Phase 1/2 study of preoperative docetaxel and mitoxantrone for high-risk prostate cancer

BACKGROUND: A study was conducted to determine the 5-year recurrence-free survival in patients with high-risk prostate cancer after neoadjuvant combination chemotherapy followed by surgery. Secondary endpoints included safety, pathologic effects of chemotherapy, and predictors of disease recurrence. METHODS: Fifty-seven patients were enrolled in a phase 1/2 study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 before prostatectomy. Patients were treated with 16 weeks of chemotherapy administered weekly on a 3 of every 4 week schedule. A tissue microarray, constructed from the prostatectomy specimens, served to facilitate the exploratory evaluation of biomarkers. The primary endpoint was recurrence-free survival. Disease recurrence was defined as a confirmed serum prostate-specific antigen (PSA) >0.4 ng/mL. RESULTS: Of the 57 patients, 54 received 4 cycles of docetaxel and mitoxantrone before radical prostatectomy. Grade 4 toxicities were limited to leukopenia, neutropenia, and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months, 27 of 57 (47.4%) patients recurred. The Kaplan-Meier recurrence-free survival at 2 years was 65.5% (95% confidence interval [CI], 53.0%-78.0%) and was 49.8% at 5 years (95% CI, 35.5%-64.1%). Pretreatment serum PSA, lymph node involvement, and postchemotherapy tissue vascular endothelial growth factor expression were independent predictors of early recurrence. CONCLUSIONS: Preoperative chemotherapy with docetaxel and mitoxantrone is feasible. Approximately half of the high-risk patients remain free of disease recurrence at 5 years, and clinical and molecular predictors of early recurrence were identified.