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© 2003 American Society for Clinical Oncology Intraperitoneal Radioactive Phosphorus (32P) Versus Observation After Negative Second-Look Laparotomy for Stage III Ovarian Carcinoma: A Randomized Trial of the Gynecologic Oncology Group
From the Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC; Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Department of Pathology, University of Iowa Hospitals, Iowa City, IA; Duke University Medical Center, Durham, NC; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL; North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN.
Address reprint requests to Denise Mackey, Gynecologic Oncology Group, Four Penn Center, 1600 JFK Blvd., Suite 1020, Philadelphia, PA 19103.
Purpose: The objectives of this prospective randomized study of consolidation therapy were to evaluate recurrence-free survival (RFS), overall survival (OS), and the morbidity of intraperitoneal (IP) chromic phosphate suspension (32P) therapy in patients with stage III epithelial ovarian carcinoma who have no detectable evidence of disease at the second-look laparotomy (SLL) procedure after primary chemotherapy. Patients and Methods: In a multi-institution clinical cooperative trial, 202 eligible patients with a negative SLL were randomly selected to receive either 15 mCi IP 32P (n = 104) or no further therapy (NFT; n = 98). Results: With a median follow-up of 63 months in living patients, 68 patients in the IP 32P group (65%) and 63 patients in the NFT group (64%) have developed tumor recurrence. The relative risk of recurrence is 0.90 (IP 32P to NFT) (90% confidence interval [CI], 0.68 to 1.19). The 5-year RFS rate is 42% and 36% for the IP 32P and NFT groups, respectively; the difference is not statistically significant (log-rank test, P = .27). There was no statistically significant difference in OS (P = .19). The relative risk of death is 0.85 (IP 32P to NFT) (90% CI, 0.62 to 1.16). Sixteen patients (8%) experienced grade 3 or 4 adverse effects, with eight in each respective group. Conclusion: Intraperitoneal chromic phosphate did not decrease the risk of relapse or improve survival for patients with stage III epithelial ovarian cancer after a negative SLL. Despite complete pathologic remission at SLL after initial surgery and platinum-based chemotherapy, 61% of stage III ovarian cancer patients had tumor recurrence within 5 years of negative SLL. This indicates a need for more effective initial therapy and further studies of consolidation therapy.
CURRENT MANAGEMENT of patients with epithelial ovarian cancer consists of an initial operation for diagnosis, staging, and primary therapy, followed by postoperative chemotherapy in all but the most favorable cases. In the 1970s and 1980s, second-look laparotomy (SLL) was introduced for asymptomatic patients in complete clinical remission after 10 to 12 cycles or 18 months of melphalan as a means of more accurately assessing their response to initial therapy.1–5 For patients with negative SLL, further chemotherapy was discontinued in view of the toxicity of continued treatment and the leukemogenic risk associated with prolonged use of alkylating agents in the treatment of ovarian cancer.2,6,7 Unfortunately, recurrence was observed in 5% to 44% of patients even when the SLL was negative.1–5,8–11 In a retrospective study of 118 ovarian cancer patients who were in complete clinical remission after initial surgery and chemotherapy, no evidence of disease (NED) was found in 57 of these patients.12 Of these 57 patients, 43 received 15 mCi of radioactive chromic phosphate (32P) suspension given intraperitoneally (IP) in the immediate postoperative period, and 14 did not receive IP 32P due to adhesions. The 4-year post-SLL survival of patients with NED at SLL was 89% for those who received 32P and 67% for those who did not. The respective figures for patients with minimal residual disease at SLL were 59% versus 22%. A group at high risk for failure with NED at SLL was identified as patients with disease greater than stage I and greater than histologic grade 1. These initial data suggested that the use of IP 32P in post-SLL may have a role in improving the progression-free interval of patients with NED or minimal residual disease at SLL. Several reports in the literature describe the use of IP radioisotopes in the treatment of ovarian carcinoma.13–19 Buchsbaum and Keetel13 reported a 94% cumulative survival with radiogold prophylactic treatment as a postsurgical adjuvant in stage IA ovarian carcinoma. Previous reports noting higher morbidity from colloidal radiogold intraperitoneal therapy were likely due to the greater penetration depth of gamma radiation. The limited penetration depth of beta irradiation in IP 32P therapy, particularly when it is not combined with external beam radiation therapy, produces minimal morbidity.12,15–19 In view of the high rate of relapse after negative SLL in patients with ovarian carcinoma, the Gynecologic Oncology Group (GOG) and the North Central Cancer Treatment Group (NCCTG) proposed a prospective randomized clinical trial to evaluate the role of IP 32P. The purpose of this study was to evaluate recurrence-free survival (RFS), overall survival, site(s) and frequency of relapse, and the morbidity of IP 32P suspension therapy, in patients with stage III epithelial ovarian carcinoma who have no detectable evidence of disease at SLL.
