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

and rectal contrast administered. 10). all patients were planned and treated with this energy. 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. Cervical 4 31 Suspected cervical 1 8 ease. Acute toxicities. 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.or 120-leaf multileaf collimator volume of small bowel. 50 recommendations. bone marrow.0 and 4.to 9-field. The prescription dose for the EF- decrease the incidence of acute Grade 2 gastrointestinal IMRT plans was 45 Gy. Because 6 As a means of reducing toxicity. Marconi Medical Systems. The gross Recurrent endometrial 1 8 tumor volume (GTV) consisted of all areas of known gross dis. 13 women with gynecologic malig. intravenous. while those planned with Eclipse at the University of Illinois–Chicago were delivered with the sliding window technique. Simulation consisted of the patient lying supine on a dedicated CT simulator couch (11).8-Gy daily fractions.0). Most patients Median 62 had oral. we generated 7. These films were checked Between 2002 and 2005.0 (CTCAE v 3. Inc. Patients were treated on a node positive endometrial and cervical cancer at our insti. After the completion of radi- fore the initiation of treatment.8-Gy daily fractions. The goal of this treatment was to reduce the CA) equipped with either an 80. bladder. parametria. OH). Varian Medical Nine 5 38 Systems. delivered in 1. The CTV was ex. Varian CL 2100 CD accelerator (Varian Associates. each pa. equally spaced coplanar IMRT plans for each patient. and bladder and automatic beam sequencing software. Some No 1 8 patients had bone marrow contoured as well. The presacral Surgery–RT 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. tution in 2002. uterus (if present). No 6 46 The EF-IMRT plans were generated using commercially avail. and para-aortic Adenosquamous 1 8 regions). Patients with clinically evident gross disease in the para-aortic We began exploring the use of extended-field IMRT. as well as the bladder were contoured on all patients. Palo Alto. A custom- ized immobilization device (Alpha cradle.. University of Illinois–Chicago. Subsequently. Sewickley. Based on our prior experience (12). and rectum (defined from the sigmoid flexure to the Chemotherapy anus). toxicity as well as Grade 2 or greater neutropenia (9. Smithers Medical Prod. PA. rectum. The kidneys. 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. 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. North Canton.0. mea- of Chicago and the Department of Radiation Oncology at the sured from the initiation of treatment to 60 days after completion. or Eclipse. Clinicopathologic characteristics of patients studied ucts. Yes 12 92 panded 1 cm uniformly to create the PTV accounting for patient Intracavitary brachytherapy motion and set-up uncertainty. Cleveland. 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. Extended-field gynecologic IMRT ● J. of patients 13 planning CT from the mid thorax to the ischial tuberosities (PQ Age (y) 5000. rectum. As previously described. Table 1. K. inverse planning software (CORVUS versions 3. Events version 3. in the step and shoot mode.5-cm margin. The IMRT treatments irradiated. then RT 11 85 small bowel. Seven 8 62 NOMOS Corporation. 1171 the delivery of concomitant chemotherapy and extended. internal and external iliacs. We report here a preliminary analysis. SALAMA et al. Abbreviations: IMRT ⫽ intensity-modulated radiation therapy. small bowel. field radiation therapy. When needed. were graded by the Common Terminology Criteria for Adverse tient underwent computed tomography (CT)– based planning be. The goals of planning were to provide a homogeneous PTV dose while minimizing dose to the kidneys. Range 51–76 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. . each patient underwent a No. before treatment by the attending radiation oncologist. RT ⫽ radiation therapy. Palo Alto. Surgery. and regional lymph Adenocarcinoma 4 31 node regions (common. 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. CA). Yes 7 54 Number of IMRT fields able. and bone marrow. in an attempt to decrease the acute toxicity of this planned with Corvus at the University of Chicago were delivered treatment. OH) was fabricated for each patient about Characteristic N % the upper and lower body to ensure reproducible daily setup and to minimize patient motion. 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. 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).

