Radiation Therapy in Treating Patients With Prostate Cancer

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01434290
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 255
• Locations: 37
• Arms: 2
• Duration (Months): 128.6
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer; Psychosocial Effects of Cancer and Its Treatment; Radiation Toxicity; Sexual Dysfunction	Radiation: 36.25 Gy IMRT; Radiation: 51.6 Gy IMRT	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 255 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Hypofractionated Radiotherapy for Favorable Risk Prostate Cancer
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 5 Fractions 36.25 Gy IMRT in 5 fractions over two and a half weeks	Radiation: 36.25 Gy IMRT; 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.
Experimental: 12 Fractions 51.6 Gy IMRT in 12 fractions over two and a half weeks	Radiation: 51.6 Gy IMRT; 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.

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With Reduction From Baseline to the One-year EPIC Bowel Domain Score That Exceeds 5 Points [Baseline and one year from the end of protocol treatment]

   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.

2. The Percentage of Patients With Reduction From Baseline to One-year EPIC Urinary Domain Score That Exceeds 2 Points [Baseline and one year from the end of protocol treatment]

   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.

Secondary Outcome Measures

1. Acute and Late Gastrointestinal (GI) and Genitourinary (GU) Toxicity for Each Arm [Start of protocol treatment to one year from the end of protocol treatment]

   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.

2. Rate of PSA Failure [Registration to five years]

   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.

3. Rate of Disease-free Survival (DFS) [Registration to 5 years]

   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.

4. Mean Quality Adjusted Life Years at 5 Years [Registration to 5 years from the end of protocol treatment]

   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.

5. Change From Baseline in EPIC Bowel and Urinary HRQOL as Continuous Variables at One Year [Baseline and one year from the end of protocol treatment]

   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.

6. The Percentage of Patients With Reduction From Baseline at One Year in EPIC Sexual Domain Score That Exceeds 11 Points [Baseline one year from the end of protocol treatment]

   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.

7. The Percentage of Patients With Reduction From Baseline at One Year in EPIC Hormonal Domain Score That Exceeds 3 Points [Baseline and one year from the end of protocol treatment]

   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.

8. Change From Baseline in EQ-5D Scores [Baseline and one year from the end of protocol treatment]

   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.

9. Utilization of Sexual Medications/Devices Questionnaire Response Frequences [Baseline and one year from the end of protocol treatment]

   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.

10. Genetic Markers Associated With Normal Tissue Toxicities Resulting From Radiotherapy [Study entry to 5 years from the end of protocol treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Arizona Center for Cancer Care - Peoria	Peoria	Arizona	United States	85381
3	Arizona Oncology Services Foundation	Phoenix	Arizona	United States	85013
4	Kaiser Permanente - Division of Research - Oakland	Oakland	California	United States	94611
5	Rohnert Park Cancer Center	Rohnert Park	California	United States	94928
6	Kaiser Permanente Medical Center - Roseville	Roseville	California	United States	95678
7	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
8	Kaiser Permanente Santa Clara Medical Center	Santa Clara	California	United States	95051
9	Kaiser Permanente Medical Center - South San Francisco	South San Francisco	California	United States	94080
10	Urology Center of Colorado	Denver	Colorado	United States	80211
11	Emory Crawford Long Hospital	Atlanta	Georgia	United States	30308
12	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
13	Queen's Cancer Institute at Queen's Medical Center	Honolulu	Hawaii	United States	96813
14	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
15	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
16	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
17	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
18	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
19	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
20	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
21	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
22	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
23	Rothman Specialty Hospital	Bensalem	Pennsylvania	United States	19020
24	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania	United States	18925
25	Academic Urology Prostate Center	King Of Prussia	Pennsylvania	United States	19406
26	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
27	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
28	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
29	Gibbs Regional Cancer Center at Spartanburg Regional Medical Center	Spartanburg	South Carolina	United States	29303
30	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
31	Columbia-Saint Mary's Cancer Care Center	Milwaukee	Wisconsin	United States	53211
32	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
33	Cross Cancer Institute at University of Alberta	Edmonton	Alberta	Canada	T6G 1Z2
34	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
35	Grand River Regional Cancer Centre at Grand River Hospital	Kitchener	Ontario	Canada	N2G 1G3
36	London Regional Cancer Program at London Health Sciences Centre	London	Ontario	Canada	N6A 4L6
37	Hopital Notre-Dame du CHUM	Montreal	Quebec	Canada	H2L 4M1

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Himu R. Lukka, MD, Margaret and Charles Juravinski Cancer Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01434290
• Other Study ID Numbers: RTOG 0938; CDR0000703580; NCI-2011-03629
• First Posted: Sep 14, 2011
• Last Update Posted: Jun 9, 2022
• Last Verified: May 1, 2022

• Keywords provided by Radiation Therapy Oncology Group: radiation toxicity; sexual dysfunction; psychosocial effects of cancer and its treatment; adenocarcinoma of the prostate; stage I prostate cancer; stage IIA prostate cancer
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT (intensity modulated radiation therapy) in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Period Title: Overall Study
STARTED	127	128
COMPLETED	119	121
NOT COMPLETED	8	7