Eligibility To be eligible for this study, patients must have had histologically confirmed epithelial carcinoma of the ovary, the International Federation of Gynaecology and Obstetrics (FIGO) stage III disease (all histologic grades), and initial surgical treatment with at least total abdominal hysterectomy and bilateral salpingo-oophorectomy. Patients must have completed and recovered from a full course of chemotherapy and be in a complete clinical remission. It was expected but not required that the chemotherapy would include a platinum agent. Before study entry, all patients underwent SLL that included surgical evaluation of the abdomen, cytologic evaluation of peritoneal fluid/washings, and multiple biopsies from the peritoneal surfaces and diaphragm. If omentectomy and para-aortic node biopsies were not previously performed, these procedures were required at SLL. Patients with no gross or microscopic evidence of persistent or recurrent cancer (negative SLL) were eligible for this trial.
Patients were required to have adequate bone marrow (WBC After the SLL and confirmation of negative microscopic findings, patients were randomly assigned (without stratification) to observation (no further therapy [NFT]) or treatment with 15 mCi IP 32P. Treatment regimens were balanced within each institution. The interval from completion of chemotherapy to SLL was not to exceed 6 weeks. It was recommended that IP 32P therapy be administered within 10 days of the SLL.
Treatment
After the 32P infusion, the IP catheters were flushed with 250 mL of normal saline; thus, a total of
Post-Treatment Follow-Up The site of first clinical relapse was recorded and classified as peritoneal or extraperitoneal distant metastasis. Patients who developed recurrence received further therapy as determined by the treating physician.
Statistical Considerations During 1993, it was estimated that 10% of eligible patients on the experimental regimen did not receive any 32P, mostly due to inadequate distribution based on 99mTc scan of the abdominal cavity. At that time, a 23% larger sample size goal was established, based on the method described by Lachin and Foulkes, to compensate for the loss in power in testing the primary hypothesis.22 The revised sample size was 185 eligible patients or, more specifically, a total of 97 recurrences needed for the final analysis of RFS, and 97 deaths for the analysis of survival. This report presents the final analysis of both RFS and OS with 131 recurrences and 111 deaths observed.
To ensure equal probability of assignment to each treatment arm, randomization was carried out using a block arrangement balancing treatment assignment across major GOG member institutions. Life-tables were computed using the Kaplan-Meier method.23 Differences in RFS and OS by treatment were evaluated using the log-rank test24 according to the intent-to-treat principle of eligible patients. Treatment effect on RFS and OS while adjusting for prognostic factors was accomplished using the Cox model.25 Screening for chance imbalances between clinical/pathologic characteristics and treatment assignment was accomplished using the Pearson’s
From June 1987 through October 1996, 44 member institutions of the GOG and the North Central Cancer Treatment Group (NCCTG) enrolled 267 patients in this study. Of the 65 patients found to be ineligible, 10 patients did not have FIGO stage III and six had tumors of low malignant potential. Other pathologic exclusions were as follows: ineligible primary (5), second primary (1), and inadequate pathology material to review (1). The SLL operative procedure did not conform to protocol requirements in 41 patients, and one additional patient had a positive SLL. The most common reason for this was the lack of bilateral para-aortic lymph node sampling. The remaining 202 eligible patients constitute the basis of this report.
There were 104 eligible patients randomly selected to receive IP 32P and 98 patients assigned to NFT. The distribution of patient characteristics by regimen is displayed in Table 1
Treatment data for patients who were randomly selected to receive IP 32P are presented in Table 2  . Sixteen patients (15%) did not receive IP 32P, primarily due to inadequate distribution of 99mTc in the peritoneal cavity.9 Five did not receive therapy based on medical reasons, including inability to place catheter, and the remaining two patients refused treatment for nonmedical reasons.
The adverse effects data are presented in Table 3 . There was a statistically significant higher frequency of grade 1 to 2 gastrointestinal toxicity, with 16 (15%) patients on the IP 32P arm and five (5%) patients on the control arm experiencing that effect. The two grade 3 to 4 gastrointestinal toxicities in the control regimen include one patient with a fistula and one with elevated AST and ALT (liver laceration). There were three bowel obstructions requiring surgery among patients in the 32P group. There were no other noteworthy differences in reported toxicities.
