RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen deprivation therapy may stop the adrenal glands from making androgens. Radiation therapy uses high-energy x-rays to kill tumor cells. PURPOSE: This randomized phase III trial studies androgen-deprivation therapy and radiation therapy in treating patients with prostate cancer.
OBJECTIVES: Primary * Demonstrate that prophylactic, neoadjuvant androgen-deprivation therapy (NADT) combined with whole-pelvic radiation therapy (WPRT) improves overall survival (OS) compared with NADT combined with prostate and seminal vesicle radiation therapy (RT), with both arms receiving a high-dose prostate boost delivered by intensity-modulated RT (IMRT), external-beam RT (EBRT), high-dose-rate (HDR) brachytherapy, or permanent prostate implant (PPI). Secondary * Demonstrate that prophylactic WPRT improves biochemical control. * Determine the distant metastasis (DM)-free survival. * Determine the cause-specific survival (CSS). * Compare acute and late treatment-adverse events between patients receiving NADT and WPRT versus NADT, P, and SV RT. * 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). * Determine whether more aggressive treatment (Arm 2, NADT + WPRT) is associated with a greater increase in fatigue (PROMIS Fatigue Short Form) from baseline to last week of treatment, and a greater increase in circulating inflammatory markers (IL-1, IL-1ra, IL-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein). * 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). * 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. * Collect paraffin-embedded tissue blocks, plasma, whole blood, and urine for planned and future translational research analyses. OUTLINE: This is a multicenter study. Patients are stratified according to moderate- to high-risk groups as listed in the Disease Characteristics of this abstract, type of radiotherapy boost (IMRT vs brachytherapy \[Low-dose rate (LDR) using PPI or HDR\]), and duration of androgen-deprivation therapy (short-term \[4-6 months\] vs long-term \[32 months\]). Patients are randomized to 1 of 2 treatment arms. All patients receive neoadjuvant androgen-deprivation therapy comprising bicalutamide orally (PO) once daily or flutamide PO thrice daily for 4-6 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 4-6 or 32 months. Radiotherapy begins within 8 weeks after beginning LHRH agonist/antagonist injection. Patients may undergo blood and urine sample collection for correlative studies. Primary tumor tissue samples may also be collected. Patients may complete the Expanded Prostate Cancer Index Composite (EPIC), the PROMIS-Fatigue Short Form, and the EuroQol (EQ-5D) quality-of-life (QOL) questionnaires at baseline and periodically during treatment. Patients who participate in the QOL portion of the study must also agree to periodic blood collection. After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 3 years, and then yearly thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
2,590
Daily fractions
Daily fractions
Implant
Percentage of Participants Alive (Overall Survival)
Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis.
Time frame: From randomization to death or last follow-up. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported.
Percent of Participants Who Died Due to Prostate Cancer
Prostate cancer death rates were estimated using the cumulative incidence method, treating death due to other causes as a competing risk, and otherwise censoring participants alive at time of analysis.
Time frame: From randomization to death due to prostate cancer or last follow-up. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported.
Percentage of Participants With Distant Metastasis
Distant metastasis rates were estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive without distant metastasis at time of analysis.
Time frame: From date of randomization to distant metastasis, death, or last follow-up, whichever occurs first. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported.
Percentage of Participants With Biochemical Failure
Biochemical failure is defined as a rise in prostate-specific antigen (PSA) of ≥2.0 ng/mL above the post-treatment PSA nadir following radiation therapy for prostate cancer (Phoenix definition). Biochemical failure rates were estimated using the cumulative incidence method, treating death as a competing risk, and otherwise censoring participants alive without biochemical failure at time of analysis.
Time frame: From date of randomization to the date of biochemical failure, death, or last follow-up, whichever occurs first. Median follow-up at time of analysis was 6.8 years. Five- and ten-year estimates are reported.
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Tablet
University of South Alabama Mitchell Cancer Institute
Mobile, Alabama, United States
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
Anchorage Oncology Centre
Anchorage, Alaska, United States
Katmai Oncology Group
Anchorage, Alaska, United States
Providence Alaska Medical Center
Anchorage, Alaska, United States
Fairbanks Memorial Hospital
Fairbanks, Alaska, United States
Arizona Breast Cancer Specialists-Gilbert
Gilbert, Arizona, United States
Arizona Center for Cancer Care-Peoria
Peoria, Arizona, United States
Cancer Center at Saint Joseph's
Phoenix, Arizona, United States
...and 468 more locations
Number of Participants by Highest Grade Acute Adverse Event Reported
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Acute adverse events are defined as those occurring within 30 days after the completion of radiation therapy. RT begins approximately weeks 8-10 after starting protocol therapy and ends approximately weeks 19-22, depending on boost technique. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: From protocol treatment start date to 30 days from completion of radiation therapy. RT begins approximately weeks 8-10 after starting protocol therapy and ends approximately weeks 19-22, depending on boost technique.
Number of Participants by Highest Grade Late Adverse Event Reported
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Late adverse events are defined as occurring ≥ 30 days after end of RT (approximately weeks 19-22, depending on boost technique). Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: From 30 days after completion of radiation therapy (approximately weeks 19-22, depending on boost technique) to highest grade late adverse event. Median follow-up at time of analysis was 6.7 years.
EPIC-26 Urinary Bowel Domain Score Change From Baseline at 6 Months
The Expanded Prostate Cancer Index Composite-26 (EPIC-26) measures health-related quality of life in men with prostate cancer across urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal domains. Possible scores range from 0 to 100, with higher scores indicating better quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and 6 months after the end of RT, approximately 19-22 weeks, depending on boost technique.
EPIC-26 Urinary Irritative/Obstructive Subscore Change From Baseline at 6 Months
The Expanded Prostate Cancer Index Composite-26 (EPIC-26) measures health-related quality of life in men with prostate cancer across urinary incontinence, urinary irritative/obstructive, bowel, sexual, and hormonal domains. Possible scores range from 0 to 100, with higher scores indicating better quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and 6 months after the end of RT, approximately 19-22 weeks, depending on boost technique.
PROMIS Fatigue Score Change From Baseline Line at Last Week of Radiation Treatment
The Patient-Reported Outcome Measurement Information System (PROMIS) fatigue score measures self-reported fatigue symptoms over the past 7 days. Possible raw scores range from 29.4 to 83.2 (higher raw score indicating greater fatigue) and are converted into standardized T-scores (mean=50, standard deviation=10) with higher scores also indicating greater fatigue. Change score is calculated by subtracting baseline T-score from later T-score, with a positive change score indicating increased fatigue.
Time frame: Baseline and last week of radiation treatment, approximately 19-22 weeks, depending on boost technique.
Quality Adjusted Life Years (QALYs)
Quality adjusted life years is calculated as the weighted sum of the number of years spent in different health states. The weight value is a utility score between 0 (worst health state) and 1 (best health state) derived from the EQ-5D questionnaire, designed to describe and value health based on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Time frame: Baseline; the week prior to radiation therapy (RT); the last week of RT; 6 months, 1 year, and 5 years after RT. RT begins about weeks 8-10 after starting protocol therapy and ends about weeks 19-22, depending on boost technique.