Hypofractionated Radiation Therapy or Conventional Radiation Therapy After Surgery in Treating Patients With Prostate Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies how well hypofractionated radiation therapy works compared to conventional radiation therapy after surgery in treating patients with prostate cancer. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Conventional radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. It is not yet known whether giving hypofractionated radiation therapy or conventional radiation therapy after surgery may work better in treating patients with prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To demonstrate that hypofractionated post-prostatectomy radiotherapy (HYPORT) does not increase patient-reported gastrointestinal (GI) or genitourinary (GU) symptoms over conventionally fractionated post-prostatectomy (COPORT) at the 2-year time point. SECONDARY OBJECTIVES: I. To compare patient-reported GI symptoms using the Expanded Prostate Cancer Index Composite (EPIC)-26 at end of radiation therapy (RT) and 6, 12, 24, and 60 months from end of treatment. II. To compare patient-reported GU symptoms using the EPIC-26 at end of RT and 6, 12, 24, and 60 months from end of treatment. III. To compare the cost effectiveness based on the cost of radiotherapy and measured utilities for health outcomes using the EuroQol five dimensions questionnaire (EQ-5D). IV. To compare time to progression (TTP) where progression is defined as the first occurrence of biochemical failure (BF), local failure, regional failure, distant metastasis (DM), institution of new unplanned anticancer treatment, or death from prostate cancer (prostate cancer specific mortality [PCSM]). V. To compare freedom from biochemical failure (FFBF) and TTP rates with an alternate prostate specific antigen (PSA) >= PSA nadir + 2 ng/mL definition of BF. VI. To compare local failure, regional failure, salvage therapy (i.e. institution of new unplanned anticancer treatment), DM, PCSM, and overall survival (OS) rates. VII. Assessment of adverse events. VIII. Paraffin-embedded tissue block, serum, plasma, whole blood, and urine for future translational research analyses for predictors of toxicity following hypofractionated or conventionally fractionated post-prostatectomy radiotherapy. After completion of study treatment, patients are followed up every 6 months for 2 years and every year for 3 years and thereafter.

Official Title
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A Randomized Phase III Trial of Hypofractionated Post-prostatectomy Radiation Therapy (HYPORT) Versus Conventional Post-prostatectomy Radiation Therapy (COPORT)

Conditions
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Prostate Adenocarcinoma, Stage I Prostate Adenocarcinoma, Stage II Prostate Adenocarcinoma, Stage III Prostate Adenocarcinoma

Intervention / Treatment
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* Radiation: Hypofractionated radiation therapy
* Radiation: Conventional radiation therapy
* Drug: Optional androgen deprivation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRIOR TO STEP 1 REGISTRATION Adenocarcinoma of the prostate treated primarily with radical prostatectomy 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 One of the following pathologic T-classifications: pT2 or pT3 Patients with positive surgical margins are eligible One of the following pathologic N-classifications: pN0, pNX If a lymph node dissection is performed, the number of lymph nodes removed per side of the pelvis and the extent of the pelvic lymph node dissection (obturator versus (vs.) extended lymph node dissection) should be noted whenever possible No clinical evidence of regional lymph node metastasis Computed tomography (CT) (with contrast if renal function is acceptable; a noncontrast CT is permitted if the patient is not a candidate for contrast), magnetic resonance imaging (MRI), nodal sampling, or dissection of the pelvis within 120 days prior to step 1 registration Patients with pelvic lymph nodes equivocal or questionable by imaging are eligible if the nodes are =< 1 cm in the short axis A post-radical prostatectomy study entry PSA >= 45 days after prostatectomy and within 30 days prior to step 1, < 2.0 ng/mL No evidence of a local recurrence in the prostate fossa based on a digital rectal examination (DRE) within 60 days prior to step 1 registration Patients with equivocal or questionable DRE findings should have an MRI of the pelvis to exclude the presence of a prostate fossa mass Patients with equivocal or questionable exam findings by DRE or MRI are eligible if a biopsy of the lesion is negative for tumor No evidence of bone metastases (M0) on bone scan (Na F positron emission tomography (PET)/CT is an acceptable substitute) within 120 days prior to step 1 registration Equivocal bone scan findings are allowed if plain films and/or MRI are negative for metastasis Zubrod performance status 0-1 within 60 days prior to step 1 registration The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration Willingness and ability to complete the Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire Only English and French-speaking patients are eligible to participate PRIOR TO STEP 2 REGISTRATION The EPIC-26 must be completed in full and entered within 10 business days after step 1 registration; NRG Oncology Statistical and Data Management Center has 3 business days to score the results and send a notification to the site to proceed