nrg oncology rtog 0534 a
untitled h2

| Study Chairs (15-Jan-2019) Principal Investigator/Radiation Oncology Alan Pollack, MD, PhD Department of Radiation Oncology University of Miami Miller School of Medicine 1475 NW 12th Avenue, Suite 1500 (D-31) Miami, FL 33136 305-243-4916/FAX 305-243-6493 APollack@med.miami.edu   | Neuropsychology Co-Chair Jeffrey S. Wefel, PhD, ABPP Section of Neuropsychology Department of Neuro-Oncology University of Texas M.D. Anderson Cancer Center Unit 431 -- P.O. Box 301402 Houston, TX 77230-1402 713-563-0514/FAX: 713-794-4999 jwefel@mdanderson.org   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Radiation Oncology Co-Chair Alex Balogh, MD Tom Baker Cancer Centre 1331 29 St NW Calgary Alberta Canada T2N4N2 403-521-3091/FAX 403-283-1651 Alex.Balogh@albertahealthservices.ca                                                                                                      | Senior Statistician Theodore Karrison, PhD NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103 773-702-9326/FAX: 773-702-1979 E-mail: karrisont@nrgoncology.org                                                                                         |
| Medical Physics Co-Chair Daniel Low, PhD Professor and Vice Chair of Medical Physics UCLA Radiation Oncology 200 Medical Plaza, Suite B265 Los Angeles, CA 90095 (310) 562-2394 /FAX 310-794-1984 dlow@mednet.ucla.edu                                                                  | Alliance (CALGB) Co-Chair Joycelyn L. Speight, MD, PhD UCSF Comprehensive Cancer Center 1600 Divisadero Street H1031, Box 1708 San Francisco, CA 94143 415-353-7175/FAX 415-353-9883 jspeight@radonc.ucsf.edu                                                          |
| Quality of Life/Outcomes Co-Chair Deborah Watkins-Bruner, RN, PhD, FAAN Nell Hodgson Woodruff School of Nursing Emory University 1520 Clifton Road, Room 232 Atlanta, GA 30322 Phone: 404-712-9695/Fax: 404-727-8514 E-mail: deborah.w.bruner@emory.edu                                 | Study details continued on next page                                                                                                                                                                                                                                   |
nrg oncology rtog 0534 a
rtog 0534

A PHASE III TRIAL OF SHORT TERM ANDROGEN DEPRIVATION WITH PELVIC
LYMPH NODE OR PROSTATE BED ONLY RADIOTHERAPY (SPPORT) IN
PROSTATE CANCER PATIENTS WITH A RISING PSA AFTER RADICAL
PROSTATECTOMY  
| Urology Co-Chair Leonard G. Gomella, MD Thomas Jefferson University 1025 Walnut Street, Suite 1102 Philadelphia, PA 19107 215-955-1702/FAX 215-923-1884 Leonard.Gomella@jefferson.edu                            | ECOG-ACRIN Co-Chair Richard Whittington, MD Department of Radiation Oncology University of Pennsylvania 3400 Spruce Street; 2 Donner Philadelphia, PA 19104 215-662-6515/FAX 215-349-5445 richard.whittington@med.va.gov   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Genitourinary Committee Chair Howard Sandler, MD Department of Radiation Oncology Cedars-Sinai Medical Center 8700 Beverly Boulevard Los Angeles, CA 90048 310-423-4234/FAX 310-423-6161 Howard.Sandler@cshs.org |                                                                                                                                                                                                                            |  
| Document History    |                   |                   |
|---------------------|-------------------|-------------------|
| Version/Update Date | Broadcast Date    |                   |
| Amendment 9         | March 1, 2019     | N/A               |
| Amendment 8         | January 15, 2019  | N/A               |
| Amendment 7         | June 22, 2017     | N/A               |
| Amendment 6         | November 16, 2015 | December 21, 2015 |
| Closure             | --                | March 30, 2015    |
| Amendment 5         | December 31, 2014 | March 2, 2015     |
| Update              | April 29, 2014    | April 29, 2014    |
| Update              | December 10, 2013 | December 10, 2013 |
| Update              | January 17, 2012  | January 17, 2012  |
| Amendment 4         | November 23, 2011 | January 17, 2012  |
| Amendment 3         | December 23, 2010 | January 11, 2011  |
| Amendment 2         | March 24, 2010    | April 20, 2010    |
| Update              | October 22, 2009  | October 22, 2009  |
| Update              | March 31, 2009    | March 31, 2009    |
| Amendment 1         | January 8, 2009   | March 31, 2009    |
| Update              | February 13, 2008 | February 13, 2008 |
| Activation          | February 13, 2008 | February 13, 2008 |  
| Protocol Agent   |            |       |       |
|------------------|------------|-------|-------|
| Agent            | Supply     | NSC # | IND # |
| Flutamide        | Commercial | N/A   | N/A   |
| Bicalutamide     | Commercial | N/A   | N/A   |  
Participating Sites U.S. Canada Approved International Member Sites NRG Oncology 1-800-227-5463, ext. 4189 This protocol was designed and developed by NRG Oncology. It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by NRG Oncology nor does NRG Oncology assume any responsibility for unauthorized use of this protocol.
nrg oncology rtog 0534
rtog 0534

A PHASE III TRIAL OF SHORT TERM ANDROGEN DEPRIVATION WITH PELVIC
LYMPH NODE OR PROSTATE BED ONLY RADIOTHERAPY (SPPORT) IN
PROSTATE CANCER PATIENTS WITH A RISING PSA AFTER RADICAL
PROSTATECTOMY  
| CONTACT INFORMATION (15-Jan-2019) For regulatory requirements: For patient enrollments:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | For study data submission:                                                                                                                                                                                                          |                                                                                                                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Regulatory documentation must  be submitted to the CTSU via  the Regulatory Submission  Portal:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Please refer to the patient  enrollment section of the protocol  for instructions on using the  Oncology Patient Enrollment  Network (OPEN) which can be  accessed at  https://www.ctsu.org/OPEN_SYS TEM/ or https://OPEN.ctsu.org. | NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19103 Do not submit study data or  forms to CTSU Data Operations.  Do not copy the CTSU on data  submissions. |
| Regulatory Submission Portal  (Sign in at www.ctsu.org,  and select the Regulatory  Submission sub-tab under the  Regulatory tab.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Contact the CTSU Help Desk  with any OPEN-related questions  at ctsucontact@westat.com.                                                                                                                                             |                                                                                                                                                                            |
| Institutions with patients  waiting that are unable to use  the Portal should alert the  CTSU Regulatory Office  immediately at 1-866-651-2878  to receive further instruction  and support. Contact the CTSU Regulatory  Help Desk at 1-866-651-2878  for regulatory assistance. The most current version of the study protocol and all supporting documents must be downloaded  from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the CTSU members' website is managed through the Cancer Therapy and Evaluation  ProgramIdentity and Access Management (CTEP-IAM) registration system and requires user log on  with CTEP-IAM username and password. Permission to view and download this protocol and its  supporting documents is restricted and is based on person and site roster assignment housed in the  CTSU RSS. For patient eligibility or treatment-related questions Contact the Study PI of the Lead Protocol  Organization. For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data  submission) contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line - 1-888-823-5923, or ctsucontact@westat.com. All calls and  correspondence will be triaged to the appropriate CTSU representative. The CTSU Website is located at https://www.ctsu.org. |                                                                                                                                                                                                                                     |                                                                                                                                                                            |  
| TABLE OF CONTENTS (15-Jan-2019)                                                                                    |                                                                                                                                                               |
|--------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA (1/8/09) (3/24/10)                                                                                          |                                                                                                                                                               |
| ELIGIBILITY CHECKLIST  (11/23/11)                                                                                  |                                                                                                                                                               |
| RTOG 0534                                                                                                          |                                                                                                                                                               |
| 1.0                                                                                                                | INTRODUCTION                                                                                                                                                  |
| Rationale for a Salvage Postoperative Radiotherapy (RT) Trial (1/8/09)......................................... 12 |                                                                                                                                                               |
| 1.1                                                                                                                |                                                                                                                                                               |
| 1.2                                                                                                                | Rationale for Using NC-STAD and PLNRT Treatment Postoperatively ............................................ 13                                               |
| Rationale for Using the PSA Nadir+2 Definition of Biochemical Failure as the Primary Endpoint                      |                                                                                                                                                               |
| 1.3                                                                                                                | 13                                                                                                                                                            |
| 1.4                                                                                                                | Rationale for Biomarker Studies  (11/16/15).................................................................................................... 15            |
| 1.5                                                                                                                | Health-Related Quality of Life and Neurocognitive Assessment ......................................................... 15                                     |
| 1.6                                                                                                                | Cost Effectiveness .                                                                                                                                          |
| 2.0                                                                                                                | OBJECTIVES .                                                                                                                                                  |
| 2.1                                                                                                                | Primary Objectives .                                                                                                                                          |
| 2.2                                                                                                                | Secondary Objectives (11/23/11)                                                                                                                               |
| 3.0                                                                                                                | PATIENT SELECTION                                                                                                                                             |
| 3.1                                                                                                                | Conditions for Patient Eligibility  (12/31/14) ...................................................................................................... 19      |
| 3.2                                                                                                                | Conditions for Patient Ineligibility  (11/23/11) .                                                                                                            |
| 4.0                                                                                                                | PRETREATMENT EVALUATIONS/MANAGEMENT                                                                                                                           |
| 4.1                                                                                                                | Required Pretreatment Evaluations/Management (1/8/09)                                                                                                         |
| 4.2                                                                                                                | Highly Recommended Pretreatment Evaluations/Management  (11/23/11)                                                                                            |
| REGISTRATION PROCEDURES                                                                                            |                                                                                                                                                               |
| 5.0                                                                                                                |                                                                                                                                                               |
| Access requirements for OPEN and TRIAD                                                                             |                                                                                                                                                               |
| Pre-Registration Requirements for IMRT (12/31/14)                                                                  |                                                                                                                                                               |
| 5.1                                                                                                                | Pre-Registration Requirements for 3D-CRT  (12/31/14) .                                                                                                        |
| 5.2                                                                                                                |                                                                                                                                                               |
| 5.3                                                                                                                | Digital RT Data Submission to RTOG Using TRIAD .                                                                                                              |
| Regulatory Pre-Registration Requirements .                                                                         |                                                                                                                                                               |
| 5.4                                                                                                                |                                                                                                                                                               |
| 5.5                                                                                                                | REGISTRATION (12/31/14)                                                                                                                                       |
| 6.0                                                                                                                | RADIATION THERAPY  (12/10/13)                                                                                                                                 |
| Dose Specifications (11/23/11) .                                                                                   |                                                                                                                                                               |
| 6.1                                                                                                                |                                                                                                                                                               |
| 6.2                                                                                                                | Technical Factors [Equipment, energies]                                                                                                                       |
| 6.3                                                                                                                | Localization, Simulation, and Immobilization  (11/23/11) .                                                                                                    |
| 6.4                                                                                                                | Treatment Planning/Target Volumes  (12/31/14)                                                                                                                 |
| 6.5                                                                                                                | Critical Structures  (12/10/13)                                                                                                                               |
| 6.6                                                                                                                | Documentation Requirements (12/31/14)                                                                                                                         |
| 6.7                                                                                                                | Compliance Criteria (3D-CRT and IMRT) (11/23/11) .                                                                                                            |
| 6.8                                                                                                                | R.T. Quality Assurance Reviews  (12/31/14) .                                                                                                                  |
| 6.9                                                                                                                | Radiation Adverse Events                                                                                                                                      |
| 6.10                                                                                                               | Radiation Adverse Event Reporting (1/8/09)                                                                                                                    |
| DRUG THERAPY .                                                                                                     |                                                                                                                                                               |
| 7.0                                                                                                                | Treatment (12/31/14) .                                                                                                                                        |
| 7.1
7.2                                                                                                                    | EULEXIN (flutamide)                                                                                                                                           |
| 7.3                                                                                                                |                                                                                                                                                               |
| 7.4                                                                                                                | Casodex (bicalutamide) .                                                                                                                                      |
| 7.5                                                                                                                | Criteria for Discontinuation of Protocol Treatment (1/8/09)                                                                                                   |
| 7.6                                                                                                                | Modality Review                                                                                                                                               |
| 7.7                                                                                                                | Adverse Events (4/29/14) .                                                                                                                                    |
| 7.8                                                                                                                | CTEP-AERS Expedited Reporting Requirements (12/31/14)                                                                                                         |
| 8.0                                                                                                                | SURGERY                                                                                                                                                       |
| 9.0                                                                                                                | OTHER THERAPY                                                                                                                                                 |
| 9.1                                                                                                                | Permitted Supportive Therapy .                                                                                                                                |
| 9.2                                                                                                                | Treatment of Patients with Subsequent Disease Progression .................................................................40                                 |
| 10.0                                                                                                               | TISSUE/SPECIMEN SUBMISSION .                                                                                                                                  |
| 10.1                                                                                                               | General Information                                                                                                                                           |
| 10.2                                                                                                               | Specimen Collection for Tissue Banking for Biomarker Studies: Strongly recommended ......... 40                                                               |
| Confidentiality/Storage (1/8/09)                                                                                   |                                                                                                                                                               |
| 1.0                                                                                                                | PATIENT ASSESSMENTS .......................................................................................................................................42 |
| 11.1                                                                                                               | Study Parameters: See Appendix I for a summary of assessments and time frames. ...............42                                                              |
| S                                                                                                                  |                                                                                                                                                               |
nrg oncology rtog 0534
table of contents (15-jan-2019)

