A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy With or Without Short-Term Androgen Deprivation Therapy for Patients With Intermediate-Risk Prostate Cancer
Overview
- Phase
- Phase 3
- Intervention
- Dose-Escalated Radiation Therapy
- Conditions
- Prostate Cancer
- Sponsor
- Radiation Therapy Oncology Group
- Enrollment
- 1538
- Locations
- 1015
- Primary Endpoint
- Percentage of Participants Alive (Overall Survival)
- Status
- Completed
- Last Updated
- last month
Overview
Brief Summary
RATIONALE: Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells and shrink tumors. Androgens can cause the growth of prostate cancer cells. Androgen-deprivation therapy may lessen the amount of androgens made by the body. It is not yet known whether radiation therapy is more effective with or without androgen-deprivation therapy in treating patients with prostate cancer.
PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with androgen-deprivation therapy in treating patients with prostate cancer.
Detailed Description
OBJECTIVES: Primary * Demonstrate an overall survival (OS) advantage in patients with intermediate-risk prostate cancer treated with dose-escalated radiotherapy (RT) with versus without short-term androgen-deprivation therapy (ADT). Secondary * Determine whether the addition of ADT to dose-escalated RT versus RT alone improves clinical failures, biochemical failure by the "nadir +2", freedom from failure, rate of salvage ADT, and prostate cancer-specific mortality in these patients. * Estimate the magnitude of benefit of ADT with respect to OS in patients treated with different RT modalities (i.e., external-beam radiation therapy alone vs low-dose rate brachytherapy boost vs high-dose rate brachytherapy boost). * Compare acute and late treatment adverse events of these regimens and correlate these events with the presence or absence of pre-existing comorbidity as documented by the Adult Comorbidity Evaluation 27 assessment. OUTLINE: This is a multicenter, dose-escalation study of radiotherapy. Patients are stratified according to number of risk factors (1 vs 2-3), comorbidity (ACE-27 grade ≥ 2 vs \< 2), and radiotherapy (RT) modality (dose-escalated external-beam RT \[EBRT\] vs EBRT and low-dose rate brachytherapy boost vs EBRT and high-dose rate brachytherapy boost). Patients are randomized to 1 of 2 treatment arms. After completion of study therapy, patients are followed up periodically.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologically) proven diagnosis of prostatic adenocarcinoma, at intermediate risk for recurrence, within 180 days prior to registration as determined by having one or more of the following intermediate-risk features: Gleason score 7; prostate-specific antigen (PSA) \>10 but ≤20; clinical stage T2b-T2c.
- •Patients previously diagnosed with low risk (Gleason score ≤ 6, clinical stage \< T2a, and PSA \< 10) prostate cancer undergoing active surveillance who are re-biopsied and found to have intermediate risk disease according to the protocol criteria are eligible for enrollment within 180 days of the repeat biopsy procedure.
- •Clinically negative lymph nodes as established by imaging (pelvic +/- abdominal CT or MRI), nodal sampling, or dissection within 60 days prior to registration, except as noted immediately below:
- •Patients with a single intermediate risk factor only do not require abdominopelvic imaging, but these studies may be obtained at the discretion of the treating physician. Patients with 2 or 3 risk factors are required to undergo pelvic +/- abdominal CT or MRI.
- •Patients with lymph nodes equivocal or questionable by imaging are eligible without biopsy if the nodes are ≤1.5 cm; any node larger than this on imaging will require negative biopsy for eligibility.
- •No evidence of bone metastases (M0) on bone scan within 60 days prior to registration.
- •Bone scan is not required for patients enrolled with a single intermediate risk factor only, but this scan may be obtained at the discretion of the treating physician. Patients with 2 or 3 risk factors will require a negative bone scan for eligibility.
- •Equivocal bone scan findings are allowed if plain film x-rays are negative for metastasis.
- •History/physical examination (to include, at a minimum, digital rectal examination of the prostate and examination of the skeletal system and abdomen, and formal comorbidity assessment via the ACE-27 instrument) within 60 days prior to registration.
- •Zubrod Performance Status 0-1
Exclusion Criteria
- •Patients with Gleason Score ≥ 8; PSA \> 20; OR Clinical Stage ≥ T3 are ineligible for this trial.
- •Should findings of extracapsular extension or seminal vesicle invasion be noted on prostate MRI, this study, if used, will not render patients ineligible for accrual to this protocol. Primary tumor staging for eligibility purposes is to be based on palpable or core biopsy evidence only with respect to extracapsular extension or seminal vesicle involvement.
- •Patients with all three intermediate risk factors who also have ≥ 50% of the number of their biopsy cores positive for cancer are ineligible for this trial.
- •Prior invasive malignancy (except non-melanomatous skin cancer) or hematological (e.g., leukemia, lymphoma, myeloma) malignancy unless disease free for a minimum of 5 years (prior diagnoses of carcinoma in situ are permitted)
- •Prior radical surgery (prostatectomy), high-intensity focused ultrasound (HIFU) or cryosurgery for prostate cancer
- •Prior hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide), antiandrogens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or bilateral orchiectomy
- •Use of finasteride within 30 days prior to registration
- •Use of dutasteride within 90 days prior to registration
- •Prior or concurrent cytotoxic chemotherapy for prostate cancer; prior chemotherapy for a different cancer is permitted.
- •Prior RT, including brachytherapy, to the region of the study cancer that would result in overlap of RT fields
Arms & Interventions
Dose-Escalated Radiation Therapy Alone
Radiation therapy consists of 79.2 Gy EBRT only or 45 Gy EBRT followed by low- or high-dose rate brachytherapy. EBRT is delivered in 1.8 Gy daily fractions.
