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This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest.Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant.The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.To assess the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer, 74 eligible patients were treated. The response rate was not better than those noted in subsequent phase 3 studies of docetaxel-based therapies. Because better-tolerated therapies have since been approved, we cannot recommend further development of this regimen.