| 11.2                                                                                                                                    | Evaluation During Treatment  (11/23/11)...........................................................................................................42     |
|-----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.3                                                                                                                                     | Evaluation Following Radiotherapy  (11/16/15)                                                                                                            |
| 1.4                                                                                                                                     | Criteria for Freedom from Progression (FFP) ..........................................................................................43                 |
| 1.5                                                                                                                                     | CC                                                                                                                                                       |
| 1.6                                                                                                                                     | Criteria for Nonlocal Failure                                                                                                                            |
| 11.7                                                                                                                                    | Other Response Parameters                                                                                                                                |
| 1.8                                                                                                                                     | Health-Related Quality of Life (HRQOL) (12/10/13) ...........................................................................45                          |
| 1.9                                                                                                                                     | Neurocognitive Test Battery (12/10/13) ...............................................................................................................46 |
| 11.10                                                                                                                                   | Beta-amyloid (Abeta) and Measures of Cognition and Mood and Depression (3/31/09) ............ 47                                                         |
| 11.11                                                                                                                                   | Cost Utility Analysis: EuroQol (EQ-5D)                                                                                                                   |
| 12.0                                                                                                                                    | DATA COLLECTION                                                                                                                                          |
| 12.1                                                                                                                                    | Summary of Data Submission (12/10/13) .....................................................................................................48            |
| 12.2                                                                                                                                    | Summary of Dosimetry Digital Data Submission for 3D-CRT or IMRT (Submit to TRIAD; see                                                                    |
| Section 5 for account access and installation instructions) [12/31/14] ..............................................................49 |                                                                                                                                                          |
| STATISTICAL CONSIDERATIONS .                                                                                                            |                                                                                                                                                          |
| 13.0                                                                                                                                    |                                                                                                                                                          |
| 13.1                                                                                                                                    | Study Endpoints  (11/23/11).                                                                                                                             |
| 13.2                                                                                                                                    | Sample Size                                                                                                                                              |
| 13.3                                                                                                                                    | Patient Accrual  (11/23/11)                                                                                                                              |
| 13.4                                                                                                                                    | Power Calculations for Selected Secondary Endpoints                                                                                                      |
| 13.5                                                                                                                                    | Analysis Plan                                                                                                                                            |
| 13.6                                                                                                                                    | Interim Report to Monitor the Study Progress .                                                                                                           |
| 13.7                                                                                                                                    | Reporting the Initial Treatment Analysis (1/8/09)                                                                                                        |
| 13.8                                                                                                                                    | Gender and Minorities                                                                                                                                    |
| REFERENCES (1/8/09)                                                                                                                     |                                                                                                                                                          |
| APPENDIX I (11/16/15)                                                                                                                   |                                                                                                                                                          |
| APPENDIX II (10/22/09)                                                                                                                  |                                                                                                                                                          |
| APPENDIX III .                                                                                                                          |                                                                                                                                                          |
| APPENDIX IV (11/16/15) .                                                                                                                |                                                                                                                                                          |
| APPENDIX V (12/10/13)                                                                                                                   |                                                                                                                                                          |
nrg oncology rtog 0534
rtog 0534

A Phase III **Trial of Short Term Androgen Deprivation with Pelvic Lymph Node or Prostate Bed**
Only Radiotherapy (SPPORT) in Prostate Cancer Patients with a Rising PSA After Radical Prostatectomy
nrg oncology rtog 0534
schema (1/8/09) (3/24/10)

| SV Involvement 1. No                                                                                                                                                |                                          |                                             |                              |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|---------------------------------------------|------------------------------|
| S                                                                                                                                                                   | 2. Yes                                   | R                                           | Arm 1: PBRT Alone            |
| T                                                                                                                                                                   | A                                        | PBRT 64.8-70.2 Gy                           |                              |
| R                                                                                                                                                                   | Prostatectomy Gleason Score              | N                                           |                              |
| A                                                                                                                                                                   | 1. Gleason ≤ 7                           | D                                           |                              |
| T                                                                                                                                                                   | 2. Gleason 8-9                           | O                                           | Arm 2: PBRT + NC-STAD        |
| I                                                                                                                                                                   | M                                        | PBRT 64.8-70.2 Gy + NC-STAD for 4-6 months, |                              |
| F                                                                                                                                                                   | Pre-Radiotherapy PSA                     | I                                           | beginning 2 months before RT |
| Y                                                                                                                                                                   | 1. PSA ≥ 0.1 and ≤ 1.0 ng/mL             | Z                                           |                              |
| 2. PSA > 1.0 and < 2.0ng/mL                                                                                                                                         | E                                        | Arm 3: PLNRT + PBRT + NC-STAD               |                              |
| Pathology Stage                                                                                                                                                     | PLNRT to 45 Gy and PBRT to 64.8-70.2 Gy, |                                             |                              |
| 1. pT2 and margin negative                                                                                                                                          | NC-STAD for 4-6 months,                  |                                             |                              |
| 2. All others                                                                                                                                                       | beginning 2 months before RT             |                                             |                              |
| SV = seminal vesicle; RT = radiotherapy; PBRT = prostate bed RT; PLNRT = pelvic lymph node RT; NC-STAD = neoadjuvant and concurrent short term androgen deprivation |                                          |                                             |                              |  
NOTE: It is mandatory the treating physician determine the radiation therapy technique (3DCRT vs. IMRT) to be used prior to the site registering the patient. See pre-registration requirements in Section 5.1. See details of radiation therapy and hormone therapy in Sections 6.0 and 7.0.  
Patient Population: (See Section 3.0 for Eligibility) (3/31/09) (3/24/10)
Lymph node negative adenocarcinoma of the prostate treated with radical prostatectomy Post-radical prostatectomy PSA of ≥ 0.1 - < 2.0 ng/mL; pathologic T3N0/Nx disease or pathologic T2N0/Nx disease, with or without a positive prostatectomy surgical margin; Gleason ≤ 9
nrg oncology rtog 0534
required sample size 1764 nrg

(Y) 1. Is there adenocarcinoma of the prostate treated primarily with radical prostatectomy, pathologically proven to be lymph node negative by pelvic lymphadenectomy (pN0) or lymph node status pathologically unknown
(undissected pelvic lymph nodes [pNx]?
(Y) 2. Is the post-radical prostatectomy entry PSA ≥ 0.1 and < 2.0 ng/mL at least 6 weeks (45 days) after prostatectomy and within 30 days of registration?  
| (Y)   | 3.   | Does the patient meet one of the following pathologic classifications:  T3N0/Nx disease; or  T2N0/Nx disease……….Margin Negative______ Margin Positive______?   |
|-------|------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|  
(Y) 4. Is the prostatectomy Gleason score 9 or less?  
| (Y)   | 5.   | Is the Zubrod Performance Status 0-1?   |
|-------|------|-----------------------------------------|  
(Y) 6. Is the age ≥ 18? (Y) 10. Is there adequate bone marrow function, within 90 days prior to registration,  
defined as follows?  
- Platelets ≥ 100,000 cells/mm3 based upon CBC; - Hemoglobin ≥ 10.0 g/dl based upon CBC  
| (Y)   | 7.   | Was there a digital rectal exam within 8 weeks (60 days) prior to registration?   |
|-------|------|-----------------------------------------------------------------------------------|  
| (Y)   | 8.   | Was a history/physical examination done within 8 weeks (60 days) prior to  registration?   |
|-------|------|--------------------------------------------------------------------------------------------|  
| (N)   | 9.   | Are there distant metastases, based upon the following minimum diagnostic work up? - A CT scan of the pelvis (with contrast if renal function is acceptable; a  noncontrast CT is permitted if the patient is not a candidate for contrast) or  MRI of the pelvis within 120 days prior to registration;  - Bone scan within 120 days prior to registration and plain films and/or MRI if  the bone scan is suspicious   |
|-------|------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
(Y) 11. Is the AST or ALT < 2 x the upper limit of normal within 90 days prior to registration?  
(Y) 13. Did the patient sign a study-specific informed consent prior to study entry?  
(Continued on the next page)  
| (Y)   | 12. Was serum total testosterone obtained within 90 days prior to registration and  ≥40% of the lower limit of normal of the assay used? Assay Lower Limit _____,  Value_____?   |
|-------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
nrg oncology rtog 0534
nrg oncology institution # nrg

(N/Y) 14. Was there a palpable prostatic fossa abnormality/mass suggestive of recurrence?  
(Y) If yes, was the abnormality/mass shown by biopsy under ultrasound guidance not to contain cancer?  
(N) 15. Does the patient have N1 disease?  
| (N/Y)   | 16. Does the patient have pelvic lymph node enlargement ≥ 1.5 cm in greatest  dimension by CT scan or MRI of the pelvis? (Y) If yes, was the enlarged lymph node sampled and found to be negative?   |
|---------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
(N) 17. Did the patient receive androgen deprivation therapy that was started prior to prostatectomy for > 6 months (180 days) duration (Note: The use of finasteride or dutasteride (±tamsulosin) for longer periods is acceptable prior to prostatectomy)?  
(N) 18. Did the patient receive androgen deprivation therapy that was started after prostatectomy and prior to registration (Note: The use of finasteride or dutasteride
(±tamsulosin) is not acceptable after prostatectomy - must be stopped within 3 months after prostatectomy. Androgen deprivation therapy must be stopped within 3 months after prostatectomy)?  
(N) 19. Did the patient have neoadjuvant chemotherapy before or after prostatectomy? (N) 21. Did the patient have prior cryosurgery or brachytherapy of the prostate?  
| (N)   | 20. Did the patient have prior chemotherapy for any other disease site if given within  5 years prior to registration?   |
|-------|--------------------------------------------------------------------------------------------------------------------------|  
(N) 22. Did the patient have prior pelvic radiotherapy?  
(N) 23. Did the patient have a prior invasive malignancy (except non-melanomatous skin  
cancer) or superficial bladder cancer within the past 5 years?  
(N) 24. Does the patient have any of the following severe, active comorbidities?  
- History of inflammatory bowel disease;
- History of hepatitis B or C; - 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;
- Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC
definition?  
(Continued on next page)
nrg oncology rtog 0534
rtog 0534 eligibility checklist (12/10/13)

Case \# (page 3 of 4)
(N) 25. Did the patient have any prior allergic reaction to the study drug(s) involved in this protocol?
nrg oncology rtog 0534
the following questions will be

3D-CRT or IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION  
  
(N/Y) Specify use of IMRT
1. Institutional person registering this case  
| (Y)   | 2.   | Has the Eligibility Checklist been completed?   |
|-------|------|-------------------------------------------------|  
| (Y)   | 3.   | In the opinion of the investigator, is the patient eligible?   |
|-------|------|----------------------------------------------------------------|  
| 4.   | Date Informed Consent signed   |
|------|--------------------------------|  
| 5.   | Participant Initials   |
|------|------------------------|  
| 6.   | Verifying Physician   |
|------|-----------------------|  
| 7.   | Patient's ID Number   |
|------|-----------------------|  
| 8.   | Date of Birth   |
|------|-----------------|  
| 9.                                                                       | Race   |
|--------------------------------------------------------------------------|--------|
| 10. Ethnicity 11. Gender 12. Country of Residence 13. Patient's Zip Code |        |  
| 14. Method of Payment   |
|-------------------------|  
| 15. Any care at VA or military hospital?   |
|--------------------------------------------|  
| 16. Calendar Base Date   |
|--------------------------|  
| 17. Randomization Date   |
|--------------------------|  
(Y/N) 18. Have you obtained the patient's consent for his specimens to be used for research to learn about, prevent or treat cancer?  
(Y/N) 19. Have you obtained the patient's consent for his specimens to be used for research to learn about, prevent or treat cancer?  
(Continued on next page)
NRG Oncology Institution \#
nrg oncology rtog 0534
rtog 0534 eligibility checklist (12/10/13)