to step 2 randomization Exclusion Criteria: A post-prostatectomy PSA nadir >= 0.2 ng/mL AND Gleason >= 7 pT2 with a negative surgical margin and PSA < 0.1 ng/mL 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 Androgen deprivation therapy started after prostatectomy and prior to step 1 registration for > 6 weeks (42 days) Neoadjuvant chemotherapy before or after prostatectomy Prior invasive (except non-melanoma skin cancer) malignancy unless disease-free for a minimum of 3 years and not in the pelvis; (for example, carcinoma in situ of the oral cavity is permissible if disease free for a minimum of 3 years; however, patients with prior history of bladder cancer are not allowed no matter the disease free duration); prior hematological (e.g., leukemia, lymphoma, myeloma) malignancy is not allowed Previous chemotherapy for any other disease site if given within 3 years prior to step 1 Prior radiotherapy, including brachytherapy, to the region of the study cancer that would result in overlap of radiation therapy treatment volumes 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 step 1 registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 1 registration Severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic disease Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol End-stage renal disease (ie, on dialysis or dialysis has been recommended) Prior allergic reaction to the study drugs involved in this protocol History of inflammatory bowel disease, prior bowel surgeries (or colostomy) for any reason, or prior partial/radical cystectomy for any reason

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional radiation therapy<br>Conventional post-prostatectomy radiation therapy (COPORT) over 7 weeks. Patients may also receive optional androgen deprivation therapy per doctor recommendation. | Radiation: Conventional radiation therapy<br>* 62.5 Gy in 25 daily fractions of 2.5 Gy to the prostate bed in the absence of disease progression or unacceptable toxicity.<br>Drug: Optional androgen deprivation therapy<br>* Any luteinizing hormone-releasing hormone (LHRH) agonist/antagonist with or without an oral antiandrogen can be used up to a six-month administration dose, starting 7-9 weeks before radiation therapy and may begin as early as 42 days prior to or any time after screening. An oral antiandrogen alone is not allowed.<br>* Other names: ADT;|
| Experimental: Hypofractionated radiation therapy<br>Hypofractionated post-prostatectomy radiation therapy (HYPORT) over 5 weeks. Patients may also receive optional androgen deprivation therapy per doctor recommendation. | Radiation: Hypofractionated radiation therapy<br>* 66.6 Gy in 37 daily fractions of 1.8 Gy to the prostate bed in the absence of disease progression or unacceptable toxicity.<br>* Other names: hypofractionation;Drug: Optional androgen deprivation therapy<br>* Any luteinizing hormone-releasing hormone (LHRH) agonist/antagonist with or without an oral antiandrogen can be used up to a six-month administration dose, starting 7-9 weeks before radiation therapy and may begin as early as 42 days prior to or any time after screening. An oral antiandrogen alone is not allowed.<br>* Other names: ADT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Urinary Domain of the Expanded Prostate Cancer Index (EPIC) at Two Years | The EPIC is a prostate cancer health-related quality of life (HRQOL) self-administered instrument measuring patient-reported urinary, bowel, sexual, and hormonal symptoms related to prostate cancer treatments. Response options for each item form a Likert scale with scores transformed linearly to a 0-100 scale. Domain scores are also on a 0-100 scale with higher scores representing better HRQOL. The urinary domain contains 12 items. Change from baseline is calculated by subtracting baseline from later score, with a positive change score indicating increased HRQOL. | Baseline (randomization), 2 years | 
| Change in Bowel Domain of the Expanded Prostate Cancer Index (EPIC) at Two Years | The EPIC is a prostate cancer health-related quality of life (HRQOL) self-administered instrument measuring patient-reported urinary, bowel, sexual, and hormonal symptoms related to prostate cancer treatments. Response options for each item form a Likert scale with scores transformed linearly to a 0-100 scale. Domain scores are also on a 0-100 scale with higher scores representing better HRQOL. The bowel domain contains 14 items. Change from baseline is calculated by subtracting baseline from later score, with a positive change score indicating increased HRQOL. | Baseline, 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Urinary Domain Score of the Expanded Prostate Cancer Index (EPIC) at End of Radiation Therapy (RT), 6 Months, 1 and 5 Years | The EPIC is a prostate cancer health-related quality of life (HRQOL) self-administered instrument measuring patient-reported urinary, bowel, sexual, and hormonal symptoms related to prostate cancer treatments. Response options for each item form a Likert scale with scores transformed linearly to a 0-100 scale. Domain scores are also on a 0-100 scale with higher scores representing better HRQOL. The urinary domain contains 12 items. Change from baseline is calculated by subtracting baseline from later score, with a positive change score indicating increased HRQOL. | Baseline, end of RT, then 6 months,1 and 5 years from the start of RT (5 year time point has not yet been reached). RT dates depend on timing and duration of androgen deprivation therapy (ADT) (optional) and RT. | 
