Chemotherapy, early surgical reassessment, and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: Results of a gynecologic oncology group study

Int. J. Kadiation

Oncology

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Phys.. Vol. 34, No. I. pp. I3Y- 147, lYY6 Copyright 0 199.5 Elsevier Saence Inc. Printed in the USA. All rights reserved 0364.30 I hi96 $ IS.00 + XX)

ELSEVIER

0360-3016(95)00252-9

l

Phase I/II Clinical

Trials

CHEMOTHERAPY, EARLY SURGICAL REASSESSMENT, AND HYPERFRACTIONATED ABDOMINAL RADIOTHERAPY IN STAGE III OVARIAN CANCER: RESULTS OF A GYNECOLOGIC ONCOLOGY GROUP STUDY MARCUS E. RANDALL, M.D., * ROLLAND J. BARRETT, M.D.,’ NICK M. SPIRTOS, M.D.,” EVA CHALAS, M.D.,” HOWARD D. HOMESLEY, M.D.,# SAMUEL L. LENTZ, M.D.’ AND MARK HANNA, M.S.** *Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN; ‘Department of Obstetrics and Gynecology, Section on Gynecologic Oncology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC; *Women’s Cancer Center of Northern California, Palo Alto, CA; $Department of Gynecologic Oncology, State University of New York, Stony Brook, NY; #Department of Obstetrics and Gynecology and Head, Section on Gynecologic Oncology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC; ‘Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Bowman Gray School of Medicine, Winston-Salem, NC; and **Indiana University School of Medicine, Indianapolis, IN

Purpose: To determine outcomesand treatment toxicities in patients with optimal (11 cm residual) Stage man carcinoma treated with three courses of cisplatin-cyclophosphamide,surgical reassessment (SRA), and hyperfractionated whole abdominal irradiation (WAD Methods and Materials: Forty-two eligible patients entered this prospective PhaseII study conducted by the Gynecologic Oncology Group (GOG). Diseasecharacteristics were as follows: age range, 32-76 years (median 58); Stage IIL4 (n = 1, 2%), IIIB (n = 2, 5%), IIIC (n = 39, 93%); histology-serouspapibary (n = 21,50%); other (n = 21,50%); Grade 1 (n = 1,2%); 2 (n = 14,33%); 3 (n = 27,54%); residual disease after initial surgery (present: n = 23, 55%; absent: II = 19, 45%). Five patients progressedwhile on chemotherapy, could not be effectively cytoreduced, and were not eligible for WAI. Of the remaining 37 patients, 35 received WAI. Surgical reassessment was not performed in five patients. Results: Of 37 patients with known SRA status after chemotherapy, 21 (57%) were grossly positive, 4 (11%) were microscopically positive, and 12 (32%) were negative. Basedon measurementsrecorded foliowing initial laparotomy and surgical reassessment,progression during chemotherapy was noted in 40%, stagediseasein 37%, and objective responsein 23%. Toxicity during hyperfractionated WA1 was limited and reversible. No patient beginning WA1 failed to complete or required a significant treatment break. Following WAI, six patients underwent laparotomiesfor abdominai symptoms;five had recurrent disease. Five additional patients were managedconservatively for small bowel obstruction (SBO) or malabsorption, of whom three subsequentlydeveloped recurrence. Twenty-two patients having pelvic boostswere signiticantly more likely to require management for gastrointestinal morbidity (p = 0.0021). Considering aii eligible patients, median disease-freeand overall survivals were 18.5 and 39 months, respectiveiy. Considering patients completing chemotherapy and WAI, median disease-freeand overall survivals were 24 and 46 months, respectively. Conclusions:(a) Diseaseprogressionoccurred within three cyclesof cisplatin and cyclophosphamidecbemotherapy in 40% of patients with optimal (cl cm residual) Stage III ovarian carcinoma. (b) Following limited chemotherapy, hyper-fractionated WA1 wasacutely well tolerated. (c) Late radiation-related toxicity