Intervention: Dose-Escalated Radiation Therapy
Dose-Escalated Radiation Therapy and Short-Term Androgen-Deprivation
Radiation therapy consists of 79.2 Gy EBRT only or 45 Gy EBRT followed by low- or high-dose rate brachytherapy. EBRT is delivered in 1.8 Gy daily fractions. Six months of androgen-deprivation therapy starts 8 weeks prior to start of radiation therapy and consists of luteinizing-hormone releasing-hormone (LHRH) agonist (antagonist) therapy (leuprolide, goserelin, buserelin. triptorelin, or degarelix) and anti-androgen therapy (bicalutamide or flutamide).
Intervention: bicalutamide
Dose-Escalated Radiation Therapy and Short-Term Androgen-Deprivation
Radiation therapy consists of 79.2 Gy EBRT only or 45 Gy EBRT followed by low- or high-dose rate brachytherapy. EBRT is delivered in 1.8 Gy daily fractions. Six months of androgen-deprivation therapy starts 8 weeks prior to start of radiation therapy and consists of luteinizing-hormone releasing-hormone (LHRH) agonist (antagonist) therapy (leuprolide, goserelin, buserelin. triptorelin, or degarelix) and anti-androgen therapy (bicalutamide or flutamide).
Intervention: flutamide
Dose-Escalated Radiation Therapy and Short-Term Androgen-Deprivation
Radiation therapy consists of 79.2 Gy EBRT only or 45 Gy EBRT followed by low- or high-dose rate brachytherapy. EBRT is delivered in 1.8 Gy daily fractions. Six months of androgen-deprivation therapy starts 8 weeks prior to start of radiation therapy and consists of luteinizing-hormone releasing-hormone (LHRH) agonist (antagonist) therapy (leuprolide, goserelin, buserelin. triptorelin, or degarelix) and anti-androgen therapy (bicalutamide or flutamide).
Intervention: LHRH agonist (antagonist) therapy
Dose-Escalated Radiation Therapy and Short-Term Androgen-Deprivation
Radiation therapy consists of 79.2 Gy EBRT only or 45 Gy EBRT followed by low- or high-dose rate brachytherapy. EBRT is delivered in 1.8 Gy daily fractions. Six months of androgen-deprivation therapy starts 8 weeks prior to start of radiation therapy and consists of luteinizing-hormone releasing-hormone (LHRH) agonist (antagonist) therapy (leuprolide, goserelin, buserelin. triptorelin, or degarelix) and anti-androgen therapy (bicalutamide or flutamide).
Intervention: Dose-Escalated Radiation Therapy
Outcomes
Primary Outcomes
Percentage of Participants Alive (Overall Survival)
Time Frame: From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.
Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Five-year rates are provided here. Analysis was planned to occur after 218 deaths were reported.
Secondary Outcomes
- Percentage of Participants With Biochemical Failure(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Percentage of Participants With Local Recurrence(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Percentage of Participants With Regional Recurrence(From randomization to last follow-up. Maximum follow-up at time of analysis was 10.3 years.)
- Percentage of Participants With Distant Metastasis(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Percentage of Participants Dead Due to Prostate Cancer (Prostate Cancer-specific Mortality)(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Percentage of Participants Dead Due to Cause Other Than Prostate Cancer (Non-Prostate Cancer-specific Mortality)(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Percentage of Participants Receiving Salvage Androgen Deprivation Therapy (ADT)(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Percentage of Participants Alive (Overall Survival) by Radiation Therapy Modality(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates reported here.)
- Number of Participants With Acute Adverse Events(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years.)
- Percentage of Participants With Late Grade 3+ Adverse Events(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates are reported here.)
- Percentage of Participants Failed (Freedom From Failure)(From randomization to last follow-up. Follow-up schedule: end of RT (2nd arm only), then every 3 months for a year, every 4 months for 4 years, then yearly. Maximum follow-up at time of analysis was 10.3 years. Five-year rates are reported here.)
- Change From Baseline in Expanded Prostate Cancer Index Composite (EPIC) Urinary Domain Score(Last week of RT (approximately 9 and 17 weeks from start of protocol treatment for Arm 1 and 2, respectively), then 6 months, 1 year and 5 years from end of RT.)
- Change From Baseline in Expanded Prostate Cancer Index Composite (EPIC) Bowel Domain Score(Last week of RT (approximately 9 and 17 weeks from start of protocol treatment for Arm 1 and 2, respectively), then 6 months, 1 year and 5 years from end of RT.)
- Change From Baseline in Expanded Prostate Cancer Index Composite (EPIC) Hormonal Domain Score(Last week of RT (approximately 9 and 17 weeks from start of protocol treatment for Arm 1 and 2, respectively), then 6 months, 1 year and 5 years from end of RT.)
- Change From Baseline in Expanded Prostate Cancer Index Composite (EPIC) Sexual Domain Score(Last week of RT (approximately 9 and 17 weeks from start of protocol treatment for Arm 1 and 2, respectively), then 6 months, 1 year and 5 years from end of RT.)
- Change From Baseline in Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Domain Score(Last week of RT (approximately 9 and 17 weeks from start of protocol treatment for Arm 1 and 2, respectively), then 6 months, 1 year and 5 years from end of RT.)
- Quality Adjusted Life Years (QALYs)(Last week of RT (approximately 9 and 17 weeks from start of protocol treatment for Arm 1 and 2, respectively), then 6 months, 1 year and 5 years from end of RT.)
- Correlation Between PROMIS Fatigue Score Change and Plasma Cytokine Change(From date of randomization to 3 weeks from start of RT.)