There were 131 recurrences, with 63 (64%) on the NFT regimen and 68 (65%) on the IP 32P regimen. These recurrences, plus 10 deaths without recurrence (five in each arm) contributed to the RFS curves displayed in Figure 1 . The 5-year RFS rate for the IP 32P and NFT groups were 42% and 36%, respectively. The relative risk of recurrence is 0.90 (IP 32P to NFT group; 90% confidence interval [CI], 0.68 to 1.19).
There was no statistically significant difference in RFS between the two regimens (log-rank test, P = .27, one-tailed). The median RFS was 32.9 months for the NFT and 43.3 months for the IP 32P arm. The recurrence rate over time did not decrease, which suggests that the number of recurrences will continue to increase with further follow-up. There were 66 patients (33%) with peritoneal and 52 patients (26%) with extraperitoneal recurrence. There is no difference between arms regarding distribution of the first reported site of recurrence (Table 4 ).
At the time of the analysis, there were 111 patients (55%) who died of their cancer. Ten patients died of other causes, and the cause of death in one patient is unknown. Median follow-up for living patients was 63 months. There was no significant difference (log-rank test, P = .19, one-tailed) in OS between the two treatment groups (Fig 2 ). The relative risk of death was 0.85 (IP 32P to NFT group) (90% CI, 0.62 to 1.16). The 5-year OS rate was 67% and 63% for IP 32P and NFT groups, respectively. The following factors were analyzed for their relationship to RFS and OS: age, performance status, cell type (clear-cell; endometrioid; mixed epithelial; serous; adenocarcinoma; unspecified; and all others), histologic tumor grade, site(s) of involvement, residual disease (microscopic, gross but optimal, and suboptimal) at initial surgery, type and amount of first-line chemotherapy. There was no difference in RFS for patients who received prior paclitaxel compared to those who did not. The analysis showed initial disease in the omentum, and gross residual disease at the completion of the initial surgery, to be the only statistically significant prognostic factors for both RFS and OS. Age at diagnosis was borderline significant (P = .07) for OS only. From the modeling of RFS, gross disease was associated with a 36% increase in risk and omental disease was associated with 85% increased risk. Exploratory analysis of the six distinct cell types revealed that only the other cell types (undifferentiated [eight], transitional cell [three], and villoglandular [one]) were associated with recurrence and a more than two-fold increase in the risk of death when compared with serous adenocarcinoma.
In this trial, IP 32P did not decrease the risk of relapse or improve survival for patients with stage III epithelial ovarian cancer after a negative SLL. Despite complete clinical remission after initial surgery and platinum-based chemotherapy and no pathologic findings of persistent disease at SLL, 61% of stage III ovarian cancer patients had tumor recurrence within 5 years of negative SLL. The use of melphalan after cytoreductive surgery for ovarian cancer was followed by SLL to assess the surgical-pathologic response and reduce toxicity associated with prolonged chemotherapy.1–5 Among patients with complete clinical response, only 50% were found to have negative SLL. However, negative SLL had raised the possibility of cure, and further treatment was discontinued. It was recognized that complete surgical responses, more commonly achieved with cisplatin than with melphalan therapy, were not durable.8–11 Two large studies confirmed these disappointing data.10,11 Rubin et al10 reported 54% of 63 stage III or IV patients had tumor recurrence after initial platinum-based chemotherapy and negative SLL with a median follow-up of 55 months. Bolis et al11 reported 44% recurrences in 140 stage III or IV patients treated with a platinum regimen and who had a negative SLL. The most common sites of recurrence after negative SLL were the pelvis and upper abdomen as reported by Gershenson et al.9 Rubin et al10 noted that 60% of recurrences were intraperitoneal. These and other studies demonstrated that subclinical residual disease remained despite negative findings at SLL. This patient population represented an opportunity for consolidation therapy geographically focused on the peritoneal cavity. The rationale for the use of 32P in this study was based on the high peritoneal recurrence rate from subclinical disease and the radiation characteristics of 32P. Radioactive 32P, with a physical half-life of 14.3 days, decays by pure beta emission with mean energy of 695 keV. The biologic effect of the isotope in colloid suspension remains within 4 mm, thus primarily treating the peritoneal surface. The absence of gamma decay limits the radiation dose to other intra-abdominal organs such as the liver, kidneys, and intestines and permits safe treatment of large peritoneal surfaces. The 32P colloid preparation is not absorbed into the systemic circulation and has no hematologic toxicity associated with other 32P compounds.