Baseline Characteristics

Arm/Group Title	5 Fractions	12 Fractions	Total
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks	Total of all reporting groups
Overall Participants	119	121	240
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	66	65
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	119 100%	121 100%	240 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With Reduction From Baseline to the One-year EPIC Bowel Domain Score That Exceeds 5 Points
Description	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.
Time Frame	Baseline and one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment and completed the bowel domain of the EPIC at baseline and one year

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	93	100
Number (95% Confidence Interval) [percentage of participants]	30.1 25.3%	28.0 23.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	≤35% was considered acceptable, ≥55% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used. For a given arm, if the null hypothesis of p ≤ 0.35 is rejected, then conclude that the regimen given on that arm is unacceptable. However if it not rejected for both bowel & urinary domains, then that regimen will be considered acceptable for further use in a Phase III study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	One sample z-test
	Comments	One-sided 0.025 significance level

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	≤35% was considered acceptable, ≥55% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used. For a given arm, if the null hypothesis of p ≤ 0.35 is rejected, then conclude that the regimen given on that arm is unacceptable. However if it not rejected for both bowel & urinary domains, then that regimen will be considered acceptable for further use in a Phase III study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	One sample z-test
	Comments	one-sided 0.025 significance level

2. Primary Outcome

Title	The Percentage of Patients With Reduction From Baseline to One-year EPIC Urinary Domain Score That Exceeds 2 Points
Description	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.
Time Frame	Baseline and one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment and completed the urinary domain of the EPIC at baseline and one year

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	93	100
Number (95% Confidence Interval) [percentage of participants]	45.2 38%	42.0 34.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	≤40% was considered acceptable, ≥60% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used. For a given arm, if the null hypothesis of p ≤ 0.40 is rejected, then conclude that the regimen given on that arm is unacceptable. However if it not rejected for both bowel & urinary domains, then that regimen will be considered acceptable for further use in a Phase III study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	One sample z-test
	Comments	One-sided 0.025 significance level

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	≤40% was considered acceptable, ≥60% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used. For a given arm, if the null hypothesis of p ≤ 0.40 is rejected, then conclude that the regimen given on that arm is unacceptable. However if it not rejected for both bowel & urinary domains, then that regimen will be considered acceptable for further use in a Phase III study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments
	Method	One sample z-test
	Comments	One-sided 0.025 significance level

3. Secondary Outcome

Title	Acute and Late Gastrointestinal (GI) and Genitourinary (GU) Toxicity for Each Arm
Description	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.
Time Frame	Start of protocol treatment to one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	119	121
Acute	1.7 1.4%	1.7 1.4%
Late	0.8 0.7%	0.8 0.7%

4. Secondary Outcome

Title	Rate of PSA Failure
Description	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.
Time Frame	Registration to five years

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment and were at risk at the given time point

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	119	121
One year	0.0 0%	0.8 0.7%
Two years	0.0 0%	0.8 0.7%
Five years	3.4 2.9%	3.5 2.9%

5. Secondary Outcome

Title	Rate of Disease-free Survival (DFS)
Description	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.
Time Frame	Registration to 5 years

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment and were at risk at the given time point

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	119	121
One year	99.2 83.4%	99.2 82%
Two years	99.2 83.4%	97.5 80.6%
Five years	89.6 75.3%	92.3 76.3%

6. Secondary Outcome

Title	Mean Quality Adjusted Life Years at 5 Years
Description	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.
Time Frame	Registration to 5 years from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment with baseline EQ-5D and at least 1 follow-up assessment (EQ-5D Index Score)

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	90	85
Mean (Standard Deviation) [quality-adjusted life years]	6.13 (10.55)	4.87 (1.14)

7. Secondary Outcome

Title	Change From Baseline in EPIC Bowel and Urinary HRQOL as Continuous Variables at One Year
Description	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.
Time Frame	Baseline and one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment and completed the respective domain of the EPIC at baseline and one year

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	93	100
1-year Bowel	1.79	0
1-year Urinary	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	[Bowel one-year results] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the normality of the data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	[Bowel one-year results] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the normality of the data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	[Urinary one-year results] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the normality of the data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	[Urinary one-year results] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the normality of the data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-side significance level of 0.017

8. Secondary Outcome

Title	The Percentage of Patients With Reduction From Baseline at One Year in EPIC Sexual Domain Score That Exceeds 11 Points
Description	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.
Time Frame	Baseline one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment and completed the specified domain of the EPIC at baseline and one year

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	88	92
Number (95% Confidence Interval) [percentage of participants]	32.9 27.6%	30.4 25.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	≤35% was considered acceptable, ≥55% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	One-sample z-test
	Comments	One-sided 0.025 significance level

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	≤35% was considered acceptable, ≥55% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	One sample z-test
	Comments	One-side significance level of 0.025

9. Secondary Outcome

Title	The Percentage of Patients With Reduction From Baseline at One Year in EPIC Hormonal Domain Score That Exceeds 3 Points
Description	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.
Time Frame	Baseline and one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment and completed the specified domain of the EPIC at baseline and one year

