels of late effects similar to that
Data from recent experiments on rodent kidney, spinal seen with continuous LDR regimens, a decrease which
cord, and lung tissue suggest that a component of repair would result in a less-than-desired effectiveness for
of later-responding damage of approximately 4 h exists tumor control. Fowler and Mount [12], therefore,
[8-10]. If this is the case, and early-responding tissues, arrived at a conclusion similar to that of Brenner and
including tumor tissue, have half-times of repair consid- Hall [2]: keeping the repetition frequency at one pulse
erably shorter than those of late-responding tissues, then every 1 or 2 h would be comparable to a continuous reg-
the pulsed approach would be expected to result in lev- imen with a negligible increase in late effects.
els of late tissue damage lower than that seen with the Due to concerns about the safety of operating a unit
continuous LDR approach (Figure 34.2) [11] with a strong source during the night shifts, many clinics
In an effort to establish the conditions least likely to
result in a decrease in the therapeutic ratio for PDR com-
pared to continuous LDR, Fowler and Mount [12] calcu-
lated the expected effect of various pulsed regimens
(with dose rates in the pulse varying from 0.5 to 120 Gy
h'1 and pulses delivered every 1-4 h) on early-respond-
ing and late-responding tissues, using a wide range of
possible half-times of repair from 0.1 h to 3 h. Duration
and total dose of the implant were kept at 70 Gy in 140
h, and all effects were considered relative to a continuous
regimen at 0.5 Gy h-1.
Looking first at early-reacting (normal and tumor)
tissues, biologic effectiveness would not be expected to
increase by more than 3% if dose rates remained in the
0.5-3 Gy h"1 range and pulses were given hourly, regard-
less of the assumed Ti. As the dose per pulse and interval
duration increase, the biologic effectiveness also Figure 34.3 The increase of relative effectiveness (RE) with
increases for all Ti. This is true for late-reacting tissues as increasing assumed values for 7| is shown for five different dose
well. If intervals increase to one pulse per 4 h, biologic rates in the pulses. When the deviation of the curves from the
effect in late tissue may increase as much as 15% (Figure straight line representing the continuous low dose rate of
34.3). Tissues with the shortestT1/2of repair would be at 0.5 Gy h-1 exceeds about 10%, the extra biologic effect (for the
greatest risk. This would necessitate a decrease in the fixed total dose) might become clinically significant [4].

have been interested in developing an approach that
would allow treatment only during normal or extended
daily working hours, with discontinuation of treatment
during the evenings. If no change in the dose per pulse
were to occur, this would result in an unacceptable prolon-
gation of the overall duration of the implant. Adhering to
a single pulse per hour would also limit the use of each unit
to only one person at a time. Increasing the length of time
between pulses to 2 or 3 h might allow several patients to be
treated concurrently in a busy clinic. Further work by
Brenner et al.[l3], Sminia et al.[14], Visser et al[!5], and
Millar et al. [16], suggests that increasing the interval
between pulses to up to 3 h, as well as increasing the dose
per pulse and switching to a daytime only treatment
schedule may, in fact, be safe. These theoretical considera-
tions are based upon assumptions regarding the a/(3 ratios
and repair kinetics of the critical tissues in the implant
region. Because these are not generally known with any
great degree of certainty for most human tissues, such
treatment regimens must be used with caution and with
close observation to determine if there are increases in late
sequelae in late-reacting tissues [ 16].
343 RESULTS: IN VITRO AND IN VIVO
It is of critical importance that validation of these theo-
retically designed treatment schemes be evaluated in
in-vivo and in-vitro animal models to minimize the risk
of severe injury to late-reacting tissues. Great is the uncer-
tainty surrounding the radiation repair times of the wide
variety of normal human cell lines likely to be affected by
novel and convenient treatment timing schemes.
Using rat 9L/SF gliosarcoma cells, Armour et al. [17]
compared continuous (0.5 Gy h-1) and pulsed (0.5 Gy h-1
averages using 0.25 Gy per 0.5-h intervals, 1 Gy per 2-h
intervals, 3 Gy per 5-h intervals) LDR approaches. No
differences were discernible between the pulsed and con-
tinuous regimens in the cell survival curves at 37 C and
41C. When cells were treated with pulses of 6 Gy every
12 h, an increase in cell killing (a relative decrease in DJ
was noted. Cell killing was equivalent between pulsed
and continuous techniques as long as the overall dose
rate remained constant and the dose per fraction was less
than the width of the shoulder of the dose-response
curve.
Pulsed regimens with constant overall total dose and
variable interfraction intervals ranging from 1 h to 12 h
were compared for three carcinoma lines (two cervix and
one breast) [18]. Schedules with hourly pulses were
found to have similar biologic effectiveness when com-
pared to continuous LDR radiation, but decreased sur-
vival was noted with increased dose per pulse, as
predicted. When cell lines of different radiosensitivity
were compared (human bladder cancer and neuroblas-
toma) using different pulsing regimens, once again little
Results: in vitro and in vivo 447
difference was noted between single hourly pulses and
continuous LDR irradiation [19]. However, larger doses
per fraction resulted in markedly different levels of
increased biologic effectiveness for cell lines of varying
radiosensitivity, much greater for the cell line of greater
radiosensitivity. In this study, a significant dose-rate
effect was also unexpectedly seen. These results reveal
that changing the dose per pulse, and possibly the dose
rate per pulse, will variably impact the biologic effective-
ness of the dose for different tumor lines. This informa-
tion also reveals the necessity of determining the impact
of such changes on normal tissues as well.
