Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 4, pp.

1170 1176, 2006

Copyright 2006 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/06/$see front matter

doi:10.1016/j.ijrobp.2006.02.041

CLINICAL INVESTIGATION Female Genital Tract

PRELIMINARY OUTCOME AND TOXICITY REPORT OF EXTENDED-FIELD,

INTENSITY-MODULATED RADIATION THERAPY FOR
GYNECOLOGIC MALIGNANCIES

JOSEPH K. SALAMA, M.D.,* ARNO J. MUNDT, M.D.,* JOHN ROESKE, PH.D.,*

AND NEIL MEHTA, M.D.*

*Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL; and Department of Radiation Oncology,
University of Illinois, Chicago, IL

Purpose: The aim of this article is to report a preliminary analysis of our initial clinical experience with
extended-field intensity-modulated radiotherapy for gynecologic malignancies.
Methods and Materials: Between November 2002 and May 2005, 13 women with gynecologic malignancies were
treated with extended-field radiation therapy. Of the women, 7 had endometrial cancer, 4 cervical cancer, 1
recurrent endometrial cancer, and 1 suspected cervical cancer. All women underwent computed tomography
planning, with the upper vagina, parametria, and uterus (if present) contoured within the CTV. In addition, the
clinical target volume contained the pelvic and presacral lymph nodes as well as the para-aortic lymph nodes. All
acute toxicity was scored according to the Common Terminology Criteria for Adverse Events (CTCAE v 3.0). All
late toxicity was scored using the Radiation Therapy Oncology Group late toxicity score.
Results: The median follow-up was 11 months. Extended-field intensity-modulated radiation therapy (IMRT)
for gynecologic malignancies was well tolerated. Two patients experienced Grade 3 or higher toxicity. Both
patients were treated with concurrent cisplatin based chemotherapy. Neither patient was planned with bone
marrow sparing. Eleven patients had no evidence of late toxicity. One patient with multiple previous
surgeries experienced a bowel obstruction. One patient with bilateral grossly involved and unresectable
common iliac nodes experienced bilateral lymphedema. Extended-field-IMRT achieved good local control with
only 1 patient, who was metastatic at presentation, and 1 patient not able to complete treatment, experiencing
in-field failure.
Conclusions: Extended-field IMRT is safe and effective with a low incidence of acute toxicity. Longer follow-up
is needed to assess chronic toxicity, although early results are promising. 2006 Elsevier Inc.

Intensity-modulated radiation therapy, Gynecology, Extended field, para-aortics.

INTRODUCTION However, treatment of the pelvis and para-aortic nodal

Extended-field radiotherapy, treatment of the pelvic and
para-aortic nodal chains in contiguity, has long been a
component of the armamentarium against gynecologic
malignancies. In cervical cancer patients, the presence of
metastatic spread to the para-aortic nodes portends a poor
prognosis (1). In patients with locally advanced cervical
cancer and positive para-aortic nodes, treatment of both
the primary and gross nodal disease is necessary for
radical treatment (2). A randomized trial conducted by
the Radiation Therapy Oncology Group (RTOG) demon-
strated an overall survival benefit to extended-field ra-
diotherapy over pelvic radiotherapy for patients with
cervical cancer (3). Furthermore, extended-field radiation
therapy has been shown to improve local control in stage
IIIC endometrial cancer patients (4).
regions is not without its own inherent toxicity. In the
recent update of the RTOG 90-01 trial, 12% of patients
treated with extended-field radiotherapy had late Grade 3
to 4 toxicity (5). RTOG 79-02 reported an 8% risk of
Grade 4 to 5 toxicity with extended-field treatment com-
pared with 4% in the pelvic-only arm, which approached
statistical significance (p 0.06) (3). The addition of
concurrent chemotherapy to extended-field radiotherapy
magnifies the acute toxicity. Single-institution studies
have reported 24% acute Grade 3 to 4 gastrointestinal
toxicity and 24% incidence of treatment interruptions
with concomitant cisplatin and extended-field radiation
therapy (6, 7). Prospective phase II cooperative group
trials have reported 49% Grade 3 to 4 acute bowel tox-
icity (8) and 49% acute Grade 3 to 4 toxicities (2) with

Reprint requests to: Joseph K. Salama, M.D., Department radonc.uchicago.edu

of Radiation and Cellular Oncology, University of Chicago, 5758 Received Nov 7, 2005, and in revised form Jan 24, 2006.
S. Maryland Avenue, MC 9006, Chicago, IL 60637-1407. Tel: Accepted for publication Feb 9, 2006.
(773) 702-6870; Fax: (773) 834-7340; E-mail: jsalama@