medical oncologists. upper pelvis. 1 with oblique fields and 1 with Two patients experienced late toxicity from their total IMRT. J. greater acute toxicity. and abdomen. Ten anti-diarrheal medication (Grade 2). The first column shows the actual isodose was uncertain whether this was caused by recurrent tumor curves from the IMRT plan compared with a four-field plan or treatment effect. and blood chemistries were Acute toxicity is summarized in Table 2. Twelve patients Although all patients experienced acute large bowel tox- received chemotherapy either before (5 patients). One was planned before the introduction of Patient characteristics are summarized in Table 1. Otherwise. vic and peritoneal lymph node sampling. patients were seen at 3-month intervals by radiation kidneys. 1 with depressed leukocyte counts (⬍1000/mm3) and 1 with isolated neutropenia (⬍500/mm3). Two patients with gross para-aortic disease re. . 1. Adverse well tolerated with only 2 patients experiencing Grade 3 or events ⬎60 days after the completion of treatment were graded according to the RTOG late-toxicity scale. and pel. At last follow-up. The 30%. Both of these RESULTS patients were treated with concurrent weekly cisplatin che- motherapy. both patients completed treatment cervical cancer primaries. in One was metastatic at presentation. dose–volume histograms (DVHs) of a representative treatment halted before the intended prescription dose was patient show how IMRT plans spare high doses to the reached because of a pulmonary embolus. The bone marrow sparing. cervical neoplasia with positron emission tomography The patient with isolated neutropenia also exhibited Grade 3 (PET) detected and biopsy-proven involved pelvic and cer- vical nodes. EF-IMRT was ordered at the discretion of the treating oncologists. quiring pharmacologic intervention. De- is 11 months (range. 90%. EF- Fig. Four of the patients had spite lowered cell counts. concur. Figure 1 shows axial images of the requiring a partial colectomy (Grade 3). quired radiotherapy boost. and 1 patient had noninvasive without requiring an interruption in scheduled radiotherapy. icity. in the second column and an anterior-posterior/posterior. Radiologic studies. Furthermore. Two patients experienced Grade 4 toxicity. although it field IMRT. enced bilateral lower-extremity lymphedema. and gynecologic oncologists. 70%. and 100% isodose curves are presented for each of these plans. and rectum. and the other had her Fig. and anterior-posterior/posterior-anterior (AP-PA) isodose distributions are presented for a representative patient in the low pelvis. and kidney region. Intensity-modulated radiation therapy (IMRT). upper pelvis. In addition. four-field. 2006 ation therapy. another lower pelvis. 1–29 months). 50%.1172 I. and this was not treatment related. Only 3 patients expe- patients had pathologically proven para-aortic nodal in. 2 patients experienced in-field failures. serum markers. anterior (AP/PA) plan in the third column. tients required blood transfusions in the first week of radio- bilateral salpingo-oophorectomy. 2. Eleven patients underwent pre-radiotherapy nausea immediately after chemotherapy infusion. therapy. none required intervention greater than intermittent rently (5). pelvic washings. cancer management. or after (2) extended-field radiation therapy. and the other had a boost region along median age of patients was 62 years old. Two pa- surgery usually consisting of total abdominal hysterectomy. Radiation Oncology ● Biology ● Physics Volume 65. with larger volumes oncologists. Median follow-up the pelvic sidewall preventing bone marrow sparing. Number 4. One patient with multiple prior ab- A high degree of conformity to the PTV was achieved in dominal surgeries experienced a small bowel obstruction all EF-IMRT plans. rienced acute genitourinary toxicity with 1 of these 3 re- volvement. small bowel. at the level of the patient with grossly involved common iliac nodes experi- kidneys for a representative patient treated with extended. receiving lower doses.

K. In addition. 2. Acute toxicity in patients studied 1-year survival of 92% (95% CI. . Grade DISCUSSION Toxicity Total 1 2 3 4 Extended-field radiotherapy. SALAMA et al. Comparison dose–volume histograms (DVHs) for a representative patient treated with extended-field. 47–99%). Six and hilar lymph nodes. chain. Extended-field gynecologic IMRT ● J. as shown in Fig. IMRT has achieved local control with 1 year actuarial local tastases. Although survival data must be interpreted cautiously in this heterogeneous patient population. intensity- modulated radiation therapy (EF-IMRT). 13). resulting in an actuarial Table 2. 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. 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. 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. at most recent follow-up 2 patients have died. 1 in mediastinal control of 90% (95% CI. 15). and 1 in the untreated para-aortic patients failed outside the radiation field. 3 with liver me. 1 with peritoneal carcinomatosis. 57%–99%). 3. many ad- Genitourinary vanced endometrial cancer patients are also treated with Dysuria 3 2 1 0 0 concurrent chemoradiotherapy (16).