Hester and White,28 in one of the earliest reports on the use of 32P in gynecology, noted that 32P was used for malignant effusions and that ovarian cancer patients often had positive washings or cytology. Pezner et al29 treated 91 patients with stage I or II disease that was totally resected, or with Additional reviews were published in the late 1970s,13,14 and by the end of the 1980s several authors evaluated the efficacy of 32P after initial operation for stage I or II ovarian cancer patients.15,16 In 1990, Young et al15 published the results of the GOG/OCSG randomized clinical trial in which 141 stage I or II patients underwent surgery followed by either 15 mCi of 32P or oral melphalan. The RFS was similar between the two regimens and there was no difference in patterns of recurrence. IP 32P appeared to have the same efficacy as melphalan without the risk of leukemia.
Also appearing in the literature are several reports of nonrandomized studies using 32P after SLL (Table 5
Two reports with overlapping patient populations presented a less optimistic view of the value of 32P.30,31 In the first report, Vergote et al30 presented data on 340 patients who were randomly selected to receive cisplatin (171 patients) or 32P (169 patients) as adjuvant therapy (169 patients). Patients had stage I–III ovarian cancer with no residual disease after surgery. Twenty-eight patients randomly selected to 32P did not receive 32P on account of adhesions and received whole abdominal radiation (WAR) therapy. Intraperitoneal distribution assessment of the colloid was not performed. After a median follow-up of 62 months, the disease-free interval (DFI) was similar (81% v 83%) in both groups at 5 years. Grade 2 bowel obstruction was more common in the 32P-treated (± WAR) group. Nine patients with small bowel obstruction required surgery: six (9%) in the 32P-only group and three (21%) in the WAR group. Although survival outcomes were similar, the authors concluded that cisplatin should be used as standard adjuvant treatment because of the morbidity observed with 32P. The second report by these investigators included 245 patients with primary disease and 68 with negative SLL.31 In this study, 32P was administered within 6 weeks of operation using doses of 7, 8.1, or 10 mCi. Scintigram was performed to assess distribution of the isotope after administration of 32P. Bowel obstruction occurred in three (4%) of the 68 patients in the SLL group. The authors concluded with a recommendation for a randomized clinical trial of 32P versus no further therapy in the negative SLL population. Gastrointestinal toxicity became an increasing focus in several of these trials,15,19,32 particularly when external radiation was administered.29,31,33 Spanos et al34 proposed that the timing of colloid administration was more relevant than the use of external radiation or the number of prior operations. The results of the randomized clinical trial presented in this report show no statistically significant difference in RFS or OS. The relative risk (experimental to control) was 0.90 (90% CI, 0.68 to 1.19) for recurrence and 0.85 (90% CI, 0.62 to 1.16) for survival when adjusting for gross residual disease status at initial surgery. There may be several explanations for the lack of beneficial effect. First, there is the possibility that the therapy itself is not effective. Second, the beneficial effect of radiation is limited to a depth of 3 to 5 mm and cannot adequately treat epithelial ovarian cancer cells to a greater depth. This would be particularly true for retroperitoneal nodes and parenchymal liver or other abdominal organs. Third, 99mTc distribution scan and the actual distribution of IP 32P may not have reached all of the target peritoneal surfaces and volumes at risk. Fourth, the volume of occult tumor burden despite a negative SLL is too great for IP 32P alone in stage III patients. At least 50% of optimal stage III ovarian cancer patients in clinical remission after paclitaxel and platinum-based contemporary chemotherapy have overt disease at SLL.35 In addition, 50% or more with negative SLL have undetected occult disease that manifests as recurrent disease within 2 years. This signifies that, at a minimum, 75% of patients have persistent disease despite apparent complete clinical remission. Improvements in first-line therapy with or without new consolidation strategies are clearly needed to reduce the incidence of persistent disease.
