Hormone Therapy Plus Radiation Therapy With or Without Combination Chemotherapy in Treating Patients With Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Hormones can stimulate the production of prostate cancer cells. Hormone therapy may fight prostate cancer by reducing the production of androgens. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether hormone therapy plus radiation therapy is more effective with or without combination chemotherapy for prostate cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of hormone therapy plus radiation therapy with or without combination chemotherapy in treating patients who have prostate cancer.

Detailed Description
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OBJECTIVES: Compare the efficacy of androgen suppression and radiotherapy with or without subsequent paclitaxel, estramustine, and etoposide, in terms of overall and disease-free survival, biochemical and local control, and freedom from distant metastasis, in patients with localized high-risk prostate cancer. Compare the toxic effects of these regimens in these patients. OUTLINE: This is a randomized study. Patients are stratified according to prostate-specific antigen level (≤ 10 ng/mL vs 11-100 ng/mL), tumor stage (T1-2 vs T3-4), Gleason score (7 vs 8-10), and prior hormone use (yes vs no). Patients are randomized to one of two treatment arms. All patients receive androgen suppression comprising a luteinizing hormone-releasing hormone (LHRH) agonist AND bicalutamide OR flutamide for 4 months. Beginning 8 weeks after the initiation of androgen suppression, all patients undergo radiotherapy once daily, 5 days a week, for 7-8 weeks. Patients who received prior androgen suppression therapy count time to radiotherapy from start date of prior hormonal therapy. Arm I: Patients continue androgen suppression therapy (LHRH agonist only) for approximately 20 more months after radiotherapy is completed. Arm II: Patients continue therapy as in arm I and receive chemotherapy beginning 28 days after completing radiotherapy. Chemotherapy comprises oral estramustine 3 times daily and oral etoposide twice daily on days 1-14 and paclitaxel IV over 1 hour on day 2. Chemotherapy repeats every 21 days for 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 1,440 patients will be accrued for this study within 6 years.

Official Title
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A Phase III Protocol of Androgen Suppression (AS) and Radiation Therapy (RT) vs AS and RT Followed by Chemotherapy With Paclitaxel, Estramustine, and Etoposide (TEE) for Localized, High-Risk, Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: bicalutamide
* Drug: estramustine phosphate sodium
* Drug: etoposide
* Drug: flutamide
* Drug: paclitaxel
* Drug: Luteinizing hormone releasing hormone [LHRH] agonist
* Radiation: Radiation therapy
* Drug: warfarin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven prostate cancer at high risk for relapse as determined by either of the following: Prostate-specific antigen (PSA) 20-100 ng/mL and Gleason score at least 7 (any T stage) Clinical stage at least T2, Gleason score at least 8, and PSA no greater than 100 ng/mL Negative lymph nodes No metastatic disease PATIENT CHARACTERISTICS: Age: Over 18 Performance status: Zubrod 0 or 1 Life expectancy: Not specified Hematopoietic: White blood cell (WBC) count of at least 3,000/mm^3 Platelet count at least 130,000/mm^3 Hemoglobin at least 11.4 g/dL Hepatic: Aspartate aminotransferase (AST) no greater than 2 times upper limit of normal Renal: Creatinine no greater than 2.5 mg/dL Other: No other invasive cancer within the past 5 years except superficial nonmelanomatous skin cancer No major medical or psychiatric illness that would preclude study participation Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: At least 5 years since prior chemotherapy Endocrine therapy: At least 60 days since prior finasteride for prostatic hypertrophy At least 90 days since prior testosterone No more than 30 days since initiation of prior pharmacologic androgen ablation for prostate cancer Radiotherapy: No prior pelvic radiotherapy No concurrent intensity-modulated radiotherapy Surgery: No prior radical prostatectomy No prior cryosurgery for prostate cancer No prior orchiectomy

