Radiation Therapy in Treating Patients With Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Given radiation therapy in different ways may kill more tumor cells. PURPOSE: This randomized phase II trial studies radiation therapy to see how well it works in treating patients with prostate cancer.

Detailed Description
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OBJECTIVES: Primary To demonstrate that 1-year health-related quality of life (HRQOL) for at least one hypofractionated arm is not significantly lower than baseline as measured by the Bowel and Urinary domains of the Expanded Prostate Cancer Index Composite (EPIC) instrument. Secondary To estimate the degree of change in HRQOL in each arm for the Sexual and Hormonal EPIC domains and the Utilization of Sexual Medications/Devices from baseline to 1 year, 2 years, and 5 years. To estimate the degree of change in global HRQOL in each arm as measured by the Euro Quality of Life, 5 dimensions (EQ-5D) from baseline to 1 year, 2 years, and 5 years. To estimate the rate of acute and late gastrointestinal (GI) and genitourinary (GU) toxicity for each arm at 1, 2, and 5 years. To estimate prostate-specific antigen (PSA) failure in each arm at 1, 2, and 5 years. To estimate disease-free survival (DFS) in each arm at 1, 2, and 5 years. To estimate Quality Adjusted Life Years for each arm at 1, 2, and 5 years using the EQ-5D and DFS. To identify genetic markers associated with normal tissue toxicities resulting from radiotherapy. To collect tumor tissue for biomarker studies. To estimate EPIC bowel and urinary HRQOL as continuous variables. OUTLINE: This is a multicenter study. Patients are stratified according to treatment techniques/machine (all linear accelerator-based treatment [excluding cyberknife] vs cyberknife vs protons). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo hypofractionated radiotherapy using intensity-modulated radiation therapy (IMRT), cyberknife, or protons twice a week for approximately 2½ weeks (36.25 Gy total). Arm II: Patients undergo hypofractionated radiotherapy using IMRT, cyberknife, or protons once a day, 5 days a week, for approximately 2½ weeks (51.6 Gy total). Patients may undergo blood and tumor tissue collection for correlative studies. Patients may also complete the Utilization of Sexual Medications/Devices, the European Questionnaire-5D, and the Bowel and Urinary domains of the Expanded Prostate Cancer Index Composite (EPIC) questionnaires at baseline and at 1, 2, and 5 years after completion of radiation therapy. After completion of study therapy, patients are followed-up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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A Randomized Phase II Trial of Hypofractionated Radiotherapy for Favorable Risk Prostate Cancer

Conditions
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Prostate Cancer, Psychosocial Effects of Cancer and Its Treatment, Radiation Toxicity, Sexual Dysfunction

Intervention / Treatment
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* Radiation: 36.25 Gy IMRT
* Radiation: 51.6 Gy IMRT


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days of randomization History/physical examination with digital rectal examination of the prostate within 60 days prior to registration Histological evaluation of prostate biopsy with assignment of a Gleason score to the biopsy material; Gleason scores 2-6 within 180 days of randomization Clinical stage T1-2a (AJCC 7th edition) within 90 days of randomization Prostate-specific antigen (PSA) < 10 ng/mL within 60 days prior to registration; PSA should not be obtained within 10 days after prostate biopsy No evidence of distant metastases No regional lymph node involvement PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Willingness and ability to complete the Expanded Prostate Cancer Index Composite (EPIC) questionnaire No prior or concurrent invasive malignancy (except non-melanomatous skin cancer) or lymphomatous/hematogenous malignancy unless continually disease-free for a minimum of 5 years (for example, carcinoma of the oral cavity is permissible; however, patients with prior history of bladder cancer are not allowed) No 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 Laboratory tests for liver function and coagulation parameters are not required for entry into this protocol Acquired Immune Deficiency Syndrome (AIDS) based upon current Center for Disease Control (CDC) definition HIV testing is not required for entry into this protocol Protocol-specific requirements may also exclude immuno-compromised patients PRIOR CONCURRENT THERAPY: No prior radical surgery (prostatectomy), cryosurgery, or high-intensity focused ultrasonography (HIFU) for prostate cancer No prior pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy No prior hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide) or LHRH antagonists (e.g., degarelix), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., diethylstilbestrol (DES)), or surgical castration (orchiectomy) No finasteride within 30 days prior to registration Prostate-specific antigen (PSA) should not be obtained prior to 30 days after stopping finasteride No dutasteride within 90 days prior to registration PSA should not be obtained prior to 90 days after stopping dutasteride No prior or concurrent cytotoxic chemotherapy for prostate cancer Patients on Coumadin or other blood-thinning agents are eligible for this study No concurrent 3D-conformal radiation therapy