Presented at the 36th Annual Meeting of the American Society For Therapeutic Radiology and Oncology, San Francisco, CA, 5 October 1994. Correspondence to: Marcus Randall, M.D., Indiana University Medical Center, Dept. of Radiation Oncology, 550 North University Blvd., Indianapolis, IN 46202. E-mail: [email protected] Reprint requests to: GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107. Acknowledgement-This study was supported by National Can-

cer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517). The following Gynecologic Oncology Group institutions participated in this study: Bowman Gray School of Medicine of Wake Forest University, State University of New York at Stony Brook, Rush-Presbyterian St. Luke’s Medical Center, Women’s Cancer Center and Cooper Hospital University Medical Center. Accepted for publication 19 May 1995.

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was observed in only three patients (8.6%) in the absence of recurrent disease. Late gastrointestinal morbidity was significantly associated with the administration of a pelvic radiotherapy (RT) boost. (d) Short duration chemotherapy followed by SRA and hyperfractionated WA1 without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or RT alone in this patient population. Ovarian

cancer, Hyperfractionation,

Combined

modality

INTRODUCTION Retrospective and prospective studies have suggested a possible role for whole abdominal irradiation (WAI) in the management of selected patients with optimally debulked Stage III ovarian carcinoma (3, 15, 22). In an attempt to improve outcomes, combinations of chemotherapy and radiotherapy (RT) have been used, often with disappointing results ( 15, 25). Possible explanations for these generally poor outcomes with combined modality therapies include poor patient selection, inadequate therapy due to toxicity, and/or emergence of radiation-resistant tumor clonogens following chemotherapy (particularly cisplatin) exposure (21). These possibilities provided the rationale for a Gynecologic Oncology Group (GOG) prospective Phase II study of a novel treatment regimen that sought to overcome some of these potential limitations to sequential chemotherapy and RT. Specifically, this regimen consisted of continuous hyperfractionated WA1 after limited chemotherapy and surgical reassessment (SRA) and cytoreduction in patients with small volume residual disease following initial laparotomy. Herein is reported data from this study including findings at SRA following limited chemotherapy, treatment toxicities, disease-free survival (DFS), and overall survival. METHODS

AND MATERIALS

Patients Between JuIy 1989 and November 1992, 47 patients consented to treatment on a GOG limited access prospective Phase II study of sequential platinum-based chemotherapy, SRA, and hyperfractionated WA1 (GOG #8812). Written informed consent was obtained from all patients prior to entry on study fulfilling all institutional, state, and federal regulations. Eligible patients were those with primary Stage III epithelial ovarian carcinomas of any histologic type, excluding “low malignant potential.” Patients were required to have initial surgical staging, total hysterectomy, bilateral salpingo-oophorectomy, and maximal cytoreduction, leaving no single site of residual disease greater than 1 cm in greatest dimension. Adjunctive chemotherapy began within 6 weeks of the surgical procedure, usually within 3 weeks. Adequate hematologic, renal, and hepatic function was required in all patients. Following GOG Pathology Committee review and grading, 42 patients remained eligible for analysis. Reasons for ineligibility included low malignant potential histology in two patients, peritoneal surface primary in one,

therapy,

Abdominal

radiotherapy.

previous primary malignancy in one, and ineligible stage (IIC) in one. Median follow-up for uncensured patients at the time of analysis was 32.5 months (range 24-57 months). Patient characteristics are shown in Table 1. Treatment Patients were to receive three courses of cisplatin (7075 mg/m’) and cyclophosphamide (500-750 mg/m*) every 3 weeks followed by open SRA and cytoreduction. Initially, the lower doses were given, but doses were increased to conform to the GOG standard regimen shortly after the study began. Four patients refused SRA and another patient did not have SRA due to chemotherapy toxicity, leaving 37 patients who had SRA. Five patients became ineligible for WA1 based on SRA findings, specifically residual disease that could not be cytoreduced to 5 1 cm. However, the 32 patients who were without residual disease or could be secondarily cytoreduced to 5 1 cm residual at the time of SRA, plus 3 patients who refused SRA, were eligible for and received hyperfractionated WA1 (80 Gy twice per day up to 30.4 Gy in 38 Table 1. Patient characteristics(n = 42) Characteristics Age (years) Range Mean/median Histology Serouspapillary Endometrioid Unspecified Mixed Mutinous Undifferentiated Histologic Grade 1 2 3 PIG0 Substage IIIA BIB IIIC Lymph Node Status Positive Negative Not assessed Residualdiseasefollowing initial surgery Yes No * One lymphovascularinvasion.