1170
 Extended-field gynecologic IMRT J. K. SALAMA et al. 1171

the delivery of concomitant chemotherapy and extended- Based on our prior experience (12), we generated 7- to 9-field,
field radiation therapy. equally spaced coplanar IMRT plans for each patient. Because 6
As a means of reducing toxicity, intensity-modulated MV photons had been shown to have a slightly sharper dose
radiation therapy (IMRT) of the pelvis has been shown to gradient over higher-energy beams (12), all patients were planned
and treated with this energy. The prescription dose for the EF-
decrease the incidence of acute Grade 2 gastrointestinal
IMRT plans was 45 Gy, delivered in 1.8-Gy daily fractions.
toxicity as well as Grade 2 or greater neutropenia (9, 10). Patients with clinically evident gross disease in the para-aortic
We began exploring the use of extended-field IMRT, to treat chain or pelvis received an additional 9-Gy boost to gross disease
the entire pelvic and para-aortic volume for the treatment of delivered in 1.8-Gy daily fractions. Patients were treated on a
node positive endometrial and cervical cancer at our insti- Varian CL 2100 CD accelerator (Varian Associates, Palo Alto,
tution in 2002. The goal of this treatment was to reduce the CA) equipped with either an 80- or 120-leaf multileaf collimator
volume of small bowel, rectum, bone marrow, and bladder and automatic beam sequencing software. The IMRT treatments
irradiated, in an attempt to decrease the acute toxicity of this planned with Corvus at the University of Chicago were delivered
treatment. We report here a preliminary analysis. in the step and shoot mode, while those planned with Eclipse at the
University of IllinoisChicago were delivered with the sliding
window technique. The accuracy of setup was verified on the first
day of treatment and then weekly with orthogonal X-ray films to
METHODS AND MATERIALS
verify the location of the isocenter. These films were checked
Between 2002 and 2005, 13 women with gynecologic malig- before treatment by the attending radiation oncologist.
nancies were treated with extended-field IMRT (EF-IMRT) in the Patients were evaluated weekly during the course of radiation
Department of Radiation and Cellular Oncology at the University therapy to assess treatment-related sequelae. Acute toxicities, mea-
of Chicago and the Department of Radiation Oncology at the sured from the initiation of treatment to 60 days after completion,
University of IllinoisChicago. As previously described, each pa- were graded by the Common Terminology Criteria for Adverse
tient underwent computed tomography (CT) based planning be- Events version 3.0 (CTCAE v 3.0). After the completion of radi-
fore the initiation of treatment. Simulation consisted of the patient
lying supine on a dedicated CT simulator couch (11). A custom-
ized immobilization device (Alpha cradle, Smithers Medical Prod- Table 1. Clinicopathologic characteristics of patients studied
ucts, Inc., North Canton, OH) was fabricated for each patient about
Characteristic N %
the upper and lower body to ensure reproducible daily setup and to
minimize patient motion. Subsequently, each patient underwent a No. of patients 13
planning CT from the mid thorax to the ischial tuberosities (PQ Age (y)
5000, Marconi Medical Systems, Cleveland, OH). Most patients Median 62
had oral, intravenous, and rectal contrast administered. Range 5176
Volumes were drawn on each individual planning CT slice and Tumor site
followed the International Commission on Radiation Units and Endometrial 7 54
Measurements (ICRU) Report No. 50 recommendations. The gross Recurrent endometrial 1 8
tumor volume (GTV) consisted of all areas of known gross dis- Cervical 4 31
Suspected cervical 1 8
ease. The clinical target volume (CTV) included all areas of gross
Histology
and potentially microscopic disease and included the upper half of Squamous 3 23
the vagina, parametria, uterus (if present), and regional lymph Adenocarcinoma 4 31
node regions (common, internal and external iliacs, and para-aortic Adenosquamous 1 8
regions). The CTV in the para-aortic region was contiguous with Carcinosarcoma 4 31
the pelvic lymph node stations and generously encompassed the Sarcoma 1 8
aorta and inferior vena cava with at least a 1.5-cm margin. The Extent of disease
superior CTV border started 1 vertebral body above the level of Localized 11 85
either any gross nodal involvement or any pathologically positive Metastatic 2 15
node and was usually at the level of T12-L1. When needed, the Highest nodal region involved
Common iliac 2 23
superior aspect of the CTV was modified laterally for kidney
Para-aortic 11 77
sparing and anteriorly for small bowel sparing. The presacral SurgeryRT sequence
region was included to the level of S3 to ensure coverage of the No surgery 2 15
presacral lymph nodes and the uterosacral ligament. The kidneys, Surgery, then RT 11 85
