Treatment of Metastatic Hormone Refractory Prostate Cancer with Ketoconazole, Hydrocortisone, and Cyclophosphamide

Objective: Patients with metastatic hormone-refractory prostate cancer have a poor overall survival rate. Newer agents have shown promise in slowing disease progression but are mostly ineffective in improving the overall survival rate, are toxic, and require intravenous administration. In an attempt to maintain treatment efficacy, but to minimize toxicity and improve ease of use, we conducted a pilot trial of an oral regimen consisting of ketoconazole, hydrocortisone, and cyclophosphamide combination therapy. Materials and Methods: Twenty-seven patients with metastatic hormone-refractory prostate cancer were treated with an oral regimen of ketoconazole, 400 mg tid, and hydrocortisone, 20 mg qam and 10 mg qpm, on Days 1–28. Cyclophosphamide, 100 mg/m2, was added on Days 1–14. Treatment was recycled every 28 days. Progression of disease was defined by a progressively rising prostate specific antigen (PSA) level, new lesions as seen on bone scans, or progression of soft-tissue disease. Patient age ranged from 57 to 87 years. Performance status (PS; Eastern Cooperative Oncology Group scale) was 0–2. Pretreatment PSA values ranged from 5.8 ng/mL to 3400 ng/mL (median 68). Results: Twenty-one (78%) of 27 patients with elevated PSA levels demonstrated a ≥50% decline in PSA level for 3 consecutive months. Of the remaining six patients (22%), two progressed within 3 months, two withdrew from the study due to toxicity, and two responded with 96 months, with a median response duration of 9 months. Twenty-two (81%) of 27 patients experienced no significant toxicity, 4 of 27 patients experienced Grade I–III gastrointestinal toxicity, and 1 of 27 patients experienced Grade III hematologic toxicity. Conclusions: The combination of ketoconazole, hydrocortisone, and cyclophosphamide is a well-tolerated oral regimen for the treatment of patients with metastatic hormone-refractory prostate cancer with significant disease activity, and it warrants further investigation.