Hormone Therapy Plus Chemotherapy in Treating Patients With Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Androgens can stimulate the growth of prostate cancer cells. Drugs such as luteinizing hormone-releasing hormone agonist, flutamide, and bicalutamide may stop the adrenal glands from producing androgens. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining hormone therapy with chemotherapy may kill more tumor cells. It is not yet known whether chemotherapy given at the same time as hormone therapy is more effective than chemotherapy given after hormone therapy in treating prostate cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy given at the same time as hormone therapy with that of chemotherapy given after hormone therapy in treating patients who have prostate cancer.

Detailed Description
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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.

Official Title
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A Phase III Randomized Study of Patients With High Risk, Hormone-Naive Prostate Cancer: Androgen Blockade With 4 Cycles of Immediate Chemotherapy Versus Androgen Blockade With Delayed Chemotherapy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: bicalutamide
* Drug: docetaxel
* Drug: doxorubicin hydrochloride
* Drug: estramustine phosphate sodium
* Drug: flutamide
* Drug: ketoconazole
* Drug: paclitaxel
* Drug: releasing hormone agonist therapy
* Drug: vinblastine sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Androgen blockade + immediate chemotherapy<br>Androgen blockade with immediate chemotherapy | Drug: bicalutamide<br> <br> Drug: docetaxel<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: estramustine phosphate sodium<br> <br> Drug: flutamide<br> <br> Drug: ketoconazole<br> <br> Drug: paclitaxel<br> <br> Drug: releasing hormone agonist therapy<br> <br> Drug: vinblastine sulfate<br> <br> |
| Experimental: Androgen blockade + delayed chemotherapy<br>Androgen blockade with delayed chemotherapy | Drug: bicalutamide<br> <br> Drug: docetaxel<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: estramustine phosphate sodium<br> <br> Drug: flutamide<br> <br> Drug: ketoconazole<br> <br> Drug: paclitaxel<br> <br> Drug: releasing hormone agonist therapy<br> <br> Drug: vinblastine sulfate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | From date of randomization to the date of death due to any cause | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical control |  | From date of randomization to the date of first PSA failure defined as a PSA doubling time <= 32 weeks | 
| Time to Clinical Failure |  | Time from study entry to positive scan or positive disease evaluation of the pelvis or chest or a PSA doubling time ≤ 32 weeks | 
| Frequency of non-hematologic (>= grade 3), hematologic (grade >=4) and fatal (grade 5) toxicities |  | From the beginning of treatment to 90 days post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer, recurrent prostate cancer