Furthermore. no patient to date has exhibited ing acute changes in bowel habits as well as increasing the any renal toxicity. delivery of mine if this low level of acute toxicity seen in our patients dose to grossly involved nodes has been limited by concerns will translate into decreased rates of chronic toxicity. the isodose curves croscopic disease were treated to a dose of 45 Gy. and was telance et al. Although our study was com- IMRT plans had a statistically significant (p ⬍ 0. Por. the volume of rectum and nodes received 54 Gy. 3.05) reduc. Although 2 patients (15%) experienced acute Grade 4 0. In these trials. CT simulation from T2 through the ischial tuberosities were However. Grade 3 to 4 nonhematologic toxicity (2). PET-guided intensity modulated that extended-field IMRT and concomitant chemotherapy radiotherapy planning was performed to determine if the . With our treatment design and dose regimen. and 31% lymph nodes. and cisplatin 75 mg/m2 on Days 1 and 22 for two or three cycles. the rectal dose failure rate (2. 8). J. Radiation Oncology ● Biology ● Physics Volume 65. 0.90 toxicity. reducing the number and Extended field-IMRT concomitantly with chemotherapy intensity of chemotherapy cycles (6). 76% acute Grade ered via opposed AP/PA fields targeting the para-aortic 3 to 4 chemotherapy related toxicity was observed. This technique has been shown diotherapy have also been treated with concurrent nephro. scored as a failure. 6. she had no evidence of recurrence in the para- planned with conventional two-field and four-field plans. One patient died of vantages of intensity modulated radiation therapy over 3-D DIC shortly before completing her parametrial boost.80 hematologic toxicity.30 PA nodes to 45 Gy while delivering 1000 mg/m2/day 5-FU 0. Therefore. topsy revealed residual disease in the para-aortics. was effective in preventing in-field failure. and tion biases. As reports (24).2 Gy twice-daily fractions. Longer follow-up is required to deter- likelihood of chronic toxicity (2). Additionally. Only 2 of our Previous investigations demonstrated the dosimetric ad. shown in Figs.4% and the RTOG 35% pelvic for the 2 and 4 field plans. local failure rate was 15%. RTOG 92-10 administered 48 Gy to the para- 0. A bowel in the high dose regions is less with IMRT plans than number of dosimetric investigations have reported varying that with conventional 2-field and 4-field plans. suggest that IMRT can reduce the renal volume receiving ogy and stage. Ten patients who underwent local pelvic failure because of in-field tumor recurrence. with and DVHs for a representative patient. and 9 fields. potential hematologic count depression could lead to creased Grade 2 leukopenia (23). respecting small bowel tolerance. (20) performed a dosimetric analysis to deter. Patients at risk for mi- formal dosimetric comparisons. Specifically. In addition.00 could be safely and effectively delivered with minimal 0. diated to dosimetrically decrease the volume of bone mar- ment portals encompass a large volume of bone marrow row irradiated (22). 1 and brachytherapy. 2006 1.20 for 96 h and 50 mg/m2 cisplatin in weeks 1 and 5 (2). the Gynecologic Oncology Group (GOG) trial treated the 0. 8). extended-field radiotherapy has been deliv. prised of a disparate patient population with inherent selec- tion in the volume of small bowel irradiated: 11%. The second patient with carcinosarcoma mine the feasibility of intensity modulated pelvic and para. dosimetrically to reduce the volume of bone marrow irra- toxic chemotherapy (2. as extended treat. Au- conformal radiotherapy for extended-field treatments. and 9 field IMRT plans vs.10 Furthermore.6% for the 4. This radiotherapy regimen was delivered with 1000 mg/m2/day 5-FU for 96 h Fig. and parametrial boosts depending on histol- 2. we to IMRT in the extended-field setting. All acute radiation related toxicity was Grade 2 or less.40 intense chemotherapy and radiation regimens. therapy (21). and to clinically correlate with de- (19). Those trials used more 0. our crude These were compared with IMRT plans of 4. 35% and 34% pelvic failure rate of 31. Furthermore.00 aortics with known metastatic para-aortic sites boosted to 54 0 3 6 9 12 15 18 21 24 27 Time (months) to 58 Gy in 1. Freedom from infield failure. bone marrow sparing IMRT. With this technique.1174 I. 17).50 motherapy and radiation therapy.70 apy nor necessitated a treatment break. patients failed in the radiotherapy portal. 15%. of toxicity to adjacent critical structures (1. In our study.60 vorably with previously reported trials of concurrent che- 0. 7. aortics. 7. the aforementioned dosimetric study demonstrated a benefit As the goal of this initial study was to reduce toxicity. Patients with gross disease in the para-aortic greater than 20 Gy. untoward treatment interruptions.001) (20). we found At Washington University. but on par with recent single institution was significantly lowered with IMRT (p ⬍ 0. 31% of patients experienced acute Traditionally. we did not perform made no attempt to dose escalate. Furthermore. or other treated nodal chains. Recently. Number 4. This compared fa- 0. neither was related to radiation ther- Freedom from Infield Failure 0. IMRT techniques to boost grossly involved para-aortic nodes. generous portions of the of patients did not complete the scheduled course of radio- small bowel have been included in the treatment field caus. However. our results compare favorably with the GOG 13. neither of the 2 patients in our study who concerns about renal toxicity (18) have become increasingly experienced Grade 4 hematologic toxicity was treated with important as many patients treated with extended-field ra. developed peritoneal carcinomatosis. and was scored as a aortic radiation in contiguity.

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