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	90	97
Number (95% Confidence Interval) [percentage of participants]	36.7 30.8%	38.1 31.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	≤38% was considered acceptable, ≥58% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	one sampe z-test
	Comments	One-sided significance level of 0.025

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	≤38% was considered acceptable, ≥58% unacceptable. Each arm analyzed separately. Average score and standard error of each arm calculated and one-sample z-test for proportion with significance level of 0.025 was used.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	One sample z-test
	Comments	One-sided significance level of 0.025

10. Secondary Outcome

Title	Change From Baseline in EQ-5D Scores
Description	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.
Time Frame	Baseline and one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment and completed the EQ-5D at baseline and the specified timepoint

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	66	67
1-year Index Score	0	0
1-year VAS	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	[One-year Index Score] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the non-normality of the data. Each arm analyzed separately.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	[One-year Index Score] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the non-normality of the data. Each arm analyzed separately.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	5 Fractions
	Comments	[One-year VAS Score] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the non-normality of the data. Each arm analyzed separately.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.83
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	12 Fractions
	Comments	[One-year VAS Score] Originally the t-test was planned to test if the change in each arm is different from 0. Wilcoxon Mann-Whitney was used instead due to the non-normality of the data. Each arm analyzed separately.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Two-sided significance level of 0.017.

11. Secondary Outcome

Title	Utilization of Sexual Medications/Devices Questionnaire Response Frequences
Description	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.
Time Frame	Baseline and one year from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment and completed the questionnaire at baseline and the specified timepoint

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	94	96
Baseline penile prosthesis question	6 5%	7 5.8%
Baseline medications/devices question	30 25.2%	29 24%
1-year penile prosthesis question	2 1.7%	5 4.1%
1-year Baseline medications/devices question	25 21%	29 24%

12. Secondary Outcome

Title	Genetic Markers Associated With Normal Tissue Toxicities Resulting From Radiotherapy
Time Frame	Study entry to 5 years from the end of protocol treatment

Outcome Measure Data

Analysis Population Description

The biomarker data will not be obtained due to lack of funding therefore no patients have outcome measure data.

Arm/Group Title	5 Fractions	12 Fractions
Arm/Group Description	36.25 Gy IMRT (intensity modulated radiation therapy) in 5 fractions over two and a half weeks	51.6 Gy IMRT in 12 fractions over two and a half weeks
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given adverse event are counted only once for that adverse event. Eligible patients with adverse event data are included.
Arm/Group Title	5 Fractions		12 Fractions
Arm/Group Description	36.25 Gy IMRT in 5 fractions over two and a half weeks		51.6 Gy IMRT in 12 fractions over two and a half weeks
All Cause Mortality
	5 Fractions		12 Fractions
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	5 Fractions		12 Fractions
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/119 (0.8%)		0/121 (0%)
Gastrointestinal disorders
Anal hemorrhage	1/119 (0.8%)		0/121 (0%)
Reproductive system and breast disorders
Ejaculation disorder	1/119 (0.8%)		0/121 (0%)
Other (Not Including Serious) Adverse Events
	5 Fractions		12 Fractions
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	101/119 (84.9%)		106/121 (87.6%)
Gastrointestinal disorders
Constipation	10/119 (8.4%)		5/121 (4.1%)
Diarrhea	28/119 (23.5%)		31/121 (25.6%)
Fecal incontinence	8/119 (6.7%)		6/121 (5%)
Gastrointestinal disorders - Other	15/119 (12.6%)		15/121 (12.4%)
Hemorrhoids	9/119 (7.6%)		8/121 (6.6%)
Proctitis	18/119 (15.1%)		21/121 (17.4%)
Rectal hemorrhage	13/119 (10.9%)		5/121 (4.1%)
Rectal pain	6/119 (5%)		2/121 (1.7%)
General disorders
Fatigue	30/119 (25.2%)		34/121 (28.1%)
Psychiatric disorders
Libido decreased	10/119 (8.4%)		6/121 (5%)
Renal and urinary disorders
Cystitis noninfective	17/119 (14.3%)		20/121 (16.5%)
Hematuria	9/119 (7.6%)		11/121 (9.1%)
Renal and urinary disorders - Other	33/119 (27.7%)		35/121 (28.9%)
Urinary frequency	66/119 (55.5%)		70/121 (57.9%)
Urinary incontinence	16/119 (13.4%)		22/121 (18.2%)
Urinary retention	22/119 (18.5%)		26/121 (21.5%)
Urinary tract obstruction	10/119 (8.4%)		6/121 (5%)
Urinary tract pain	13/119 (10.9%)		21/121 (17.4%)
Urinary urgency	39/119 (32.8%)		47/121 (38.8%)
Reproductive system and breast disorders
Ejaculation disorder	11/119 (9.2%)		12/121 (9.9%)
Erectile dysfunction	51/119 (42.9%)		44/121 (36.4%)
Reproductive system and breast disorders - Other	6/119 (5%)		6/121 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.