Hormone Therapy Plus Chemotherapy in Treating Patients With Prostate Cancer

OBJECTIVES:

Primary

• Compare the survival of patients with high-risk hormone-naive prostate cancer treated with androgen blockade with concurrent chemotherapy vs delayed chemotherapy.

Secondary

• Compare biochemical control in patients treated with these regimens.
• Determine the toxicity of these regimens in these patients.
• Compare the time to clinical failure, as measured by progression on bone scan or CT scan or a prostate-specific antigen (PSA) doubling time of ≤ 32 weeks, in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior therapy (surgery vs radiotherapy and/or brachytherapy vs both), original combined Gleason score (6 vs 7 vs 8-10), and prior vaccine therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive androgen blockade (AB) comprising a luteinizing-hormone releasing-hormone agonist continuously and oral flutamide or oral bicalutamide once daily for at least 1 month. Within 4 weeks of initiation of AB, patients begin chemotherapy. Patients receive 1, and only 1, of the following chemotherapy regimens:

• Regimen A: Patients receive oral estramustine 3 times daily on days 1-5 and docetaxel IV on day 3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Regimen B: Patients receive oral estramustine 3 times daily on days 1-5 and paclitaxel IV on days 3, 10, 17, 24, 31, and 38. Treatment repeats every 56 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Regimen C: Patients receive oral ketoconazole 3 times daily on days 1-7, 15-21, and 29-35; doxorubicin IV on days 1, 15, and 29; vinblastine IV on days 8, 22, and 36; and oral estramustine 3 times daily on days 8-14, 22-28, and 36-42. Treatment repeats every 56 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Regimen D: Patients receive oral estramustine 3 times daily on days 1-4 and docetaxel IV over 1 hour on days 3, 10, and 17. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Regimen E: Patients receive docetaxel IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Regimen F: Patients receive docetaxel IV on days 1, 8, and 15. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
• Regimen G: With approval from the protocol chair, patients may receive a regimen that has been demonstrated in a published phase II study to have at least a 50% response rate as measured by PSA decrease from baseline over 2 measurements 28 days apart or a decrease in measurable soft tissue disease by 50% in 2 dimensions.
• Arm II: Patients receive AB as in arm I. Patients continue with AB until clinical failure, at which time patients receive chemotherapy as in arm I. Patients who have a response may continue to receive chemotherapy beyond 4 courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,050 patients will be accrued for this study within 4-6 years.

DISEASE CHARACTERISTICS:

• Diagnosis of adenocarcinoma of the prostate

• Failed local treatments (surgery and/or radiotherapy and/or brachytherapy) as defined by a rising prostate-specific antigen level of at least 2.0 ng/mL (confirmed by 2 measurements at least 2 weeks apart) and a doubling time of 32 weeks or less
• No clinical or radiographic evidence of disease
• Original Gleason score of at least 7 OR Gleason score of 6 with capsular penetration or positive seminal vesicles or lymph nodes
• No metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10 g/dL
• No history of bleeding disorders that would contraindicate warfarin, including clotting factor defects

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST/ALT no greater than 1.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL
• Blood Urea Nitrogen (BUN) no greater than 1.2 times normal

Cardiovascular:

• No symptomatic heart disease
• No history of myocardial infarction
• No history of thromboembolic events (e.g., deep vein thrombosis, symptomatic cerebrovascular events, or pulmonary embolism)

Other:

• No other major medical or psychiatric illness that would preclude study entry
• No other prior or concurrent invasive malignancy within the past 5 years except superficial skin cancer
• No history of esophageal varices
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 6 weeks since prior vaccine therapy

Chemotherapy:

• At least 5 years since prior chemotherapy

Endocrine therapy:

• Prior adjuvant or neoadjuvant hormonal therapy of less than 8 months duration allowed
• At least 1 year since prior androgen therapy

Radiotherapy:

• See Disease Characteristics
• At least 5 years since prior radiotherapy to sites other than prostate

Surgery:

• See Disease Characteristics

Other:

• Concurrent warfarin allowed
• Concurrent bisphosphonate therapy initiated prior to or after randomization allowed