Hormone Therapy and Radiation Therapy in Treating Patients With 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.