Radiation Therapy in Treating Patients With Stage II Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving radiation therapy that uses a 3-dimensional (3-D) image of the tumor to help focus thin beams of radiation directly on the tumor, and giving hypofractionated radiation therapy (higher doses over a shorter period of time), may be less costly with fewer side effects and just as effective in treating prostate cancer. PURPOSE: This randomized phase III trial is studying several different radiation therapy regimens to compare how well they work in treating patients with stage II prostate cancer.

Detailed Description
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OBJECTIVES: Primary Compare the disease-free survival (DFS) of patients with favorable-risk stage II prostate cancer treated with hypofractionated vs conventionally fractionated three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). Secondary Compare time to local progression, freedom from biochemical recurrence, and disease-specific and overall survival of patients treated with these regimens. Determine the incidence of gastrointestinal and genitourinary toxic effects in patients treated with these regimens. Compare the degree, duration, and significant differences in disease-specific health-related quality of life (HRQOL) decrements, using the Expanded Prostate Cancer Index Composite (EPIC), in patients treated with these regimens. Determine whether anxiety and/or depression, as measured by the Hopkins Symptom Checklist-25 (HSCL-25), are decreased with therapy that improves DFS of these patients . Determine whether the incremental gain in DFS outweighs decrements in the generic domains of HRQOL (i.e., mobility, self care, usual activities, pain/discomfort, and anxiety/depression) in patients treated with these regimens. Conduct a cost-utility analysis of hypofractionated 3D-CRT or IMRT as a prostate cancer therapy if this regimen is shown to be as effective as conventionally fractionated 3D-CRT or IMRT in improving DFS. OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to Gleason score (2-4 vs 5-6), prostate-specific antigen (PSA) level (< 4 ng/mL vs 4-<9 ng/mL), and planned radiotherapy modality (three-dimensional conformal radiotherapy [3D-CRT] vs intensity-modulated radiotherapy [IMRT]). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo conventionally fractionated 3D-CRT or IMRT once daily 5 days a week for 8.2 weeks (total of 41 treatments). Arm II: Patients undergo hypofractionated 3D-CRT or IMRT once daily 5 days a week for 5.6 weeks (total of 28 treatments). Quality of life, anxiety, and depression are assessed at baseline and then at 6 months and 1, 2, and 5 years after the start of radiotherapy. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 1,067 patients will be accrued to this study.

Official Title
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A Phase III Randomized Study of Hypofractionated 3D-CRT/MRT Versus Conventionally Fractionated 3D-CRT/MRT in Patients With Favorable-Risk Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Radiation: Conventional 3D-CRT or IMRT
* Radiation: Hypofractionated 3D-CRT or IMRT