Case \# (page 4 of 4)  
(Y/N) 20. Did the patient consent to having someone contact them in the future for new research not included in this consent?  
21. Specify SV involvement  
 22. Specify Prostatectomy Gleason score 23. Specify Pre-radiotherapy PSA 24. Specify Pathology Stage 25. Specify LHRH agonist planned duration
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, and dated checklist used at study entry must be retained in the patient's study file and will be evaluated during an institutional NCI/NRG Oncology audit.  
Completed by Date
nrg oncology rtog 0534
1.0 introduction 1.1 rationale for

application of post-prostatectomy radiotherapy (RT). RT is the mainstay of salvage treatment for men with a persistently detectable PSA (PD-PSA) or a delayed rise in PSA (DR-PSA) without evidence of metastasis.1-13 Because there are no published salvage RT randomized trials, the rationale for this treatment is derived mostly from small retrospective series. The largest retrospective analysis was a multi-institutional effort reported by Stephenson et al.13 They examined predictors of response to salvage RT and found that high Gleason score, high preradiotherapy PSA, negative prostatectomy surgical margins, short PSA doubling time (PSADT),
and seminal vesicle involvement were independently associated with adverse outcome. Similar factors have been reported in many of the other retrospective series as well.14 Despite gains in understanding how to select patients for salvage treatment, level I evidence on the outcome of patients receiving well-delineated treatment (e.g., RT technique and use of androgen deprivation)
is lacking.  
Level I evidence supporting the application of RT to patients treated postoperatively has been reported for adjuvant RT, and the results are encouraging. The findings of a European Organization for Research and Treatment of Cancer trial (EORTC 22911)15 showed that adjuvant RT resulted in a significant delay in biochemical and clinical failure. The results from a Southwest Oncology Group trial, SWOG 8794, 16 were similar, as were those from a preliminary report of a German Cancer Society trial, ARO 96-02, 17 reported at the 2005 American Society of Clinical Oncology meeting. Adjuvant RT is effective at reducing progression.  
Although, there are no published phase III clinical trials examining the efficacy of salvage radiotherapy for a rising PSA after radical prostatectomy, one study has completed accrual.  
RTOG 96-01 compares salvage RT alone to salvage RT plus 2 years of androgen deprivation (AD), accomplished using 150 mg/day of Casodex. The trial described here differs from RTOG
96-01 in several ways. First, the eligibility criteria are stricter; more favorable patients have been selected for RTOG 0534. Second, short-term AD is being tested, while in RTOG 96-01 long-term AD was examined. Third, pelvic lymph node radiotherapy was not allowed in RTOG 96-01 and has never been studied in a randomized trial in post-prostatectomy patients. There is no consensus on how to apply these treatment methods in the postoperative setting, yet AD and pelvic lymph node irradiation (PLNRT) are being used.18-26 The proposed three-arm trial is designed to address the following key questions: 1) Is neoadjuvant and concurrent short-term AD
(NC-STAD) plus prostate bed radiotherapy (PBRT) superior to PBRT alone? and 2) Is NC-STAD
plus pelvic lymph node RT (PLNRT) superior to NC-STAD+PBRT? In the context of this study description, reference to PLNRT is made with the understanding that the prostate bed will receive the same total dose in all three treatment arms.  
RTOG 0534 is not intended to address the efficacy of RT alone over observation. The complete response rate (a drop in PSA to undetectable levels) after salvage RT is 70%-80% and durable responses are observed in 30%-40% of patients. For these reasons, it is likely not feasible or appropriate to randomize men between observation and salvage RT. The more important issue is whether the proportion of durable responses is increased by altering the therapeutic approach, such as the use of NC-STAD with or without extended RT fields.  
The pre-salvage radiotherapy PSA doubling time has been reported in several series to be an important determinant of outcome after radical prostatectomy. Until recently, the consensus was that men with short PSADTs of ≤6 mo would respond unfavorably to salvage PBRT because of an increased risk of distant metastasis. Thus, the initial stratification criteria for RTOG protocol 0534 excluded patients with a PSADT of ≤6 mo from eligibility. However, Trock et al, 27 in a recent series from Johns Hopkins reported just the opposite. Those men with a post-prostatectomy PSADT of
≤6 mo experienced the greatest cause-specific survival benefit from salvage radiotherapy, when compared to men who did not receive salvage PBRT. There are no other comparable data available. As a consequence, the eligibility and stratification criteria based on PSADT have been removed from RTOG 0534. We plan to collect all PSA data so that any information pertinent to calculating PSADT will be recorded for secondary analyses later. The eligibility criterion of a PSA ≥0.2 ng/mL has been relaxed to a PSA ≥0.1 ng/mL because many patients have a documented rise in PSA using hypersensitive assays and are pathologically high risk by virtue of having pT3 disease and/or a positive margin. These patients should be treated as early as possible.  
1.2 **Rationale for Using NC-STAD and PLNRT Treatment Postoperatively**
No postoperative randomized trials investigating AD plus RT have been published, but three prior phase III studies of men treated primarily for prostate cancer, one by the RTOG (86-10),28 one by investigators at Harvard,29 and one by the Trans-Tasman Radiation Oncology Group, 30 concluded that neoadjuvant and concurrent short-term NC-STAD plus RT reduces cause-specific mortality compared with RT alone. The results of RTOG protocol 94-1331 extend these observations.  
RTOG 94-13 compared PLNRT to prostate-only RT and NC-STAD to adjuvant STAD plus RT in men with newly diagnosed prostate cancer using a 2x2 design. PLNRT significantly delayed progression, while the timing of STAD did not. When the four treatment groups were examined individually, the men who received PLNRT plus NC-STAD had significantly fewer failures
(including biochemical) than those in the other three groups. The findings from RTOG 94-13 suggest that there was an interaction between PLNRT and NC-STAD, resulting in a reduction in progression by more effectively eradicating microscopic pelvic lymph nodal disease. RTOG 0534 builds on the observations of 94-13 and the other randomized trials of men treated primarily with NC-STAD plus RT in a population of patients who were initially treated with prostatectomy. RTOG 0534 is a three-arm trial that does not include a PLNRT alone arm. The rationale for a three-, as opposed to a four-, arm trial is based on two primary considerations. First, a control arm of PLNRT alone was not included because in RTOG 94-13, it was the NC-STAD plus PLNRT arm that was superior to all other arms. No difference was seen for PLNRT plus adjuvant STAD,
prostate-only RT plus adjuvant STAD, or NC-STAD plus prostate-only RT, and all were inferior to NC-STAD plus PLNRT. The hypothesis here is that the combination of NC-STAD plus PLNRT is necessary to significantly improve outcome when PLNRT is used. Second, a four-arm study that includes a PLNRT alone arm is prohibitive in terms of patient numbers. As described below, the three-arm trial design requires 1764 patients, a target that the RTOG is capable of completing within 9.2 years.
nrg oncology rtog 0534
1.3 rationale for using the

