124 Treatment of high risk uterine cancer with whole abdominopelvic radiation therapy

Proceedings

123

of the 41st Annual

ASTRO

INTENSITY MODULATED RADIATION THERAPY (IMRT) RECTUM, AND BLADDER COMPLICATIONS IN PATIENTS TO THE PELVIS AND PARAAORTIC AREA

Portelance Mallinckrodt

L. Chao C, Grigsby Institute

PW.

of Radiology,

Bennet

Meeting

21 I

MAY REDUCE SMALL BOWEL, WITH CERVICAL CANCER TREATED

H

St. Louis,

MO,

USA

Purpose: The prevalence of the combined-modality approach (chemotherapy and irradiation) to treat patients with locally advanced cervical cancer is increasing because of the recently published RTOG 90-01 results. However, alarming higher gastrointestinal (GI) and genitourological (GU) complications were documented in patients who received chemoirradiation. Measures that allow adequate doses to the tumor and lymphatic drainage while sparing normal structures will greatly improve complication-free disease control. Theoretically, IMRT has the potential not only to achieve these objectives but also to permit dose escalation to the grossly enlarged metastatic lymph nodes in the pelvis and paraaortic area without increasing GI/GU complications. However, information in this area has been scarce. In this study, we assess whether IMRT can effectively deliver prescribed doses to the different lymph node regions in the pelvic and paraaortic areas while more effectively sparing small bowel, rectum, and bladder. Methods and Materials: Ten patients with cervical cancer underwent computed tomography (CT) simulation. The archived CT images were retrieved to a Voxel-Q computer for target contouring. The target volumes (paraaortic, common iliac, external iliac, internal iliac lymph nodes, and cervix/uterus) and the pertinent normal structures were also defined. These images and contours were transferred to both an IMRT planning system (Corvus 2.0, Nomos) and a 3-D planning system (Focus, CMS). IMRT plans were compared with conventional two- (2CF) and four-(4CF) field techniques following the guidelines of the RTOG 90-01 protocol for pelvic and paraaortic treatments. IMRT was planned to be delivered by dynamic multileaf collimators using a step-n-shoot technique. Three IMRT field arrangements (4, 7, and 9 fields) were tested in each patient. For this comparative study, we prescribed 45 Gy in 25 fractions using a 18 MV photon beam to all targets. The IMRT treatment plans were designed to cover the target by at least 95% of the prescribed dose. A Student-T test was performed to compute the statistical significance in the fraction of normal tissue (rectum, small bowel, bladder) receiving 66%, 88%, and 100% of the prescribed dose between IMRT and conventional beam arrangements. Results: The amount of small bowel receiving the prescribed dose with the IMRT technique was: 4 fields, 11.01 + 5.67%; 7 fields, 15.05 i 6.76%; 9 fields, 13.56 2 5.30%. These were all significantly better than with 2CF (35.28 i 13.84%) and 4CF (34.24 i- 17.82%) (pcO.05). The fraction of rectal volume receiving a dose greater than the prescribed dose was: 4 fields, 8.55 I 4.64%; 7 fields, 6.37 I 5.19%; 9 fields, 3.34 2 3.0%, in contrast to 84.01 i 18.37% with 2CF (p=O.OOl) and 46.37 i 24.97% with 4CF (p=O.OOl). Similarly, the fractional volume of bladder receiving the prescribed dose was: 4 fields, 30.29 i 4.64%; 7 fields, 31.66 t 8.26%; 9 fields, 26.91 f 5.57%. It was significantly worse with 2CF (92.89 ? 35.26%) (pcO.05) and with 4CF (60.48 t 31.80%) (p
i

24

Smith Stanford

TREATMENT THERAPY RS, Teng University,

NN,

OF HIGH Kapp Stanford,

RISK

UTERINE

CANCER

WITH

WHOLE

ABDOMINOPELVIC

RADIATION

DS CA, USA

Purpose: To evaluate the treatment outcomes in patients with optimally debulked endometrial adenocarcinoma (ACA), or stages I to IV uterine papillary serous (UPS) postoperatively with whole abdominopelvic irradiation (WAPI).

