RATIONALE: Hormones can stimulate the growth 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. It is not yet known which regimen of hormone therapy and radiation therapy is more effective for prostate cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of two different regimens of hormone therapy and radiation therapy in treating patients who have prostate cancer.

OBJECTIVES:

• Compare the efficacy of moderate-duration (28 weeks) neoadjuvant total androgen suppression (TAS) and radiotherapy (RT) with short-duration (8 weeks) neoadjuvant TAS and RT, as related to disease-specific survival, in patients with intermediate-risk adenocarcinoma of the prostate.
• Compare these regimens, in terms of overall survival, disease-free survival, time to local tumor progression or distant failure, time to first biochemical failure, hormone-refractory state, and treatment-induced morbidity, in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prostate-specific antigen level (no greater than 10 ng/mL vs greater than 10 but no greater than 20 ng/mL vs greater than 20 ng/mL), tumor stage (T1b-2 vs T3-4), Gleason score (2-4 vs 5-6 vs 7-10), and prior hormonal therapy (yes vs no). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive total androgen suppression for 8 weeks prior to the initiation of radiotherapy and throughout radiotherapy. A luteinizing hormone-releasing hormone (LHRH) agonist is administered every 1-3 months AND bicalutamide OR flutamide is given orally daily for a total duration of 16 weeks. Beginning with week 9, patients undergo radiotherapy 5 days a week for 8 weeks.
• Arm II: Patients receive total androgen suppression for 28 weeks prior to the initiation of radiotherapy and throughout radiotherapy. An LHRH agonist AND bicalutamide OR flutamide are administered as in arm I for a total duration of 36 weeks. Beginning with week 29, patients undergo radiotherapy as in arm I.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,540 patients (770 per treatment arm) will be accrued for this study within 4 years.

Inclusion Criteria

1. Adenocarcinoma of prostatic origin histologically-confirmed within 180 days of the randomization date.

2. Zubrod Performance Status 0-1 (Appendix II).

3. Prostatic biopsy tumor grading by the Gleason Score classification (Appendix VI) is mandatory prior to randomization.

4. Patients at intermediate risk for disease relapse as determined by any of the following combinations of factors (NOTE: tumor found in one or both lobes on biopsy, but not palpable, will not alter T stage):

   • Clinical stage T1b-4, Gleason score 2-6, and prostate-specific antigen >10 but ≤ 100.
   • Clinical stage T1b-4, Gleason score 7, and prostate-specific antigen < 20.
   • Clinical stage T1b-1c, Gleason score 8-10, and prostate-specific antigen <20.

5. Clinically negative (N0) lymph nodes (LN) as established by imaging (pelvic ± abdominal CT, MRI or LAG), or negative LN by nodal sampling or dissection (laparoscopy or laparotomy). Patients with radiologic (e.g., CT, MRI or LAG) or radioimmunoscintigraphy (i.e., ProstaScint™) findings suggestive of regional nodal involvement are eligible if cytologic (e.g., needle aspiration) or histologic (e.g., surgical sampling) evaluation shows no evidence of a neoplastic process (i.e., prostatic or non-prostatic malignancy). Patients with equivocal radiologic findings (maximum nodal size ≤ 1.5 cm) are eligible.

6. No distant (M0) metastases. Patients with radionuclide imaging (e.g., bone scintigraphy, ProstaScint™) findings suggestive, but not diagnostic of metastatic disease are eligible if radiologic (e.g., standard or tomographic radiography, or CT/MRI) imaging does not confirm metastatic disease.

7. Pretherapy serum (total) prostate-specific antigen value performed with a Federal Drug Administration approved assay method, e.g. Abbott, Hybritech, etc.

8. Treatment must begin within 6 weeks after randomization.

9. Alanine aminotransferase (ALT) must be within 2 x upper normal limit.

10. Patients must sign a study-specific informed consent form (Appendix I) prior to randomization.

Exclusion Criteria

1. Patients at high risk for disease relapse as determined by either:

   • Prostate-specific antigen ≥ 20 and Gleason score ≥ 7 (any T stage).
   • Clinical stage ≥T2 and Gleason score ≥ 8 (any prostate-specific antigen).

2. Patients at low risk for disease relapse as determined by:

   • Clinical stage ≤T2, Gleason score ≤ 6, and prostate-specific antigen ≤ 10.

3. Clinical stage Tx, T0, or T1a.

4. Histologic or radiologic evidence of tumor involvement of regional lymph nodes (N1) or the presence of metastatic disease (M1).

5. Pretherapy serum prostate-specific antigen level > 100.

6. Co-morbid medical illness which in the opinion of the investigator is expected to result in a life expectancy of <10 years.

7. Any of the following prior therapies:

   • Pelvic external beam radiation therapy.
   • Radionuclide prostate brachytherapy.
   • Prostatectomy or prostatic cryosurgery.
   • Prior bilateral orchiectomy.
   • Prior androgen suppression therapy; however, patients begun on LHRH agonist therapy remain eligible if (1) LHRH agonists were started no more than 30 days before randomization, and (2) Casodex or Eulexin was (or will be) started no more than 14 days before or after the date that the LHRH agonist injection was given. Any finasteride therapy administered for prostatic hypertrophy must be discontinued.
   • Chemotherapy for prostatic carcinoma.

8. Previous or concomitant invasive cancer, other than localized basal cell or squamous cell skin carcinoma (AJCC Stage 0-II), unless continually disease free for at least 5 years.

9. Major medical or psychiatric illness which, in the opinion of the investigator, would prevent completion of treatment or would interfere with follow-up.

10. The patient's participation in another medical research study that involves prostate cancer treatment.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.