small bowel, and rectum (defined from the sigmoid flexure to the Chemotherapy
anus), as well as the bladder were contoured on all patients. Some No 1 8
patients had bone marrow contoured as well. The CTV was ex- Yes 12 92
panded 1 cm uniformly to create the PTV accounting for patient Intracavitary brachytherapy
motion and set-up uncertainty. No 6 46
The EF-IMRT plans were generated using commercially avail- Yes 7 54
Number of IMRT fields
able, inverse planning software (CORVUS versions 3.0 and 4.0,
Seven 8 62
NOMOS Corporation, Sewickley, PA; or Eclipse, Varian Medical Nine 5 38
Systems, Palo Alto, CA). The goals of planning were to provide a
homogeneous PTV dose while minimizing dose to the kidneys, Abbreviations: IMRT intensity-modulated radiation therapy;
small bowel, bladder, rectum, and bone marrow. RT radiation therapy.
1172 I. J. Radiation Oncology Biology Physics
ation therapy, patients were seen at 3-month intervals by radiation
oncologists, medical oncologists, and gynecologic oncologists.
Radiologic studies, serum markers, and blood chemistries were
ordered at the discretion of the treating oncologists. Adverse
events 60 days after the completion of treatment were graded
according to the RTOG late-toxicity scale.
RESULTS
Patient characteristics are summarized in Table 1. The
median age of patients was 62 years old. Median follow-up
is 11 months (range, 129 months). Four of the patients had
cervical cancer primaries, and 1 patient had noninvasive
cervical neoplasia with positron emission tomography
(PET) detected and biopsy-proven involved pelvic and cer-
vical nodes. Eleven patients underwent pre-radiotherapy
surgery usually consisting of total abdominal hysterectomy,
bilateral salpingo-oophorectomy, pelvic washings, and pel-
vic and peritoneal lymph node sampling. Twelve patients
received chemotherapy either before (5 patients), concur-
rently (5), or after (2) extended-field radiation therapy. Ten
patients had pathologically proven para-aortic nodal in-
volvement. Two patients with gross para-aortic disease re-
quired radiotherapy boost, 1 with oblique fields and 1 with
IMRT.
A high degree of conformity to the PTV was achieved in
all EF-IMRT plans. Figure 1 shows axial images of the
lower pelvis, upper pelvis, and abdomen, at the level of the
kidneys for a representative patient treated with extended-
field IMRT. The first column shows the actual isodose
curves from the IMRT plan compared with a four-field plan
in the second column and an anterior-posterior/posterior-
anterior (AP/PA) plan in the third column. Furthermore, in
Fig. 2, dosevolume histograms (DVHs) of a representative
patient show how IMRT plans spare high doses to the
Fig. 1. Intensity-modulated radiation therapy (IMRT), four-field, and anterior-posterior/posterior-anterior (AP-PA)
isodose distributions are presented for a representative patient in the low pelvis, upper pelvis, and kidney region. The
30%, 50%, 70%, 90%, and 100% isodose curves are presented for each of these plans.
Volume 65, Number 4, 2006
kidneys, small bowel, and rectum, with larger volumes
receiving lower doses.
Acute toxicity is summarized in Table 2. EF-IMRT was
well tolerated with only 2 patients experiencing Grade 3 or
greater acute toxicity. Two patients experienced Grade 4
toxicity, 1 with depressed leukocyte counts (1000/mm3)
and 1 with isolated neutropenia (500/mm3). Both of these
patients were treated with concurrent weekly cisplatin che-
motherapy. One was planned before the introduction of
bone marrow sparing, and the other had a boost region along
the pelvic sidewall preventing bone marrow sparing. De-
spite lowered cell counts, both patients completed treatment
without requiring an interruption in scheduled radiotherapy.
The patient with isolated neutropenia also exhibited Grade 3
nausea immediately after chemotherapy infusion. Two pa-
tients required blood transfusions in the first week of radio-
therapy, and this was not treatment related.
Although all patients experienced acute large bowel tox-
icity, none required intervention greater than intermittent
anti-diarrheal medication (Grade 2). Only 3 patients expe-
rienced acute genitourinary toxicity with 1 of these 3 re-
quiring pharmacologic intervention.
Two patients experienced late toxicity from their total
cancer management. One patient with multiple prior ab-
dominal surgeries experienced a small bowel obstruction
requiring a partial colectomy (Grade 3). In addition, another
patient with grossly involved common iliac nodes experi-
enced bilateral lower-extremity lymphedema, although it
was uncertain whether this was caused by recurrent tumor
or treatment effect.
At last follow-up, 2 patients experienced in-field failures.
One was metastatic at presentation, and the other had her
treatment halted before the intended prescription dose was
reached because of a pulmonary embolus. Otherwise, EF-
 Extended-field gynecologic IMRT J. K. SALAMA et al. 1173