In the mouse model, Mason et al. [24] delivered total-
body irradiation (19-40 Gy), using two continuous and
two pulsed regimens. Mice were sacrificed and the sur-
viving cells per circumference of jejunum counted and
plotted against the total dose for each regimen. In the
continuous radiation schemas, average dose rates of 4.2
Gy h"1 and 0.7 Gy h-1 were used. For both of the pulsed
schedules, average dose rates of 0.7 Gy h-1 were delivered
in either 1 or 10 min and resulted in nearly identical cell
survival curves. The shorter pulse duration of 1 min (a
ten-fold increase in dose rate) resulted in only a 3-4%
shift in the cell survival curve to the left of the curve for
the 10-min pulse.
Experiments evaluating the cataractogenic potential
of pulsed versus continuous regimens in the rat lens
model showed no major difference in cataract formation
between continuous and pulsed regimens with similar
doses delivered in 10-min pulses h-1, 10-min pulses every
4 h, or 100-s pulses every hour [20]. Armour et al. [21]
evaluated the histologic response of injury to the rat rec-
tum caused by the same total dose delivered via contin-
uous or pulsed strategies. The pulse intervals were 30
min, 1 h, 2 h, 4 h, and 8 h. The therapeutic ratio
remained relatively constant for continuous irradiation
and pulsed regimens where the dose per pulse remained
below 1.5 Gy, or 2-h intervals. Pulse fraction size greater
than 1.5 Gy resulted in a steady increase in the damage to
rectal tissue using five different assessment scales. Pulsed
regimens utilizing intervals greater than 2 h might there-
fore be expected to result in a decrease in the therapeu-
tic ratio for the rectum, if the rat rectum has
characteristics similar to the human and if the dose per
pulse is allowed to exceed a certain threshold as one
attempts to keep the overall treatment duration con-
stant. Haustermans.et al. [22] reported on the effects of
continuous versus pulsed regimens of radiation directed
at the rat cervical spinal cord. Continuous LDR irradia-
tion was delivered using a specially designed collar with
iridium wires, over a 72-h period. The pulsed doses were
delivered over 9-h periods daily with overnight gaps,
with radiation delivered using a linear accelerator at a
constant dose rate per pulse, but with pulse intervals
ranging from 1 to 3 h, and required from 5 to 7 days to
deliver the full dose. Total doses ranged up to 68 Gy. No
rats treated with continuous LDR irradiation developed
448 Pulsed low dose-rate brachytherapy in clinical practice
myelopathy up to 9 months. Pulsed regimens resulted in
a 50% myelopathy incidence at an average of 60 Gy. The
reason for this absence of observed effect in the contin-
uous group put forth by the authors is that there are two
components of repair in the rat spinal cord, one of which
is very rapid. This leads to the suggested need for caution
when utilizing pulsed regimens of increasing pulse size
when the spinal cord may be affected. Hall and Brenner
[23] published a note of caution in the editorial, how-
ever, regarding extrapolating the results of this study to
clinical experience in humans.
34.4 CLINICAL RESULTS
A limited number of clinical studies of the use of pulsed
LDR irradiation has been published to date. These stud-
ies are for the most part retrospective analyses of limited
numbers of patients with various tumor types, with rel-
atively short follow-up.
From 1992 to 1995, Swift et al [25] reported on 65
patients with pelvic malignancies (54 primary and 11
recurrent) who underwent a total of 77 brachytherapy
procedures, 45 intracavitary and 32 interstitial. Isodose
distributions were planned using the Nucletron PLATO
system, with geometric optimization carried out on all
cases. Patients were treated with a combination of external-
beam radiation plus the brachytherapy procedures, with
the implant dose being determined by the clinical situa-
tion. In adherence to the recommendations of Brenner
and Hall [2], all patients were treated at a dose per pulse
of 0.4-0.85 Gy, with hourly pulses delivered around the
clock. Extreme care was taken during the implantation
and planning process to keep rectal dose at a minimum.
At a median follow-up of 16 months, local control was
78%, and 2-year survival 67%. An absolute incidence of
6.5% for RTOG acute grade 3 or greater complications
was seen, with a 15% incidence of RTOG delayed grade
3 or greater complications. Of four cases with recto-
vaginal fistulae, three had massive central recurrence
contributing to the fistula formation. Omitting these
patients as treatment-related complications, the compli-
cation rate dropped to 8%. The authors make it clear
that longer follow-up is essential to determine the true
delayed complication rate seen with this approach, but
the results to that point are quite similar to those seen
with continuous LDR implants.
Rogers et al. [26] reported on 46 patients with cervical
carcinoma treated with 28 intracavitary and 18 intersti-
tial implants in conjunction with external-beam radia-
tion. All patients were treated with hourly pulses of
0.40.7 Gy, with plans derived from the Nucletron
PLATO planning system. Mention of the type of opti-
mization used was not made. Median follow-up was 25
months. Pelvic control at 4 years was 86%, with a 4-year
disease-free survival of 65%. Acute complications were
not discussed, but the late complication rate (RTOG
grade 3 or greater) was only 7%. One vesico-vaginal fis-
tula and one recto-vaginal fistula were seen, both after
biopsies were obtained that revealed benign tissue. The
delayed complication rate compares quite favorably with
those seen using standard continuous LDR approaches.