Endpoint The primary endpoint is freedom from progression (FFP), including a biochemical parameter that is highly related to clinical progression (CP; includes local, regional, or distant progression). After radical prostatectomy, a detectable PSA of ≥ 0.2 ng/mL has been associated with a median time to distant metastasis from prostate cancer of 7-8 years.32-33 There has been debate about the absolute biochemical cut-point that best correlates with eventual disease relapse (mainly in the range from 0.1-0.5 ng/mL). In a detailed analysis by Amling, et al34 a biochemical failure cut-point of 0.4 or greater was found to be more significantly related to eventual CP than lower cut-point values and was nearly the same as higher cut-point values.  
Since the goal here is to use an endpoint that is strongly related to clinical progression and, ultimately, death due to prostate cancer, we compared a number of PSA-based definitions in a large cohort of men treated with RT post-prostatectomy.35-36This IRB-approved analysis included more than 1200 men with lymph node negative disease who were treated with either adjuvant
(23%) or salvage (77%) RT. Median follow-up after RT was 61 months, and there were 147 patients who manifested clinical failure: 13% and 22% at 5 and 10 years, respectively.  
Table 1 (below) displays the relationships of different biochemical estimates of CP (BECPs) to CP
for men treated with salvage RT. There are four categories of biochemical parameters displayed: a) PSA of x ng/mL; b) PSA of x ng/mL plus 2 consecutive rises with the second rise above the cut-point being tested; c) Three consecutive PSA rises with backdating to between the nadir and first rise per the ASTRO consensus definition,37 and d) PSA ≥ 2 ng/mL above the nadir PSA per the "RTOG Phoenix" definition.38-42 The RTOG Phoenix definition was the favored biochemical failure (BF) definition for men treated primarily for prostate cancer with RT at a consensus conference organized by the RTOG and ASTRO in January 2005.43 The Phoenix definition has also been previously referred to as the "Houston" definition40 or simply as nadir +2 ng/mL.38-42 The reports examining the sensitivity, specificity, positive predictive value (PPV), and accuracy have consistently pointed to the RTOG Phoenix definition as being nearly ideal. Not only does the RTOG Phoenix definition have high specificity, sensitivity, PPV, and accuracy, the definition also addresses the pitfalls of the ASTRO definition. The ASTRO definition involves backdating, which alters the shape of Kaplan-Meier curves (causes an artificial flattening at the tail end), results in inaccurate estimates of BF when follow-up is short,40,42,44 and overestimates BF after release from androgen deprivation.42,44,45 Moreover, during the first two years of follow up after radiotherapy, the RTOG Phoenix definition identifies patients with BF in greater numbers than the ASTRO
definition, indicating that the classification of BF by the RTOG Phoenix definition is not delayed in patients treated primarily for prostate cancer.  
42 Table 1 confirms that the RTOG Phoenix definition is useful for men treated with salvage RT postprostatectomy. The highest sensitivity, specificity, and PPVs were obtained for the definitions that incorporated a 2-ng/mL cut-point. Three definitions were similar: ≥ 2 ng/mL, ≥ 2 ng/mL + two rises, and nadir + 2 ng/mL or higher. Since the RTOG Phoenix definition has emerged as the BF
definition of choice after definitive RT for prostate cancer, and the findings in Table 1 show that it is likewise a very appropriate BECP definition in the postoperative setting, the RTOG Phoenix definition will be the primary endpoint in the proposed trial. Biochemical criteria have previously been included as the primary endpoint in an RTOG randomized trial examining NC-STAD (RTOG
94-13),31 which supports the rationale for the Phoenix definition as the primary endpoint in the proposed trial. The initiation of further "salvage" therapy in any form (e.g., androgen deprivation therapy, vaccine therapy, or chemotherapy) after completion of protocol treatment and prior to nadir + 2 ng/mL failure will not be counted as a failure and is strongly discouraged. The success of the trial depends upon allowing the nadir + 2 ng/mL failure criteria to be met before any other therapeutic intervention. The use of this BECP endpoint facilitates a trial sample size of 1764 patients (see below), a sample size that is feasible for the RTOG to accrue in this patient population.  
| BECF Definition   | %5 / 8 yr.   | Specificity   | Sensitivity   | PPV   |
|-------------------|--------------|---------------|---------------|-------|
| Failure           |              |               |               |       |
| 1. ≥ 0.2          | 59% / 72%    | 56%           | 95%           | 23%   |
| 2. ≥ 0.4          | 47% / 64%    | 66%           | 94%           | 27%   |
| 3. ≥ 1.0          | 35% / 52%    | 77%           | 92%           | 35%   |
| 4. ≥ 2.0          | 29% / 41%    | 84%           | 90%           | 43%   |
| 5. ≥ 0.2+2 rises  | 42% / 59%    | 72%           | 93%           | 31%   |
| 6. ≥ 0.4+2 rises  | 39% / 57%    | 74%           | 93%           | 32%   |
| 7. ≥ 1.0+2 rises  | 32% / 46%    | 80%           | 90%           | 39%   |
| 8. ≥ 2.0+2 rises  | 29% / 39%    | 85%           | 90%           | 45%   |
| 9. ASTRO          | 33% / 36%    | 82%           | 90%           | 40%   |
| 10. Phoenix       | 31% / 40%    | 83%           | 91%           | 43%   |
| (nadir+2)         |              |               |               |       |  
BECF = biochemical estimate of clinical failure; PPV = positive predictive value Other PSA-related measures will be examined as secondary endpoints. A more conventional early estimate of biochemical failure after radical prostatectomy is a PSA of ≥ 0.4 ng/mL and rising (two consecutive rises with one being at or above 0.4 ng/mL) at a given time point. A two-year time point was chosen to reduce the effect of potential delays from short-term AD. In the analysis shown in Table 1, this endpoint had slightly lower specificity as a BECP. Our plan is to compare the primary and secondary PSA-related endpoints to the other secondary endpoints of time to development of hormone refractory disease based on biochemical criteria (three consecutive rises in PSA modeled after the ASTRO criteria, but without backdating), distant metastasis, causespecific mortality, and overall mortality. Local failure is not included as a separate endpoint because palpable evidence of local recurrence is rare after radiotherapy, and patients are typically started on salvage AD without prostate bed biopsy. However, local failure will be recorded and is part of the primary endpoint of biochemical and clinical failure.  
1.4 Rationale for Biomarker Studies **(11/16/15)**
The RTOG has been collecting pretreatment diagnostic tissue from all prostate cancer protocols for over 10 years. A number of histologic, cell kinetic/proliferation, and molecular markers of apoptosis and angiogenesis are under investigation, with several showing promise for the stratification of patients in future trials. A focus of prior biomarker studies from the principal investigators and genitourinary committee has been DNA-ploidy, Ki-67, p53, MDM2, bcl-2, bax, p16 and Cox-2.  
46-51 These markers have shown promise in complementing the standard clinical parameters of PSA, Gleason score, and stage in prior RTOG (or other) analyses of men with high-risk features treated primarily with RT, with or without AD. With the exception of DNA-ploidy, the protein expression of these markers was measured using immunohistochemical methods.  
While these markers have been selected based on prior analyses, it is likely that some other markers and/or methods will be investigated when the proposed trial matures. The quantification of gene expression based on the RNA level in formalin fixed archival tissue is now possible after laser capture microdissection and the initial studies on proteomics in archival tissue are encouraging. Approximately 7 years will be required for this protocol to mature; by that time, a clearer definition of the markers to be studied will be evident. The plan is to collect and store tissue from the prostatectomy specimens. The findings are expected to contribute to better risk group classification, enhance our understanding of radiation response and distant spread, and lead to therapeutic strategies based on correcting or counterbalancing the abnormalities detected.  
The collection of blood and urine before and after treatment for proteomic and genomic studies is also proposed. Preliminary findings of other studies indicate that serum protein patterns defined through patterns of ion signatures generated from high-dimensional mass spectrometry data may be of value in determining the presence of prostate cancer.52-53 Likewise, the presence of prostate cancer has been accurately determined through the identification of hypermethylation of the glutathione S transferase p1 (GSTP1) gene locus in urine.54 Both of these methods have potential for predicting outcome in pretreatment samples and the presence of recurrence in specimens obtained during follow-up. Blood (serum, plasma, and whole blood) and urine will be collected prior to treatment and during the 6th week of RT. Some blood (serum and plasma) and urine will continue to be collected after completion of RT per Section 10 and Appendix IV.  
1.5 Health-Related Quality of Life **and Neurocognitive Assessment**
Some of the side effects associated with RT and AD are deleterious and affect quality of life, and others may contribute to increased risks for serious health concerns associated with aging.  
Urinary, bowel, and erectile dysfunction are well-known side effects of pelvic RT. Sexual side effects are the most well recognized adverse effects from AD and include loss of libido, erectile dysfunction, and hot flashes. Loss of libido is distressing to many men, and they may not pursue treatments for erectile dysfunction that they may have otherwise pursued after radical prostatectomy or RT. The incidence of hot flashes, which may not abate over the course of AD, is close to 80%. Physiologic effects, including gynecomastia, changes in body composition (weight gain, reduced muscle mass, increase in body fat), and changes in lipids, are less commonly recognized as side effects of AD. These effects may lead to an exacerbation of potentially more serious conditions, such as hypertension, diabetes, and coronary artery disease.55 Loss of bone mineral density, anemia, and hair changes also may occur. Additionally, both the diagnosis of prostate cancer and the hormonal therapy can cause psychological distress. These side effects need more systematic study in clinical trials. Such studies would provide well-defined side effect profiles for better informing physicians of the far-reaching consequences of AD therapy and improve the awareness that they should incorporate into routine practice strategies for preventing and managing toxicities.56 AD has been shown to have a negative impact on health-related quality of life (HRQOL) in patients with asymptomatic lymph node positive prostatic carcinoma. One study showed significantly worse sexual, emotional, and physical function, with more hot flushes and worse overall HRQOL (using the Functional Assessment of Cancer Therapy-General [FACT-G] scale) in those patients, compared with patients receiving no therapy.57 To address HRQOL, RTOG 0534 will compare the treatment arms for differences in prostate cancer HRQOL outcomes (as measured by change over time in the Expanded Prostate Cancer Index Composite [EPIC]) in a subset of patients in each treatment arm. The EPIC is a prostate cancer HRQOL instrument that measures a broad spectrum of urinary, bowel, sexual, and hormonal symptoms related to radiotherapy and hormonal therapy.57 Studies also suggest selective associations with decline in testosterone and estradiol, including cognitive performance. The cognitive domains of verbal fluency, visual recognition, and visual memory were associated with decline in estradiol. Visual-motor slowing and slowed reaction times in some attentional domains including working memory, impaired delayed recall, and recognition speed of letters were associated with decline in testosterone during AD.58-59Cognition will be measured by a brief battery of reliable and valid tests previously tested for feasibility within the RTOG,60 including the Hopkins Verbal Learning Test-Revised (HVLT-R)
61-62 for memory, the Controlled Oral Word Association Test (COWAT) for verbal fluency, 63 the Trail Making Test Part A
for cognitive processing speed, and the Trail Making Test Part B for executive function.  
The incidence of suicide among older men with prostate cancer is higher than previously recognized. Depression, recent diagnosis, pain, and being foreign-born are important clinical correlates.64 The results of several recent studies suggest that estrogen and testosterone play an important role in the modulation of mood and cognitive function in women and men, and preliminary evidence indicates that these hormones may also modulate the levels of beta-amyloid
(Abeta),65 a 4 Kilo Dalton peptide that is likely to be involved in the pathogenesis of cognitive disorders such as Alzheimer's disease. A recent study assessed the physiological and clinical effects of reversible chemical castration on 40 men with prostate cancer who were treated with androgen blockade therapy (flutamide and leuprolide) for 36 weeks and subsequently followed for another 18 weeks after treatment was discontinued.66 The results indicated that chemical castration is associated with a significant rise in the plasma levels of Abeta and, clinically, with increased depression and anxiety scores. The discontinuation of treatment is associated with better cognitive performance, most noticeably of verbal memory. The performance of subjects on a word list memory test was negatively correlated with plasma levels of Abeta, but the clinical significance of this finding remains to be determined. Depression and mood will be measured in this study by the Hopkins Symptom Checklist (HSCL-25). Serum levels of beta-amyloid will be assessed at the same time points as the HSCL-25 and the neurocognitive test battery; associations among Abeta levels and cognitive tests will be evaluated.  
1.5.1 Urinary symptom and function assessment Urinary function assessment has become a mainstay of routine clinical practice using the American Urological Association Symptom Index Score (AUA SI) or International Prostate Symptom Score (IPSS) questionnaire.80 This questionnaire is routinely administered before and after radiotherapy, and treatment decisions, such as the administration of an alpha-blocker, are often based on the results. We propose to collect urinary symptom data on the entire patient cohort (not just those in the HRQOL subset) to explore the relationship between the questionnaire parameters and urinary morbidity using the CTCAE v. 3.0 (see section 7.7) grading system.  
1.6 **Cost Effectiveness**
Almost every incremental improvement in survival or progression-free survival comes at a cost.  
The cost is both financial and experienced in terms of quality of life. Measurement of primary outcomes such as freedom from progression and the most important aspects of human functioning and quality of life will permit a summary equation allowing for differences in quality of life, clinical outcomes, and cost to be incorporated into one equation. This equation is the Quality Adjusted Life Year (QALY) and a study-specific modification, the Quality Adjusted Freedom From Progression Year (QAFFPY). The QALY has been modified in a similar manner for different treatments where survival is not the primary outcome. Much of the work in modifying the QALY
began in ophthalmology, where sight-years, not life-years, are the outcome of interest. Examples of modifications to the QALY have included incremental cost per vision-year gained to assess the cost effectiveness of photodynamic therapy with verteporfin for age-related macular degeneration,66 costs per sight-year saved with screening for diabetic retinopathy,67 cost-utility analysis for treatments of retinal detachment associated with severe proliferative vitreoretinopathy,68 and the cost-utility of cataract surgery.69 However, the QALY has been used in other studies where survival is not the primary outcome of interest, such as the costeffectiveness of memantine in the treatment of patients with moderately severe to severe cognitive impairment from Alzheimer's70 and cochlear implantation for patients unable to gain effective speech recognition with hearing aids.71 We will model costs using Medicare reimbursement and measure utilities with the brief five-item EuroQol (EQ-5D).  
The EQ-5D is a method for obtaining valuations (utilities) of health-related quality of life (HRQOL)
to be used as an adjustment to survival and in the cost-utility analysis. Developed in 1987, the EQ-5D is used by investigators and the pharmaceutical industry throughout the United States, Europe, and Asia. It is one of only several measures recommended for use in cost-effectiveness analyses by the Washington Panel on Cost Effectiveness in Health and Medicine.72 The EQ-5D
instrument is intended to complement other forms of QOL measures, and it has been purposefully developed to generate a generic cardinal index of health, thus giving it considerable potential for use in economic evaluation. The argument by some that a generic measure does not capture some of the disease- or treatment-specific concerns of a given study misses the point. This costeffectiveness analysis is being done for purposes of exploring the means to inform macro (health policy, payer) decision making, not micro (individual) decision making. The findings from the disease-specific QOL instruments and treatment-related side effect QOL instruments described above will help inform individual decision making. The role of the EQ-5D is to measure HRQOL at a macro level, in the same metric as it has been measured across numerous diseases, including cancer. This instrument gives us the ability to compare across and within diseases the "big picture" of what the experts who developed the EQ-5D considered the primary health states of interest to humans: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Further, there is no standardized measure to assess and compare disease-specific utilities across or within diseases. Unlike the EQ-5D, the actual content of standard gamble (SG) and time trade-off
(TTO) methods vary widely among studies and are subject to wide variations in amount and type of information presented, message framing, and visual aids, making replication of utilities with the SG or TTO extremely difficult. Therefore, using the EQ-5D, an exploratory aim is to evaluate the cost-utility of the treatment arm demonstrating the most significant benefit (in terms of the primary outcome), in comparison to other widely accepted cancer and non-cancer therapies (see Table 2 below). We will also assess cost-utility among the arms to assess which therapy dominates. We will assess the value added of the summary score known as a Quality Adjusted Life Year (QALY),
and for this study the Quality Adjusted FFP Year, that combines benefits of duration of freedom from progression (FFP) and decrements of quality of life with financial cost of increasingly aggressive and costly therapy.  
| $U.S./Life Year Gained73                                                 |                 |          |        |         |         |               |
|--------------------------------------------------------------------------|-----------------|----------|--------|---------|---------|---------------|
| Intervention                                                             | Incremental Cost                 |          |        |         |         |               |
| effectiveness ($U.S.)                                                    |                 |          |        |         |         |               |
| Liver                                                                    | transplantation | compared | with   | medical | 237,000 |               |
| management Mammography, age < 50 yrs.                                    |                 | 232,000  |        |         |         |               |
| Dialysis compared with medical management                                | 50,000          |          |        |         |         |               |
| Drug therapy for moderate hypertension                                   | 32,600          |          |        |         |         |               |
| Mammography                                                              | screening       | for      | breast | cancer  | in      | 20,000-50,000 |
| patients aged 50-75 years ABMT compared with salvage CT for Hodgkin's    | 21,100          |          |        |         |         |               |
| recurrent after MOPP-ABV Induction CT and standard RT on RTOG trials for | 7,500-18,50073  |          |        |         |         |               |
| Non-Small Cell Carcinoma of the Lung                                     |                 |          |        |         |         |               |  
The EQ-5D has been used across numerous disease sites, including cancer. For example, the EQ-5D mean score for 95 patients with NSCLC (93% male, mean age 62 years) was 0.58 (SD
0.32) as measured by the questionnaire and 0.58 (SD 0.20) as measured by the visual analogue scale (VAS) version.75 The EQ-5D has been used to assess QALYs and the economic value of prostate cancer screening,76 and treatment of pain related to prostate cancer metastasis.77 Further, the EQ-5D was used in a recent study to estimate the economic value of the welfare loss due to prostate cancer pain by estimating the extent to which pain affects health-related quality of life among patients with prostate cancer. Health status and economic outcomes were modeled among a well-defined population of 200,000 Swedish prostate cancer patients. Health utility ratings (using the EQ-5D) were obtained from a subset of 1,156 of the prostate cancer patients. A
descriptive model showed that optimal treatment that would reduce pain to zero during the whole episode of disease would add on average 0.85 quality-adjusted life years (QALY) to every man with prostate cancer; the economic value of this welfare loss due to prostate cancer pain was approximately $121,240,000 per year.78 1.6.1 Quality-Adjusted Survival and Freedom from Progression Quality-adjusted survival and freedom from progression can be defined in the same manner, by the weighted sum of different time episodes added up to a total quality-adjusted life-year or freedom from progression–year [U= sum of quality (qi) of health states K times the duration (si)
spent in each health state.79 1.6.2 Cost-Effectiveness and Cost-Utility Cost-utility will be analyzed for planned publication at two time points: 1) at 1 year post-therapy, looking at initial treatment costs and quality of life and 2) at five years post-therapy. The cost-utility analysis will be done after the primary endpoint results are published.  
1.6.3 Measurement of Costs Direct medical costs fall into three categories: 1) initial therapy costs; 2) costs of managing the most common side effects as determined by this study; and 3) costs of managing recurrence. Costs for external beam radiotherapy will be determined using CPT coding and Medicare reimbursement rates. Costs of common management strategies of the most common side effects documented in this study (e.g., Imodium® for diarrhea) will be estimated from regional costs per unit. Costs for managing recurrence will assume the following salvage therapies:
hormone therapy and chemotherapy. Costs will include professional fees, cost/inpatient day, drugs, and supplies. Direct non-medical costs such as the cost of work lost or of transportation will not be measured. Incremental differences in costs and outcomes will be compared for the different alternatives and for the dominant alternative to other established therapies documented in the literature.
nrg oncology rtog 0534
2.0 objectives 2.1 primary objectives