| Change in Bowel Domain Score of the Expanded Prostate Cancer Index (EPIC) at End of RT, 6 Months, 1 and 5 Years | The EPIC is a prostate cancer health-related quality of life (HRQOL) self-administered instrument measuring patient-reported urinary, bowel, sexual, and hormonal symptoms related to prostate cancer treatments. Response options for each item form a Likert scale with scores transformed linearly to a 0-100 scale. Domain scores are also on a 0-100 scale with higher scores representing better HRQOL. The bowel domain contains 14 items. Change from baseline is calculated by subtracting baseline from later score, with a positive change score indicating increased HRQOL. | Baseline, end of RT, then 6 months,1 and 5 years from the start of RT (5 year time point has not yet been reached). RT dates depend on timing and duration of ADT (optional) and RT. | 
| Percentage of Participants With Biochemical Failure | Biochemical failure was analyzed using two different definitions. The protocol definition of biochemical failure is a PSA measurement ≥ 0.4 ng/mL and rising (i.e. PSA ≥ 0.4 ng/mL followed by a value higher than the first by any amount) or followed by initiation of salvage hormones. The Phoenix definition of biochemical failure is a PSA measurement ≥ PSA nadir + 2 ng/mL where nadir is the lowest post-RT PSA value. Time to biochemical failure is defined as time from randomization to the date of first biochemical failure, last known follow-up (censored), or death without biochemical failure (competing risk). Biochemical failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. | 
| Percentage of Participants With Progression | Progression (failure) is defined as the first occurrence of biochemical failure, local failure, regional failure, distant failure, institution of new unplanned anticancer treatment, or death from prostate cancer. Time to progression is defined as time from randomization to the date of progression, last known follow-up (censored), or death without progression (competing risk). Progression rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Two-year rates reported here. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. | 
| Percentage of Participants With Local-Regional Failure | Local-regional failure is defined as local or regional failure. Local failure is defined as the development of a new biopsy-proven mass in the prostate bed. Regional failure is defined as radiographic evidence (CT or MRI) of lymphadenopathy (lymph node size ≥ 1.0 cm in the short axis) in a patient without the diagnosis of a hematologic/lymphomatous disorder associated with adenopathy. Time to local-regional failure is defined as time from randomization to the date of first local-regional failure, last known follow-up (censored), or death without local-regional (competing risk). Local-regional failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Two-year rates reported here. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. | 
| Percentage of Participants Receiving Salvage Therapy | Salvage therapy is defined as the initiation of new unplanned anticancer treatment. Time to salvage therapy initiation is defined as time from randomization to the date of first salvage therapy, last known follow-up (censored), or death without salvage therapy (competing risk). Salvage therapy rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of salvage initiation times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Two-year rates reported here. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. | 
| Percentage of Participants With Distant Metastasis | Distant metastasis (failure) is defined as radiographic evidence of hematogenous spread evaluated by bone scan, CT, or MRI. Time to distant metastasis is defined as time from randomization to the date of first distant metastasis, last known follow-up (censored), or death without local recurrence (competing risk). Distant metastasis rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year rates are provided. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Two-year rates reported here. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. | 
| Percentage of Participants Who Died From Prostate Cancer (Prostate Cancer Specific Mortality) | Cause of death was centrally reviewed. Count and percentage at time of analysis are reported. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Two-year rates reported here. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. | 
| Percent of Participants Alive (Overall Survival) | Overall survival time is defined as time from registration/randomization to the date of death (failure) 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. 2-year rates are provided. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Two-year rates reported here. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. | 
| Number of Participants With Grade 3+ Adverse Events | Common Terminology Criteria for Adverse Events (CTCAE) version 4 grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. Counts of participants with any grade 3 or higher adverse event, any grade 3 or higher gastrointestinal adverse events, and any grade 3 or higher genitourinary adverse events are reported. Adverse events of any attribution are included. | From randomization to last follow-up. Maximum follow-up at time of analysis was 3.0 years. Follow-up schedule: end of RT, then 6, 12, 18, 24 months from start of RT, then yearly. |