Background. To apply our preclinical findings of cytotoxic synergy with the combination of estramustine phosphate (EP) and docetaxel as the basis of treatment of hormone refractory metastatic prostate cancer in man. To determine the optimal dosage and the toxicities of these two agents for future trials. Patients and methods: Seventeen patients with hormone refractory metastatic prostate cancer who were ambulatory with performance status less than or equal to 2, normal marrow, renal and hepatic function were entered. Prior exposure to EP or a taxane were exclusion factors. EP was given orally at a dose of 14 mg/kg of body weight daily with concurrent docetaxel administered every 21 days as an intravenous infusion over 1 hour with dexamethasone 8 mg. PO BID for five days. EP dosages were kept static: docetaxel dosages were explored in a minimum of three patients per level for dosages of 40, 60, 70, and 80 mg/m(2) Patients were evaluated weekly. Prostate specific antigen (PSA) was measured every three weeks. Results: Five patients were entered at a docetaxel dose of 40 mg/m(2), three at 60 mg/m(2), six at 70 mg/m(2), and three at 80 mg/m(2). Only one patient had received prior chemotherapy Grades 1 or 2 hypocalcemia and hypophosphatemia were seen at all dosage levels. Other grade 2 or less toxicities not related to dosage included alopecia, anorexia, stomatitis, diarrhea, and epigastric pain. Dose limiting toxicities (DLT) as grade 4 leukopenia and grade 4 fatigue were seen at 80 mg/m(2). The phase II dose was defined at 70 mg/m(2) with rapidly reversible leukopenia and minor liver function abnormalities. At this dosing level, dose intensity was 88% and 86% over consecutive cycles for docetaxel and EP, respectively. Two vascular events occurred at this dose level (70 mg/m(2)): one arterial and the other venous. PSA decreases greater than 50% from baseline were seen in 14 of 17 patients at all dosage levels. Four of the 17 patients demonstrated a complete biochemical response (PSA less than or equal to 4 ng/ml). One patient had a partial response with measurable lung and liver lesions. Conclusion: EP given continuously with every three-week docetaxel at a dose of 70 mg/m(2) is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are warranted.