2.1.1 To determine whether the addition of NC-STAD to PBRT improves freedom from progression
(FFP) [maintenance of a PSA less than the nadir+2 ng/mL, absence of clinical failure and absence of death from any cause] for 5 years, over that of PBRT alone in men treated with salvage RT after radical prostatectomy; 2.1.2 To determine whether NC-STAD+PLNRT+PBRT improves FFP over that of NC-STAD+PBRT and PBRT alone in men treated with salvage RT after radical prostatectomy.  
2.2 Secondary Objectives **(11/23/11)**
2.2.1 To compare the rates of a PSA ≥ 0.4 ng/mL and rising at 5 years after randomization (secondary biochemical failure endpoint), the development of hormone refractory disease (3 rises in PSA during treatment with salvage androgen deprivation therapy), distant metastasis, cause-specific mortality and overall mortality; 2.2.2 To compare acute and late morbidity based on CTCAE, v. 3.0; 2.2.3 To measure the expression of cell kinetic, apoptotic pathway, and angiogenesis-related genes in archival diagnostic tissue to better define the risk of FFP, distant failure, cause-specific mortality, and overall mortality after salvage radiotherapy for prostate cancer, independently of conventional clinical parameters now used; 2.2.4 To quantify blood product–based proteomic and genomic (single nucleotide polymorphisms)
patterns, and urine-based genomic patterns before and at different times after treatment to better define the risk of FFP, distant failure, cause-specific mortality, and overall mortality after salvage radiotherapy for prostate cancer, independently of conventional clinical parameters now used; 2.2.5 To assess the degree, duration, and significant differences of disease-specific health related quality of life (HRQOL) decrements among treatment arms; it is hypothesized that QOL as measured by the EPIC will significantly worsen by the increasing aggressiveness of treatment and that cognition as measured by the neurocognitive test battery (the HVLT-R, Trail Making Test, parts A & B, and the COWAT) will be significantly worse in the arms with NC-STAD.  
2.2.6 To assess whether mood is improved and depression is decreased with the more aggressive therapy if it improves FFP; it is hypothesized that QOL as measured by the HSCL-25 will significantly improve with the increasing aggressiveness of treatment due to improved FFP.  
2.2.7 An exploratory aim is to assess whether an incremental gain in FFP and survival with more aggressive therapy outweighs decrements in the primary generic domains of health related quality of life (i.e., mobility, self care, usual activities, pain/discomfort, and anxiety/depression). This aim is reported as the Quality Adjusted FFP Year (QAFFPY) and as the Quality Adjusted Life Year (QALY). The QAFFPY and QALY will be compared among treatment arms and to the literature as described in Section 1.6.  
2.2.8 An exploratory aim is to evaluate the cost-utility of the treatment arm demonstrating the most significant benefit (in terms of the primary outcome) in comparison with other widely accepted cancer and non-cancer therapies. Cost-utility will be assessed by the EQ-5D among treatment arms to determine which therapy dominates.  
2.2.9 An exploratory aim is to assess associations between serum levels of beta-amyloid (Abeta) and measures of cognition (as measured by the HVLT-R, Trail Making Tests, parts A & B, or the COWAT) and mood and depression (as measured by the HSCL-25).  
2.2.10 To collect paraffin-embedded tissue blocks, serum, plasma, urine, and whole blood for future translational research analyses 2.2.11 An exploratory aim is to assess the relationship(s) between the American Urological Association Symptom Index (AUA SI) and urinary morbidity using the CTCAE v. 3.0 grading system.
nrg oncology rtog 0534
3.0 patient selection note per

3.1.1 Adenocarcinoma of the prostate treated primarily with radical prostatectomy, pathologically proven to be lymph node negative by pelvic lymphadenectomy (N0) or lymph node status pathologically unknown (undissected pelvic lymph nodes [Nx]), i.e. lymph node dissection is not required;
- Any type of radical prostatectomy will be permitted, including retropubic, perineal, laparoscopic or robotically assisted. If performed, the number of lymph nodes removed per side of the pelvis and the extent of the pelvic lymph node dissection (obturator vs.  
extended lymph node dissection) should be noted. There is no time limit for the date of radical prostatectomy.  
3.1.2 A post-radical prostatectomy entry PSA of ≥ 0.1 and < 2.0 ng/mL at least 6 weeks (45 days) after prostatectomy and within 30 days of registration; 3.1.3 One of the following pathologic classifications:
- T3N0/Nx disease with or without a positive prostatectomy surgical margin; or
- T2N0/Nx disease with or without a positive prostatectomy surgical margin; 3.1.4 Prostatectomy Gleason score of 9 or less; 3.1.5 Zubrod Performance Status of 0-1; 3.1.6 Age ≥ 18; 3.1.7 No distant metastases, based upon the following minimum diagnostic workup:
- History/physical examination (including digital rectal exam) within 8 weeks (60 days) prior to registration;
- A CT scan of the pelvis (with contrast if renal function is acceptable; a noncontrast CT is permitted if the patient is not a candidate for contrast) or MRI of the pelvis within 120 days prior to registration;
- Bone scan within 120 days prior to registration; if the bone scan is suspicious, a plain x-ray and/or MRI must be obtained to rule out metastasis.  
3.1.8 Adequate bone marrow function, within 90 days prior to registration, defined as follows:
- Platelets ≥ 100,000 cells/mm3 based upon CBC;
- Hemoglobin ≥ 10.0 g/dl based upon CBC (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is recommended).  
3.1.9 AST or ALT < 2 x the upper limit of normal within 90 days prior to registration; 3.1.10 Serum total testosterone must be ≥ 40% of the lower limit of normal (LLN) of the assay used
(testosterone ÷ LLN must be ≥ 0.40) within 90 days prior to registration (Note: Patients who have had a unilateral orchiectomy are eligible as long as this requirement is met);
3.1.11 Patients must sign a study-specific informed consent prior to study entry.  
3.2 Conditions for Patient Ineligibility **(11/23/11)**
3.2.1 A palpable prostatic fossa abnormality/mass suggestive of recurrence, unless shown by biopsy under ultrasound guidance not to contain cancer; 3.2.2 N1 patients are ineligible, as are those with pelvic lymph node enlargement ≥ 1.5 cm in greatest dimension by CT scan or MRI of the pelvis, unless the enlarged lymph node is sampled and is negative; 3.2.3 Androgen deprivation therapy started prior to prostatectomy for > 6 months (180 days) duration.  
Note: The use of finasteride or dutasteride (±tamsulosin) for longer periods prior to prostatectomy is acceptable; 3.2.4 Androgen deprivation therapy started after prostatectomy and prior to registration (Note: The use of finasteride or dutasteride (±tamsulosin) after prostatectomy is not acceptable - must be stopped within 3 months after prostatectomy. Androgen deprivation therapy must be stopped within 3 months after prostatectomy);
3.2.5 Neoadjuvant chemotherapy before or after prostatectomy; 3.2.6 Prior chemotherapy for any other disease site if given within 5 years prior to registration; 3.2.7 Prior cryosurgery or brachytherapy of the prostate; prostatectomy should be the primary treatment and not a salvage procedure; 3.2.8 Prior pelvic radiotherapy; 3.2.9 Prior invasive malignancy (except non-melanomatous skin cancer) or superficial bladder cancer unless disease free for a minimum of 5 years [for example, carcinoma *in situ* of the oral cavity is permissible];
3.2.10 Severe, active co-morbidity, defined as follows:
- History of inflammatory bowel disease;
- History of hepatitis B or C; Blood tests are not required to determine if the patient has had hepatitis B or C, unless the patient reports a history of hepatitis.  
- 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;
- **(01/8/09)**Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; AST or ALT are required (see Section 3.1.9); note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol.  
- Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may result in increased toxicity and immunosuppression.  
3.2.11 Prior allergic reaction to the study drug(s) involved in this protocol.
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4.0 pretreatment evaluations/management note this

4.1.1 A measure of urinary function is the American Urological Association Symptom Index Score (AUA
SI) or International Prostate Symptom Score (IPSS),80 which is now routinely the basis for treatment decisions. This scoring system has been established as a measure of radiation morbidity in patients treated for prostate cancer.  
81-84 The American Urological Association Symptom Index (AUA SI) will be administered to all protocol patients. The AUA SI questionnaire should be completed within 30 days prior to the start of treatment.  
4.2 Highly Recommended Pretreatment Evaluations/Management **(11/23/11)**
Within 30 days prior to the start of any protocol treatment:
4.2.1 Baseline alkaline phosphatase; 4.2.2 Some form of apical prostate bed localization, in addition to a non-contrast CT simulation, is recommended, but not required. The methods include CT scan with urethrogram at the time of simulation or MRI (see Section 6.3.1) simulation to localize the inferior aspect of the prostate bed.
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5.0 registration procedures (15-jan-2019) access

Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and Access Management (IAM) account. This is the same account (user id and password) used for the CTSU
members' web site. To obtain an active CTEP-IAM account, go to https://eapps-ctep.nci.nih.gov/iam. Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all individuals contributing to NCI-sponsored trials to register and to renew their registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their annual registration using CTEP's web-based Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type are outlined in the table below.  
| Documentation Required                                                       | IVR   | NPIVR   | AP   | A   |
|------------------------------------------------------------------------------|-------|---------|------|-----|
| FDA Form 1572                                                                |      |        |      |     |
| Financial Disclosure Form                                                    |      |        |     |     |
| NCI Biosketch (education, training, employment,  license, and certification) |      |        |     |     |
| HSP/GCP training                                                             |      |        |     |     |
| Agent Shipment Form (if applicable)                                          |      |         |      |     |
| CV (optional)                                                                |      |        |     |     |  
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the following:
- Added to a site roster
- Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN
- Act as the site-protocol PI on the IRB approval Additional information can be found on the CTEP website. For questions, please contact the RCR *Help Desk* by email at < RCRHelpDesk@nih.gov >.  
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
IRB Approval Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to enroll patients. Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria including but not limited to the following:
- An active Federal Wide Assurance (FWA) number
- An active roster affiliation with the Lead Network or a participating organization
- A valid IRB approval
- Compliance with all protocol specific requirements.  
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria:
- Active registration status
- The IRB number of the site IRB of record listed on their Form FDA 1572
- An active status on a participating roster at the registering site.  
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally. The CIRB's approval of the SSW is then communicated to the CTSU Regulatory Office. In order for the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with the Signatory Institution are participating in the study.  
NOTE: It is mandatory that the treating physician determine the radiation therapy technique (3D-CRT vs.  
IMRT) to be used prior to the site registering the patient.
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5.1 pre-registration requirements for imrt