advanced stage (FIG0 stage III or IV) or clear cell (CC) uterine cancer treated

Materials and Methods: Between 1979 and 1998, 48 patients received adjuvant WAPI at our institution. Twenty-two patients had FIG0 stage III (n= 18) or stage IV (n=4) endometrial ACA and 26 patients had FIG0 stages I to IV disease with UPS or CC histologies (stage 1~6: 11=2, III=13 and IV=5). The average age of the patients was 62.1 years (59 and 64.7 years in the ACA and UPS/CC groups, respectively). The treatment goal was 30 Gy to the upper abdomen (mean delivered dose of 27.5 Gy) and 50 Gy to the pelvis (mean delivered dose of 48.3 Gy). Twenty-one patients received a boost to the paraaortic nodes and/or diaphragm to a mean total dose of 42 Gy. Twenty-three patients received a boost to the vaginal mucosa by either low-dose rate or high dose rate brachytherapy. The Kaplan-Meier method was used in the survival analysis. The mean duration of follow-up was 36 months (2.4 to 135 months). The association of age, stage, grade, depth of myometrial invasion, histology, and nodal involvement with outcome were tested in univariate and multivariate analyses. Results: The 3.year actuarial disease free (DFS) and overall survival (OS) rates for the entire group were 60% and 75%, respectively. Analysis by histology revealed 3-year actuarial DFS of 74% and 49%, and OS of 84% and 68% for the ACA and UPS/CC groups, respectively. Early stage patients (stage I and II) with UPS/CC histologies had DFS and OS of 87%. However, those with advanced stage UPS/CC histologies (stage III and IV), had DFS and OS of 36% and 61%. Four patients in the ACA group failed, all with extraabdominal recurrences. Eleven of the 26 patients in the UPS/CC group recurred: 2 in the abdomen, 2 in the lungs, 2 with simultaneous failures in the abdomen and lungs, 3 at the vaginal apex and 2 in the supraclavicular nodes. Ten of these 11 patients had stage III or IV disease. A total of 10 patients experienced acute treatment related toxicity (3 with GI toxicities and 7 due to hematologic suppression) which required a treatment break of one week or more (n=8) or discontinuation of WAPI (n=2). No treatment related deaths occurred. One patient developed a small bowel obstruction requiring surgery 25 months following completion of treatment. The 3-year actuarial complication rate was 5%. Univariate analysis of factors prognostic for DFS and OS revealed that only age (either as a continuous variable or dichotomized at the mean age of 62 years) was statistically significant, with older patients having poorer survival. Multivariate analysis confirmed that age was the only significant prognostic factor.

212

I. J. Radiation

Oncology

l

Biology

0 Physics

Volume

45, Number

3 Supplement

1999

Conclusions: WAPI is an effective adjuvant treatment with relatively low toxicity for patients with high risk uterine cancer. Excellent results were obtained in optimally debulked patients with stage III or IV ACA, and stage I or II UPS/CC. However, in the subset of UPS/CC patients, 10 of the 11 who recurred, had stage III or IV disease and 9 of these patients had components of failure outside of the abdomen. ‘Ibis suggests the need for systemic therapy to complement WAPI in this subset of patients. We recommend future trials utilizing WAPI with concurrent, or subsequent systemic therapy in patients with advanced stage UPS or CC uterine carcinoma.

125 Wara WM, University

HYPERFRACTIONATED Weil

MD,

California,

Larson

RADIOTHERAPY DA,

Lamborn

San Francisco,

OF MEDULLOBLASTOMA

K, Edwards

San Francisco,

MS

CA, USA

Purpose: The morbidity of craniospinal radiation for medulloblastoma has prompted efforts to reduce dose to the normal tissues while maintaining efficacy. Hyperfractionation should produce higher tumor doses and lower dose to normal structures. Efforts to improve the outcome of conventional radiotherapy have employed multiple daily doses. Materials and Methods: radiotherapy at University

We evaluated of California,

all 109 pediatric patients with primary medulloblastoma, San Francisco between 1970 and 1995.

