Androgen-Deprivation Therapy and Radiation Therapy in Treating Patients With Prostate Cancer

PRIMARY OBJECTIVE:

I. Demonstrate that prophylactic, neoadjuvant, androgen-deprivation therapy (NADT) and
whole-pelvic radiation therapy (WPRT) will result in improvement in overall survival (OS) of
patients with "unfavorable" intermediate-risk or "favorable" high-risk prostate cancer
compared to NADT and high-dose prostate and seminal vesicle (SV) radiation therapy (prostate
[P] + SV radiation therapy [RT]) using intensity-modulated radiotherapy (IMRT) or
external-beam RT (EBRT) with a high-dose rate (HDR) or a permanent prostate (radioactive
seed) implant (PPI) boost.

SECONDARY OBJECTIVES:

I. Demonstrate that prophylactic WPRT improves biochemical control. II. Distant metastasis
(DM)-free survival. III. Cause-specific survival (CSS). IV. Compare acute and late
treatment-adverse events between patients receiving NADT and WPRT versus NADT + P and SV RT.

V. Determine whether health-related quality of life (HRQOL), as measured by the Expanded
Prostate Cancer Index Composite (EPIC), significantly worsens with increasing aggressiveness
of treatment (i.e., Arm 2, NADT + WPRT). (closed to patient accrual 3/9/15) VI. Determine
whether more aggressive treatment (Arm 2, NADT + WPRT) is associated with a greater increase
in fatigue (Patient-Reported Outcome Measurement Information System [PROMIS] Fatigue Short
Form) from baseline to last week of treatment, and a greater increase in circulating
inflammatory markers (interleukin [IL]-1, IL-1 receptor antagonist [ra], IL-6, tumor
necrosis factor [TNF]-alpha, and C-reactive protein). (closed to patient accrual 3/9/15)
VII. Demonstrate an incremental gain in OS and CSS with more aggressive therapy that
outweighs any detriments in the primary generic domains of HRQOL (i.e., mobility, self-care,
usual activities, pain/discomfort, and anxiety/depression). (closed to patient accrual
3/9/15) VIII. Determine whether changes in fatigue from baseline to the next three time
points (week prior to RT, last week of treatment, and 3 months after treatment) are
associated with changes in circulating cytokines, mood, sleep, and daily activities across
the same time points.

IX. Collect paraffin-embedded tissue blocks, plasma, whole blood, and urine for planned and
future translational research analyses.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

All patients receive neoadjuvant androgen-deprivation therapy comprising bicalutamide orally
(PO) once daily (QD) or flutamide PO thrice daily (TID) for 6 months, and luteinizing
hormone-releasing hormone (LHRH) agonist/antagonist therapy comprising leuprolide acetate,
goserelin acetate, buserelin, triptorelin, or degarelix subcutaneously (SC) or
intramuscularly (IM) every 1 to 3 months beginning 2 months prior to radiotherapy and
continuing for 6 or 32 months. Radiotherapy begins within 8-10 weeks after beginning LHRH
agonist/antagonist injection.

ARM I: Patients undergo high-dose radiotherapy of the prostate and seminal vesicles using
IMRT* or 3D-conformal radiation therapy (3D-CRT)* QD, 5 days a week, for approximately 9
weeks. Patients may also undergo PPI brachytherapy or high-dose rate brachytherapy (iodine I
125 or palladium Pd 103 may be used as the radioisotope).

ARM II: Patients undergo WPRT* (3D-CRT or IMRT) QD, 5 days a week, for approximately 9
weeks. Patients may also undergo brachytherapy as in Arm I.