PTV GTV

100 100

80 80

Percent Volume

Percent Volume
60 60
2-Fields 2-Fields
4-Fields 4-Fields
IMRT IMRT
40 40

20 20

0
0
0 20 40 60 80 100 120
0 20 40 60 80 100 120
Percent Dose
Percent Dose

Left Kidney Right Kidney

100 100

80 80

Percent Volume
Percent Volume

60 60

2-Fields 2-Fields
4-Fields
4-Fields
IMRT
IMRT
40
40

20
20

0
0
0 20 40 60 80 100 120
0 20 40 60 80 100 120
Percent Dose
Percent Dose

Rectum Bowel

100 100

80 80
Percent Volume
Percent Volume

60 60
2-Fields 2-Fields
4-Fields 4-Fields
IMRT IMRT
40 40

20 20

0 0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Percent Dose Percent Dose

Fig. 2. Comparison dosevolume histograms (DVHs) for a representative patient treated with extended-field, intensity-
modulated radiation therapy (EF-IMRT).

IMRT has achieved local control with 1 year actuarial local tastases, 1 with peritoneal carcinomatosis, 1 in mediastinal
control of 90% (95% CI, 4799%), as shown in Fig. 3. Six and hilar lymph nodes, and 1 in the untreated para-aortic
patients failed outside the radiation field; 3 with liver me- chain. Although survival data must be interpreted cautiously
in this heterogeneous patient population, at most recent
follow-up 2 patients have died, resulting in an actuarial
Table 2. Acute toxicity in patients studied 1-year survival of 92% (95% CI, 57%99%).
Grade
DISCUSSION
Toxicity Total 1 2 3 4
Extended-field radiotherapy, treating both the para-aortic
Hematologic nodal region and the pelvis has been shown to improve
Blood leukopenia 7 2 3 1 1 survival in endometrial and cervical cancer patients with
Neutropenia/granulocytopenia 2 0 1 0 1
Anemia 12 5 7 0 0
pathologically involved para-aortic lymph nodes (3, 13).
Gastrointestinal Randomized trials have demonstrated a benefit to concur-
Large intestine 13 2 11 0 0 rent cisplatin based chemotherapy and radiation therapy for
Nausea 5 2 2 1 0 advanced cervical cancer (14, 15). In addition, many ad-
Genitourinary vanced endometrial cancer patients are also treated with
Dysuria 3 2 1 0 0
concurrent chemoradiotherapy (16).
1174 I. J. Radiation Oncology
1.00
0.90
0.80
Freedom from Infield Failure
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0 3 6 9 12 15 18
Time (months)
Fig. 3. Freedom from infield failure.
Traditionally, extended-field radiotherapy has been deliv-
ered via opposed AP/PA fields targeting the para-aortic
lymph nodes. With this technique, generous portions of the
small bowel have been included in the treatment field caus-
ing acute changes in bowel habits as well as increasing the
likelihood of chronic toxicity (2). Furthermore, delivery of
dose to grossly involved nodes has been limited by concerns
of toxicity to adjacent critical structures (1, 17). Recently,
concerns about renal toxicity (18) have become increasingly
important as many patients treated with extended-field ra-
diotherapy have also been treated with concurrent nephro-
toxic chemotherapy (2, 6, 8). In addition, as extended treat-
ment portals encompass a large volume of bone marrow
(19), potential hematologic count depression could lead to
untoward treatment interruptions, reducing the number and
intensity of chemotherapy cycles (6).
Previous investigations demonstrated the dosimetric ad-
vantages of intensity modulated radiation therapy over 3-D
conformal radiotherapy for extended-field treatments. Por-
telance et al. (20) performed a dosimetric analysis to deter-
mine the feasibility of intensity modulated pelvic and para-
aortic radiation in contiguity. Ten patients who underwent
CT simulation from T2 through the ischial tuberosities were
planned with conventional two-field and four-field plans.
These were compared with IMRT plans of 4, 7, and 9 fields.
IMRT plans had a statistically significant (p 0.05) reduc-
tion in the volume of small bowel irradiated: 11%, 15%, and
13.6% for the 4, 7, and 9 field IMRT plans vs. 35% and 34%
for the 2 and 4 field plans. Furthermore, the rectal dose
was significantly lowered with IMRT (p 0.001) (20). As
the aforementioned dosimetric study demonstrated a benefit
to IMRT in the extended-field setting, we did not perform
formal dosimetric comparisons. However, the isodose curves
and DVHs for a representative patient, shown in Figs. 1 and
2, suggest that IMRT can reduce the renal volume receiving
greater than 20 Gy. Furthermore, the volume of rectum and
