.4ctu Oncologicu Vol. 34. No. 4, pp. 517-523.

1995
MONITORING OF BLOOD-'OB CONCENTRATION FOR BORON NEUTRON
CAPTURE THERAPY USING PROMPT GAMMA-RAY ANALYSIS
CORNELIS P.J . RAAI J MAKERS. MARK W. KONIJ NENBERG, L uc DEWIT, DIETRICH HARI TZ. RENE HUI SKAMP.
KATHARI NA PHI LI PP, AXEL SI EFERT. FI NN STECHER-RASMUSSEN and BEN J. MIJ NHEER
The aim of the present study was to monitor the blood-"B concentration of laboratory dogs receiving
boron neutron capture therapy, in order to obtain optimal agreement between prescribed and actual
dose. A prompt gamma-ray analysis system was developed for this purpose at the High Flux Reactor
in Petten. The technique was compared with inductively coupled plasma-atomic emission spectrometry
and showed good agreement. A substantial variation in loB clearance pattern after administration of
borocaptate sodium was found between the different dogs. Consequently, the irradiation commencement
was adjusted to the individually determined boron elimination curve. Mean blood-"B concentrations
during irradiation of 25.8 l- 2.2 pg/g (1 SD, n = 18) and 49.3 5.3 pg/g (1 SD, n = 17) were obtained
for intended concentrations of 25 pg/g and 50 pglg, respectively. These variations are a factor of two
smaller than irradiations performed at a uniform post-infusion irradiation starting time. Such a careful
blood-"B monitoring procedure is a prerequisite for accurately obtaining such steep dose-
response curves as observed during the dog study.
Boron neutron capture therapy (BNCT) is a bimodal
treatment modality taking advantage of the high cross-sec-
tion of the 1B nucleus for capturing thermal neutrons in
comparison with other nuclei present in the body ( 1-3). In
BNCT the dose received by the patient is strongly depen-
dent on the boron concentration in the various tissues in
the irradiation field. Different boron-containing com-
pounds for different types of tumours are under develop-
ment or are being investigated for clinical use ( 2 ) . In
J apan, borocaptate sodium (Na,B,,H,, SH, BSH) has
been used for several years to treat patients with brain
Received 25 J uly 1994.
Accepted 1 December 1994.
From the Netherlands Cancer Institute, Antoni van Leeuwenhoek
Huis. Amsterdam, The Netherlands (C.P.J . Raaijmakers, M. W.
Konijnenberg. L. Dewit. B.J . Mijnheer), University Hospital,
Hamburg, Germany ( D. Haritz), Netherlands Energy Research
Foundation ( R. Huiskamp. K. Philipp. F. Stecher-Rasmussen),
Commission of the European Communities, J oint Research Cen-
tre (A. Siefert), Petten, The Netherlands.
Correspondence to: Dr C.P.J . Raaijmakers, The Netherlands Can-
cer Institute. Plesmanlann 121. NL-1066 CX Amsterdam, The
Netherlands.
tumours, using a thermal neutron beam (4). BSH has also
been proposed for clinical studies of glioma treatment using
the HBl l epithermal neutron beam (5) at the High Flux
Reactor (HFR) in Petten and is therefore used for a healthy
tissue tolerance study on beagle dogs ( 6) . This dose escala-
tion study aims at obtaining the necessary information on
normal tissue tolerance before clinical trials can start. BSH
does not pass the blood-brain barrier, and this results in a
large concentration difference between the tumour and the
healthy brain (7- 1 I ). Because the I0B concentration in the
blood is comparable to the tumour concentration (7, 9, 11)
radiation damage to the brain vasculature is generally
considered to be the limiting factor when using BSH for
BNCT (8, 12). The blood-"B concentration at a specific
time point can only be roughly predicted from the pre-
scribed dose of BSH because of large variations in pharma-
cokinetics observed in animals (9) and patients (7, 11).