In order to utilize IMRT on this study, the institution must have met specific technology requirements and have provided baseline physics information. Instructions for completing these requirements or determining if they already have been met are available on the Imaging and Radiation Oncology Core (IROC) Houston web site. Visit http://irochouston.mdanderson.org and select "Credentialing" and "Credentialing Status Inquiry".  
An IMRT phantom study with the IROC Houston must be successfully completed (if the institution has not previously met this credentialing requirement. Instructions for requesting and irradiating the phantom are available on the IROC Houston web site at http://irochouston.mdanderson.org; select "Credentialing" and "RTOG". Upon review and successful completion of the phantom irradiation, the IROC Houston will notify both the registering institution and NRG Oncology that the institution has completed this requirement. Subsequently, NRG Oncology will notify the institution that the site can enroll patients on the study. Institutions that previously have been credentialed for one IMRT delivery technique (e.g., standard gantry mounted linear accelerator using fixed gantry angles) must repeat the credentialing process when they change to a different technology (e.g. tomotherapyor volume delivery methods like RapidArc or VMAT). The institution or investigator must complete or update an IMRT Facility Questionnaire (one per institution, available on the IROC Houston web site at http://irochouston.mdanderson.org) and send it to IROC Houston for review prior to enrolling any patients. IROC Houston will notify the institution and NRG Oncology when all requirements have been met. NRG Oncology will notify the institution that they are eligible to enter patients onto this study.
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5.2 pre-registration requirements for 3d-crt

Only institutions that have met the technology requirements and that have provided the baseline physics information may enter patients onto this study.  
The new Facility Questionnaire (one per institution, available on the IROC Houston web site at http://irochouston.mdanderson.org) is to be sent to IROC Houston for review prior to enrolling any patients. IROC Houston will notify the institution and NRG Oncology when all requirements have been met. NRG Oncology will notify the institution that they are eligible to enter patients onto this study. Institutions that have previously enrolled patients on 3D-CRT trials of this same disease site may enroll patients on this study without further credentialing with the exception of submitting an updated Facility Questionnaire..
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5.3 digital rt data submission

This trial will not utilize the services of the ITC for dosimetry digital treatment data submission. TRIAD, the American College of Radiology's (ACR) image exchange application that is used by NRG Oncology, will be used. TRIAD provides sites participating in NRG clinical trials a secure method to transmit DICOM RT and other objects. TRIAD anonymizes and validates the images as they are transferred.
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triad installations when a user

This process can be done in parallel to obtaining your CTEP-IAM account username and password. If you have any questions regarding this information, please send an e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org.  
5.4 Regulatory Pre-Registration Requirements **(19-Feb-2019)**
5.4.1 This study is supported by the NCI Cancer Trials Support Unit (CTSU). Prior to the recruitment of a patient for this study, investigators must be registered members of a lead protocol organization.  
TRIAD Access Requirements:
- Site physics staff who will submit images through TRIAD will need to be registered with The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and Access Management (IAM) account. Please refer to Section 5.0 of the protocol for instructions on how to request a CTEP-IAM account.  
- To submit images, the site physics user must have been assigned the 'TRIAD site user' role on the relevant Group or CTSU roster. NRG Oncology users should contact your site Lead RA to be added to your site roster. Users from other cooperative groups should follow their procedures for assignment of roster roles.  
- RAs are able to submit standard of care imaging through the same method.
Each investigator must have an NCI investigator number and must maintain an "active" investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch (PMB), CTEP, DCTD, NCI. These forms are available on the CTSU registered member web site:
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm . For questions, please contact the CTEP Investigator Registration Help Desk by e-mail at pmbregpend@ctep.nci.nih.gov The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM)
application is a web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored clinical trials).  
Associates will use the CTEP-IAM application to register (both initial registration and annual reregistration) with CTEP and to obtain a user account. Investigators will use the CTEP-IAM
application to obtain a user account only. (See CTEP Investigator Registration Procedures above for information on registering with CTEP as an Investigator, which must be completed before a CTEP-IAM account can be requested.)
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications, including the CTSU members' web site. Additional information can be found on the CTEP web site at http://ctep.cancer.gov/branches/pmb/associate_registration.htm. For questions, please contact the CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov.  
Downloading Site Registration Documents Site registration forms may be downloaded from the RTOG 0534 protocol page located on the CTSU members' web site. Go to https://www.ctsu.org. Permission to view and download this protocol and its supporting documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.  
- Go to https://www.ctsu.org and log in to the members' area using your CTEP-IAM
username and password
- Click on the Protocols tab in the upper left of your screen
- Either enter the protocol \# in the search field at the top of the protocol tree, or
- Click on the By Lead Organization folder to expand Click on the Protocols tab in the upper left of your screen
- Click on the link to expand, then select trial protocol, RTOG-0534
- Click on LPO Documents, select the Site Registration documents link, and download and complete the forms provided.  
- Click on the Site Registration Documents link
Requirements for RTOG 0534 site registration:
- IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted)
- IRB/REB approved consent (English and native language versions*)
*Note: Institutions must provide certification/verification of IRB/REB consent translation to NRG Oncology (See "Non-English Speaking Canadian and Non-North American Institutions" below)
- IRB/REB assurance number renewal information as appropriate NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy component must participate in the Imaging and Radiation Oncology Core (IROC) monitoring program. For non-lead group institutions an RT Facilities Inventory Form must be on file with CTSU. If this form has been previously submitted to CTSU it does not need to be resubmitted unless updates have occurred at the RT facility.  
- IRB/REB approval letter (for sites not participating via the NCI CIRB);
- IRB/REB approved consent (English and native language versions*)
*Note: Institutions must provide certification/verification of IRB/REB consent translation to NRG
Oncology (See "Non-English Speaking Canadian and Non-North American Institutions" below)
- IRB/REB assurance number renewal information as appropriate Non-English Speaking Canadian and Non-North American Institutions Translation of documents is critical. The institution is responsible for all translation costs. All regulatory documents, including the IRB/REB approved consent, must be provided in English and in the native language. Certification of the translation is optimal but due to the prohibitive costs involved NRG Oncology will accept, at a minimum, a verified translation. A verified translation consists of the actual REB approved consent document in English and in the native language, along with a cover letter on organizational/letterhead stationery that includes the professional title, credentials, and signature of the translator as well as signed documentation of the review and verification of the translation by a neutral third party. The professional title and credentials of the neutral third party translator must be specified as well.
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submitting regulatory documents

Submit required forms and documents to the CTSU Regulatory Office via the Regulatory Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members' area)  Regulatory Tab Regulatory Submission When applicable, original documents should be mailed to:
CTSU Regulatory Office 1818 Market Street, Suite 3000 Philadelphia, PA 19103 Institutions with patients waiting that are unable to use the Portal should alert the CTSU
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and support.
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checking your site's registration status

You can verify your site registration status on the members' section of the CTSU website.  
- Go to https://www.ctsu.org and log in to the members' area using your CTEP-IAM
username and password
- Click on the Regulatory tab - Click on the Site Registration tab
- Enter your 5-character CTEP Institution Code and click on Go
Note: The status given only reflects compliance with IRB documentation and institutional compliance with protocol-specific requirements outlined by the Lead Network. It does not reflect compliance with protocol requirements for individuals participating on the protocol or the enrolling investigator's status with the NCI or their affiliated networks.  
5.4.2 Pre-Registration Requirements FOR CANADIAN INSTITUTIONS
Prior to clinical trial commencement, Canadian institutions must complete and send the following documents to the CTSU Regulatory Office via the Regulatory Submission Portal (sign in at www.ctsu.org and select the Regulatory Submission sub-tab under the
nrg oncology rtog 0534
regulatory tab).

- Health Canada's Therapeutic Products Directorates' Clinical Trial Site Information Form, - Qualified Investigator Undertaking Form, and
- Research Ethics Board Attestation Form.  
5.4.3 Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS
For institutions that do not have an approved LOI for this protocol: International sites must submit an LOI to NRG Oncology to receive approval to participate in this trial. For more details see link below:
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx .  
For institutions that have an approved LOI for this protocol: All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling patients to this study.
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5.5 registration (15-jan-2019)

5.5.1 OPEN Registration Instructions Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have been met, and the study site is listed as 'approved' in the CTSU RSS. Patients must have signed and dated all applicable consents and authorization forms.  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and a
'Registrar' role on either the LPO or participating organization roster. Registrars must hold a minimum of an AP registration type. . All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise System for regulatory and roster data. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members' web site https://www.ctsu.org.  
Prior to accessing OPEN site staff should verify the following:
- All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group or CTSU web site as a tool to verify eligibility.  
- All patients have signed an appropriate consent form and HIPPA authorization form (if applicable).
The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records. Further instructional information is provided on the CTSU members' web site OPEN tab or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. In the event that the OPEN system is not accessible, participating sites can contact web support for assistance with web registration: websupport@acr.org or call the Registration Desk at (215)
574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax in the eligibility checklist and will need the registering individual's e-mail address and/or return fax number. This information is required to assure that mechanisms usually triggered by the OPEN
web registration system (e.g. drug shipment and confirmation of registration) will occur.
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6.0 radiation therapy (12/10/13) this

Note: Intensity Modulated RT (IMRT) is allowed for this study. See Section 5.0 **for preregistration requirements for IMRT and 3D-CRT treatment techniques.**
Radiotherapy will start within 42 days (+/-14 days) after registration in Arm 1 and 60 days **(+/-14** days) after starting LHRH agonist treatment in Arms 2 and 3.
arm 1 pbrt alone pbrt
6.0 radiation therapy (12/10/13) this

Arm 2, PBRT + NC-STAD: PBRT 64.8-70.2 Gy (1.8 Gy per fraction) + NC-STAD for 120-180 **days,**
beginning 60 days (+/- 14 days) before RT
arm 1 pbrt alone pbrt
arm 3 plnrt + pbrt

