Estramustine Phosphate Sodium

Abstract

Abstract Estramustine phosphate sodium (estramustine phosphate) [Emcyt®] acts as a microtubule inhibitor through its metabolites, estramustine and estromustine, and has demonstrated cytotoxic activity in vitro. It showed activity in hormone-refractory prostate cancer (HRPC) when administered concurrently with agents with synergistic mechanisms of action (intravenous taxanes, vinca alkaloids, oral etoposide) in three comparative (n = 127–193) and numerous small noncomparative trials. The prostate-specific antigen (PSA) response rates for estramustine phosphate-based regimens with docetaxel (67% and 63%), paclitaxel (48%) or vinblastine (25%) were greater than those for comparators, mitoxantrone, paclitaxel or vinblastine, respectively. Median times to PSA progression were also longer with estramustine phosphate plus docetaxel or vinblastine, compared with mitoxantrone or vinblastine. Survival durations (beyond the 9–12 months observed with historical controls) in comparative and noncomparative studies demonstrate a trend in favor of estramustine phosphate-based regimens; there was a significant survival advantage with cyclic administration of estramustine phosphate (840 mg/day for 5 days per 21-day cycle) plus docetaxel (70 mg/m2 given in one or two doses per cycle) over mitoxantrone (secondary endpoint, p = 0.002) and a trend for a survival advantage for estramustine phosphate with vinblastine over vinblastine alone (primary endpoint, p = 0.051). Adverse effects of estramustine phosphate are mainly estrogenic, and those of combination treatment largely reflect the profile of the individual agents. Estramustine phosphate combination therapy was associated with nausea, vomiting, and edema in comparative trials, and cardiovascular events were reported in 6–14% of patients; concurrent anticoagulant therapy may be beneficial. Intermittent therapy with lower-dose estramustine phosphate has improved the tolerability of the drug. Estramustine phosphate lacks the myelosuppression, neurotoxicity and alopecia associated with some other cytotoxic agents. Moreover, in comparative trials, neutropenia, and granulocytopenia occurred less often with estramustine phosphate combinations than with the concomitant agents administered alone. Conclusion: Oral estramustine phosphate, administered concurrently with other cytotoxic agents (taxanes, vinca alkaloids or etoposide), has shown activity in comparative and noncomparative trials in patients with HRPC. Of note are the better PSA response rates and the improved survival duration for some estramustine phosphate-based regimens versus comparators. The apparent survival advantage with estramustine phosphate plus docetaxel compared with mitoxantrone plus prednisone may be confirmed in a large, ongoing, randomized, phase III trial. Current efficacy data, the manageable tolerability profile, and the convenient oral route of administration of estramustine phosphate suggest potential for estramustine phosphate-based treatment regimens in patients with HRPC.