Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

Abstract

Background: A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab.

Methods: We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival.

Results: A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%).

Conclusions: Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).

Figures

Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients

Patients who were randomly assigned to dose-dense therapy received paclitaxel at a dose of 80 mg per square meter of body-surface area on days 1, 8, and 15 of a 21-day cycle, plus a carboplatin dose in milligrams (dose equivalent to an area under the curve [AUC] of 6) on day 1 of the cycle, for six cycles; patients who were assigned to the conventional regimen received paclitaxel at a dose of 175 mg per square meter on day 1 of a 21-day cycle, plus carboplatin (AUC, 6) on day 1 of the cycle, for six cycles. Patients in either group could opt to receive bevacizumab, starting from cycle 2, at a dose of 15 mg per kilogram of body weight, every 3 weeks until disease progression occurred.

Figure 2. Primary and Subgroup Analyses of Progression-free Survival, According to Treatment Group

In the overall intention-to-treat analysis, dose-dense weekly therapy with paclitaxel did not prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively) (Panel A). In the case of progression-free survival, the hazard ratio is for disease progression or death. In the overall intention-to-treat analysis, weekly paclitaxel did not prolong overall survival, as compared with paclitaxel administered every 3 weeks (Panel B). In the case of overall survival, the hazard ratio is for death. No P value is available for the analysis of overall survival because the prespecified number of events has not occurred yet for this analysis. In the analysis of progression-free survival among patients who opted not to receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio for disease progression or death, 0.62; 95% CI, 0.40 to 0.95; P = 0.03) (Panel C). In the analysis of progression-free survival among patients who opted to receive bevacizumab, weekly paclitaxel did not prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P = 0.60) (Panel D). A forest plot of progression-free survival, according to randomized treatment, in subgroups defined according to prognostic factors is also shown (Panel E). Performance-status scores ranged from 0 (fully active) to 2 (ambulatory and capable of self-care but unable to work; up and about >50% of waking hours). In the subgroup of patients with stage II disease, there were too few patients to reliably estimate the treatment hazard ratio. The size of residual disease was not assessed in patients who underwent neoadjuvant therapy.