Accurate monitoring of the blood-"B concentration is
therefore required if good agreement between prescribed
and actual dose is to be obtained. In the ideal situation the
'OB concentration in the tumour, the healthy brain and the
blood is known. Techniques for determining 1B concentra-
tions in vivo, however. are not yet available.
ic) Scandinavian University Press 1995. ISSN 0284- I86X 517
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518 C. P. J . RAAIJMAKERS ET AL.
Various techniques have been developed for determining
the 'OB concentration in biological samples. Atomic emis-
sion spectrometry (13, 14) and neutron activation (15, 16)
have been reported as being methods by which boron
concentrations in the pg/g range can be measured. Prompt
gamma-ray analysis (PGRA) (15, 17, 18) and direct cur-
rent plasma-atomic emission spectrometry (DCP-AES)
(19) have been used to analyse 1B containing samples
within a time period of about 10 min which is suitable for
the monitoring of the blood-"B concentration.
PGRA is a method for measuring the 1B content of a
sample based on the same nuclear reaction as BNCT:
1B +n-'Li +4He +y
When a sample containing a homogeneous "B distribution
is irradiated with thermal neutrons, a measurement of the
emitted 478 keV gamma rays, e.g. by means of a Ge
detector, may yield the 1B content. Due to the short
acquisition time and the ease of sample preparation, a
PGRA system located near the therapy beam can be used
for monitoring the blood-I0B concentration.
At the HFR in Petten, a PGRA system has been in-
stalled near the HBl l beam. The design, technical and
physical characteristics and some preliminary results of the
PGRA facility have been described elsewhere ( 17, 20). The
PGRA facility has been cross-calibrated against induc-
tively coupled plasma atomic emission spectrometry (ICP-
AES), also available in Petten, and has been used to obtain
the blood-"B level before and during the irradiation of 44
laboratory dogs in the healthy tissue tolerance study (6).
The aims of the present study were: 1) to monitor the
blood-"B concentration of dogs irradiated with BNCT in
such a way that optimal agreement between planned and
actual dose could be obtained; and 2) to test the procedure
for future clinical use, i.e. treatment of glioma patients.
Materials and Methods
Prompt gamma-ray analysis. Since the initial design of
our PGRA set-up, the shielding of both the sample posi-
tion and the detector has been improved, resulting in a
reduction in the background level of the photon energy
spectra. Typical spectra from a distilled water sample
containing 100 pg/g "B and a pure distilled water sample,
obtained with the current set-up are shown in Fig. 1.
Computer analysis of the spectra was performed by sub-
tracting a background spectrum, obtained from a distilled
water sample, from the measured spectrum. The area
under the Doppler broadened line in the stripped spectrum
was determined by aggregating the counts in a window
containing this peak and subtracting the background
counts in the same number of channels at both sides of this
window. Slight variations in reactor power and positioning
of the sample were taken into account by normalizing the
resulting net number of 1B counts to the counts in the
6000 8ooo 8
c
m
-
5 n 4000 'OB
2000
0
450 460 470 480 490 500 510 520 530
~ " " ' ~ " ' ~ " ' ~
Ener gy (keV)
Fig. I . Photon energy spectra from a distilled water sample
containing lOOpg/g "B ( 0 ) and a pure distilled water sample
(0), obtained using the PGRA method. The measuring time was
5min and the sample volume was 1 ml. Only the region of the
spectra containing the Doppler broadened 478 keV "B line is
depicted. The area under this peak is proportional to the boron
concentration of the sample.
2.23 MeV hydrogen capture line of the same spectrum.
The count rate of the hydrogen line functions as a neutron
fluence monitor at the sample position if the hydrogen
content of all samples is the same. Care was therefore
taken to reproduce the sample volume ( 1 .OO ml) to within
1%.
The present PGRA set-up has a sensitivity of about 2
counts per pg 1B per second. The PGRA data presented
in this paper refer to a counting time of 5 min, which has
been chosen as an optimum between accuracy and the
need for rapid analysis during dog irradiations. A com-
plete determination of the 'OB content of a sample, includ-
ing data transfer and analysis, took about 10 min.