The following GOG institutions participated in the study: University of Alabama at Birmingham, Birmingham, AL (CA 12484); Duke University Medical Center, Durham, NC (CA 12534); Abington Memorial Hospital, Abington, PA; University of Rochester Medical Center, Rochester, NY; (CA 12482), Walter Reed Army Medical Center, Washington, DC (CA 23501); University of Minnesota Medical School, Minneapolis, MN (CA 23088); University of Mississippi Medical Center, Jackson, MS (CA 13633); Colorado Gynecologic Oncology Group, P.C., Denver, CO (CA 15975); University of California Medical Center at Los Angeles, Los Angeles, CA (CA 13630); Milton S. Hershey Medical Center, Hershey, PA (CA 16386); Georgetown University Hospital, Washington, DC (CA 16938); University of Cincinnati, Cincinnati, OH; University of Iowa Hospitals and Clinics, Iowa City, IA (CA 19502); Indiana University Medical Center, Indianapolis, IN (CA 21720); Wake Forest University School of Medicine, Winston-Salem, NC (CA 21946); Albany Medical College, Albany, NY (CA 27469); University of California Medical Center at Irvine, Irvine, CA (CA 23765); Tufts-New England Medical Center, Boston, MA (CA 37569); Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL (CA 12485); University of Kentucky, Lexington, KY; The Cleveland Clinic Foundation, Cleveland, OH; Johns Hopkins Oncology Center, Baltimore, MD; Eastern Pennsylvania Gynecology/Oncology Center, P.C., Philadelphia, PA; Washington University School of Medicine, St. Louis, MO; Cooper Hospital/University Medical Center, Camden, NJ; Columbus Cancer Council, Columbus, OH; North Central Cancer Treatment Group, Mayo Clinic, Rochester, MN; M.D. Anderson Cancer Center, Houston, TX; University of Massachusetts Medical Center, Worcester, MA; Fox Chase Cancer Center, Philadelphia, PA; Medicial University of South Carolina, Charleston, SC; Women’s Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK; University of Chicago, Chicago, IIL; Tacoma General Hospital, Tacoma, WA; Case Western Reserve University, Cleveland, OH; Tampa Bay Cancer Consortium, Tampa, FL; Brookview Research Inc., Nashville, TN
This study was supported by National Cancer Institute grants to member institutions of the Gynecologic Oncology Group (GOG).
1. Smith JP, Delgado G, Rutledge F: Second-look operation in ovarian carcinoma. Cancer 38:1438–1442, 1976[CrossRef][Medline] 2. Schwartz PE, Smith JP: Second-look operations in ovarian cancer. Am J Obstet Gynecol 138:1124–1130, 1980[Medline] 3. Curry SL, Zembo MM, Nahhas WA, et al: Second-look laparotomy in ovarian cancer. Gynecol Oncol 11:114–118, 1981[CrossRef][Medline] 4. Webb MJ, Snyder JA, Williams TJ, et al: Second-look laparotomy in ovarian cancer. Gynecol Oncol 14:285–293, 1982[CrossRef][Medline] 5. Stuart GCE, Jeffried M, Stuart JL, et al: The changing role of "second-look" laparotomy in the management of epithelial carcinoma of the ovary. Am J Obstet Gynecol 142:612–616, 1982[Medline] 6. Reimer RR, Hoover R, Fraumeni JF, et al: Acute leukemia after alkylating agent therapy of ovarian cancer. N Engl J Med 297:177–181, 1977[Abstract] 7. Kapadia SB, Krause JR: Ovarian carcinoma terminating in lymphocytic leukemia following alkylating agent therapy. Cancer 297:177–181, 1978 8. Smirz LR, Stehman FB, Ulbright TM, et al: Second-look laparotomy after chemotherapy in the management of ovarian malignancy. Am J Obstet Gynecol 152:661–668, 1985[Medline] 9. Gershenson DM, Copeland LJ, Wharton JT, et al: Prognosis of surgically determined complete responders in advanced ovarian cancer. Cancer 55:1129–1135, 1985[CrossRef][Medline] 10. Rubin SC, Hoskins WJ, Saigo PE, et al: Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy. Gynecol Oncol 42:137–141, 1991[CrossRef][Medline] 11. Bolis G, Villa A, Guarnerio P, et al: Survival of women with advanced ovarian cancer and complete pathologic response at second-look laparotomy. Cancer 77:128–131, 1996[CrossRef][Medline] 12. Varia M, Rosenman J, Venkatraman S, et al: Intraperitoneal chromic phosphate therapy after second-look laparotomy for ovarian cancer. Cancer 61:919–927, 1988[CrossRef][Medline] 13. Buchsbaum HJ, Keetel WC: Radioisotopes in treatment of stage I ovarian cancer. NCI Monogr 42:127–128, 1975 14. Rosenshein NB, Leichner PK, Vogelsang G: Radiocolloids in the treatment of ovarian cancer. Obstet Gynecol Surv 34:708–719, 1979[Medline] 15. Young RC, Walton LA, Ellenberg SS, et al: Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials N Engl J Med 322:1021–1027, 1990[Abstract] 16. Potter ME, Partridge EE, Shingleton HM, et al: Intraperitoneal chromic phosphate in ovarian cancer. Risks and benefits. Gynecol Oncol 32:314–318, 1989[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3,000/µL and platelets 
2 test with a significance level of P =.20.
.05 (one-sided). 
