Hypofractionated Radiation Therapy for Treating Prostate Cancer High-Risk Features Following Radical Prostatectomy

Study Overview
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Brief Summary
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This phase II trial studies how well hypofractionated radiation therapy works in treating participants with prostate cancer high-risk features following radical prostatectomy. 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.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine if stereotactic body radiation therapy (SBRT) would result in similar freedom from failure (FFF) than standard fractionation photon therapy. EXPLORATORY OBJECTIVES: I. After completion of radiation therapy, determine the incidence of grade 2 or greater genitourinary (GU) and gastrointestinal (GI) toxicity at 6 months (Common Terminology Criteria for Adverse Events [CTCAE] version 4). II. After completion of radiation therapy, determine the incidence of grade 3 or greater GU and GI toxicity at 6 months (CTCAE version 4). III. After completion of radiation therapy, determine the incidence of quality of life issues following completion of radiation therapy. IV. After completion of radiation therapy, determine the incidence of impotence after the use of radiation therapy at 3 years. V. After completion of radiation therapy, determine the incidence of freedom from biochemical failure (FFBF) at 5 years. VI. After completion of radiation therapy, determine the incidence of clinical failure: local and/or distant at 5 years. VII. After completion of radiation therapy, determine the incidence of salvage androgen deprivation use (SAD) at 5 years. VIII. After completion of radiation therapy, determine the incidence of progression free survival: using clinical, biochemical and SAD as events at 5 years. IX. After completion of radiation therapy, determine the incidence of overall survival at 5 years. X. After completion of radiation therapy, determine the incidence of disease-specific survival at 5 years. XI. Determine the impact of radiation therapy on quality of life. XII. Determine overall GI and GU toxicity. XIII. Determine prostate and normal structure movement during radiation therapy (RT) with the use of scans. XIV. Correlate pathologic and radiologic findings with outcomes. XV. Correlate pre-RT prostate specific antigen (PSA) levels with outcomes. XVI. Correlate variation in proton therapy or x-ray dosimetry and outcomes. XVII. Develop a quality assurance process for prostate proton therapy. XVIII. Prospectively collect information that will help to define dose-volume relationships of normal structures with acute and chronic toxicity. XIX. Allow for future research of pathologic risk factors that may influence prognosis; this information will help us to attempt to characterize their presence in prostate cancer with high risk features after prostatectomy and their potential effect on outcomes. XX. Possibly compare dosimetric parameters of an IMRT plan with the proton therapy radiation plan. OUTLINE: Participants are assigned to 1 of 3 groups. GROUP I: Participants undergo hypofractionated radiation therapy over 15-30 minutes every other day over 2 weeks, for 5 treatments. GROUP II: Beginning 8-10 weeks before radiation therapy, participants receive androgen suppression therapy subcutaneously (SC) or intramuscularly (IM) for up to 6 months (at the discretion of the treating physician). Participants then undergo hypofractionated radiation therapy as Group I. GROUP III: Participants receive androgen suppression therapy as Group II for up to 18 months (at the discretion of the treating physician), then undergo hypofractionated radiation therapy over 15-30 minutes every other day over 1-2 weeks, for 1-5 treatments. After completion of study treatment, participants are followed up at 3 and 12 months, annually for 4 years, then every 2 years thereafter.

Official Title
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A Phase II Trial of Hypofractionated Radiation Therapy for Prostate Cancer With High Risk Features After Radical Prostatectomy

Conditions
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Prostate Adenocarcinoma, Stage IIB Prostate Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8

Intervention / Treatment
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* Drug: Androgen Suppression
* Radiation: Hypofractionated Radiation Therapy
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed prostate adenocarcinoma at the time of surgery Pathologic stages T2-T3b, N0-Nx-N1, M0-1 as staged by the pathology report (American Joint Committee on Cancer [AJCC] criteria 8th edition [Ed.]) One or more high risk features including: seminal vesicle invasion, extracapsular extension, positive margins, or a PSA post surgery between 0.2 and < 2.0 PSA values < 2 ng/ml within 90 days prior to enrollment. Obtained at least 6 weeks after surgery Eastern Cooperative Oncology Group (ECOG) performance status 0-2 assessed within 90 days of enrollment Patients must sign Institutional Review Board (IRB) approved study specific informed consent Patients must complete all required pre-entry tests within the specified time frames Patients must be able to start treatment (androgen suppression [AS] or radiation) within 120 days of study registration Members of all races and ethnic groups are eligible for this trial Patients from outside of the United States may participate in the study Exclusion Criteria: Previous pelvic radiation Prior androgen suppression therapy for prostate cancer for more than 6 months Active rectal diverticulitis, Crohn's disease affecting the rectum or ulcerative colitis (non-active diverticulitis and Crohn's disease not affecting the rectum are allowed) Prior systemic chemotherapy for prostate cancer History of proximal urethral stricture requiring dilatation Current and continuing anticoagulation with warfarin sodium (coumadin), heparin, low- molecular weight heparin, Clopidogrel bisulfate (plavix), or equivalent (unless it can be stopped to manage treatment related toxicity, to have a biopsy if needed, or place markers) Major medical, addictive or psychiatric illness which in the investigator's opinion, will prevent the consent process, completion of the treatment and/or interfere with follow-up. (Consent by legal authorized representative is not permitted for this study) Evidence of any other cancer within the past 5 years and < 50% probability of a 5 year survival. (Prior or concurrent diagnosis of basal cell or non-invasive squamous cell cancer of the skin is allowed) History of myocardial infarction or decompensated congestive heart failure (CHF) within the last 6 months

