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© 2002 American Society for Clinical Oncology Randomized Controlled Trial of Single-Agent Paclitaxel Versus Cyclophosphamide, Doxorubicin, and Cisplatin in Patients With Recurrent Ovarian Cancer Who Responded to First-Line Platinum-Based RegimensByFrom the Department of Gynaecology Oncology, Università degli Studi di Milano-Bicocca, Ospedale San Gerardo dei Tintori, Monza; Laboratory of Oncological Clinical Research, Istituto di Ricerche Farmacologiche "Mario Negri"; and Department of Gynaecology Oncology, European Institute of Oncology, Milan, Italy. Address reprint requests to Valter Torri, MD, Laboratory of Oncological Clinical Research, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62-20157, Milan, Italy; email: torri{at}marionegri.it
PURPOSE: To assess the activity, efficacy, and tolerability of single-agent paclitaxel and a platinum-containing regimen in previously treated patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients who achieved complete remission with platinum-based regimens and whose disease recurred after a progression-free interval of more than 12 months were included in the study. Every 21 days, patients received paclitaxel 175 mg/m2 intravenously (IV) over 3 hours or cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and cisplatin 50 mg/m2 (CAP) IV. RESULTS: Between June 1992 and May 1995, 97 consecutive patients with assessable or measurable disease were randomized to paclitaxel (n = 50) or CAP (n = 47). The median number of cycles on each arm was six. Toxicities included grade 3/4 leukopenia (4% for paclitaxel v 34% for CAP), grade 3/4 neutropenia (13% v 36%), grade 1/2 myalgia (19% v 4%), allergic reactions (15% v 2%), and grade 2/3 nausea and vomiting (17% v 51%). Complete responses were achieved in 17% and 30% of patients receiving paclitaxel and CAP, respectively, and partial responses were achieved in 28% and 25%, respectively (P = .062). At a median follow-up time of 49 months, median progression-free intervals were 9 months for paclitaxel and 15.7 months for CAP (Cox analysis: hazards ratio [HR], 0.60; 95% confidence interval [CI], 0.37 to 0.97; P = .038); median overall survival times were 25.8 months for paclitaxel and 34.7 months for CAP (Cox analysis: HR, 0.58; 95% CI, 0.34 to 0.98; P = .043). CONCLUSION: Rechallenge with either single-agent paclitaxel or platinum-based chemotherapy is effective in this patient population. Preliminary results suggest that single-agent paclitaxel may not be as active as platinum-based chemotherapy in recurrent ovarian cancer. Larger randomized trials are needed.
OVARIAN CANCER is the fifth leading cause of death from cancer among European women and is the leading cause of death among women with gynecologic malignancies.1 It is often diagnosed in the advanced phase (stage III or IV), and the prognosis is generally poor, despite activity by chemotherapy agents. Although up to 80% of patients achieve an objective response with platinum-containing regimens, 40% of patients generally relapse or have disease progression within 12 months, and the percentage decreases to 20% after 12 months have passed since the end of first-line chemotherapy. Patients with recurrent ovarian cancer who previously responded to platinum therapy can be rechallenged with the same agent, but for these patients there is no agreed-on second-line treatment.2,3 Secondary responses to chemotherapeutic agents by patients who have previously experienced tumor regression in response to the same or similar drugs have been described in a number of malignancies other than ovarian cancer, including Hodgkin’s disease and small-cell lung cancer.4,5 Several reports have suggested that patients with ovarian cancer who initially respond to platinum-based treatment and whose disease recurs may demonstrate a second response to retreatment with platinum-based regimens. The probability of a second response increases with the relapse-free period.6-11 Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ), an antimitotic agent derived from bark of the Pacific yew tree (Taxus brevifolia),12 is active against recurring and platinum-resistant ovarian cancer.13-17 The drug is also well tolerated by most patients; significant side effects other than alopecia, such as peripheral neurotoxicity, are less common than with other agents.18 However, it is not clear whether paclitaxel would be more beneficial than a rechallenge with conventional platinum-based chemotherapy. To answer this question, we conducted a randomized study aimed at evaluating the efficacy of a platinum-containing regimen and paclitaxel, administered as second-line chemotherapy for recurrent epithelial ovarian cancer.
Eligibility Patients with histologically proven ovarian carcinoma that recurred or progressed after 12 months had elapsed since the end of first-line therapy including cisplatin or carboplatin were eligible for the study. Further eligibility criteria included measurable disease, World Health Organization performance status  2, adequate bone marrow function (absolute granulocyte count  2,000/µL, platelet count 100,000/µL), and adequate renal, hepatic, and cardiac function. An institutional review board had not been established at the beginning of this trial, and therefore the study did not undergo formal institutional review board review. During the recruitment period, however, informed consent was obtained from all patients in accordance with local or national legislation. The conduct of the trial was in compliance with the principles outlined in the Declaration of Helsinki.19
Chemotherapy Regimens Paclitaxel 175 mg/m2 was infused over 3 hours. The following premedication was administered to reduce the risk of paclitaxel hypersensitivity: dexamethasone 40 mg, given in 20-mg doses 12 and 6 hours before paclitaxel administration; and cimetidine 300 mg IV and chlorpheniramine 10 mg IV, both given 30 minutes before the treatment. The CAP regimen consisted of cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and cisplatin 50 mg/m2.
