RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as flutamide, bicalutamide, and luteinizing hormone-releasing hormone agonist, may lessen the amount of androgens made by the body. It is not yet known which regimen of radiation therapy with or without androgen-deprivation therapy is more effective for prostate cancer.

PURPOSE: This randomized phase III trial is studying prostate radiation therapy to see how well it works compared with short-term androgen deprivation therapy given together with pelvic lymph node radiation therapy with or without prostate radiation therapy in treating patients with a rising PSA after surgery for prostate cancer.

OBJECTIVES:

Primary

• To determine whether the addition of short-term androgen deprivation (STAD) to prostate bed radiotherapy (PBRT) improves freedom from progression (FFP) (i.e., maintenance of a prostate-specific antigen [PSA] less than the nadir+2 ng/mL, absence of clinical failure, and absence of death from any cause) for 5 years, over that of PBRT alone in men treated with salvage radiotherapy after radical prostatectomy.
• To determine whether STAD, pelvic lymph node radiotherapy (PLNRT), and PBRT improves FFP over that of STAD+PBRT and PBRT alone in men treated with salvage radiotherapy after radical prostatectomy.

Secondary

• To compare secondary biochemical failure, the development of hormone-refractory disease , distant metastasis, cause-specific mortality, and overall mortality at five years.
• To compare acute and late morbidity based on Common Toxicity Criteria for Adverse Effects (CTCAE), v. 3.0.
• To measure the expression of cell kinetic, apoptotic pathway, and angiogenesis-related genes in archival diagnostic tissue to better define the risk of FFP, distant failure, cause-specific mortality, and overall mortality after salvage radiotherapy for prostate cancer, independently of conventional clinical parameters now used.
• To quantify blood product-based proteomic and genomic (single nucleotide polymorphisms) patterns and urine-based genomic patterns before and at different times after treatment to better define the risk of FFP, distant failure, cause-specific mortality, and overall mortality after salvage radiotherapy for prostate cancer, independently of conventional clinical parameters now used.
• To assess the degree, duration, and significant differences of disease-specific health-related quality of life (HRQOL) decrements among treatment arms.
• To assess whether mood is improved and depression is decreased with the more aggressive therapy if it improves FFP.
• To collect paraffin-embedded tissue blocks, serum, plasma, urine, and buffy coat cells for future translational research analyses.

Tertiary

• To assess whether an incremental gain in FFP and survival with more aggressive therapy outweighs decrements in the primary generic domains of HRQOL (i.e., mobility, self care, usual activities, pain/discomfort, and anxiety/depression).
• To evaluate the cost-utility of the treatment arm demonstrating the most significant benefit (in terms of the primary outcome) in comparison with other widely accepted cancer and non-cancer therapies.
• To assess associations between serum levels of beta-amyloid and measures of cognition and mood and depression.
• An exploratory aim is to assess the relationship(s) between the American Urological Association Symptom Index (AUA SI) and urinary morbidity using the CTCAE v. 3.0 grading system.

OUTLINE: Patients are stratified according to seminal vesicle involvement (yes vs no), prostatectomy Gleason score (≤ 7 vs 8-9), pre-radiotherapy PSA (≥ 0.1 and ≤ 1.0 ng/mL vs > 1.0 and < 2.0 ng/mL), and pathology stage (pT2 and margin negative vs all others). Patients are randomized to 1 of 3 treatment arms.

Follow-up occurs 3, 6, and 12 months after the completion of radiation therapy, then every 6 months for 6 years, and then annually thereafter.

Inclusion Criteria:

1. Adenocarcinoma of the prostate treated primarily with radical prostatectomy, pathologically proven to be lymph node negative by pelvic lymphadenectomy (N0) or lymph node status pathologically unknown (undissected pelvic lymph nodes [Nx]), i.e. lymph node dissection is not required;

   • Any type of radical prostatectomy will be permitted, including retropubic, perineal, laparoscopic or robotically assisted. There is no time limit for the date of radical prostatectomy.

