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12 vs 3 Months of Maintenance Paclitaxel in Patients with Advanced Ovarian Cancer after Platinum and Paclitaxel-Based Chemotherapy
Abstract & Commentary
Synopsis: Twelve cycles of single-agent paclitaxel administered to women with advanced ovarian cancer who attain a clinically defined complete response to initial platinum/paclitaxel-based chemotherapy significantly prolongs the duration of progression-free survival.
Source: Markman M, et al. J Clin Oncol. 2003;21: 2460-2465.
Markman and colleagues conducted a study of the Gynecologic Oncology Group in which patients were randomly assigned to either 3 or 12 cycles of single-agent paclitaxel administered every 28 days and were then followed up for progression-free survival and overall survival. The primary objective of this study was to determine whether continuing paclitaxel for an extended time period in women with advanced ovarian cancer who had achieved a clinically defined complete response to a platinum/paclitaxel-based chemotherapy regimen could prolong subsequent progression-free survival and overall survival. Two hundred seventy-seven patients entered the trial at the time of the analysis, with a total of 54 progression-free survival events having developed among 222 patients with follow-up data. With the exception of peripheral neuropathy, there were no major differences in toxicity between the regimens. The median progression-free survivals were 21 and 28 months in the 3-cycle and 12-cycle paclitaxel arms, respectively. The Cox model-adjusted 3-cycle vs the 12-cycle progression hazard ratio was estimated to be 2.31 (99% confidence interval, 1.08-4.94). This preliminary analysis led the Southwest Oncology Group Data Safety Monitoring Committee to discontinue the trial. As of the date of study closure, there was no difference in overall survival between the treatment arms. Markman et al concluded that 12 cycles of single-agent paclitaxel administered to women with advanced ovarian cancer who attain a clinically defined complete response to initial platinum-paclitaxel-based chemotherapy significantly prolongs the duration of progression-free survival.
Comment by David M. Gershenson, MD
Standard management of patients who are disease-free at completion of primary surgery/chemotherapy for advanced epithelial ovarian cancer is discontinuation of treatment and subsequent surveillance. While the findings of this randomized, clinical trial are provocative and suggest that there are benefits in prolonged chemotherapy in patients who are clinically disease-free at the completion of primary chemotherapy for advanced ovarian cancer, this study has resulted in considerable controversy. Prior randomized studies focusing on this topic had not demonstrated any benefits. However, they were grossly underpowered and poorly designed. A retrospective study from M.D. Anderson Cancer Center had previously suggested a benefit in progression-free survival associated with prolonged chemotherapy. This prospective study confirms those findings. Previous breast cancer studies had also found a delay in disease progression associated with prolonged chemotherapy. This study is controversial for the following reasons: 1) The early termination of the trial by the Data Safety Monitoring Committee was not felt to be justified by several experts; 2) The 12-cycle arm was associated with excessive neurotoxicity; 3) No benefit in overall survival was demonstrated in this study; and; 4) The difference in disease progression was less than the increased length of maintenance treatment. In addition, the investigators were compelled to reduce the dose of maintenance paclitaxel from 175 mg/m2 to 135 mg/m2. Further studies will be needed to elucidate the true benefits of maintenance or prolonged chemotherapy after completion of primary treatment. In the interim, oncologists need to apprise their patients who are disease-free after primary treatment for advanced epithelial ovarian cancer of the various management options, including prolonged chemotherapy.