A calibration curve using boric acid samples (natural
H,BO,, atomic absorption standard solution, Sigma) of
different dilution, was obtained before every measurement
session. Minor changes in the position of the sample, the
shielding and the detector, and in the performance of the
electronics, were taken into account in this way.
ICP-AES. The standard analysis of boron containing
samples using ICP-AES requires digestion of the sample.
Details of our digestion procedure have been described
elsewhere (21). After digestion of the sample, 0.5 ml of a
40 mg/kg yttrium solution was added as an internal stan-
dard. The digested samples were analysed using a J obin-
Yvon J Y plus ICP-AES machine (Instrument S.A.
Longjumeau Cedex, France). Light emitted by the ele-
ments in the plasma was simultaneously analysed with a
J Y 32 plus polychromator using the 208.959nm and
249.773 nm boron lines, the 259.940 nm iron line, the
228.616 nm cobalt line and the 361.380 nm yttrium line.
To correct for differences in gravity, viscosity and nebu-
lization, all measurements were expressed as element/
yttrium ratios. Boron concentrations were calculated using
the recovery standard and the initial sample weight.
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BLOOD-'"B MONITORING FOR BNC? 519
For comparisons between PGRA and ICP-AES, the
ICP-AES result (total boron concentration) were con-
verted to 1B concentration using either natural abundance
(18.5% wt) or the enrichment factor as given by the manu-
facturer (Centronic Ltd.) .of the BSH.
Blood-"B concentration monitoring. The PGRA facility
was used to monitor the blood-"B concentration of 44
beagle dogs irradiated with the HBl 1 therapy beam after
administration of BSH. In this study 20 dogs were irradi-
ated with an intended blood-"B concentration during
irradiation of 25 pg/g, 19 dogs with an intended concentra-
tion of 50 pg/g and 3 dogs without BSH administration.
Five dogs received fractionated irradiation (4 fractions at
25 pg/g, with a 24-h interval). The first two irradiated dogs
in the 50pg/g group, which served as pilot irradiations,
and two dogs in the 25 pg/g group, which did not receive
the normal BSH administration, are omitted from this
study.
BSH was administered intravenously at 25 and 50 mg 1B
per kg body weight for the 25 and 50pg/g group respec-
tively. As soon as the 1-h infusion of the BSH was finished,
blood samples were taken at frequent time intervals (about
every 20 min) and analyzed immediately using PGRA. The
results were fitted optically and an estimation was made of
the 1B level at which the irradiation should start, taking
into account the measured rate of boron decline as well as
the total irradiation time. About half an hour before the
estimated irradiation commencement start, the dogs were
anaesthetized. When the required blood level value was
reached, another sample was taken, followed immediately
by the start of irradiation. In order to determine the mean
I0B concentration accurately during the whole irradiation
period, the irradiation was briefly interrupted half-way and
another blood sample taken. A final sample was taken
immediately after the end of irradiation.
The average 1B concentration during irradiation and
the elimination half-life within each individual dog were
determined by fitting the data (about 12 data points per
dog) to a one-compartment (single exponential decay) as
well as a two compartment (bi-exponential decay) phar-
macokinetic model. The data points were weighted by their
inverse value in order to reduce the influence of the data
points obtained at small time intervals.
Results
Detection limit and accuracy. The detection limit of the
PGRA set-up, defined as three times the standard devia-
tion (SD) in the distilled water measurement, amounted to
3 pg for 1 g samples. Accuracy in the 1B concentration for
1 g samples amounted to 1 pg/g ( 1 SD) in the range from
1 to lOOpg/g and was mainly caused by variation in
sample position. Some variation in sample volume oc-
curred when taking blood samples for the blood-"B mon-
itoring procedure, resulting in an overall accuracy of
-
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0
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0 0
m
,-
50
40
30
20
10
0
I CP- AES
PGRA
0 20 40 60 80
Time (hours)
Fig. 2. Pharmacokinetic study of a patient receiving a BSH infu-
sion on two occasions with a time interval of 48 h. The '"B
concentration of the blood samples was analysed using PGRA
and ICP-AES. The accuracy amounts to l.Opg/g ( 1 SD) and
0.5 p g / g ( 1 SD) for PGRA and ICP-AES respectively.