An additional report from Jensen et al. [27] deals with 34
patients with locally advanced or recurrent gynecologic
malignancies, treated with 46 Gy external beam followed
by 30 Gy delivered in hourly pulses of 0.6 Gy, using vol-
ume optimization. At a median follow-up of 14 months,
17 chronic grade 3 or higher complications were
reported in ten patients (five in one patient alone). The
median treatment volume for these patients was 177.5
cm3, with volumes ranging from 200 to 650 cm3 for those
who developed late complications. DePree et al. [28]
reported on 43 patients treated with PDR regimens for
tumors of various sites, including 34 pelvic sites. All
patients were treated using the hourly pulse of 0.4-1.0
Gy, with a 10% reduction in the overall dose compared
to what would have been prescribed in the setting of
continuous LDR brachytherapy. No excess of acute or
delayed toxicities was reported compared to historical
results at a median follow-up of 18 months.
Seventeen patients with anal carcinoma were treated
with external-beam radiation to a dose of 46 Gy, without
chemotherapy, followed by a PDR implant of 25.2 Gy,
delivered at 0.6 Gy rr1 over 42 h [29]. Although only
three local recurrences were noted, the toxicity level was
unacceptable. Thirteen patients developed necrosis, and
eight required a colostomy. The volume that received in
excess of 25 Gy (71 Gy including the external compo-
nent) ranged from 21 cm3 to 400 cm3, with higher vol-
umes being associated with a greater risk of colostomy.
Fritz et al. [30] reported on 65 patients with breast
cancer considered to be at high risk for local recurrence,
who underwent external-beam irradiation to a dose of
50 Gy, followed by a PDR boost (usually with a two-
plane implant) of 20 Gy, using 1 Gy h-1 intervals. In the
initial 35 cases, concurrent plans were run using the PDR
with geometric volume optimization and static iridium
wire plans for comparison of the quality and hetero-
geneity indices of these implants. These comparisons
showed a clear superiority in the majority of cases favor-
ing the PDR approach with geometric volume optimiza-
tion over continuous LDR plans in terms of dose
homogeneity within the reference volume and increased
minimal dose within the volume. At a median follow-up
of 30 months, there has been only one local failure, only
one acute complication noted (temporary erythema),
and 11% with minimal telangiectasis, with no breast
retraction, soft-tissue necrosis, or severe fibrosis noted.
Care was taken by the authors to point out that the dwell
positions were selected with an increased offset from the
skin surface compared to the continuous LDR plans to
avoid overdosing the skin, resulting in the superior cos-
metic results in these high-risk patients.

Levendag et al. [31] used two different treatment reg-
imens for 38 patients with squamous cell carcinoma of
the soft palate or tonsillar fossa, the majority of whom
received external-beam radiation first to a dose of 46-50
Gy. These patients were then treated either with a day-
time fractionated HDR approach using 3 Gy fractions
twice daily at 6-h intervals to a dose of 21-27 Gy, or a
PDR approach consisting of a schedule of 3-h intervals
between pulses, with either four fractions of 2 Gy during
the daytime only or eight fractions of 1-1.5 Gy given
over 24-h periods. These patients had identical results, in
terms of both local control and observed toxicities. No
increase in toxicity was noted compared to historical
controls using a continuous LDR approach, with a sug-
gestion of an increased efficacy of this approach com-
pared to the continuous LDR approach. The authors
point out that this lack of increased toxicity with the
longer pulse intervals was not unexpected, assuming a
rather long T1/2 of repair for late effects in the normal tis-
sues of this region of the anatomy, and cannot necessar-
ily be extrapolated to other regions of the body. To our
knowledge, this is the only major report to date that uti-
lizes intervals in excess of greater than 2 h.
34.5 CONCLUSION
The pulsed LDR approach to brachytherapy has a number
of technical advantages that relate to improved patient
and staff safety. It has a theoretic advantage over HDR
approaches in terms of the risk to late-reacting tissues. It
also has been shown to have the capacity to decrease the
underdosage in areas of the implant as well as increase the
conformity of the implant reference volume to the target
volume in a way not generally possible with static
implants. Early clinical reports, with a few notable excep-
tions, show no increase in early or acute complication
rates, as long as a conservative dosing schedule of < 1.5 Gy
is delivered in pulse intervals of 2 h or less. Longer follow-
up is clearly needed to substantiate these early findings.
More convenient approaches with longer pulse intervals
may be safe in certain settings, but this needs to be tested
further. A regimen that is safe and effective in the manage-
ment of tumors with one type of normal surrounding tis-
sues may not be as safe in other regions. On the other
hand, an approach with larger doses per pulse may actu-
ally improve the local control rate in certain settings with-
out decreasing the therapeutic ratio. Much work still
remains to be done in terms of defining theT1/2of various
normal and tumor tissues in humans.