Number

%

36-78 58158 21 9 7 2 2 1

50 21 17 5 5 2

1 14 27

2 33 64

1 2 39

2 5 93

17* 9 16

65 35 -

23 19

55 4s

Hyperfractionated WA1 in Stage III ovarian carcinoma

fractions), beginning within 8 weeks of SRA or completion of chemotherapy. All patients receiving WAI were treated on linear accelerators of at least 6 MV capacity. Initially, patients also received a hyperfractionated pelvic boost of 14.4 Gy in 18 fractions, over 9 treatment days. This was discontinued in late 1991 due to some toxicity, substituting small field boosts only to localizable gross disease identified at SRA. An interval of 4 to 8 h between daily fractions was required. Both anteriorly and posteriorly directed fields were treated twice daily, 5 days per week. The volume of WA1 included all peritoneal surfaces including the diaphragm at all phases of quiet respiration. Kidneys were localized and blocked from the posterior-anterior field at initiation of WAI. No liver shielding was used. Responseand toxicity assessment

Measurements of residual disease after initial laparotomy and SRA, if any, were used to determine whether patients progressed, had stable disease, or responded to chemotherapy. Following WAI, patients were observed. Serial CA125 measurements were done inconsistently, making analysis of these values not meaningful. Upon relapse, patients received further chemotherapy if their condition permitted. Responses to salvage chemotherapy were not evaluated and patients were not subsequently considered disease-free whether or not they entered clinical remission with salvage chemotherapy. Acute chemotherapy and RT toxicities were graded according to the GOG Common Toxicity Criteria. Late toxicities potentially attributable to WAI were also evaluated and the possible effect of the use of a pelvic boost following WA1 was assessed. Statistical methods

Disease-free survival (DFS) and survival for each patient were calculated from the date of initial laparotomy. Cox’s proportional hazards regression was used to analyze both survival and DFS for significant differences with regard to histology (serous papillary vs. other), tumor grade (1 and 2 vs. 3), lymph node status, status of disease following initial laparotomy (gross residual 11 cm vs. no residual), and SRA status (positive vs. negative) (2). For this analysis, each variable was investigated on a univariate basis and those variables that yielded a p-value less than 0.2 were included in the multivariable model. The multivariable analysis was performed using a “backward” procedure, meaning that all variables are initially included in the model. Then, variables are removed one at a time, starting with the least significant variable having a p-value greater than 0.05. This process is continued until all variables still in the model are significant at the 0.05 level. Survival plots were constructed using the KaplanMeier method (13). A Fisher’s exact test (27) was per-

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Table 2. Documented chemotherapy response at surgical reassessment (SRA) as a function of status after initial surgery Status After Initial Surgery Status at SRA

Gross residual (n = 20)

Progression

Stable Decreased size

8 4

8

No residual (n =

-

6 9

Totals (%)

15) 14 W) 13 (37)

8 (23)

formed to determine whether an association existed between the use of a pelvic boost and the occurrence of late gastrointestinal morbidity. Pearson’s chi-square analysis (27) was performed to test whether an association existed between disease progression during chemotherapy and tumor histology. RESULTS Chemotherapy