2. A post-radical prostatectomy entry prostate-specific antigen (PSA) of ≥ 0.1 and < 2.0 ng/mL at least 6 weeks (45 days) after prostatectomy and within 30 days of registration;

3. One of the following pathologic classifications:

   • T3N0/Nx disease with or without a positive prostatectomy surgical margin; or
   • T2N0/Nx disease with or without a positive prostatectomy surgical margin;

4. Prostatectomy Gleason score of 9 or less;

5. Zubrod Performance Status of 0-1;

6. Age ≥ 18;

7. No distant metastases, based upon the following minimum diagnostic workup:

   • History/physical examination (including digital rectal exam) within 8 weeks (60 days) prior to registration;
   • A computerized tomography (CT) scan of the pelvis (with contrast if renal function is acceptable; a noncontrast CT is permitted if the patient is not a candidate for contrast) or magnetic resonance imaging (MRI) of the pelvis within 120 days prior to registration;
   • Bone scan within 120 days prior to registration; if the bone scan is suspicious, a plain x-ray and/or MRI must be obtained to rule out metastasis.

8. Adequate bone marrow function, within 90 days prior to registration, defined as follows:

   • Platelets ≥ 100,000 cells/mm^3 based upon compete blood count (CBC);
   • Hemoglobin ≥ 10.0 g/dl based upon CBC (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is recommended).

9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 x the upper limit of normal within 90 days prior to registration;

10. Serum total testosterone must be ≥ 40% of the lower limit of normal (LLN) of the assay used (testosterone ÷ LLN must be ≥ 0.40) within 90 days prior to registration (Note: Patients who have had a unilateral orchiectomy are eligible as long as this requirement is met);

11. Patients must sign a study-specific informed consent prior to study entry.

Exclusion Criteria:

1. A palpable prostatic fossa abnormality/mass suggestive of recurrence, unless shown by biopsy under ultrasound guidance not to contain cancer;

2. N1 patients are ineligible, as are those with pelvic lymph node enlargement ≥ 1.5 cm in greatest dimension by CT scan or MRI of the pelvis, unless the enlarged lymph node is sampled and is negative;

3. Androgen deprivation therapy started prior to prostatectomy for > 6 months (180 days) duration. Note: The use of finasteride or dutasteride (±tamsulosin) for longer periods prior to prostatectomy is acceptable;

4. Androgen deprivation therapy started after prostatectomy and prior to registration (Note: The use of finasteride or dutasteride (±tamsulosin) after prostatectomy is not acceptable - must be stopped within 3 months after prostatectomy. Androgen deprivation therapy must be stopped within 3 months after prostatectomy);

5. Neoadjuvant chemotherapy before or after prostatectomy;

6. Prior chemotherapy for any other disease site if given within 5 years prior to registration;

7. Prior cryosurgery or brachytherapy of the prostate; prostatectomy should be the primary treatment and not a salvage procedure;

8. Prior pelvic radiotherapy;

9. Prior invasive malignancy (except non-melanomatous skin cancer) or superficial bladder cancer unless disease free for a minimum of 5 years [for example, carcinoma in situ of the oral cavity is permissible];

10. Severe, active co-morbidity, defined as follows:

    • History of inflammatory bowel disease;
    • History of hepatitis B or C; Blood tests are not required to determine if the patient has had hepatitis B or C, unless the patient reports a history of hepatitis.
    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
    • Transmural myocardial infarction within the last 6 months;
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
    • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration;
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; AST or ALT are required; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol.
    • Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; Note, however, that human immunodeficiency viruses (HIV) testing is not required for entry into this protocol. The need to exclude patients with acquired immunodeficiency syndrome (AIDS) from this protocol is necessary because the treatments involved in this protocol may result in increased toxicity and immunosuppression.

11. Prior allergic reaction to the study drug(s) involved in this protocol.