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 Index
Page references in italics refer to figures; those in bold refer to tables
AAPM recommendations 15-17
general AAPM formalism 15-16
low energy emitters 15-16
aberration yield 174
accident prevention 433-42
afterloading systems 103-10
advantages 103
costs 414-15
high dose-rate systems 108-10
low dose-rate remote systems 107-8
manual 105-6,439-40
pulsed dose-rate systems 110
air kerma strength 13, 16, 20
americium-241 4,10
Amersham crimping tool 105
Amersham Gynecological System 106
Amersham Iridium Wire Loader crimping
tool 105
Amersham Manual Afterloading System 5,5,6
anaplastic astrocytoma 373
anisotropy constant 17
anisotropy factor 17
anisotropy function 17
anorectal carcinoma, interstitial
brachytherapy in 387-92
aftercare 391
equipment 388
pretreatment assessment/investigations
387-8
technique 388-90
treatment protocol 388
apoptosis 171
applicator orifice method 143
applicator tip localization method 143
arm, skin tumors 397-8
astrocytoma, anaplastic 373
ataxia telangiectasia 208-9
attenuation in irradiated medium 14-15
autoradiograph device 125, 126
autoradiography _149
average dimension method 42-3
basal cell carcinomas 393
basal dose rate (BD) 84
becquerel 13
bile duct carcinoma 325-30
brachytherapy 326-7
chemotherapy 325-6
dose-fractionation schemes 328
dose specification 327-8
general management 325-9
high dose-rate therapy 329
intraoperative radiation therapy 326
low dose-rate therapy 328-9
multimodality 326
planning and technique 326
pretreatment assessment 325
radiation therapy 326
surgery 325
target volume 327
bioeffect dose model 77-8
biologically effective dose (BED) 190
biophysical modeling in radiotherapy
189-90
bismuth-214 (radium C) 214
bladder, high dose-rate brachytherapy in
cervical cancer, effects on 368
bladder reference point 96
brain tumours, brachytherapy for 373-7
low-grade tumors 376-7
newly diagnosed malignant gliomas 375-6
recurrent malignant gliomas 3745
treatment technique 373-4
breast cancer, low dose-rate brachytherapy
266-79
costs 419
early-stage 267-74
boost treatment 267-73
after breast-conserving therapy 274
as sole radiation treatment 273-4
historical perspective 266-7
locally advanced breast cancer 274
technique 274-7
treatment planning 277-9
British National Radium Standard 20
buccal mucosa 289
Buchler system 108
calibration methods 21-4
calibration of sources in remote afterloading
systems 2432
low dose-rate preloaded cesium-137
source trains 25
low dose-rate sources in form of wires or
ribbons 25
multiple high dose-rate sources 27-8
multiple low dose-rate sources 257
single high dose-rate sources 28-32
'in-air' calibrations 28-31,29
re-entrant ionization chamber
measurements 31-2
solid phantom (or water phantom)
measurements 32
pulse dose-rate sources 32
capital costs 411
catheter image points 52
catheter image tracking 52
cell adhesive matrix (CAM) assay 206-7
central plane 87
cervical cancer
costs of brachytherapy 419
Fletcher applicators, use of 47
Manchester system 44-7, 45-6, 46
see also cervical cancer, high dose-rate
brachytherapy in; cervical cancer,
low dose-rate brachytherapy in;
cervical carcinoma, interstitial
brachytherapy in
cervical cancer, high dose-rate
brachytherapy in 354-69
age groups affected 355
combined intracavitary/external-beam
irradiation 356, 360
dose distribution 358
dose-volume specification 359
early-stage disease 356
combined intracavitary/external-beam
irradiation 356
intracavitary irradiation alone 356
intracavitary irradiation/Wertheim
hysterectomy 356
historical background 3545
intracavitary treatment 357-8
late-stage disease 3567
external-beam, irradiation 356-7
lymph node status 355-6
normal-tissue effects 365-8
bladder 368
delayed tissue damage 366
early tissue damage 366
rectum and sigmoid colon 366-7
small bowel 368
source position relationships 358
special considerations 359-60
target volume 359
tumor size 355
treatment planning 360-5
bladder dose 363
combined intracavitary/external-beam
irradiation 360
homogeneous external-beam/high
dose-rate intracavitary boost
irradiation 360
intracavitary high dose-rate/shielded
external-beam boost irradiation
360-1
optimal dose regimen 365
pelvic disease control, factors affecting
363-5
pelvic failure and distant metastasis
365
rectal dose 362
survival rates 365
treatment procedure 361-2
wedge position 361
cervical cancer, low dose-rate brachytherapy
in 343-53
clinical trials 350-2
external-beam (unwedged)/
intracavitary therapy 351-2
external-beam (wedged)/intracavitary
therapy 351
intracavitary therapy alone 3501
historical background 343-4
international experience 352-3
pretreatment assessment and
investigations 344-6
452 Index
cervical cancer, low dose-rate brachytherapy
in (contd)
pretreatment assessment and
investigations (contd)
biochemical profile 345
biopsy 345
cystoscopy 346
full blood count 345
imaging 345
treatment methods 346-50
external-beam techniques 3467
intracavitary technique 347
low dose-rate remote afterloading
347
treatment planning 347