All patients received at least one course of chemotherapy. Forty of 42 patients received all planned chemotherapy in recommended doses. Grades 1 and 2 gastrointestinal toxicities were frequently reported. Grades 3 and 4 toxicities, predominantly hematologic, were experienced by eight and five patients, respectively, at some time during chemotherapy (3 1%) . SRA fmdings

Of 37 patients undergoing SRA, disease status at SRA was known in 36. Of these, 20 (56%) were grossly positive, four (11%) were microscopically positive, and 12 (33%) were negative. Considering only these 36 patients, following initial cytoreductive surgery, 21 patients had gross residual disease, of whom 15 had grossly positive SRA (71%), three had microscopically positive SRA (14%), and three SRAs were negative (14%). Fifteen patients without residual tumor following initial surgery had SRA findings as follows: grossly positive: 5,33%; microscopically positive: 1, 7%; negative: 9, 60%. In 35 patients, specific measurements of residual disease (if any) following both initial and second-look surgeries were available, making it possible to compare disease status prior to and after three cycles of platinum-based chemotherapy (Table 2). It is notable that 40% of patients had disease progression within the first three cycles of chemotherapy. Progression was more common in patients with serous papillary histology than nonserous papillary histology (10 out of 18, 56% vs. 4 out of 17, 24%). A marginally significant association was detected @ = 0.053). There was no significant difference in progression rates between Grade 2 vs. Grade 3 tumors.

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abdominal

Hematologic Gastrointestinal Genitourinary Hepatic

1 4 18

2 5

2 15 8 1 0

34, Number

Pelvic boost 3

8 1 0 0

1, I996

Table 4. Relationship

Grade Adverse effect

Volume

4 1 1 0 0

Grade 3 and 4 toxicities were reported in eight and two patients, respectively. Eleven Grade 3 and 4 toxicities were reported in these 10 patients (10 out of 35 = 29%).

WAI

Thirty-five patients completed WAI. Twenty-two patients (63%) received a pelvic boost, whereas 13 did not. WA1 was not given due to patient refusal (n = 2, both with no evidence of disease (NED) clinically at time of refusal), disease progression making patient ineligible (n = 3), renal toxicity from chemotherapy (n = l), and SBO following initial laparotomy, in which case WA1 was not recommended (n = 1). WA1 was well tolerated acutely. Grade 1 and 2 gastrointestinal toxicities (nausea and diarrhea) were frequently seen during RT, but did not result in treatment interruptions. Grade 3 and 4 toxicities, mainly hematologic, were recorded in eight and two patients, respectively (29%). All patients completed WAI, although one patient did not complete a planned pelvic boost due to thrombocytopenia (Table 3). Late toxicity clearly related to WA1 was uncommon. Six patients underwent laparotomies for SBO with recurrent disease found in five. The other patient had a negative laparotomy and died postoperatively. Three patients developed partial SBOs that resolved with conservative management. Recurrent disease was subsequently diagnosed in two of these patients. One patient required total parenteral nutrition for malabsorption following WAI but subsequently relapsed. An additional patient without known recurrence suffered considerable weight loss and required nutritional support. Therefore, only 3 of 35 patients (8.6%) experienced late gastrointestinal toxicity in the absence of known recurrent disease, only 1 of these (3%) requiring surgery. Of the 12 patients having no evidence of disease at the time of analysis, only 1 (8.3%) developed a late Grade 3-4 complication. However, it is clearly possible that the symptomatology leading to laparotomy was, at least in part, related to therapy. Considering the possibility that each of these 11 toxicities is related in part or in total to WAI, it is interesting that all 11 such patients were in the group of 22 patients who received a pelvic boost. None of the 13 patients not receiving a pelvic boost has developed gastrointestinal morbidity. This association of late gastrointestinal morbidity with administration of the pelvic boost was statisti-

of pelvic boost to late toxicity Number of patients

Number of late toxicities

22

11 (50%)*

Yes No

13

0*

*p=o.o02

tally significant @ = 0.002) (Table 4). The addition of a pelvic boost did not significantly impact on overall survival (p = 0.96) or DFS (p = 0.82). Median follow-up periods (and ranges) in nonrelapsing patients receiving or not receiving pelvic boosts were 35 months (31-57 months) and 29.5 months (24-33 months), respectively. DFS