NOTE: * Patients undergoing brachytherapy implant receive 5 weeks of IMRT, 3D-CRT, or WPRT.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 3 years, and then yearly thereafter.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of prostatic
adenocarcinoma within 180 days of registration at moderate- to high-risk for
recurrence as determined by one of the following combinations:

- Gleason score 7-10 + T1c-T2b (palpation) + prostate-specific antigen (PSA) < 50
ng/mL (includes intermediate- and high-risk patients)

- Gleason score 6 + T2c-T4 (palpation) + PSA < 50 ng/mL OR Gleason score 6 + >=
50% (positive) biopsies + PSA < 50 ng/ml

- Gleason score 6 + T1c-T2b (palpation) + PSA > 20 ng/mL

- Patients previously diagnosed with low risk prostate cancer undergoing active
surveillance who are re-biopsied and found to have unfavorable intermediate risk
disease or favorable high risk disease according to the protocol criteria are
eligible for enrollment within 180 days of the repeat biopsy procedure

- History/physical examination (to include at a minimum digital rectal examination of
the prostate and examination of the skeletal system and abdomen) within 90 days prior
to registration

- Clinically negative lymph nodes as established by imaging (pelvic and/or abdominal
computed tomography [CT] or magnetic resonance [MR]), (but not by nodal sampling, or
dissection) within 90 days prior to registration

- Patients with lymph nodes equivocal or questionable by imaging are eligible if
the nodes are =< 1.5 cm

- No evidence of bone metastases (M0) on bone scan within 120 days prior to
registration (sodium fluoride [NaF] positron emission tomography [PET]/CT is an
acceptable substitute)

- Equivocal bone scan findings are allowed if plain films (or CT or magnetic
resonance imaging [MRI]) are negative for metastasis

- Baseline serum PSA value performed with a Food and Drug Administration (FDA)-approved
assay (e.g., Abbott, Hybritech) within 120 days prior to registration

- Study entry PSA should not be obtained during the following time frames:

- 10-day period following prostate biopsy

- Following initiation of hormonal therapy

- Within 30 days after discontinuation of finasteride

- Within 90 days after discontinuation of dutasteride

- Zubrod performance status 0-1 (unless otherwise specified)

- Absolute neutrophil count (ANC) >= 1,500/mm³

- Platelets >= 100,000/mm³

- Hemoglobin (Hgb) >= 8.0 g/dL (Note: the use of transfusion or other intervention to
achieve Hgb >= 8.0 g/dL is acceptable)

- Patient must be able to provide study specific informed consent prior to study entry

Exclusion Criteria:

- Prior invasive (except non-melanoma skin cancer) malignancy unless disease-free for a
minimum of 3 years (1095 days) not in the pelvis (for example, carcinoma in situ of
the oral cavity is permissible; however, patients with prior history of bladder
cancer are not allowed); prior hematological (e.g., leukemia, lymphoma, myeloma)
malignancy not allowed

- Previous radical surgery (prostatectomy) or cryosurgery for prostate cancer

- Previous pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy

- Previous hormonal therapy, such as LHRH agonists (e.g., leuprolide, goserelin,
buserelin, triptorelin) or LHRH antagonist (e.g. degarelix), anti-androgens (e.g.,
flutamide, bicalutamide, cyproterone acetate), estrogens (e.g., diethylstilbestrol
[DES]), or surgical castration (orchiectomy)

- Prior pharmacologic androgen ablation for prostate cancer is allowed only if the
onset of androgen ablation (both LHRH agonist and oral anti-androgen) is =< 45 days
prior to the date of registration

- Use of finasteride within 30 days prior to registration

- Use of dutasteride or dutasteride/tamsulosin (Jalyn) within 90 days prior to
registration

- Previous or concurrent cytotoxic chemotherapy for prostate cancer; note that prior
chemotherapy for a different cancer is allowable

- Prior radiotherapy, including brachytherapy, to the region of the study cancer that
would result in overlap of radiation therapy fields

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

- 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
or severe liver dysfunction

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this
protocol; protocol-specific requirements may also exclude immuno-compromised
patients

- Patients who are sexually active and not willing/able to use medically acceptable
forms of contraception

- Prior allergic reaction to the hormones involved in this protocol

- Patients status post a negative lymph node dissection are not eligible