treated

with

postoperative

Results: Standard radiotherapy was delivered to 77 patients and 32 patients received hyperfractionation. Conventional radiation consisted of 1.8 Gy daily fractions to deliver 54 Gy to the posterior fossa, and 36 Gy to the craniospinal axis. Hyperfractionated radiotherapy employed 1 Gy twice daily for a total dose of 72 Gy to the posterior fossa, and 24-40 Gy to the craniospinal axis. Adjuvant chemotherapy was used in 58 conventional patients and in 18 hyperfractionated patients. Median follow-up of living patients was 96 months, overall survival was 59 months, and a total of 58 patients died. Five-survival was 51% for the conventional radiotherapy versus 46% for hyperfractionation, and 49% overall. Conclusions: Multivariate analysis of survival, relapse, and location of failure did not demonstrate any benefit for hyperfractionation. It is possible that the non-randomized nature of this report and the use of chemotherapy in the majority of patients receiving both types of radiation have obscured a dose response. This large single institution study demonstrates no improvement in survival with twice-daily radiation to the craniospinal axis for medulloblastoma.

126

SYNTHETIC INTRACRANIAL

Yuan X, Dillehay The Jolokns Hopkins

IMPLANTABLE HUMAN

LE, Fahlman University

POLYMERS MALIGNANT

C, Williams School

JR, Williams

of Medicine,

FOR IUdR GLIOMA

RADIOSENSITIZATION

OF EXPERIMENTAL

JA

Baltimore,

MD,

USA

Background: Local polymeric delivery enhances IUdR radiosensitization gliomas (MG) (.I. Neuro-Oncology 32: 181-92). We tested the local delivery tization and survival of experimental MG.

of experimental subcutaneous human malignant of IUdR via polymers and measured radiosensi-

Methods: In vitro: To measure release, increasing (lo%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed. In viva: For flank vs. i.c. tumors mice (male nu/nu 25 g) had 6 x lo6 S.C. vs 2 x lo5 i.c. U251 MG cells. To compare local vs. systemic delivery, mice bearing flank xenografts (0.5 g) had intratumoral or contralateral flank IUdR polymer (50% loading) treatments. Mice bearing intracranial (ic.) xenografts (day 4 after i.c. cellular injection) had craniectomy and i.c. vs. flank IUdR polymer treatments. Four or 8 days after implantation of polymers, mice were sacrificed and the percentage tumor cells that were labeled with IUdR was measured using quantitative immunohistochemistry. For comparisons of radiosensitization, mice bearing i.c. xenografts had i.c. vs. flank IUdR polymers and cranial fractionated high dose-rate external beam irradiation (2 Gy BID x 4 days). Results: In vitro: Increasing percentage loadings of IUdR resulted in higher percentages of release: 43.7 + 0.1, 70.0 + 0.2, and 90.2 + 0.2 (p < 0.001 ANOVA) for the 10, 30, and 50% loadings, respectively, after 8 days. In vivo: For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentages labeling of the tumors vs. time. For the ipsilateral IUdR polymers, the percentages of tumor cellular labeling after 4 vs. 8 days were 45.8 ? 7.0 vs. 40.6 f 3.9 (p = NS). For the contralateral polymer implants, the percentages tumor cellular labeling were 43.9 2 10.1 vs. 35.9 + 5.2 (p = NS) measured 4 vs. 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentages of tumor cellular labeling were low: 13.9 i 8.8 and 11.2 t 5.7 measured 4 and 8 days after implantation. For the i.c. tumors having the i.c. IUdR polymers, however, the percentages labeling were comparatively much higher: 34.3 5 4.9 and 35.3 -t 4.0 (p < 0.05 vs. extracranial IUdR) on days 4 and 8. respectively. For the i.c. tumors, examination of the percentage cellular labeling vs. distance from the implanted IUdR polymer showed labeling was highest closest to the polymer disc. Radiosensitization: For mice bearing i.c. tumors and receiving flank vs. intracranial IUdR polymer treatments, the survival after external beam irradiation was significantly higher for the intracranial treatments: 49 C 8.9 vs. 80 i 4.1 (p = 0.03) days, respectively. Conclusions: Implantable biodegradable polymers provide the local, intracranial, high, local delivery of IUdR to experimental intracranial human malignant glioma. in radiosensitization and improved survival following radiotherapy. This technique for radiosensitization of human brain tumors.

controlled release of IUdR and result in the The local delivery and cellular labeling result holds promise for the local delivery of IUdR