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the prostate within the past 6 months Clinical stage T1-2c Combined Gleason score 2-6 Prostate-specific antigen (PSA) < 10 ng/mL within the past 6 months PSA evaluated at least 10 days after prostate biopsy For patients who received finasteride, PSA evaluated at least 30 after completion of finasteride For patients who received dutasteride, PSA evaluated at least 90 after completion of dutasteride No regional lymph node involvement No distant metastases PATIENT CHARACTERISTICS: Zubrod performance status 0-1 No unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months No transmural myocardial infarction within the past 6 months No acute bacterial or fungal infection requiring IV antibiotics No chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study treatment No hepatic insufficiency resulting in clinical jaundice and/or coagulation defects No known AIDS No prior or concurrent lymphomatous/hematogenous malignancy or other invasive malignancy except nonmelanomatous skin cancer or any other cancer for which the patient has been continually disease-free for ≥ 5 years (e.g., carcinoma in situ of the bladder or oral cavity) No other severe, active comorbidity PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior radical prostatectomy or cryosurgery for prostate cancer No prior hormonal therapy, including any of the following: Luteinizing hormone-releasing hormone agonists (e.g., goserelin or leuprolide) Antiandrogens (e.g., flutamide or bicalutamide) Estrogens [e.g., diethylstilbestrol (DES)] Surgical castration (bilateral orchiectomy) No prior pelvic radiotherapy or prostate brachytherapy No prior or concurrent cytotoxic chemotherapy for prostate cancer At least 30 days since prior finasteride At least 90 days since prior dutasteride No concurrent neoadjuvant or adjuvant hormonal therapy Concurrent warfarin or other blood-thinning agents allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 3D-CRT<br>Conventional 3D-CRT or IMRT to 73.8 Gy in 41 fractions | Radiation: Conventional 3D-CRT or IMRT<br>* Radiation therapy will be given once daily, five days a week, at 1.8 Gy per fraction, for 41 fractions and a total dose of 73.8 Gy<br>* Other names: Intensity-modulated radiation therapy (IMRT);|
| Experimental: Hypofractionated 3D-CRT<br>Hypofractionated 3D-CRT or IMRT to 70 Gy in 28 fractions | Radiation: Hypofractionated 3D-CRT or IMRT<br>* Radiation therapy will be given once daily, five days a week, at 2.5 Gy per fraction, for 28 fractions and a total dose of 70 Gy.<br>* Other names: Intensity-modulated radiation therapy (IMRT);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Five-year Disease-free Survival (DFS) Rate | Five-year rates are estimated by the Kaplan-Meier method. DFS events included local progression, distant metastatic progression, biochemical recurrence as defined by the Radiation Therapy Oncology Group (RTOG) Phoenix definition, or death from any cause. Patients who experienced second primary cancers remained under observation for DFS events. | Analysis occurs after all patients have been followed for five years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Five-year Local Progression Rate | Clinical criteria for local recurrence are progression (increase in palpable abnormality) at any time, failure of regression of the palpable tumor by 2 years, and redevelopment of a palpable abnormality after complete disappearance of previous abnormalities. Histologic criteria for local recurrence are presence of prostatic carcinoma upon biopsy and positive biopsy of the palpably normal prostate more than 2 years after the start of treatment. The arms were not statistically compared because of an insufficient number of events. | Analysis occurs after all patients have been followed for five years. | 
| Five-year Disease-specific Survival Rate | An event was death in association with any of the following conditions: Primary cause of death certified as due to prostate cancer Further clinical tumor progression occurring after initiation of salvage anti-tumor (e.g., (androgen suppression) therapy A rise (that exceeds 1.0 ng/mL) in the serum prostate-specific antigen (PSA) level on at least two consecutive occasions that occurs during or after salvage androgen suppression therapy Disease progression in the absence of any anti-tumor therapy Death from a complication of therapy, irrespective of disease status. The arms were not statistically compared because of an insufficient number of events. | Analysis occurs after all patients have been followed for five years. | 
| Five-year PSA Failure Rate | Five-year rates are shown (cumulative incidence estimates). Note, although the protocol calls this endpoint Freedom from biochemical recurrence, it defines the endpoint as The time to PSA failure. An event for PSA, i.e. biochemical, failure was the first of the following: initiation of non-protocol (e.g., salvage) hormone therapy, or an increase in PSA of at least 2 ng/mL. Time to biochemical failure was measured from study entry until the date of failure. | Analysis occurs after all patients have been followed for five years. | 
| Five-year Overall Survival Rate | Five-year rates Kaplan-Meier estimates. Overall survival (OS) was measured from study entry until the date of death. Patients still alive at the time of analysis were censored at the date of last follow-up | Analysis occurs after all patients have been followed for five years. | 
| Frequency of Patients With GU and GI Acute and Late Toxicity | The frequency of genitourinary (GU) and gastrointestinal (GI) adverse events as defined and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3) were compared between treatment arms. Acute toxicity was defined as any toxicity beginning within 90 days of completion of RT, and late toxicity was defined as any toxicity beginning more than 90 days after the completion of RT. Acute and late GU and GI toxicity rates were tabulated and reported in two ways: dichotomized as < grade 2 vs ≥ grade 2, and dichotomized as < grade 3 vs ≥ grade 3. Higher grade indicates more severity. | Acute toxicity is measured from start of treatment to 90 days from the completion of treatment. Late toxicity is defined as toxicity occuring after 90 days from completion of treatment. Analysis occured at the time of the primary endpoint analysis. | 
| Comparison of Disease-specific HRQOL Change in Expanded Prostate Cancer Index Composite (EPIC); the Utilization of Sexual Medications/Devices Supplements the EPIC | Prostate cancer (PC) Health-Related Quality of Life (HRQOL) outcomes as measured by change over time in the Expanded Prostate Cancer Index Composite [EPIC], a PC HRQOL instrument measuring a broad spectrum of urinary, bowel, and sexual symptoms related to radiotherapy, is compared between arms. The EPIC questionnaire was grouped into four domains (bowel, urinary, sexual, hormonal), each with a score ranging from 0 (worst) to 100 (best), and was assessed at baseline, 6, 12, and 24 months, and 5 years. The difference in score from baseline to each time point was calculated and the Wilcoxon test statistic was used to test the null hypothesis that responses are the same across the two treatment arms vs. the alternative hypothesis that they are different, using a 2-sided alpha of 0.05 at each timepoint, resulting in an alpha of 0.0125 for each domain. Each row refers to a separate analysis. | Baseline, 6, 12, and 24 months, and 5 years | 
| The Utilization of Sexual Medications/Devices Questionaire | 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 percentage of Yes responses to the following questions are reported: Do you have a penile prosthesis, Have you used an medications or devices to aid or improve erections?. | Baseline, 6, 12, and 24 months, and 5 years | 
| Change From Baseline in Assessment of Anxiety and Depression Using the HSCL-25 | Anxiety and depression were measured with the Hopkins Symptom Checklist (HSCL-25). It consists of 25 items: Part I of the HSCL-25 has 10 items for anxiety symptoms; Part II has 15 items for depression symptoms. The scale for each question includes four categories of response (Not at all, A little, Quite a bit, Extremely, rated 1 to 4, respectively). Two scores are calculated: the total score is the average of all 25 items and ranges from 0 to 100. A higher score indicates worse symptoms. The HSCL-25 tool was assessed at baseline, 6 months, 12 months, 24 months, and 5 years. For each patient, the change in score from baseline to the time point is calculated by subtracting the baseline value from the time point value. | Baseline, 6 months, 12 months, 24 months, and 5 years | 
| 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. Both the 5-item index score and the VAS score are transformed into a utility score between 0 -Worst health stat and 1 -Best health state. A two-sided Wilcoxon test with alpha 0.05 was used due to the skewed, thus non-normal, nature of the data. | Baseline, 6 months, 12 months, 24 months, and 5 years | 
| Assessment of Trade-off Between Disease-free Survival and Quality of Life. | To examine trade-offs between the survival time and QOL, we were to combine them for each patient into two single measurements: quality adjusted live year (QALY) and quality adjusted disease-free survival year (QADFSY). We were to use Glasziou's multiple health-state (Q-TWiST) models to use the repeated measures of EQ-5D. | From baseline to 5 years from the start of treatment | 
| Statistical Modeling of Genomic Biomarkers |  | Baseline biomarker collection. Analysis would occur after the primary endpoint analysis. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, stage IIB prostate cancer, stage IIA prostate cancer