Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian Cancer

Background. Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide longterm control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. Methods. We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin (75 mg per square meter of body-surface area) with either cyclophosphamide (750 mg per square meter) or paclitaxel (135 mg per square meter over a period of 24 hours). Results. Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin–paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin–paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin–cyclophosphamide group (P 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P 0.001) in the cisplatin–paclitaxel group than in the cisplatin–cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P 0.001) in the cisplatin–paclitaxel group (median, 38 vs. 24 months). Conclusions. Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer. (N Engl J Med 1996;334:1-6.)  1996, Massachusetts Medical Society. From the Department of Medicine, Emory University, Atlanta (W.P.M.); the Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, and the Department of Obstetrics and Gynecology, Cornell University Medical College, New York (W.J.H.); the Gynecologic Oncology Group Statistical Office, Roswell Park Cancer Institute, Buffalo, N.Y. (M.F.B.); the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Oregon Health Sciences University, Portland (P.R.K.); the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham (E.E.P.); the Division of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis (K.Y.L.); the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, N.C. (D.L.C.-P.); and the Department of Pathology and Area Laboratory Sciences, Walter Reed Army Medical Center, Washington, D.C. (M.D.). Address reprint requests to Dr. McGuire at the GOG Administrative Office, Suite 1945, 1234 Market St., Philadelphia, PA 19107. Supported by grants from the National Cancer Institute to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517). A STANDARD therapy for women with advanced epithelial ovarian cancer in the United States is an alkylating agent plus cisplatin. Cisplatin-based combination therapy has been found to be more effective than alkylating agents alone 1 or combinations without cisplatin, 2,3 when measured by clinical response rates and progression-free intervals. However, the evidence of benefit in overall survival is less compelling. 4 When alkylating agents or combinations not containing platinum were used in advanced ovarian cancer, the anticipated average response rate was 40 to 50 percent (10 to 20 percent complete pathological response), with a median survival of 12 to 15 months. In women treated with cisplatin combinations as primary therapy, the response rates are 60 to 80 percent, with complete responses being most common in women who have had adequate surgical therapy. 5 The only large prospective, randomized study comparing cisplatin with a cisplatin-containing combination in advanced ovarian cancer suggested that cisplatin by itself is as effective as platinum-based combinations 6 and is less toxic and less likely to lead to secondary tumors. Nevertheless, an overview of randomized therapeutic trials suggested that platinum-containing combinations are better than cisplatin alone. 7 In patients with advanced ovarian cancer, a combination of cisplatin and cyclophosphamide is now standard treatment. Unfortunately, long-term disease control with this regimen occurs in less than 10 percent of women with incompletely resected stage III disease and less than 5 percent of women with stage IV disease. 8 After cisplatin emerged as an active drug in epithelial ovarian cancer, over a decade passed before another Copyright © 1996 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITY OF WISCONSIN on July 31, 2007 . 2 THE NEW ENGLAND JOURNAL OF MEDICINE Jan. 4, 1996 drug was developed that could elicit responses in women with platinum-refractory disease. In 1989, paclitaxel was reported to produce a response rate of 24 percent in women with platinum-resistant ovarian cancer (30 percent overall response rate). 9 The activity of the drug was confirmed in a less heavily pretreated group of women who received a higher starting dose. 10 The response rate in these women was 37 percent, which made paclitaxel the most active single drug ever evaluated by the Gynecologic Oncology Group in a phase 2 study of ovarian cancer. Subsequently, a phase 1 trial of the paclitaxel and cisplatin combination demonstrated that the two drugs could be safely combined, with the paclitaxel administered first as a 24-hour infusion, followed immediately thereafter by cisplatin. 11 The use of paclitaxel in epithelial ovarian cancer has recently been reviewed. 12,13 The reproducible activity of paclitaxel as salvage therapy, the ability to combine it easily and safely with cisplatin, and the poor long-term results of standard therapy led the Gynecologic Oncology Group to initiate a prospective, randomized phase 3 trial to compare cisplatin plus paclitaxel with standard therapy in women with incompletely resected stage III or any stage IV ovarian cancer. M ETHODS Women with pathologically verified stage III epithelial ovarian cancer (borderline tumors excluded) who had undergone a surgical procedure and were left with residual disease ( 1 cm residual mass) or stage IV disease were eligible for study. They could have clinically measurable or unmeasurable (but able to be evaluated) disease. Other eligibility criteria included having undergone no previous chemotherapy; having given informed consent; having a Gynecologic Oncology Group performance-status score 14 of 0, 1, or 2; and having a white-cell count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level of 2.0 mg per deciliter (177 m mol per liter) or less, and serum bilirubin and serum aspartate aminotransferase values of no more than twice the upper level of normal for the institution. Patients had to enter the study within six weeks after the surgical procedure, and could have had no previous chemotherapy or radiation for the ovarian cancer nor any previous cancer other than nonmelanoma skin cancer. Women with a history of cardiac arrhythmia or who were currently taking an antiarrhythmic medication were excluded. Pathological material was centrally reviewed to verify that it conformed with acceptable diagnoses. Similarly, each case was reviewed for adequacy of the initial surgical procedure, and one of us reviewed all the operative and pathology reports to assess the volume of tumors before and after surgery as well as to record the findings at secondlook surgery. On entry into the study, the women underwent a review of their history, physical examination, and laboratory procedures. Appropriate imaging procedures to measure the extent of disease were performed before and after every other course of therapy. The women in the standard-therapy group received cyclophosphamide (750 mg per square meter of body-surface area intravenously) and cisplatin (75 mg per square meter intravenously at the rate of 1 mg per minute) every three weeks for a total of six courses. The women in the experimental-therapy group received paclitaxel (135 mg per square meter intravenously as a 24-hour continuous infusion) and cisplatin (75 mg per square meter intravenously at a rate of 1 mg per minute) every three weeks for a total of six courses. The women assigned to the experimental group were premedicated with dexamethasone (20 mg orally or intravenously 14 and 7 hours before the start of the paclitaxel infusion). Both diphenhydramine (50 mg) and any histamine H 2 antagonist were administered intravenously 30 minutes before the paclitaxel infusion. Treatments were randomly assigned by the Statistical Office of the Gynecologic Oncology Group, with equal probability after stratification according to institution and the clinical measurability of disease. Women with clinically measurable disease formed the basis of the determination of the clinical response. Those without measurable disease and those with measurable disease and complete clinical responses at the end of their assigned treatment were required to have a reassessment laparotomy to determine the pathological response. All adverse effects were graded according to the toxicity criteria of the Gynecologic Oncology Group. 14 The women had to have a whitecell count of at least 3000 per cubic millimeter and a platelet count of at least 100,000 per cubic millimeter before the next course could be administered. Courses were delayed week by week until these counts were achieved. If this delay exceeded three weeks, the woman was withdrawn from the study. No delay in the subsequent courses was allowed for any gastrointestinal toxicity, periphe