Table 1
The concentration of "B in canine blood ufler administration qf
BSH, determined using ICP-AES und PGRA
ICP-AES ICP-AES PGRA PGRA/ICP-AES
( p g / g B) ( p g / g '"B) ( a / g '"B) ratio
49.3 47.2 45.8
61.3 58.7 59.6
54.0 51.7 51.2
47.0 45.0 46.0
40.2 38.5 37.0
33.1 31.7 31.1
31.0 29.7 28.7
Average
0.97
1.02
0.99
1.02
0.96
0.98
0.97
0.99 0.02 (1 SD)
For this batch of BSH an enrichment factor of 95.8% has been
used to convert the ICP-AES result to '"B concentration. The
accuracies amount to 1.5 p g / g and 0.5 p g / g ( I SD) for PGRA and
ICP-AES, respectively.
1.5 pg/g ( 1 SD) for these samples. For ICP-AES, the mean
detection limit ( 3 SD) for the 249.773 nm line, determined
over about 3 000 samples, was 0.05 pg in 5 g. Samples of
30 mg containing 5 pg/g B can be analysed with an accu-
racy of 0.5 pg/g ( 1 SD).
Cross-calibration. Cross-calibrations between PGRA
and ICP-AES were performed on a regular basis, using
samples of boric acid diluted in water as well as in tissue
(mouse liver) and BSH samples diluted in water. Further-
more, canine blood and human blood and urine samples,
taken after administration of BSH, were analysed using
both methods. Good agreement was obtained in cross-cal-
ibrations using blood samples from a beagle dog in the
healthy tissue tolerance study (Table 1) and of a patient in
a pharmacokinetic study on BSH ( 11) (Fig. 2). No system-
atic differences were detected. Good agreement was also
obtained in the other cross-calibrations.
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520 C. P. J . RAAIJMAKERS ET AL
20 '
I
0 50 100 150 200 250 300 350
20' ' ' . ' ' ' . '
I
0 100 200 300 400 500
Ti me after end of infusion (rnin)
Fig. 3. Five examples, including the two extremes, of the blood-
"B concentration of beagle dogs after administration of
BSH (25mg I0B per kg body weight). Each symbol indicates
a specific dog. The concentrations have been determined
using PGRA with an accuracy of 1.5 p g / g ( 1 SD). To get
good agreement between intended (25 p g / g ) and actual 'OB
concentration during irradiation, the start of the treatment
(indicated with an arrow) was adjusted to the measured
"B values of the individual dog. To accurately determine the
mean boron concentration during irradiation, blood samples
were also taken half-way and immediately after the end of the
irradiation.
Table 2
Bl o o ~l - ' ~B monitoring in ihe 25 p g / g group
Dog TI,, Post-infusion Mean 1B
number (min) irradiation concentration
starting (pg/g)
time (rnin)
180 252 134 26.0
480 240 268 25.7
644 23 1 120 25.6
813 305 240 26.2
561 329 259 29.3
660 446 208 24.8
659 336 253 26.4
817 346 230 23.8
764 429 262 25.4
637 360 298 24.1
773 270 3.58 23.5
467 242 208 20.6
812 416 190 26.2
820 269 199 25. 1
626 378 155 28.2
1059 414 170 29.3
1283 417 193 29.2
01 18 278 209 25.4
Average 25.8 & 2.2 ( 1 SD)
The elimination half-life and the mean loB concentration
during irradiation have been derived from a one compartment
pharmacokinetic model with exclusion of points obtained in the
first hour after end of infusion. The uncertainty in the mean 1B
concentration during irradiation amounts to about 0.3 p g / g (1
SD).
Ti me after end of infusion (mi n)
Fig. 4. The blood-"B concentration of a beagle dog after admin-
istration of BSH, determined using PGRA. The arrow indicates
the start of the BNCT irradiation. A bi-exponential decay func-
tion (solid line) has been fitted to obtain the elimination half-life
and the mean blood-lOB concentration during irradiation.