6.1 Dose Specifications **(11/23/11)**
Radiotherapy will start within 42 days (+/-14 days) of registration in Arm 1 and 60 days (+/-14 days) after starting LHRH agonist treatment in Arms 2 and 3. Radiotherapy dose will be specified to the Planning Target Volume (PTV), as described in section 6.4. For the treatment methods outlined for prostate bed RT (3D-CRT, and IMRT), ≥ 95% of the PTV should receive the prescribed dose. The total dose to the prostate bed for all treatment arms is 64.8-70.2 Gy at 1.8 Gy per fraction. IMRT is strongly encouraged over 3D-CRT.  
6.2 **Technical Factors [Equipment, energies]**
Megavoltage equipment is required with effective photon energies ≥ 6 MV.  
6.3 Localization, Simulation, and Immobilization (11/23/11)
6.3.1 3D-Conformal Radiotherapy (3D-CRT) or IMRT
A urethrogram or MRI is recommended, but not required, to establish the most inferior portion of the prostate bed. Use of contrast, other than for the urethrogram, is discouraged. The placement of contrast in the rectum may cause the rectum to appear more anterior than it will be during treatment. Simulation should be with the rectum as empty as possible (an enema 1-2 hours prior to simulation) and with a moderately full bladder (the patient should not be uncomfortable at simulation and probably will have more difficulty maintaining a full bladder during treatment). An overly distended rectum can introduce a systematic positioning error that may increase the probability of missing the CTV. This is the reasoning behind an enema before the planning CT
scan; although other methods, such as the use of a hollow (robnel) catheter to evacuate flatus to reduce the size of the rectum may accomplish the same result. Immobilization of the hips and feet using a cradle should be considered.  
A treatment planning CT scan will be required to define the clinical and planning target volumes, and the critical normal structures. The treatment planning CT will be acquired with the patient set up in the same position as for daily treatments. Each patient will be positioned in the supine position. Prone positioning for treatment is not permitted. Rectal balloons for planning and treatment are not permitted. The CT scan of the pelvis should start at or above the iliac crest down to below the perineum (below the ischial tuberosities). All tissues to be irradiated must be included in the CT scan. CT scan thickness should be ≤ 0.3 cm through the region that contains the target volumes. The regions above and below the target volume region may be scanned with slice thickness ≤ 1.0 cm.  
6.4 Treatment Planning/Target Volumes (22Jun2017)
Note: All required structures must be labeled exactly as listed in the table in Section 6.4.3 below for digital RT data submission. Resubmission of data may be required if labeling of structures does not conform to the standard DICOM name listed.  
6.4.1 Prostate Bed Planning for 3D-CRT
The definition of volumes will be in accordance with ICRU Report \#50: Prescribing, Recording, and Reporting Photon Beam Therapy. Please see Section 6.8.2 for common contouring mistakes.  
CTVp (1/8/09) **(3/24/10)**
Contrast may be used for simulation but can distort the anatomy slightly and so is not recommended. The bladder should be reasonably full for simulation, keeping in mind that patients may not be able to maintain as full a bladder during radiotherapy. Having a somewhat full bladder at simulation ensures that the CTVp will be of maximal dimensions. The seminal vesicles or remnants thereof, if identified on CT or MRI as being present, will receive the full dose. The immediate periprostatic bed surgical clips should receive the full dose. The CTVp will extend from the top of the penile bulb inferiorly, or 1.5 cm below the urethrogram peak if done, to just above the pubic symphysis superiorly (at least for the anterior-most portion of the bladder). Laterally, the CTVp will extend from the medial edge of one obturator internus muscle to the other. Anteriorly, the CTVp will include the entire bladder neck until above the pubic symphysis, where a gradual reduction off of the anterior bladder is made. Superiorly, above the pubic symphysis, at least the posterior 2 cm of bladder should be included in the CTVp, as well as the area between the bladder and rectum, to the anterior rectal wall. The CTVp should extend superiorly to cover any clips in the seminal vesicle bed and the seminal vesicle remnants if present and should extend at least 2 cm above the pubic symphysis. Posteriorly, the CTVp is defined by the anterior-most aspects of the anus-rectum. The CTVp may be increased (not decreased) beyond these limits based on pre-prostatectomy imaging information.  
A consensus definition of the prostate bed85 and an anatomically-based description86 should be considered in defining the CTVp. There has been considerable variability in how the prostate bed has been defined in the past. Although consensus definitions are not based on clinical outcome, they are extremely valuable in making the transition from conventional to conformal volumes. The consensus definition is not much different than the CTVp originally described above, but subtle differences are evident and should be considered. Either CTVp definition will be accepted in this clinical trial.  
1) Superiorly: The prostatic fossa CTV (CTVp) should extend superiorly from the level of the caudal vas deferens remnant. In some cases, the vas deferens remnant may be difficult to visualize. In the absence of gross disease or seminal vesicle remnants, the superior limit of the CTVp should extend at least 2 cm and need not extend more than 3-4 cm above the level of the pubic symphysis. The consensus definition calls for "inclusion of the seminal vesicle remnants, if present, in the CTVp if there is pathologic evidence of their involvement. However, inclusion of any seminal vesicle remnants seen is recommended.  
2) Inferiorly: The CTVp should extend inferiorly to > 8-12 mm inferior to vesicourethral anastomosis
(VUA). With axial CT imaging, the VUA can often be seen in the retropubic region as one slice below the most inferior urine-containing image (the bladder must be modestly full). Magnetic resonance (MR) imaging defines this landmark more clearly with the hyperintense urine signal on T2 images. Inferiorly, the border of the CTVp should be at least 8-12 mm below the VUA. A sagittal reconstruction facilitates identification of the position of the VUA and the inferior border of the CTVp below it. If visualization of the VUA is problematic due to image quality or surgical clip artifacts, the inferior limit of the CTVp can extend to a level just above the penile bulb (same border as described above). It should be noted that there was considerable discussion about this definition versus extending the inferior border of the CTVp to just above the penile bulb; both definitions were deemed acceptable.  
3) Anteriorly: Below the superior border of the pubic symphysis, the anterior border is at the posterior aspect of the pubis. The CTVp extends posteriorly to the rectum where it may be concave at the level of the VUA. At this level the lateral border extends to the levator ani. Above the pubic symphysis the anterior border should encompass the posterior 1-2 cm of the bladder wall at the minimum and posteriorly it is bounded by the mesorectal fascia. At this level the lateral border is the sacrorectogenitopubic fascia. This is not well-defined in textbooks. If in question, the lateral border should extend to the obturator internus muscle.  
4) Posteriorly: The CTVp extends posteriorly to the anterior rectal wall, but may be somewhat concave around the anterior-lateral aspect of the rectum to adequately encompass the prostate bed.
arm 1 pbrt alone pbrt
ptvp (11/23/11)

The PTVp margins should be a minimum of 0.8 cm and a maximum of 1.5 cm in all dimensions. A reduction of the PTVp margin from 0.8 cm to ≥ 0.6 cm to minimize rectal exposure will be considered a variation acceptable. A posterior margin of < 0.6 cm will be considered an unacceptable deviation. A margin for penumbra for 3D-CRT, usually 0.5–0.7 cm beyond the PTVp should be added such that ≥ 95% of the PTVp receives the prescribed dose (64.8-70.2 Gy); an acceptable variation will be noted if < 95% to 90% of the PTVp receives the prescribed dose, and an unacceptable deviation will be noted if < 90% of the PTVp receives the prescribed dose. Care should be taken to conform the prescribed dose as closely to the PTVp as possible, so as to avoid including the entire width of the rectum in the posterior blocked margin at the bladder neck-rectum interface. The maximum dose in the PTVp above the prescribed dose will be 7%; a variation acceptable will be > 7% to ≤ 12% and an unacceptable deviation will be > 12%. The planned dose between 64.8 to 70.2 will be declared after the patient is planned and all dosimetric parameters finalized.  
Normal Tissue *Definitions* **(11/23/11)** Normal tissues will be outlined as solid structures, including the rectum, bladder and femoral heads. The penile bulb will be outlined as a reference structure. No constraints will be placed on the penile bulb, but doses will be recorded. The rectum will be outlined from the anterior flexion of the rectosigmoid superiorly to the ischial tuberosities inferiorly. The entire bladder should be outlined down to the anastamosis. The DVH calculations will include doses to the entire bladder and the bladder minus the CTVp (BladdermCTV; Section 6.4.2).The femoral heads should be outlined down to the region between the greater and lesser trochanters. The planning parameters outlined below for IMRT should be used as a guide; formal 3D-CRT normal tissue prostate bed constraints have not been the standard in the past and are not specified here. It should be possible to come close to achieving the constraints outlined for IMRT, at least within the variation range.
arm 1 pbrt alone pbrt
6.4.2 prostate bed planning for

The CTVp and PTVp will be the same as for 3D-CRT. There is no need to add margin for penumbra. A series of dose-volume histograms will be generated and analyzed to determine the adequacy of the plan.  
Planning Parameters **(11/23/11)**
The plan will be deemed acceptable under the following conditions.  
PTVp: The dose marker levels for bladder and rectum have been modeled after prior studies in men treated definitively with IMRT for prostate cancer.87-88 At least 95% of the PTVp should receive the prescribed dose (64.8-70.2 Gy); a variation acceptable will be noted if < 95% to 90% of the PTVp receives the prescribed dose, and a deviation unacceptable will be noted if < 90% of the PTVp receives the prescribed dose. The maximum dose within the PTVp, above the prescribed dose, will be 15%; an acceptable variation will be > 15% to ≤ 20% and an unacceptable deviation will be > 20%.  
Rectum: Less than or equal to 35% and 55% of the rectum should receive ≥ 65 Gy and ≥ 40 Gy, respectively. An acceptable variation will be noted if up to an additional 10% of the rectal volume at either cutpoint receives above the target doses specified. The inclusion of rectal volumes beyond these constraints will be considered a secondary acceptable variation and the extent of the variation should be recorded. In most patients, these constraints may be easily met and every attempt should be made to achieve the best dose distribution possible. The constraints will be harder to achieve in patients enrolled on Arm 3 (those receiving pelvic irradiation).  
Bladder: Less than or equal to 50% and 70% of the bladder minus CTVp **(BladdermCTV)**
should receive ≥ 65 Gy and ≥ 40 Gy, respectively. The criteria for the bladder are relaxed because the dosimetric relationship of volume exposed to the specified marker doses is much less clear and the bladder neck is included in the CTVp. Note that the DVH for the entire bladder should be recorded, but the bladder - CTVp is the volume that should be used for the calculations described here. An acceptable primary variation will be noted if up to an additional 7.5% of the bladder volume receives above the target doses specified. The inclusion of bladder volumes beyond these constraints will be considered an acceptable secondary protocol variation; it will not be considered a protocol violation. In some patients, the bladder will be relatively empty and the majority will be in the PTV.  
Femoral Heads: Less than or equal to 10% of each femoral head should receive ≥ 50 Gy. A
variation will be noted if up to an additional 5.0% of either femoral head receives > 50 Gy.  
Penile Bulb: The penile bulb will be outlined as a reference structure. No constraints will be placed on the penile bulb, but doses will be recorded.  
Small Bowel: See PLNRT section below.  
Use of Cone Beam CT and Plan Adjustment: There may be cases in which the target and surrounding normal tissues are found not to be reproducible relative to the simulation CT and consequent plan. Replanning will invalidate the dosimetry and is considered a deviation. If all attempts to reproduce bladder and rectal filling by coaching the patient do not work and replanning is thought to be necessary, the patient should be replanned in the same supine position with the same target volumes as specified per the randomization. The patient will remain on the trial, despite the deviation.  
6.4.3 Pelvic Lymph Node Radiotherapy (PLNRT) (11/23/11)
For Arm 3, the prostate bed and pelvic lymph nodes (CTVn/PTVn) will receive 45 Gy at 1.8 Gy per fraction. A total dose of 64.8–70.2 Gy at 1.8 Gy/fraction should be given to the prostate bed
(CTVp/PTVp). Planning and treatment of the pelvic lymph nodes must be using the same method (3DCRT or IMRT) as for the prostate bed.  
PLNRT Planning for 3D-CRT **(11/23/11)**)
The CTVn **will include the obturator, external iliac, proximal internal iliac and common iliac**
nodes, estimated using the vascular structures, **up to the level of L5-S1.** The recommended volumes are on the NRG Oncology/RTOG website under the "Core Lab/Contouring Atlases" menu
(**http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx**). The CTVn is described as being 7 mm around the iliac vessels, carving out bowel, bladder and bone, which translates into just contouring the iliac/obturator areas with essentially no extra margin because of the proximity to these structures (this is well-illustrated in the contouring Atlas). Thus, the PTVn margins described above are the margins that venture into the potential bowel space, bladder and bone. **The remainder of the CTVn, including the prostate bed and seminal** vesicle bed are as described above (Section 6.4.1). The CTVp will include the prostate bed
(64.8 - 70.2 Gy), as described for PBRT above. The PTVn and PTVp margins should be a minimum of 0.8 cm and a maximum of 1.5 cm in all dimensions. A reduction of the PTV margin from 0.8 cm to ≥ 0.6 cm to minimize rectal exposure will be considered an acceptable variation. A
posterior margin of < 0.6 cm will be considered an unacceptable deviation. A margin for penumbra (usually 0.5–0.7 cm beyond the PTVs for 3D-CRT) should be added such that ≥ 95% of the PTVs receive the prescribed dose; an acceptable variation will be noted if < 95% to 90% of either PTV receives the prescribed dose, and an unacceptable deviation will be noted if < 90% of the PTV receives the prescribed dose. The maximum dose in the PTVp (the PTVn is expected to have greater heterogeneity and no specific constraints are given) above the prescribed dose will be 7%; an acceptable variation will be > 7% to ≤ 12% and an unacceptable deviation >12%. The planned dose between 64.8 to 70.2 will be declared after the patient is planned and all dosimetric parameters finalized. A minimum of four treatment fields should be used.  
The normal tissue outlines will be the same as described in Section 6.4.1, with the added contouring of the potential space for small/large bowel in the pelvis. The potential bowel space will include the space on either side of the bladder to the medial edge of the lymph node outline laterally, beginning approximately at the top of the prostate bed field to one CT axial imaging level above the most superior level displaying a CTVn contour. Care should be taken to avoid the presacral lymph node region in the bowel volume. No constraints will be placed on the bowel for 3D-CRT planning.  
PLNRT Planning for IMRT **(11/23/11)**
The volumes, prescriptions and margins for the CTVns and PTVns will be the same as for 3DCRT and IMRT. The recommended volumes are on the NRG Oncology/RTOG website under the
"Core Lab/Contouring Atlases" menu
(**http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx**). No specific field arrangement is required, although typically 5-9 fields are used. Rotational IMRT
treatments are permitted, as long as the constraints are met (See Section 5.2). The posterior PTVn margin at the bladder neck-rectum interface should not include the entire width of the rectum. A composite plan should be generated showing that at least 95% of the PTVn and PTVp receive the prescribed dose; a variation acceptable will be noted if < 95% to 90% of the PTV(s)
receives the prescribed dose, and a deviation unacceptable will be noted if < 90% of the PTV(s)
receives the prescribed dose. The maximum dose within the PTVp (the PTVn is expected to have greater heterogeneity and no specific constraints are given), above the prescribed dose, will be 15%; an acceptable variation will be > 15% to ≤ 20% and an unacceptable deviation > 20%. The other dosimetric parameters for IMRT are the same as for PBRT, except for the addition of a small bowel constraint.  
Small/Large Bowel: The volume to be contoured is described in Section 6.4.3. For the patients receiving PLNRT, ≤ 150 cc of potential bowel space should receive ≥ 45 Gy. A variation will be noted if > 150 cc to 200 cc of potential small bowel space receives ≥ 45 Gy. A secondary variation will be noted if >200 cc receives >45 Gy (see Section 6.5.6). Since there are not protocol violations for bowel, treatment volumes should not be dramatically altered to adjust for bowel. In prior protocols, considerable bowel was in the field and patients tolerated treatment well. Thus, these constraints act as a guide.  
Overlap of the Bowel with the Prostate Bed PTV: This situation has been one of concern in cases where the high dose PTVp overlaps with loops of bowel. Since these patients have had prior surgery, bowel is not as mobile as for the patient with an intact prostate. However, it should be kept in mind that such compromises were not done in prior studies and that this should be an infrequent occurrence.  
Overlap of the Bowel with the Lymph Node PTV: No adjustments in the PTVn are permitted. Since the potential bowel contour abuts the lymph node CTV, there should be an overlap with the lymph node PTV(PTVn). The overlap is expected.  
Use of cone beam CT and plan adjustment: There may be cases in which the target and surrounding normal tissues are found to not be reproducible relative to the simulation CT and consequent plan. It should be emphasized that replanning should be avoided if at all possible because this will be considered a deviation. If the patient must be replanned in the opinion of the treating physician, then a deviation will be recorded, but continue to treat the patient per protocol in terms of dose and CTV/PTV volumes. The following table summarizes the naming of targets and critical structures for submission of data to NRG Oncology.  
Note: All required structures must be labeled as listed in the table below for digital RT data submission. Resubmission of data may be required if labeling of structures does not conform to the standard DICOM name listed.  
| Arms 1 and 2 Only                                                                                                                                                                                               |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CTVp PTVp Bladder BladdermCTV Rectum Femur_R Femur_L PenileBulb SeminalVesicle External Arm 3 Only CTVn CTVp PTVn PTVp Bladder BladdermCTV Rectum Femur_R Femur_L PenileBulb SmallBowel SeminalVesicle External |  
6.5 Critical Structures (12/10/13)
6.5.1 The critical normal structures are the bladder, rectum, small/large bowel above the rectum, and femoral heads. The normal tissues will be contoured and considered as solid organs.  
6.5.2 The bladder should be contoured from its base to the dome, excluding the CTVp (the CTVp includes the bladder neck).  
6.5.3 The rectum should be contoured from the anus (at the level of the ischial tuberosities) to the rectosigmoid flexure (this is roughly at about 10 cm) or for a maximum length of 15 cm if the sigmoid flexure if felt to be higher.  
6.5.4 Each femoral head should be outlined down to the interface between the greater and lesser trochanters. Each femoral head should be considered separately.  
6.5.5 For the patients who will undergo PLNRT treatment in Arm 3 using 3D-CRT or IMRT, the external iliac, obturator, internal iliac and common iliac vessels/lymph node regions should be outlined inferiorly from where the external iliacs become the inguinal vessels and superiorly from the level of the common iliacs at L5-S1. The presacral lymph nodes from L5-S1 to S3 should be included.  
6.5.6 For the patients who will undergo PLNRT treatment in Arm 3 using 3D-CRT or IMRT, the potential bowel space (not individual loops of bowel) where the small and large bowel may fall should be outlined. The borders are the abdominal wall anteriorly, pelvic sidewalls laterally (excluding the pelvic lymph node regions), superiorly to one cut above the last axial CT image on which the lymph nodes are outlined and inferiorly from the level of the top of CTVp (outlining around the sides of the bladder near the top of the bladder to encompass the bowel that may fall into these regions). Posteriorly, the small bowel potential space should extend to in front of the sacrum, abutting the anterior presacral nodal contours.  
6.5.7 The tissue within the skin and outside all other critical normal structures and PTV's is designated as unspecified tissue. See the NRG Oncology/RTOG web site at http://www.rtog,org to view examples of target and normal tissue contours.  
6.6 Documentation Requirements (12/31/14)
6.6.1 The institution will archive treatment prescription and verification images for later review by the study chair if requested. For conformal RT, at least one portal image or pretreatment alignment portal image per field along with the digital reconstructed radiographs (DRRs) from the treatment planning software or, alternatively, a simulation verification radiograph shall be acquired and kept for evaluation if requested except where geometrically impractical. For IMRT, at least one portal image from each orthogonal image along with the digital reconstructed radiographs (DRRs) from the treatment planning software shall be acquired and kept for evaluation. **Note**: Images are required to be taken but not submitted.  
6.6.2 NRG Oncology will display isodose distributions through the planning target volume to verify correct digital submission and conversion.  
6.6.3 NRG Oncology will compare the submitted DVHs for the PTV, designated critical structures, and unspecified tissues with DVHs calculated by NRG Oncology.
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6.7 compliance criteria (3d-crt and