Overall, the median DFS for the entire group of 42 patients is 18.5 months with 10 patients remaining without evidence of disease at 30-53 months (Fig. 1). Two patients, in addition, died intercurrent deaths without disease at 25 and 47 months, one due to treatment-related complications and one from a second malignancy. Considering the 35 patients who completed both chemotherapy and WAI, the median DFS is 24 months (Fig. 2). Cox’s proportional hazards regression was used to analyze the stated variables for significance in DFS on a univariate basis. Based on the univariate results, residual disease after initial surgery and SRA status were included in the multivariable proportional hazards regression model. The multivariable analysis found neither variable to be significant at the 0.05 level. However, SRA status was a marginally significant variable in predicting DFS @ = 0.087).

0

10

Fig. 1. Kaplan-Meier

20

30

40

so

60

DFS plot, all patients entered in study.

Hyperfractionated

WA1 in Stage III ovarian

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0.6.

%

0.2.

Fig. 2. Kaplan-Meier DFS plot, all patients completing chemotherapy and hyperfractionated WAI.

Patients with residual disease following initial surgery (n = 23) had a median DFS of 14 months compared with a median DFS of 30 months in the 19 patients without residual disease (logrank p = 0.024). There was no difference in median DFS between patients having grossly positive and microscopically positive SRAs. Therefore, patients with positive SRAs (n = 25) were compared to those in whom SRA was negative (n = 12). The positive SRA group had a median DFS of 15 months compared to 25.5 months for the negative SRA group (logrank p = 0.087). As noted above, 35 patients could be evaluated for response to chemotherapy based on surgicopathologic findings before and after chemotherapy. Of the 13 patients progressing on chemotherapy, 9 received RT and 4 did not. Median DFSs were 17 and 4 months, respectively, in these two dissimilar groups. Median overall survivals were 24 and 12 months, respectively, although no treatment effect is implied. Overall survival Median overall survival of all 42 eligible patients is 39 months (Fig. 3). Considering the 35 patients completing scheduled chemotherapy and WAI, the median overall survival was 46 months (Fig. 4). Cox proportional hazards regression was used to analyze residual disease after initial surgery, SRA status, histology, grade, and lymph node status for significance with regard to survival. On a univariate basis, only SRA status yielded a p-value less than 0.2 (p = 0.0805). Therefore, a multivariable model was not performed and it was concluded that SRA status is a marginally significant variable in predicting overall survival.

Fig. 3. Kaplan-Meier survival plot, all patients entered in study. As shown in Fig. 5, patients with negative SRA had a median survival of 47 months vs. 27 months in patients having positive SRA (logrank p = 0.080). Patients with documented response or stable disease while receiving chemotherapy had a median survival of 47 months. It is interesting to note that patients with documented progression during chemotherapy had, nevertheless, a median survival of 24 months. Patterns of failure Of the 42 patients, recurrence has been documented in 30. In 25 of these (83%), recurrence was documented in

0.6.

Fig. 4. Kaplan-Meier survival plot, all patients completing chemotherapy and WAI.

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16

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27:0

survival plot, positive vs. negative surgi-

the peritoneal cavity. Other sites of recurrence included axillary and groin lymph nodes, spleen, lung, pleura, liver, and breast. Isolated pelvic recurrence was uncommon, but was noted in 2 out of 13 patients not receiving a pelvic boost. None of the 22 patients receiving pelvic boosts developed isolated pelvic relapse.