Ages Eligible for Study
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Minimum Age: 18 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: Hormones and RT<br>Androgen suppression (AS) (Luteinizing hormone releasing hormone agonist and bicalutamide [Casodex] or flutamide [Eulexin]) x 8 weeks followed by RT to 70.2 Gy with concurrent AS (LHRH agonist and bicalutamide [Casodex] or flutamide [Eulexin]). AS will continue for a total of 24 months from initiation of all treatment. Oral anti-androgen will be discontinued at the end of radiation therapy (RT). | Drug: bicalutamide<br>* Administered orally at a dose of one 50mg tablet per day. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.<br>* Other names: Casodex;Drug: flutamide<br>* Administered orally at a dose of two 125 mg capsules three times a day for a total daily dose of 750 mg. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.<br>* Other names: Eulexin;Drug: Luteinizing hormone releasing hormone [LHRH] agonist<br>* Releasing hormone agonists (such as leuprolide, goserelin, buserelin, triptorelin) will be given for 4 months<br>Radiation: Radiation therapy<br>* Radiation will begin 8 weeks following the initiation of hormone administration: 46.8 Gy to the regional lymphatics followed by a 23.4 Gy boost to the prostate to bring the total dose to the prostate to 70.2 Gy. Daily tumor doses will be 1.8 Gy per day, 5 days per week x 7-8 weeks.<br>|
| Experimental: Hormones and RT plus Chemotherapy<br>AS (LHRH agonist and bicalutamide [Casodex] or flutamide [Eulexin]) x 8 weeks followed by RT to 70.2 Gy with concurrent AS (LHRH agonist and bicalutamide [Casodex] or flutamide [Eulexin]) and estramustine phosphate sodium, etoposide, paclitaxel, and warfarin [Coumadin®]. AS will continue for a total of 24 months from initiation all treatment. Oral antiandrogen will be discontinued at the end of RT. | Drug: bicalutamide<br>* Administered orally at a dose of one 50mg tablet per day. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.<br>* Other names: Casodex;Drug: estramustine phosphate sodium<br>* 280 mg three times a day for 14 days and repeated every 3 weeks for 4 cycles<br>Drug: etoposide<br>* 50 mg/m^2 in divided doses b.i.d. for 14 days and repeated every 3 weeks for 4 cycles<br>Drug: flutamide<br>* Administered orally at a dose of two 125 mg capsules three times a day for a total daily dose of 750 mg. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.<br>* Other names: Eulexin;Drug: paclitaxel<br>* 135 mg/m^2 given as a 1-hour infusion (on day 2 of each cycle) and repeated every 3 weeks for 4 cycles<br>Radiation: Radiation therapy<br>* Radiation will begin 8 weeks following the initiation of hormone administration: 46.8 Gy to the regional lymphatics followed by a 23.4 Gy boost to the prostate to bring the total dose to the prostate to 70.2 Gy. Daily tumor doses will be 1.8 Gy per day, 5 days per week x 7-8 weeks.<br>Drug: warfarin<br>* To keep international normalized ratio (INR) > 1.5 and < 2.5; begins with the start of chemotherapy and will be given continuously until 4 weeks after the end of the fourth cycle of chemotherapy<br>* Other names: Coumadin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (5-year Rate Reported) | Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact. This analysis was planned to occur when all patients had been potentially followed for 5 years. | From the date of randomization to the date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Biochemical Failure at 5 Years | Biochemical failure uses the American Society for Radiation Oncology (ASTRO) definition of prostate-specific antigen (PSA) rises on three consecutive occasions, with biochemical failure date being midway between the last non-rising PSA and the first rise in PSA. Time to biochemical failure is defined as time from randomization to biochemical failure, last known follow-up (censored), or death (competing risk). Biochemical failure rates are estimated using the cumulative incidence method. | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | 
| Rate of Local Progression at 5 Years | Local progression is defined as documented clinical local and/or regional progression. Time to local progression is defined as time from randomization to local progression, last known follow-up (censored), or death (competing risk). Local progression rates are estimated using the cumulative incidence method. | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | 
| Rate of Distant Metastasis at Five Years | Distant metastasis (DM) is defined as documented metastatic disease. Time to distant metastasis is defined as time from randomization to distant metastatic disease, last known follow-up (censored), or death (competing risk). Distant metastasis rates are estimated using the cumulative incidence method. | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | 
| Disease-free Survival Rate at 5 Years | Disease-free survival (DFS) was measured from the date of randomization to the date of documentation of progression (local, distant, biochemical failure), death, or last follow-up (censored). The Kaplan-Meier method was used to estimate DFS rates. | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | 

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