Blood-"B concentration monitoring. Five examples, in-
cluding the two extremes, of the monitoring procedure for
5 different dogs in the 25 pg/g grmp are depicted in Fig. 3.
The magnitude of the blood-I0B values at a specific time
point as well as the shape of the curve varied considerably
between the different dogs. Consequently, the time of start
of the irradiation varied widely from 120 to 358 rnin
(Table 2).
For most dogs, the bi-exponential decay model resulted
in a better fit than the single exponential decay model, due
to a more rapid decrease in the first hour, as shown in Fig.
4. When the data points obtained in the first hour were
excluded, however, no significant difference was found in
the elimination half-life nor in the mean boron concentra-
tion obtained from the fitted curves during irradiation. The
loB concentration during irradiation was obtained from
the integral of the fitted curve over the irradiation time.
The uncertainty in this value, determined from the stan-
dard error of the fit, amounted to about 0.3 pg/g (1 SD).
A mean blood-"B concentration during irradiation of
25.8 2.2 pg/g (1 SD, n =18) and 49.3 & 5.3 pg/g (1 SD,
n= 17) was obtained for the 25pg/g and 50pg/g group
respectively. The mean elimination constant was obtained
by averaging the individual elimination constants, deter-
mined using the one-compartment model with exclusion of
the data points obtained in the first hour. The elimination
constants in the two boron groups were not significantly
different. The resulting mean elimination half-life was
320f20mi n (1 SE of the mean, n =35). The results
obtained in the 25 pg/g group are given in Table 2.
From the fitted curves it was possible to calculate the
loB concentrations during irradiation if a uniform time
interval between end of infusion and start of irradiation
was used. This would result in a standard deviation of the
distribution in mean 1B concentrations of about 20%. I n
other words, if a uniform post-infusion irradiation starting
time had been used instead of an individually determined
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BLOOD-"'B MONITORING FOR BNCT 521
starting time, the same mean '"B concentration would have
been obtained (if the proper time interval had been cho-
sen) but the spread in this value would have been twice as
large.
Discussion
A PGRA system was developed and used at the HFR in
Petten to monitor the blood-"B concentration of labora-
tory dogs receiving BNCT irradiation in a healthy tissue
tolerance study. The time of start of irradiation was ad-
justed to the individually determined boron elimination
curve for each dog, resulting in a good agreement between
intended and obtained I0B concentration during irradia-
tion. The standard deviation in the mean blood-'"B con-
centration amounted to 8% and 11% for the 25 pg/g and
50 pg/g groups respectively and was reduced by a factor of
two compared with irradiations at a uniform post-infusion
irradiation starting time.
PGRA and DCP-AES, have both been used in support
of a large animal healthy tissue tolerance study in
Brookhaven (19, 22). The results reported by Gavin et al.
(22) indicate, however, that despite their use of blood-'"B
monitoring, differences between intended and obtained
mean blood-'"B concentration during irradiation occurred
which, considering the expected steepness of the dose-
response curves, are undesirable for a dose-response study
at a predefined boron level and would be unacceptable for
clinical trials. To some extent a comparison is possible
between our results and the actual data obtained in the
Brookhaven study (22). From the data presented in that
paper, a standard deviation in the mean '"B concentration
during irradiation of about 18% for the 25 pg/g and 50 p g /
g groups can be deduced. This value is about twice as high
as the uncertainty we obtained.
From the preliminary dose-response curves resulting
from the Petten healthy tissue tolerance study (23) it can
be deduced that an increase in dose of lo'%) can result in an
increase in response of about 40'%. Approximately 60%)
and 80% of the total dose results from the boron neutron
capture reaction for the 25 p g / g and 50 pg/g group respec-
tively. The agreement between prescribed and actual dose,
therefore, largely depends on the agreement between in-
tended and obtained blood-"B concentration during irra-
diation. Consequently, a careful blood-"'B monitoring
procedure is essential for obtaining accurately the observed
steep BNCT dose response curves.