DISCUSSION

Current treatments for advanced ovarian carcinoma are clearly inadequate. Although both chemotherapy and RT as surgical adjuncts have some curative potential in small volume ovarian carcinoma, their relative merits as primary adjuvant therapy are the subject of debate. A number of investigators have made efforts to improve patient outcomes by combining chemotherapy and RT, in some cases with promising results. For example, Godhirsch et al. reported a nonrandomized comparison of 45 patients with pathologically negative SRAs (8). Relapses occurred in only 5 of 24 (21%) patients receiving WA1 vs. 9 of 21 (43%) patients observed (p = 0.03). Kuten et al. noted that patients with negative SRA treated with WA1 had a 100% survival probability at 2 years (14). Patients with microscopic positive SRA had a 66% actuarial probability of 5-year survival after WAI. Ledermann et al. compared results of WA1 vs. combined chemotherapy and WA1 in patients with “high risk” optimally debtiked ovarian cancer, finding a significant relapse-free and cause-specific survival advantage with the combination ( 17).

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Other series report disappointing results from combined modality therapy (IO, 12, 16, 23). There are a number of possible explanations for these results, including poor patient selection (e.g., patients with “suboptimal” disease), inadequate RT due to limited patient tolerance after intense or prolonged chemotherapy, and the emergence of chemotherapy-RT cross resistance during chemotherapy exposure that might significantly lessen the therapeutic ratio. The limited access GOG trial reported herein was designed to avoid these potential problems to the extent possible. Evidence supports the prognostic importance of amount of residual disease at the conclusion of initial surgery. It is possible, therefore, that a significant treatment effect from WA1 could be missed in patients with optimal disease by administering combined modality therapy predominantly in patients with “suboptimal” disease. Therefore, patients eligible for this trial were those with residual disease 51 cm at the conclusion of initial staging laparotomy and debulking. However, the patient population did have a preponderance of other adverse prognostic factors, such as advanced stage (93% Stage IllC) and grade (64% Grade 3). Furthermore, patients continued on study and received WA1 even if they progressed on chemotherapy and/or required second surgical debulking to 11 cm residual. It was, in fact, surprising to find a surgically documented progression rate of 40% during only three cycles of platinum-based chemotherapy. This surprising finding was based on size estimates by the operating surgeon with some inherent subjectivity. The optimum intensity and duration of chemotherapy given prior to SRA remain unclear. It was apparent that the ability to deliver potentially tumoricidal doses of radiation to the abdomen is compromised in patients heavily pretreated with myelotoxic chemotherapy. Fuks et al. reported that 42% of patients given WA1 following chemotherapy required more than a 2week interruption of WA1 due to myelosuppression (7). Patients with Stages IIIA and IIIB disease received a median of six courses of chemotherapy and patients with Stage IIIC disease received a median of eight courses. Other investigators have reported similar difficulty when giving WA1 to heavily pretreated patients (9, 11). In the current trial, only three courses of standard dose platinumbased chemotherapy were given in an effort to limit myelosuppression during WAI. Furthermore, WA1 was given in hyperfractionated fashion (80 Gy twice per day) to further improve tolerance. Hyperfractionated WA1 was completed in a timely fashion in all patients, supporting the stated hypothesis. Another potential advantage of limiting the amount of chemotherapy administered is that emergence of cisplatin-radiation cross resistance might be limited. Data from in vitro and in vivu studies suggest that radiationresistance develops in a number of cell lines after exposure to cisplatin. Ensley et al. found a strong correlation