bowel in the high dose regions is less with IMRT plans than
that with conventional 2-field and 4-field plans.
With our treatment design and dose regimen, we found
that extended-field IMRT and concomitant chemotherapy
Biology Physics Volume 65, Number 4, 2006
could be safely and effectively delivered with minimal
toxicity. All acute radiation related toxicity was Grade 2 or
less. Although 2 patients (15%) experienced acute Grade 4
hematologic toxicity, neither was related to radiation ther-
apy nor necessitated a treatment break. This compared fa-
vorably with previously reported trials of concurrent che-
motherapy and radiation therapy. Those trials used more
intense chemotherapy and radiation regimens. Specifically,
the Gynecologic Oncology Group (GOG) trial treated the
PA nodes to 45 Gy while delivering 1000 mg/m2/day 5-FU
for 96 h and 50 mg/m2 cisplatin in weeks 1 and 5 (2).
Furthermore, RTOG 92-10 administered 48 Gy to the para-
aortics with known metastatic para-aortic sites boosted to 54
21 24 27
to 58 Gy in 1.2 Gy twice-daily fractions. This radiotherapy
regimen was delivered with 1000 mg/m2/day 5-FU for 96 h
and cisplatin 75 mg/m2 on Days 1 and 22 for two or three
cycles. In these trials, 31% of patients experienced acute
Grade 3 to 4 nonhematologic toxicity (2), 76% acute Grade
3 to 4 chemotherapy related toxicity was observed, and 31%
of patients did not complete the scheduled course of radio-
therapy (21). In our study, no patient to date has exhibited
any renal toxicity. Longer follow-up is required to deter-
mine if this low level of acute toxicity seen in our patients
will translate into decreased rates of chronic toxicity.
Additionally, neither of the 2 patients in our study who
experienced Grade 4 hematologic toxicity was treated with
bone marrow sparing IMRT. This technique has been shown
dosimetrically to reduce the volume of bone marrow irra-
diated to dosimetrically decrease the volume of bone mar-
row irradiated (22), and to clinically correlate with de-
creased Grade 2 leukopenia (23).
Extended field-IMRT concomitantly with chemotherapy
was effective in preventing in-field failure. Only 2 of our
patients failed in the radiotherapy portal. One patient died of
DIC shortly before completing her parametrial boost. Au-
topsy revealed residual disease in the para-aortics, and was
scored as a failure. The second patient with carcinosarcoma
developed peritoneal carcinomatosis, and was scored as a
local pelvic failure because of in-field tumor recurrence.
However, she had no evidence of recurrence in the para-
aortics, or other treated nodal chains. Therefore, our crude
local failure rate was 15%. Although our study was com-
prised of a disparate patient population with inherent selec-
tion biases, our results compare favorably with the GOG
pelvic failure rate of 31.4% and the RTOG 35% pelvic
failure rate (2, 8), but on par with recent single institution
reports (24).
As the goal of this initial study was to reduce toxicity, we
made no attempt to dose escalate. Patients at risk for mi-
croscopic disease were treated to a dose of 45 Gy, with
brachytherapy, and parametrial boosts depending on histol-
ogy and stage. Patients with gross disease in the para-aortic
nodes received 54 Gy, respecting small bowel tolerance. A
number of dosimetric investigations have reported varying
IMRT techniques to boost grossly involved para-aortic nodes.
At Washington University, PET-guided intensity modulated
radiotherapy planning was performed to determine if the
 Extended-field gynecologic IMRT
pelvis could be treated with conventional AP/PA fields
while treating the para-aortic nodes with IMRT. The authors
found that dose to PET avid grossly involved para-aortic
nodes could be planned to receive 59.4 Gy while delivering
50.4 Gy to the pelvis and limiting dose the small bowel,
kidney, and spinal cord (25, 26).
In addition, a dosimetric analysis performed at the Uni-
versity of Alabama Birmingham demonstrated that EF-
IMRT could be delivered with dose sculpting to boost
grossly positive para-aortic lymph nodes to 60 Gy in 2.4 Gy
fractions, while simultaneously delivering 45 Gy in 1.8 Gy
fractions to the para-aortics and pelvis (27). These doses
were achieved while still maintaining significant reduc-
tions in maximal dose to the spinal cord, as well as reducing
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