A large spread in '"B concentrations reveals additional
problems in the analysis of biological responses. The total
dose in BNCT consists of a '"B related component and
components which are independent of the boron concen-
tration. The main boron independent dose components are
the gamma-ray dose and the dose from epithermal neu-
trons. These various components have a different relative
biological effectiveness (RBE). The proportions of the
components change with "B concentration and subsequent
irradiation time. Due to the uncertainties in the applied
RBE values and the not fully understood interrelationship
of blood-"'B levels and irradiation time (22). uncertainties
are introduced when comparing irradiations at different
blood-'"B levels. Good agreement between intended and
obtained "B concentration, therefore, is not only a prereq-
uisite for obtaining steep dose-response curves at a pre-
defined blood-"B concentration, it also allows systematic
investigation of the various parameters that determine the
dose in BNCT.
The main source of discrepancy between intended and
obtained blood-'"B concentration was estimation of the
optimal start of irradiation which was based on an extrap-
olation of the '"B levels obtained before irradiation. Owing
to the relatively long irradiation times ( 1.3 to 2.2 h) the
rate of boron decline during irradiation, which obviously
influences the mean "B concentration, is not always ex-
actly predicted by the extrapolation, as can be deduced
from the examples presented in Fig. 3.
Unexpected drops in boron level, presumably due to
statistical and biological variations, sometimes resulted in
too early a start of the irradiation and consequently too
high a "B concentration during irradiation. By careful
analysis, using a computer fit through the values already
obtained, such errors can be avoided. In one case an
erroneous administration of BSH was detected. The irradi-
ation was cancelled, again illustrating the usefulness of a
'"B monitoring system.
Differences between intended and obtained blood-'"B
concentration were also partly caused by the uncertainty
of the PGRA method. Some variation in sample vol-
ume occurred resulting in an uncertainty of about
1.5 pg/g (1 SD) for each data point. The PGRA set-up
can be further improved. Optimisation of the shielding
(more 'Li containing shielding), the use of a second detec-
tor, a better reproducibility in sample position, an inde-
pendent neutron fluence monitor and faster data
acquisition and analysis software can improve accuracy of
the PGRA result and shorten acquisition time. Some of
these features will be tested in the near future for our
PGRA set-up.
Given the above considerations, it will be possible to
further optimize the accuracy in the mean '"B concentra-
tion during irradiation. Due to the biological nature of the
"'B elimination, an uncertainty of less than about 5% ( 1
SD) would, be difficult to achieve. Adjusting the irradia-
tion time to the measured "'B concentrations before and
halfway through the irradiation is another way to achieve,
in principal, a higher accuracy in the delivery of the
prescribed dose but will introduce additional uncertainties
until the problems of dose calculation of BNCT are better
understood.
In the present study only the parameters which directly
influence the mean blood-'('B concentration during irradia-
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522 C. P. J. RAAIJMAKERS ET AL.
tion and the inter-animal variation in 'OB elimination were
investigated. The results of the complete pharmacokinetic
study will be published later. The obtained elimination
half-life and the variation in 'OB concentration at a fixed
time point appear similar to the results reported by Kraft
et al. (9) in a heterogeneous group of tumour bearing
dogs. Detailed comparison however, is difficult because in
that study only 2 data points were obtained within 8 h of
the end of infusion. The elimination half-life obtained in
this study agrees well with the half-life of approximately
300 min reported by Gavin et al. (24). No evidence was
found in our study of a disruption in the 1B elimination
after anaesthetization, contrary to the preliminary blood-
IOB monitoring results for one dog reported by Bauer et al.
(19).
Our study showed that the blood boron values obtained
during irradiation were extremely consistent. While this
eases analysis of the response, the other uncertainties in
the interpretation of BNCT remain very large. The "B
measurements in blood samples provide an accurate value
for the "B levels for the vasculature of the brain. Obvi-
ously, no direct information is obtained in this way about
the "B concentration in the healthy tissues or in the
tumour. The dose to these tissues will have to be derived
from blood/healthy-tissue and blood/tumour ratios
obtained from biodistribution studies. Due the uncer-
tainty in these ratios (7, 9, 11) and the large heterogeneity
in the 'OB distribution reported for tumour tissue ( I I ),
the uncertainty in the dose to the tumour will be rel-
atively large, despite an accurate blood-"B concentration
monitoring. However, since the 1B concentration in
the blood can be monitored, the dose to the brain vascula-
ture, which is generally believed to determine the healthy
tissue tolerance for BNCT using BSH, can well be con-
trolled.