treatment results 349-50
cervical carcinoma, interstitial
brachytherapy in 379-84
loading and unloading of radioactive
sources 381-2
localization films 381
pretreatment work-up 379-80
technique 380-1
treatment protocol 382
cesium-137 4, 5-6,12
for Buchler afterloading 6
for curietron 6
forms for annual afterloading 5
properties 5
remote afterloading 6
sources 5-6
spherical sources 6, 6
checkpoint 165, 184
clinical target volume (CTV) 83
closed radiation source 7
cobalt-60 4
production 4
properties 6
sources 6
complex aberrations 172
computer-assisted dose calculation 4950
Conformal Index (COIN) 75
contact-inhibited monolayers 166
continuous low dose-rate (CLDR) 105,
219-20
cost benefit 417-18
cost-effectiveness 417
cost minimization 415-17
brachytherapy and electron therapy 416
brachytherapy and external-beam therapy
416
brachytherapy and surgery 416-17
LDR vs. ]HDR 415-16
manual vs. remote afterloading 415
cost utility 417
costs of brachytherapy 410-20
charging for healthcare 413
cost areas 414
costs of afterloading 414-15
costs of manual techniques 414
economic evaluation 415-18
failure 412-13
healthcare resource groups 413-14
principles 411-13
radiotherapy costs 410-11
variables 411
UK funding 413
USA funding 413
Courtenay-Mills soft agar assay 2078
coverage index (CI) 74, 75
Creteil System 47
CT-based brachytherapy treatment planning
75
CT scanner with a gantry tilt option 77
CTV 91
curie 12-13
Curietron 107
Detex paper 139
direct operating costs 413
discounting 411
dose anisotropy function 51-2
dose calculation, computer-assisted 49-50
dose distribution in interstitial therapy
86-92
Dose Homogeneity Index (HI) 74
dosenon-uniformity ratio (DNR) 74
dose rate 91
dose-rate constant 16
dose-rate corrections 12
dose-rate effects 180-7
bias of tumor size and dose rate 217-18
cell killing around an implanted radiation
source 185-7
differences in repair rates 219-20
early-responding and later-responding
tissues 218-19
in human tumor cells 182-3
implications for clinical brachytherapy
187
iridium wire implants and 216-17
irradiation on cell-cycle progression
184-5
mechanisms 181-2
models 183-4
radium needle implants and 215-16
sublethal damage repair rates 219
time-scale of radiation action 1801
dose specification (ICRU recommendations)
81-100
dose uniformity parameters 91
dose-volume histograms 43-4, 65-75
cumulative 72
differential, of a single point source 67-8
differential, of multiple point sources
68-9
evaluation of dose distributions with 723
natural 69-72
prescription dose in non-
optimized/optimized volume
implants 73-4
dwell position 57
dwell time 57
dwell time gradient 59-60
dwell time gradient restriction 60
ear 288
skin tumors 398
endobronchial brachytherapy (EBBT)
225-40
background 225-6
complications 238
endobronchial catheters 226
management 238-9
pros and cons 239-40
protocol 233-7
eligibility 233-4
indications 234
protocol 1.0 curative intent 234
protocol 2.0 palliative intent 234
protocol 3.0 recurrent patients 234-5
in stages I, II, III or recurrent lung cancer
229-33
treatment prescription 226-7
treatment strategies 2279
endometrial cancer, brachytherapy for 333-9
clinical aspects 333-4
dose rates and choice of nuclide 334
Freiburg study of therapy and recurrent
disease 337-9
management and clinical practice 334-9
applicators 335-6
dose rate 336
fractionation schemes and different
dose rate 336
postoperative brachytherapy of vagina
336
preoperative and postoperative
irradiation 336
recurrence rates after surgery and
irradiation 337
uterine packing in 99
energy response curve method 30-1
equipment checks 437
equipment design 433-4
equivalent activity 13
equivalent annual costs (EAC) 411
esophageal carcinoma, brachytherapy of
243-54
clinical staging and pretreatment
investigations 244-5
complications 253
costs 419
history and treatment rationale 244
intraluminal brachytherapy technique
246-7
natural history 2434
radiological and clinical considerations
248-50
therapy decision process 245-6
TNM classification 244
treatment results 250-3
exposure rate constant 13
eyelid 288
face, skin tumors 398
Farmer ionization chamber 26
Filmless planning 77
financial accounting 413
fixed costs 411
Fletcher-Suit afterloading 113
Fletcher-Suit ovoids 121
Fletcher-Suit rigid, applicators 88, 96,106
Fletcher-Suit technique 384
Fletcher-type applicators 47
use in cervical cancer 47
fractionated stereotactic radiotherapy 199
fundholding 413
Gafchromic film 139
Gammamed 109
geometric optimization 57
geometric optimization on distance 63
geometric optimization on volume 62-3
geometry factor 16, 51
glioblastoma multiforme 373
gold-198 4,12, 15
gross tumour volume (GTV) 82-3
Gustave-Roussy technique 47
gynecological applicators 107
hand, skin tumors 397-8
head and neck cancer, brachytherapy in
284-93
clinical brachytherapy 302-10
base of tongue/mobile tongue:
interstitial volume implant 302-3
nasal vestibule brachytherapy 304
nasal vestibule: interstitial single-plane
implant 303-4
nasal vestibule: mould techniques 304
nasopharynx: endocavitary