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 |
| --- | --- |
| Experimental: 5 Fractions<br>36.25 Gy IMRT in 5 fractions over two and a half weeks | Radiation: 36.25 Gy IMRT<br>* 36.25 Gy in 5 fractions of 7.5 Gy twice a week over 15-17 days. A minimum of 72 hours and a maximum of 96 hours will separate each treatment. IMRT or similar techniques that use inverse treatment planning or protons are required.<br>|
| Experimental: 12 Fractions<br>51.6 Gy IMRT in 12 fractions over two and a half weeks | Radiation: 51.6 Gy IMRT<br>* 51.6 Gy in 12 fractions of 4.3 Gy 5 days a week over 16-18 days. IMRT or similar techniques that use inverse treatment planning or protons are required.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Reduction From Baseline to the One-year EPIC Bowel Domain Score That Exceeds 5 Points | The co-primary endpoint is the percentage of patients with a reduction in the Expanded Prostate Cancer Index Composite (EPIC) bowel domain score from baseline to 1 year that exceeds 5 points (baseline - one year > 5). The EPIC is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal). Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life. Arms are not compared to each other. | Baseline and one year from the end of protocol treatment | 
| The Percentage of Patients With Reduction From Baseline to One-year EPIC Urinary Domain Score That Exceeds 2 Points | The co-primary endpoint is the proportion of patients with a reduction in the Expanded Prostate Cancer Index Composite (EPIC) urinary domain score from baseline to 1 year that exceeds 2 points (baseline - one year > 2). The EPIC is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal). Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life. Arms are not compared to each other. | Baseline and one year from the end of protocol treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute and Late Gastrointestinal (GI) and Genitourinary (GU) Toxicity for Each Arm | Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. An acute adverse event is defined as the first occurrence of worst severity of the adverse event ≤30 days after the completion of radiation therapy (RT). The high dose RT arm of Radiation Therapy Oncology Group (RTOG) study RTOG-0126 (NCT00033631) reported 1% of patients experienced grade 3+ GI/GU acute toxicity with no patient experiencing a grade 4 or 5 toxicity. If the lower confidence interval is >1%, then that arm will be further investigated for acceptability. A late adverse event is defined as the first occurrence of worst severity of adverse event >30 days after RT completion. Arms are not compared to each other. | Start of protocol treatment to one year from the end of protocol treatment | 
| Rate of PSA Failure | Failure occurs when the PSA is first noted to be 2 ng/mL or more than the current nadir value (PSA > current nadir + 2) post RT completion. Time to PSA failure is defined as time from registration to the date of PSA failure, last known follow-up (censored), or death without PSA failure (competing risk). Rate of PSA failure is estimated by the cumulative incidence method. The protocol specified that one-, two-, and five-year rates would be reported. Arms are not compared to each other. | Registration to five years | 
| Rate of Disease-free Survival (DFS) | Disease-free survival duration is time from the date of randomization to the date of documentation of disease progression or until the date of death from any cause (censored). DFS is estimated by the Kaplan-Meier method. The protocol specified that one-, two-, and five-year rates would be reported. Arms are not compared to each other. | Registration to 5 years | 
| Mean Quality Adjusted Life Years at 5 Years | Quality-adjusted survival time combines disease-free survival time and quality of life as measured by the EuroQol 5-dimensional (EQ-5D) index score. It is calculated for each patient as the weighted sum of different time episodes and added up to total quality-adjusted life years . The EQ-5D measures health-related quality of life and consists of two parts, a general health visual analog scale and 5 general health questions. The latter questions are transformed into a single index score ranging from 0 (worst health state) to 1 (best health state). Arms are not compared to each other. | Registration to 5 years from the end of protocol treatment | 
| Change From Baseline in EPIC Bowel and Urinary HRQOL as Continuous Variables at One Year | The EPIC is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal). Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life and a positive change from baseline indicating improvement over time. For this endpoint, in each domain, the actual change score calculated as timepoint score - baseline score will be used as the statistic. | Baseline and one year from the end of protocol treatment | 
| The Percentage of Patients With Reduction From Baseline at One Year in EPIC Sexual Domain Score That Exceeds 11 Points | The percentage of patients with a reduction in the EPIC sexual domain score from baseline that exceeds 11 points (baseline - one year > 11). The EPIC is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal). Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life. Arms are not compared to each other. | Baseline one year from the end of protocol treatment | 
| The Percentage of Patients With Reduction From Baseline at One Year in EPIC Hormonal Domain Score That Exceeds 3 Points | The percentage of patients with a reduction in the EPIC hormonal domain score from baseline that exceeds 3 points (baseline - one year > 3). The EPIC is a 50-item, validated tool to assess disease-specific aspects of prostate cancer and its therapies and comprises of four summary domains (bowel, urinary, sexual, and hormonal). Response options for each EPIC item form a Likert scale and multi-item scale scores are transformed linearly to a 0-100 scale, with higher scores representing better health related quality of life. Arms are not compared to each other. | Baseline and one year from the end of protocol treatment | 
| Change From Baseline in EQ-5D Scores | The EQ-5D is a 2-part self-assessment questionnaire. First part is 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 3 problem levels (1-none, 2-moderate, 3-extreme). Health states are defined by the combination of the leveled responses to the 5 dimensions, generating 243 health states to which unconsciousness and death are added. The 2nd part is a visual analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point interval scale. Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable health state is scored as 100 at the top. The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state). Change from baseline is calculated as score at the timepoint of interested - baseline score. One, 2, and 5 years will be entered when they are available. Arms are not compared. | Baseline and one year from the end of protocol treatment | 
| Utilization of Sexual Medications/Devices Questionnaire Response Frequences | The Utilization of Sexual Medications/Devices questionaire is designed to assess the use of erectile aids among patients treated for prostate cancer. This instrument is used to complement the sexual symptom domain in the EPIC. The number of subjects responding Yes to the following questions are reported: Do you have a penile prosthesis, Have you used an medications or devices to aid or improve erections?. Arms are not compared to each other. One, 2, and 5 years will be entered when they are available. | Baseline and one year from the end of protocol treatment | 
| Genetic Markers Associated With Normal Tissue Toxicities Resulting From Radiotherapy |  | Study entry to 5 years from the end of protocol treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiation toxicity, sexual dysfunction, psychosocial effects of cancer and its treatment, adenocarcinoma of the prostate, stage I prostate cancer, stage IIA prostate cancer