In the present investigation, PGRA and ICP-AES were
used to determine "B concentrations in blood. In various
cross-calibrations, it was shown that both techniques are
reliable and accurate. The use of PGRA for monitoring the
"B blood concentration of beagle dogs receiving BNCT
irradiation proved to be very useful. Good agreement was
obtained between intended and obtained 1B blood concen-
tration during irradiation by adjusting the time of start of
the irradiation to the individual 1B elimination curves. The
spread in the "B concentration during irradiation was
reduced by a factor of two, compared with irradiations at
a uniform post-infusion irradiation starting time. A careful
blood-'"B monitoring procedure is a prerequisite for ob-
taining accurately steep dose response curves and assures a
well controlled dose to the brain vasculature.
ACKNOWLEDGEMENTS
This work was financially supported by a grant of the Nether-
lands Cancer Foundation (NKB Grant NKI 90-03).
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REFERENCES
Allen BJ, Moore DE, Harrington BV, eds. Progress in neu-
tron capture therapy for cancer. New York: Plenum Press,
1992.
Barth RF, Soloway AH, Fairchild RG, Brugger RM. Boron
neutron capture therapy for cancer. Cancer 1992; 70: 2995-
3007.
Dewit L, Moss R, Gabel D. New developments in neutron
capture therapy. Eur J Cancer 1990; 26: 912-4.
Hatanaka H, Sano K, Yasukochi H. Clinical results of boron
neutron capture therapy. In: Allen BJ , Moore DE, Harrington
BV, eds. Progress in neutron capture therapy for cancer. New
York: Plenum Press, 1992: 561-8.
Moss RL. Current overview of the approach of clinical trials
at Petten. In: Gabel D, Moss RL, eds. Boron neutron capture
therapy; Toward clinical trials of glioma treatment. New
York: Plenum Press, 1992: 33-46.
Philipp K, Gavin P, Casado J , Siefert A, Moss R, Huiskamp
R. Developments in healthy tissue tolerance studies as a
precondition for clinical application of boron neutron capture
therapy. In: Soloway AH, Barth RF, Carpenter DE, eds.
Advances in neutron capture therapy. New York: Plenum
Press, 1993: 571-4.
Fankhauser H, Stragliotto G, Zbinden P. Borocaptate sodium
(BSH) pharmacokinetics in glioma patients. In: Gabel D,
Moss RL, eds. Boron neutron capture therapy; Toward clini-
cal trials of glioma treatment. New York: Plenum Press, 1992:
155-62.
Gavin PR, Kraft SL, DeHaan CE, Griebenow ML, Moore
MP. A large animal model for boron neutron capture therapy.
In: Allen BJ, Moore DE, Harrington BV, eds. Progress in
neutron capture therapy for cancer. New York: Plenum Press,
1992: 479-84.
Kraft SL, Gavin PR, DeHaan CE, et al. Borocaptate sodium:
A potential boron delivery compound for boron neutron
capture therapy evaluated in dogs with spontaneous intracra-
nial tumors. Proc Natl Acad Sci USA 1992; 89: 11973-7.
Slatkin D, Micca P, Forman A, Gabel D, Wielopolski L,
Fairchild R. Boron uptake in melanoma, cerebrum and blood
from Na,B,,H, ,SH and Na,B,,H22S, administered to mice.
BiochemPharmacol 1986; 35: 1771-6.
Haritz D, Gabel D, Huiskamp R. Clinical phase-I study of
Na,B,,H,,SH (BSH) in patients with malignant glioma as
precondition for boron neutron capture therapy (BNCT). Int
J Radiat Oncol Biol Phys 1994; 28: 1175-81.