brachytherapy 307-9
tonsil and soft palate: single plane
interstitial implant 304-6
tumor control of tonsillar fossa and
soft palate 306-7
costs 419

fixture directions 291-3
high dose-rate interstitial/endocavitary
brachytherapy 296-315
choice of type of remote-controlled
afterloaders 297
different repair half-times/alpha/beta
values 299-301
dose fractionation 302
fractionated HDR and PDR schedules
297-301
overall effect of external radiotherapy/
brachytherapy boost 301
radiobiological model 298-9
schedules in Rotterdam 297-302
historical background 284
Institut Gustave-Roussy results 289-91
integrated brachytherapy unit (ITU)
310-15
neck: flexible intraoperative template
310-15
re-irradiation 311
pretreatment assessment and
investigations 284-5
dental assessment 285
neck assessment 285
primary tumor 284-5
Rotterdam viewpoint 315
treatment 285-7, 288-9
hypodermic needle technique 286-7
iridium-192 285
iridium-192 hairpins 285-6
Paris System 287
plastic tube technique 286
silk suture technique 287
treatment planning 287-8
general assessment 287
geometric configuration 288
tumor evaluation 287
radioactive sources 288
Heyman capsules 47
high dose regions 90-1
high dose-rate (HDR) 49, 104-5, 108-10
high dose-rate remote afterloading, quality
assurance 133-45
documentation 143-5
facility design 134-6
machine function tests 136-7
regulatory requirements 134
treatment precision tests 137-43
positional reproducibility 138-42
positional reproducibility in interstitial
brachytherapy 142-4
high dose-rate vs. low-dose rate
brachytherapy 196-9
in cervical cancer 196-9
general principles 196
hyperthermia 400-7
biological factors 400-2
simultaneous, brachytherapy and 4035
systems considerations 403
thermometry requirements 403
hyperthermic universal perineal implant
template (HUPIT) 404
'in-air' calibration jigs 29
'in-air' measurement using ionization
chambers 234
Incomplete Repair (IR) model 183-4
indirect operating costs 413
inpatient/outpatient costs 412
input budget 413
installation 435
treatment protocols 435
internal market 413
interstitial therapy, recording and reporting
92-4
Index 453
dose distribution 934 low dose-rate (LDR) 49, 104-5, 107-8
sources 93 vs. pulsed dose-rate brachytherapy
technique and source pattern 93 199-201
time-dose pattern 93 low dose-rate and fractionated irradiation
TRAK93 161-77
volumes 93 aberration yield and survival change 174
intracavitary therapy in gynecology apoptosis and signal transduction 176
applicator 95 changes with linear energy transfer 175-6
reporting, recommendations for multiple dose fractionation 168-70
absorbed dose at reference points 958 potentially lethal damage 166-8
close to sources and related to potentially lethal damage repair 174-5
sources 95 repair of radiation damage
related to bony structures 978 cell-cycle complication 163-5
relatively close to sources but related cell-cycle progression, effect on 165
to organs at risk 96-7 history of 162
calculation of dose distribution 989 split-dose recovery from sublethal
description of reference volume 95 damage 162-3
dose level 95 variation in recovery 163
pear-shaped volume 95 selection of mutants 176-7
60-Gy reference volume in special subcellular changes 170-1
situations 99 sublethal damage 171-4
TRAK95 low dose-rate remote afterloading, quality
simulation of linear sources 94-5 assurance 112-31
sources 94 acceptance testing 116-20
intraoperative radiation therapy (IORT) 319 acceptance test report 120
iodine-125 4 brachytherapy source testing 116-17
forms of seed 8-9, 9 functional tests 119-20
production 4 radiation surveys 117
properties 9 safety features 117-18
source 8-9 source transport and applicator tests
iodine seeds 106 118-19
Ionising Radiation (Outside Workers) equipment selection 112-13
Regulations 1993 148 ongoing quality assurance program
Ionising Radiation Regulations (IRR) 147 124-31
iridium hairpins 1056 documentation 129
iridium ribbons 106 machine-testing schedules 126-9
iridium wire implants 216-17 practical operational considerations
iridium wires 105 130-1
iridium-191, production of 4-5 shield placement and surveys 125-6
iridium-192 4, 15 training personnel for remote
hairpins 7-8, 8 afterloading 129-30
miniature, for high dose rate 8 treatment verification 124-5
production 4 preparation 11216
properties 7 quality assurance procedures 121-3
seeds 8 dose computations 123
source strength 7, 8 iridium seed ribbon preparation 122
sources 6-8 localization radiographs 1223
wire 6-7 motor-driven sourcecable assemblies
isocentric reconstruction method 53-4, 85 121-2
source-spacer pellet configurations 121
Joslin-Flynn applicator 109 treatment planning 122-3
treatment prescription 123
Kaposi sarcoma 398 site preparation 113-16
kerma rate calculations in water 27 authorization for remote afterloading
kerma rate measurements in water 26 115
Kodak X-Omat Verification film 139 facility design 114-15
installation 115-16
lead-214 (radium B) 11 location 113
legs, skin tumors 398 shielding considerations 113-14