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (hypofractionated radiation therapy)<br>Participants undergo hypofractionated radiation therapy over 15-30 minutes every other day over 2 weeks, for 5 treatments. | Radiation: Hypofractionated Radiation Therapy<br>* Undergo hypofractionated radiation therapy<br>* Other names: Radiation, Hypofractionated;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Group II (radiation therapy, androgen suppression therapy)<br>Beginning 8-10 weeks before radiation therapy, participants receive androgen suppression therapy SC or IM for up to 6 months (at the discretion of the treating physician). Participants then undergo hypofractionated radiation therapy as Group I. | Drug: Androgen Suppression<br>* Given androgen suppression therapy<br>* Other names: androgen deprivation;Radiation: Hypofractionated Radiation Therapy<br>* Undergo hypofractionated radiation therapy<br>* Other names: Radiation, Hypofractionated;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Group III (radiation therapy, androgen suppression therapy)<br>Participants receive androgen suppression therapy as Group II for up to 18 months (at the discretion of the treating physician), then undergo hypofractionated radiation therapy over 15-30 minutes every other day over 1-2 weeks, for 1-5 treatments. | Drug: Androgen Suppression<br>* Given androgen suppression therapy<br>* Other names: androgen deprivation;Radiation: Hypofractionated Radiation Therapy<br>* Undergo hypofractionated radiation therapy<br>* Other names: Radiation, Hypofractionated;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from failure (FF) | Will be defined as the first occurrence of clinical failure (local recurrence, regional recurrence, or distant metastasis), the start/re-start of salvage therapy including androgen suppression, and biochemical failure (PSA >= 0.5 ng/ml). Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute grade 2 or higher and grade 3 or higher genitourinary (GU) and gastrointestinal (GI) toxicity | Will be performed using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria. Descriptive measurements of frequency will be compiled. The maximum grade for each type of acute adverse events (AE) will be recorded for each patient. Data will be summarized as frequencies and relative frequencies. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. Similarly, grade 3 or higher GU and GI events will be estimated along with overall toxicity. | Up to 5 years | 
| Grade 2 or higher and grade 3 or higher GI and GU toxicity | Will be performed using NCI-CTCAE version 4 criteria. The maximum grade for each type of acute adverse events (AE) will be recorded for each patient. Data will be summarized as frequencies and relative frequencies. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. Similarly, grade 3 or higher GU and GI events will be estimated along with overall toxicity. | 3 years | 
| Local/distant failure | Will be measured from the date of the start of treatment to the date of documented local failure as determined either by clinical exam, imaging, or by prostate rebiopsy. | Start of treatment assessed up to 5 years | 
| Distant metastasis |  | Up to 5 years | 
| Quality of life (QOL) | Summation of relative scores for quality of life items from the Expanded Prostate Cancer Index Composite (EPIC) instrument will be used to measure each individual's quality of life. The difference in mean scores will be assessed with the t-test. To assess changes in health-related QOL from baseline, a clinically significant difference will be defined as half of a standard deviation (SD) and at least a 10-point change. Scale score trajectories over time will be examined using stream plots and mean plots with standard deviation error bars overall. Analysis will include percent change from baseline using t-tests and generalized linear models to test for changes at each time point and non-zero slope respectfully. | Up to 5 years | 
| Impotence | Summation of relative scores for sexual function items (items 31 through 39) from the Expanded Prostate Cancer Index Composite (EPIC) instrument will be used to measure each individual's quality of life. Will be estimated as the number of patients experiencing the event of interest divided by the total number of evaluable patients. 95% confidence intervals will be calculated for each estimate. | Up to 3 years | 
| Salvage androgen suppression use | Will be estimated as the number of patients experiencing the event of interest divided by the total number of evaluable patients. 95% confidence intervals will be calculated for each estimate. | Up to 5 years | 
| Overall survival | Will be estimated with a Kaplan-Meier estimator and curve. Estimates will be given for specific time points along with 95% confidence intervals (CIs). | Up to 5 years | 
| Progression free survival | Will use clinical, biochemical and SAD as events. Will be estimated with a Kaplan-Meier estimator and curve. Estimates will be given for specific time points along with 95% CIs. | Up to 5 years | 
| Disease-free survival | Will be estimated with a Kaplan-Meier estimator and curve. Estimates will be given for specific time points along with 95% CIs. | Up to 5 years | 
| Freedom from biochemical failure (FFBF) | Will be estimated as the number of patients experiencing the event of interest divided by the total number of evaluable patients. 95% confidence intervals will be calculated for each estimate. | Up to 5 years |