Slatkin DN, Stoner RD, Rosander KM, Kalef-Ezra J A, Lais-
sue J A. Central nervous system radiation syndrome in mice
from preferential "B(n, c()'Li irradiation of brain vasculature.
Proc Natl Acad Sci USA 1988; 85: 4020-4.
Barth RF, Adams DM, Soloway AH, Mechetner EB, Alam
F, Anisuzzaman AKM. Determination of boron in tissues and
cells using direct-current plasma atomic emission spec-
troscopy. Anal Chem 1991; 63: 890-3.
Tamat SR, Moore DE, Allen BJ . Determination of boron in
biological tissues by inductively coupled plasma atomic emis-
sion spectrometry. Anal Chem 1987; 59: 2161-4.
Fairchild RG. Gabel D, Laster BH, Greenberg D, Kiszenick
W, Micca PL. Microanalytical techniques for boron analysis
using the l0B(n, cc)'Li reaction. Med Phys 1986; 13: 50-6.
Gabel D, Holstein H, Larsson B, et al. Quantitative neutron
capture radiography for studyinp the biodistribution of tu-
mor-seeking boron-containing compounds. Cancer Res 1987;
47: 5451-4.
Konijnenberg MW, Raaijmakers CPJ . Constantine G, et al.
Prompt gamma-ray analysis to determine "B concentrations.
A
c
t
a

O
n
c
o
l

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

1
1
0
.
1
6
8
.
1
3
.
2
0
8

o
n

0
7
/
1
7
/
1
4
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
BLOOD-'"B MONITORING FOR BNCT 523
In: Soloway AH,
neutron capture
419-22.
Barth RF. Carpenter DE. eds. Advances in
therapy. New York: Plenum Press, 1993:
18. Kobayashi T, Kanda K. Microanalysis system of ppm-order
'OB concentrations in tissue for neutron capture therapy by
prompt gamma-ray spectrometry. Nucl Instrum Meth 1983;
204: 525-31.
19. Bauer WF. Micca PL, White BM. A rapid method for the
direct analysis of boron in whole blood by atomic emission
spectroscopy. In: Soloway AH, Barth RF, Carpenter DE, eds.
Advances in neutron capture therapy. New York: Plenum
Press, 1993: 403-7.
20. Konijnenberg MW. Stecher-Rasmussen F. Raaijmakers CPJ ,
et al. Boron concentration measurements for the Petten
BNCT project. In: Allen BJ. Moore DE. Harrington BV. eds.
Progress in neutron capture therapy for cancer. New York:
Plenum Press, 1992: 293-6.
21. Gregoire V, Begg AC, Huiskamp R, Verrijk R, Bartelink H.
Selectivity of boron carriers for boron neutron capture ther-
apy: pharmacological studies with borocaptate sodium, L-
boronophenylalanine and boric acid in murine tumors.
Radiother Oncol 1993; 27: 46-54.
22. Gavin PR, Kraft SL. DeHaan CE, Swartz CD, Griebenow
ML. Large animal normal tissue tolerance with boron neut-
ron capture. Int J Radiat Oncol Biol Phys 1994; 28: 1099-
106.
23. Philipp KH, Huiskamp R, Casado J , Siefert A, Moss RL.
Healthy tissue tolerance studies in dogs after boron neutron
capture therapy. In: Auterinen I, Kallio M, eds. Proceedings
of the CLINCT BNCT Workshop. Helsinki: Helsinki Univer-
sity of Technology Report TKK-F-A718. 1994: 94-6.
24. Gavin PR, Kraft SL, Wendling LR. Miller DL. Canine
spontaneous brain tumours-a large animal study for BNCT.
Strahlenther Onkol 1989; 65: 225-8.
A
c
t
a

O
n
c
o
l

D
o
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n
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o
a
d
e
d

f
r
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i
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f
o
r
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a
h
e
a
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t
h
c
a
r
e
.
c
o
m

b
y

1
1
0
.
1
6
8
.
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o
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y
.