Leksell stereotactic system 374 lung cancer
Lethal-Potentially Lethal damage (LPL) costs of brachytherapy 418-19
model 183-4 endobronchial brachytherapy in 22540
linear energy transfer (LET) 175-6 lymphatic trapezoid 97, 98
linear-quadratic (LQ) model 76, 189, 191-6
calculations for cervical cancer 198-9 machine quality assurance 438
extensions to 1926 maintenance 438-9
moving isodose surfaces 1956 management accounting 413
redistribution and reoxygenation 193 Manchester System 12, 35, 38-41, 82, 218
repopulation 192-3 carcinoma of body of the uterus 47
tumour shrinkage 193-5 cervical cancer and 447, 45-6, 46,
mechanistic basis 191-2 343-53
parameters 192 dosage 40, 84
lip 288, 290 interstitial planar implants 40-1, 40
local minimum doses 86 moulds 39-40, 39, 39
local rules 439 volume implants 41,41
low dose regions 91 manual afterloading 105-6, 439-40
454 Index
marginal costs 412
MARS Regulations 148
Martinez Universal Perineal Implant
Template (MUPIT) 383, 404
mean central dose 82, 87-90
Meisberger polynomials 15
microSelectron-HDR 103,109
microSelectron-LDR 107-8,112
microSelectron-PDR 110
milligram-hour concept 12
minimum peripheral dose (MPD) 67, 74, 90
minimum target dose 82, 84, 90
Monte Carlo techniques 11,14-15,16, 17,
31,76
mouth, floor of 289, 290
MRI 75-6
multiple damaged sites 181
multiple dose fractionation 168-70
nasal vestibule
brachytherapy 304
interstitial single-plane implant 3031
mould techniques 304
nasopharynx 289, 290
endocavitary brachytherapy 3079
National Institute of Standards and
Technology (NIST) (US) 20
natural dose ratio (NDR) 74
natural prescription dose (NPD) 74
natural volume dose histogram (NVDH)
43-4,46, 92
Newcastle System 47
'no system' method 43
Nominal Standard Dose (NSD) approach
189
normal tissue complication probability
(NTCP) 190,191-2,298
normal-tissue cellular radiosensitivity 2089
Norman-Simon capsules 118-19
nose 288, 290, 303-4
operating costs 411
optimization on distance 57
optimization on volume 57
optimization techniques in stepping source
brachytherapy 57-64
distance and volume implants 57
geometric optimization
on American volume implants 62-3
on European distance implants 63
on European volume implants 63
least square minimization 58-61
dwell time gradient 59-60
polynomial optimization 60-1
linear programming 61
polynomial optimization on volume 64
rules of optimization 57-8
simulated annealing 61-2
volume implants 62-4
oropharynx 290
orthogonal reconstruction method 52-3
output budget 413
paediatric head and neck malignancies 291
palladium-103 4, 9,10
pancreatic cancer, brachytherapy in 317-24
chemotherapy 318
intraoperative brachytherapy 31920
available isotopes 320
indications 319
intraoperative radiation therapy (IORT)
319
pretreatment assessment 317-18
radiation therapy 318-19
surgery 318
treatment planning and technique 3204
Paris Dosimetry System 35-8, 47, 61, 64, 82,
92
basic principles 35-6
dose calculation 37, 37, 38
dose specification 84-5
positioning the sources 367
problems 38
Paris System 287
Paterson-Parker System, see Manchester
System
pelvic-wall reference point 97
perspex phantom 27
pillar and soft palate 289
pinna, skin tumors 398
planning target volume (PTV) 834
polonium-214 (radium C') 214
polynomial optimization on volume 64
POPUMET Regulations 147
potentially lethal damage 166-8
potentially lethal damage repair (PLDR)
166, 174-5
predictive assays 205-20
cell-cycle analysis and tumor response 211
oxygen measurements and tumor
response 209-11
requirements 206
survival assays 206-9
cell adhesive matrix (CAM) assay
206-7
Courtenay-Mills soft agar assay 207-8
normal-tissue cellular radiosensitivity
208-9
tumor-cell radiosensitivity 206
prescription dose 67
pretreatment checks 437
primary care groups 413
procedural checks 437
prostate cancer 75, 257-64
catheter insertion and fixation 259-60
complications and toxicity 263-4
computed tomography-based 3D
planning 261
costs of brachytherapy 419-20
dose prescription 261-3
fluoroscopic implantation procedure 258
implant reconstruction 260-1
implant techniques 258
Mount Vernon applicator and template
technique 260
procedure 258
transrectal ultrasound implantation
technique 258-9
treatment results 263
provider units 413
PTW-Freiburg re-entrant chamber 22
pulsed dose rate (PDR) 105, 110,199-200
'daytime' 200
equivalent regimens 200-1
pulsed low dose-rate brachytherapy 443-9
advantages and disadvantages 443-5
clinical results 448-9
in vitro and in vivo 447-8
radiobiologic rationale 4457
purchases units 413
quality assurance 424
high dose-rate remote afterloading
133-15
low dose-rate remote afterloading 112-31
Quality Index (QI) 69, 72
quality management 423
administrative requirements 429-31
communications 431
motivation and training 429-31
resource requirements 421
audit 424-5
clinical aspects 424-9
confirmation of delivery of treatment
428
effectiveness of treatment 427-8
local tumor control 428
normal-tissue effects 428-9
time scale for follow-up 429
patient, the 426
prescription and treatment procedure
427-8
pretreatment 426