Hyperfractionated

WA1

in Stage

111 ovarian

between cisplatin resistance and subsequent radiation resistance in previously untreated patients with head and neck cancers (5). Louie et al. reported that resistance to platinum and radiation developed simultaneously in an ovarian cell line (18). Brinen e? al. also reported that resistance to ionizing radiation was associated with cisplatin resistance in human ovarian cell lines (1). Rotmensch er al. studied inherent cellular radiosensitivity of ovarian carcinoma cell lines, finding that prior exposure to cisplatin correlated with radioresistance (24). Therefore, it is theoretically possible that RT subsequent to short duration platinum-based chemotherapy might be not only more tolerable, but also more efficacious compared to patients whose tumors have had prolonged platinum exposure. The recognition that cisplatin drug resistance probably develops quickly has produced interest in earlier SRAs and this would appear to be particularly reasonable if adequate consolidation or salvage therapy were identified. The possibility that hyperfractionated WA1 might be an effective salvage or consolidation therapy in some patients is supported by this experience. Patients having negative SRAs had a median survival of 47 months. More suggestive is the median survival of 27 months in patients with positive SRAs. Furthermore, 10 patients remain without evidence of disease at 30 to 53 months follow-up. The hyperfractionated WA1 schedule used in this trial was based on the favorable experience reported by Morgan et al.. who found minimal severe toxicities and encouraging survivals with its use as salvage treatment for patients with persistent disease following chemotherapy ( 19). This experience has now been supplemented and further analyzed by Fein et al. (6) who reported 5year survival and relapse-free survival rates of 21 and 19%, respectively, in 28 patients. In those with no gross residual, more than one-fourth of patients were alive at 5 years. Acute toxicity requiring a treatment break, as well as late toxicity requiring surgery, were distinctly uncommon. Our experience has been similarly rewarding in view of the excellent acute tolerance and the limited late toxicity. One patient has developed a bowel obstruction requiring surgery in the absence of recurrent disease, and no patient has experienced clinically significant renal or hepatic toxicity after WAI. No serious gastrointestinal morbidity was seen in the absence of a pelvic boost. Table 5. Median GOG study #52 #8812

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Split-course hyperfractionated WA1 has been investigated as salvage therapy in patients with positive SRAs following chemotherapy (4). In their experience, Eifel et al. found that patients rarely were unable to complete hyperfractionated WA1 and that bowel obstruction in the absence of recurrent tumor was not observed. Unfortunately, limited, if any, treatment effect was seen with this particular regimen. It is not possible to determine whether this was due to patient selection or treatment factors such as the use of the split-course technique. Compared to the one-per-day WA1 regimen reported by Whelan ef al. at Princess Margaret Hospital, it does not appear that the hyperfractionated regimen of WA1 results in improved acute tolerance following chemotherapy (26). However, the incidence of late gastrointestinal toxicity reported by Whelan et al. was small and essentially identical to that reported herein. It is interesting to review the results of an earlier GOG trial (GOG #52), which used platinum-based chemotherapy in patients with optimal Stage III ovarian cancer (20). Although patients in the current trial were prognostically unfavorable in some respects compared to GOG #52 with a higher percentage of Grade 3 lesions (63 vs. 35%) and 93% of patients having Stage IIIC disease, the median DFS is essentially the same and the median overall survival is greater (Table 5). Furthermore, it appears that limited chemotherapy and hyperfractionated WA1 is associated with a lower rate of Grade 3 or 4 toxicities. In GOG #52, approximately 56% of patients developed Grade 3 and 4 leukocyte toxicity during chemotherapy. Other Grade 3 and 4 hematologic toxicity, gastrointestinal, cardiac, and renal toxicities were also seen, although less frequently. In the current trial, only 13 of 42 patients (3 1%) developed Grade 3 or 4 toxicity of any type during chemotherapy, and only 10 of 35 patients (29%) developed Grade 3 or 4 toxicity of any type during WAI. Overall, 19 patients (45%) experienced acute Grade 3 or 4 toxicities of any type. Clearly this comparison might not be relevant to chemotherapy regimens currently in common usage. In summary, this treatment regimen is well tolerated. Limiting chemotherapy and/or hyperfractionation seems to decrease acute and, possibly, late toxicity from WAI. The efficacy of this regimen compared to chemotherapy regimens considered “best current therapy” can only be determined from a prospective randomized trial.

disease-free survival (DFS) and overall survival for patients in GOG #52 and #8812

Treatment

No. of patients

CP CAP All eligible patients All treated oatients

176 173 42 35

DFS: Disease-free survival; OS: Overall survival; CP: cyclopbosphamidekisplatin;

Median

DFS (mo.) 22.7 24.6 18.5 24.0

Median

OS (mo.) 31.2 38.9 39.0 47.0

CAP: cyclophosphamide/cisplatin/doxorubicin.

