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