pretreatment assessment 426
target volume 427
treatment intent 426
treatment plan 426-7
tumor volume 427
treatment optimization 427
common elements in programs 133
quality assurance 424
quality control 424
Quimby System 12, 35, 41-2, 47, 82
dose specification 84
radial dose function 16
radiation protection 147-56
afterloading 152
quality assurance in 1489
autoradiography and radiography 149
source identification and description
148
source integrity checks 148-9
source strength measurements 149
source handling 149-52
insertion of sources into patients 150-1
preparation of sources/applicators
149-50
removal of sources from patients 151
source and applicator cleaning 151-2
storage of sealed sources 149
transportation of sources 150
treatment delivery 151
treatment rooms 152-6
radiation protection, cost of 418
radionuclides, production of 4-5
radium 3
radium mass equivalent 12
radium substitutes 3-4
radium-226 11
radon 3
radon-22211,12
Rapid Strand 8, 9
recharging 413
reconstruction of source localization 52-7
localization using film imaging techniques
52-4
isocentric reconstruction method 53-4
orthogonal reconstruction method
52-3
reconstruction methods using
correspondence lines 54
semi-orthogonal reconstruction
method 53
stereo-shift reconstruction method 54
variable angle reconstruction method
54
reconstruction accuracy 55-6
using CT or MRI slices 56
using catheter describing points 56
using catheter image tracking 56
specification of coordinates 52
tracking of catheter images 54-5
rectal dose, reference point for 96-7, 98
rectum
absorbed dose rate 97
high dose-rate brachytherapy in cervical
cancer, effects on 366-7

re-entrant ionization chambers 21-3
reference air kerma rate 13-14
cylindrical line sources and 15
equivalent activity and 14
radium mass equivalent and 14
spherical sources with isotropic emission
and 14
reference dose 90
reference standards 19-21
reference volume 94
retroactive synchronization 165
revenue costs 411-12
rodent ulcers 393
room, treatment, see treatment room
safe practice 433-42
samarium-145 4,10
scalp, skin tumors 398
scattering in irradiated medium 1415
sealed radiation source 7
secondary traceability 19
seed sources 15
Selectron-HDR 109
Selectron-LDR112
Selectron-LDR/MDR 107
Selectron Source Dosimetry System 22
semi-fixed costs 411
semi-orthogonal reconstruction method 53
semi-variable costs 411
servicing 438-9
Sievert Integral 11-12,12, 15
sigmoid colon, high dose-rate brachytherapy
in cervical cancer, effects on 3667
singular value decomposition (SVD) 59
skin, brachytherapy 288
skin tumors, high dose-rate brachytherapy
in 393-9
absorbed dose distribution 394
afterloading systems 394
clinical practice 397-8
dose fractionation schedules 397
mould production 395-7
applicator supports 396
casts 395
disposition of sources 396
Index 455
dosimetry measurement 397 production of plan 436
provisional treatment times 396-7 treatment prescription 435
selection of treatment distance 395 treatment rooms 1526
small bowel, high dose-rate brachytherapy design 153, 434-5
in cervical cancer, effects on 368 for gynecological intracavitary treatments
soft palate 289, 304-7 155
source measurements in solid phantoms 24 high dose-rate remote afterloading 156
source strength 51 intended use 153
specific dose-rate constant 51 location 153
specific gamma ray constant 11, 13 low dose-rate/medium dose-rate remote
specification by activity content 12-13 afterloading 155
specification emission 13-14 radiation and protection requirements
squamous cell carcinoma 393 154
staff (labour) 439 size and layout 153
costs 412 types 152-3
step costs 411 treatment room scatter correction factors
Stepping Source Dosimetry System 64-5 29-30,30
stereo-shift reconstruction method 54, 85 trust hospitals 413
Stockholm System, carcinoma of body of tumor-cell radiosensitivity 206
the uterus and 47 tumor control probability (TCP) 189-90,
sublethal damage repair (SLDR) 162-3 191-2, 298
sunk cost 411
Syed-Neblett applicator 380, 383, 384 ultrasound imaging 75
Syed-Neblett rectal template 389 three-dimensional 77
systems of work 439 Uniformity Index (UI) 69, 72
uterus, body of, carcinoma of
tantalum wire 106 Manchester System and 47
TEM Cathetron 108-9 Stockholm System 47
thermoluminescent dosimetry (TLD) 25
three-dimensional imaging techniques 75-6 vaginal irradiation 47
time-dose factor (TDF) 189 variable angle reconstruction method 54
tissue attenuation factors 52 variable costs 411
tongue 289, 290 VariSource 103, 109, 140, 141
interstitial volume implant 302-3 volume-dose calculations 91
tonsil 289, 306-7 volume specification 82
top-slicing 413 volumes, definition of 82-4
total reference air kerma (TRAK) 93, 94, 95
traceability 19-21 Walstam-type sources of cesium-137 5-6, 6
training 440-1 water phantom 27
treated volume 84 whole breast external-beam irradiation
treatment delivery 437-8 (WBRT) 266-79
treatment planning 435-7
information transfer to staff 436 X-ray transition point 165
information transfer to treatment unit
436-7 ytterbium-169 4,10