Treatment administration was regulated by evaluation of blood cell count before the start of the treatment cycle. Treatment was administered if the granulocyte count was
Statistical Methods The primary objective of the study was to estimate survival on the single-agent paclitaxel treatment arm and the platinum-based chemotherapy (CAP) arm. Overall survival time was defined as the time from randomization to death by any cause; patients still alive at the time of analysis were censored at the time of last follow-up. Secondary objectives were to determine progression-free intervals and overall responses to therapy. A progression-free interval was defined as the time from randomization to first appearance of progressive disease. Eastern Cooperative Oncology Group criteria were used to assess response to chemotherapy.20 Kaplan-Meier curves were applied for describing overall survival and progression-free intervals; survival curves were compared using the Cox-Mantel log-rank test.21,22 The Cox proportional hazards regression model23 was also used for progression-free intervals and overall survival to estimate treatment hazards ratios (HRs), while adjusting for multiple prognostic factors. All analyses for efficacy were done on an intention-to-treat basis. Toxicity was investigated for all patients who received at least one cycle of treatment.
All P values are two-sided, and all
Patient Characteristics Between June 1992 and May 1995, a total of 97 patients were enrolled on the study (Fig 1). We analyzed data from 94 patients because three patients were lost to follow-up just after randomization. Each patient had a prior complete response (CR) to a platinum-based regimen and a progression-free interval greater than 12 months.
Patient characteristics are listed in Table 1. Median ages were 53 years (range, 27 to 69 years) on the CAP arm and 54.8 years (range, 35 to 72 years) for patients receiving paclitaxel. Sixty-two patients (66%) had serous histology, and 63 patients (67%) had grade III disease. There were more patients with bulky disease at the time of first diagnosis of ovarian cancer in the paclitaxel treatment group (57%) than on the CAP arm (34%).
Treatment Delivery Before Randomization Median doses of cisplatin and carboplatin previously administered were 530 mg/m2 (range, 300 to 1000 mg/m2) and 2,400 mg/m2 (range, 2,400 to 2,400 mg/m2), respectively, in the CAP group and 553 mg/m2 (range, 240 to 1,000 mg/m2) and 2,130 mg/m2 (range, 600 to 2,400 mg/m2), respectively, in the paclitaxel treatment group. All 97 patients had been previously treated with two or three chemotherapy regimens. Median times from last chemotherapy were 38.8 months on the CAP arm and 30.2 months among patients receiving paclitaxel.
Toxicity Table 2 lists the numbers and proportions of patients with toxic effects noted during treatment. Levels of hematologic toxicity were quite different across the arms. CAP was associated with higher rates of grade 3 or 4 hematologic toxicity (leukopenia, neutropenia, and thrombocytopenia). Nausea and vomiting were also more common on the CAP arm. Grade 2 myalgia was noted in nine patients receiving paclitaxel (19%). Paclitaxel was also associated with higher rates of alopecia and allergic reactions compared with CAP. Finally, moderate to severe sensory neuropathy was experienced by nearly 11% of patients receiving paclitaxel. Other toxicities were rare on both arms.
Response A total of 94 patients were assessable for response. The overall response rate was 50% (22 CRs and 25 partial responses [PRs]). Twenty-four patients (26%) had stable disease, whereas 23 patients (24%) experienced disease progression during treatment. Fourteen patients in the CAP group (30%) and eight patients in the paclitaxel treatment group (17%) had CRs. Twelve patients on the CAP arm (25%) and 13 patients on the paclitaxel treatment arm (28%) achieved PRs (Mantel-Haenszel test for trend, 3.487; P = .062). A total of 53 patients were crossed over because of chemotherapy failure. Twenty-three patients not responding to CAP were crossed over to paclitaxel treatment, and five (22%) of these patients achieved CRs or PRs. Thirty patients not responding to paclitaxel treatment were crossed over to CAP, and CRs or PRs were noted in 14 (47%) of these patients. Responses are listed in Table 3.
Progression-Free Intervals At a median follow-up time of 49 months (range, 40 to 54 months), 85 patients had disease progression or had died (41 in the CAP group and 44 in the paclitaxel treatment group). Of these, 24 had disease progression and were still alive at the time of analysis, 54 had disease progression and died, and seven died without evidence of progression. Median progression-free intervals were 15.7 and 9 months in the CAP and paclitaxel treatment groups, respectively. Comparison of the curves yielded an HR of 0.65 in favor of CAP (95% CI, 0.41 to 1.02; P = .08). After adjustment for prognostic factors (residual tumor, time since the end of last therapy, and age), the HR was 0.60 (95% CI, 0.37 to 0.97; P = .038). Progression-free interval curves are shown in Fig 2.