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CONCLUSIONS 1. Disease progression occurred within three cycles of cisplatin-cyclophosphamide chemotherapy in 40% of patients with optimal Stage III ovarian carcinoma. 2. Following limited chemotherapy, hyperfractionated whole abdominal irradiation was acutely well tolerated with only eight and two patients experiencing Grades 3 and 4 toxicities, respectively. No patient beginning WA1 failed to complete or required a significant treatment break. 3. Late radiation-related toxicity was observed in only three patients (8.6%) in the absence of intercurrent disease. Late toxicity was absent in patients not receiving a pelvic boost.

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4. Median survival and DFS for all patients entered was 39 months and 18 months, respectively. Median survival and DFS for patients completing chemotherapy and WA1 was 47 and 24 months, respectively. Although direct comparisons are problematic, these results appear comparable to those achieved with chemotherapy alone in previous GOG trials, possibly with less acute toxicity. 5. Short-duration chemotherapy followed by hyperfractionated WA1 without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or radiotherapy alone in this patient population.

REFERENCES 1. B&ten, R. A.; Peacock, J.; Warenius, H. M. Collateral resistance to photon and neutron irradiation is associated with acquired c&platinum resistance in human ovarian tumor cells. Radiother. Oncol. 23:170- 175; 1992. 2. Cox, D. R. Regression models and lifetables. J. Royal Stat. Sot. 34: 187-220; 1972. 3. Dembo, A. J. Epithelial ovarian cancer: The role of radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 22:835-845; 1992. 4. Eifel, P. J.; Gershenson, D. M.; Delclos, L.; Wharton, J. T.; Peters, L. J. Twice-daily, split-course abdominopelvic radiation therapy after chemotherapy and positive secondlook laparotomy for epitbelial ovarian carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 21:1013-1018; 1991. 5. Ensley, J. F.; Jacobs, J. R.; Weaver, A.; Kinzie, J.; Crissman, J.; Kish, J. A.; Cummings, G.; Al-Sarraf, M. Correlation between response to cisplatin-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer 54:811-814; 1984. 6. Fein, D. A.; Morgan, L. S.; Marcus, R. B.; Mendenhall, W. M.; Stombeck, M. D.; Freeman, D. E.; Million, R. R. Stage III ovarian carcinoma: An analysis of treatment and complications following hyperfractionated abdominopelvic irradiation for salvage. Int. J. Radiat. Oncol. Biol. Phys. 29:169-176; 1994. 7. Fuks, Z.; Rizel, S.; Biran, S. Chemotherapeutic and surgical induction of pathologic complete remission and whole abdominal irradiation for consolidation does not enhance the cure of stage III ovarian carcinoma. J. Clin. Oncol. 6:509516; 1988. 8. Goldhirsch. A.; Greiner, R.; Dreher. E.; Sessa. C.; Krauer, F.; Fomi, M.; Jung, F. W.; Brunner, K. W.; Veraguth, P.; Engeler, V.; Leyvraz, S.; Siegentbaler, P.; Gloor, E.; Buser, K.; Gelber, R. D; Cavalli, F. Treatment of advanced ovarian cancer with surgery, chemotherapy, and consolidation of response by whole abdominal radiotherapy. Cancer 62:4047; 1988. 9. Hainswortb, J. D.; Malcolm, A.; Johnson, D. H.; Burnett, L. S.; Jones, H. W; Greco, F. A. Advanced minimal residual ovarian carcinoma: Abdominopelvic irradiation following combination chemotherapy. Obstet. Gynecol. 61:619-623; 1983. 10. Hoffman, M. S.; Greenberg, H.; Finan, M.; Roberts, W. S.; LaPolla, J. P.; Praphat, H.; Cavanagh, D. Whole-abdomen

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15. 16.

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18.

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