Overall Survival Sixty-one patients died (27 in the CAP group and 34 in the paclitaxel treatment group). Median survival times were 34.7 and 25.8 months on the CAP and paclitaxel treatment arms, respectively. Comparison of these curves yielded a HR of 0.70 in favor of CAP (95% CI, 0.42 to 1.15; P = .160). After adjustment for prognostic factors (residual tumor, time since the end of last therapy, and age), the HR was 0.58 (95% CI, 0.34 to 0.98; P = .043). The presence of a larger residual tumor at the time of first surgery was associated with lower mortality. Survival curves are shown in Fig 3. Results of a multivariate analysis of risk of progression and mortality are listed in Table 4.
Recurrent epithelial ovarian cancer is usually incurable. The current treatment of patients with recurrent ovarian carcinoma who responded to initial platinum-based chemotherapy is based on the results of the initial chemotherapy. Previous experience showed that carboplatin can be the treatment of choice because of a favorable toxicity profile7,25: patients who achieved prior CRs to platinum-based chemotherapy, with disease-free intervals greater than 12 months, and who receive second-line treatment with cisplatin or carboplatin have a response rate ranging from 30% to 60%. In a Gynecologic Oncology Group phase II trial, patients with recurrent, persistent, or progressive ovarian carcinoma during or after platinum-based chemotherapy received paclitaxel 170 mg/m2 IV over 24 hours every 3 weeks.26 All patients had measurable disease and received premedication (dexamethasone, diphenhydramine, and ranitidine). Of the 49 patients, 45 were eligible and assessable. Among 43 patients assessable for response, there were eight CRs and eight PRs (37%). The median progression-free interval was 4.2 months, and the median survival time was 16 months. Among 27 treatment-resistant patients whose disease progressed during or within 6 months of prior platinum-based therapy or whose best response was stable disease, five CRs (18%) and four PRs (15%) were noted. The median progression-free interval was 4 months. Among 16 treatment-sensitive patients who responded and whose disease progressed more than 6 months after prior platinum-based treatment, three CRs (19%) and four PRs (25%) were noted. The median progression-free interval was 4.9 months. These results indicate that paclitaxel is clearly active as salvage therapy for ovarian carcinoma. Different data emerged from the study by Uziely et al.27 In that National Cancer Institute study, 68 patients with advanced pretreated ovarian cancer, who had either measurable or assessable disease and who had disease progression, received paclitaxel 135 mg/m2 IV over 24 hours (after receiving steroid-containing premedication). The treatment was repeated every 3 weeks and was continued while there was no evidence of progression. Of the 68 patients enrolled, only 10 patients (15%) had PRs, and one patient assessable by marker only had improvement of disease. Our study confirms that rechallenge is effective in patients who have relapsed after an interval of 12 months has passed since the end of previous chemotherapy. The findings suggest that paclitaxel has a less toxic profile but does not offer the same efficacy as platinum-containing regimens. Results indicate reduced risks of progression and death, in favor of CAP, but our limited sample makes the estimates too imprecise for drawing firm conclusions. To our knowledge, this is the first randomized trial aimed at comparing paclitaxel therapy and platinum-based therapy in patients relapsing after 12 months of complete remission. Therefore, it is not possible to discuss findings of other similar randomized trials. Although our results are clearly not definitive and require further confirmation, they suggest that paclitaxel as a single agent may not be as active as platinum-containing chemotherapy in patients who have relapsed. Paclitaxel and platinum analogs, given simultaneously or sequentially, may be the best treatment to be compared with platinum-containing regimens in a future study. Moreover, the association between survival and tumor size at the time of first diagnosis requires further insights. It is possible that our results are due to chance, but it could also be possible that patients with large residual tumors who respond to treatment and remain in remission for a long time represent a group with a different prognosis. Moreover, evidence that paclitaxel plays a role in platinum-resistant clones of cells that overexpress mutated p53 protein suggests that more studies are needed to clarify its efficacy in selected groups of patients.28,29 Larger trials comparing single-agent carboplatin and the combination of paclitaxel and carboplatin as second-line treatments are therefore awaited, as are studies of predic-tive factors.
Supported in part by the Fondazione Nerina e Mario Mattioli, Milan, Italy. Presented in part at the Thirty-Second Annual Meeting of the American Society of Clinical Oncology, Philadelphia, PA, May 18-21, 1996.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 values are with 1 df unless otherwise specified. We performed analyses using SAS (Version 6.12, SAS Institute, Cary, NC). 