6.7.1 Dose Heterogeneity 3D-CRT The maximum dose in the PTV above the prescribed dose will be 7%; an acceptable variation will be > 7% to ≤ 12% and an unacceptable deviation > 12 (see Section 6.4.1). IMRT The dose heterogeneity in IMRT treatment plans is greater than that for 3D-CRT. The maximum dose within the PTV, above the prescribed dose, will be 15%; an acceptable variation will be > 15% to ≤ 20% and an unacceptable deviation > 20%. Although, the maximum dose allowable in the PTV(s) will be 15% above the prescribed dose, it is possible in the vast majority of cases to achieve less than 15%.
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6.7.2 normal tissue deviations

3D-CRT No specific constraints for 3D-CRT are included, but the dose-volume criteria described for IMRT
below should be used as a guide. The dose volume histograms for the bladder, rectum, femoral heads, penile bulb, and small/large bowel (for Arm 3–PLNRT plans) should be included and the marker dose volumes when relevant (BladdermCTV, rectum each femoral head and small bowel) for IMRT should be recorded.  
IMRT (11/23/11)
Less than or equal to 35% and 55% of the rectum should receive ≥ 65 Gy and ≥ 40 Gy, respectively. Less than or equal to 50% and 70% of the bladder minus CTVp **(BladdermCTV)**
should receive ≥ 65 Gy and ≥ 40 Gy, respectively. The criteria for the bladder are relaxed because the dosimetric relationship of volume exposed to the specified marker doses is much less clear and the bladder neck is included in the CTVp. Less than or equal to 10% of each femoral head should receive ≥ 50 Gy. A variation acceptable will be noted if up to an additional 5.0% of either the femoral head receives > 50 Gy. For the patients receiving PLNRT, ≤ 150 cc of potential small/large bowel space should receive ≥ 45 Gy. A primary variation will be noted if > 150 cc to 200 cc of potential small/large bowel space receives ≥ 45 Gy. A secondary variation will be noted if > 200 cc of potential small/large bowel space receives ≥ 45 Gy.  
6.8 R.T. Quality Assurance Reviews (12/31/14)
6.8.1 The NRG Oncology Radiation Oncologist Study PI and Co-Chair will oversee quality assurance RT reviews as complete RT data is received. These case reviews will be ongoing and facilitated by NRG RTQA. The reviews will be performed remotely.  
6.8.2 Common Contouring Mistakes to Avoid CTVp (prostate bed): Do not follow European or Australian/New Zealand guidelines. The NRG
Oncology/RTOG guidelines should be followed very closely. Do not exclude the posterior bladder from the CTVp above the pubic symphysis (this is the Australian/New Zealand consensus, but not ours). The entire bladder neck is in the contour below the pubic symphysis; do not compromise this volume by excluding any bladder. The anterior border is the posterior aspect of the pubic symphysis.  
Pelvic Lymph Nodes: Do not leave out the presacral lymph nodes. Femoral Heads: Do not just contour the heads. The contours should extend down to the interface between the lesser and greater trochanters.  
Penile Bulb: Needs to be contoured.  
Bowel: Contour the space, not individual loops of bowel.  
6.9 **Radiation Adverse Events**
6.9.1 All patients will be seen weekly by their radiation oncologist during radiation therapy. Any observations regarding radiation reactions will be recorded and should include attention toward the following potential side effects:
- Small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal urgency, proctitis, or hematochezia;
- Bladder complications including urinary frequency/urgency, dysuria, hematuria, urinary tract infection, and incontinence;
- Radiation dermatitis.  
6.9.2 Clinical discretion may be exercised to treat side effects from radiation therapy as described in Section 9.1. Examples of typical medications used in the management of rectal side effects, such as diarrhea, include diphenoxylate or loperamide. Bladder or rectal spasms are usually treated with anticholinergic agents or tolterodine. Bladder irritation may be managed with phenazopyridine. Erectile dysfunction is often treated with medical management or mechanical devices.
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6.10 radiation adverse event reporting

See Section 7.7 for Adverse Events and 7.8 for Adverse Event Reporting Guidelines.
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7.0 drug therapy

(11/23/11) **Short term androgen deprivation (STAD) will be administered to patients randomized to**
Arms 2 and 3. STAD will begin, from the start of LHRH agonist injection, within 6 weeks **(+/-** 2 weeks) **after registration.**
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7.1 treatment (12/31/14)

7.1.1 Dose definition Short term androgen deprivation (STAD) will be administered to patients randomized to Arms 2 and 3, will begin from the start of LHRH agonist injection within 6 weeks after registration, and will consist of total androgen deprivation, using a combination of antiandrogen and LHRH agonist therapy for a total of 4-6 months. The antiandrogen will be either flutamide at 250 mg p.o. TID or bicalutamide at 50 mg p.o. QD. Antiandrogen therapy should begin at approximately the same time as LHRH agonist injection but may be started up to two weeks earlier (1-14 days prior to LHRH agonist injection). **The antiandrogen will be stopped on the last day of radiation** treatment ± 14 days, which should be approximately 4 months of antiandrogen therapy. LHRH
agonist injection will consist of analogs approved by the FDA (or by Health Canada for Canadian institutions), e.g., leuprolide, goserelin, buserelin, or triptorelin and may be given in any possible combination, such that the total LHRH treatment time is 4-6 months. For example, LHRH agonist injection(s) may be given as a single 4-month injection, a 4-month injection and one to two 1month injection(s), two 3-month injections, one to three 1-month and a 3-month injection (4-6 months total), four to six 1-month injections, or a 6-month injection.  
7.1.2 Duration of treatment As outlined above, STAD, when administered, will be for a duration of 4-6 months. Antiandrogen therapy will be given for approximately 4 months (started within 1-14 days prior to the LHRH
agonist and ending the last day of radiotherapy ± 14 days); LHRH agonists will be given for 4-6 months.  
7.1.3 Calcium and Vitamin D supplementation Patients who are randomized to receive androgen deprivation therapy are encouraged to take calcium at 500-1200 mg/day and vitamin D at 400-800 IU/day during androgen deprivation therapy; however, these supplements are not required.  
7.2 Study Agents: LHRH Agonists (11/23/11)
7.2.1 Description LHRH agonists are long-acting analogs of the native LHRH peptide and are effective at reducing serum testosterone. Analogs approved by the FDA (or by Health Canada for Canadian institutions) can be used in this study.  
7.2.2 Administration LHRH analogs are administered with a variety of techniques, including subcutaneous insertion of a solid plug in the abdominal wall (Zoladex), intramuscular injection (Lupron, Trelstar) or subcutaneous injection (Eligard).The manufacturer's instructions should be followed.  
7.2.3 Adverse Events Consult the package insert for comprehensive adverse event information. Class-related toxicity is generally a manifestation of the mechanism of action and due to low testosterone levels. In the majority of patients testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week of treatment. The most common side effect of LHRH analogs is vasomotor hot flashes; edema, gynecomastia, bone pain, thrombosis, and gastrointestinal disturbances have occurred. Potential exacerbations of signs and symptoms during the first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms. Other side effects include impotence and loss of libido, weight gain, depression, dizziness, loss of bone density, anemia, increased thirst and urination, unusual taste in the mouth, skin redness or hives, pain at injection site, muscle mass and strength loss, hair changes, penile length and testicular volume loss, increased cholesterol, hypertension, diabetes exacerbation, emotional lability, nausea, vomiting, and rarely allergic generalized rash and difficulty breathing.  
7.2.4 Storage LHRH analogs should be stored as directed by the commercial supplier.  
7.2.5 Supply Commercially available; Note: Buserelin is not commercially available in the United States. It is commercially available for use in Canada and other countries outside of the United States.  
7.3 **Eulexin (flutamide)**
7.3.1 Description Flutamide is a substituted anilide. It is a fine, light, yellow powder, insoluble in water but soluble in common organic solvents such as aromatic or halogenated hydrocarbons. Its concentration in plasma can be determined by gas chromatography. Flutamide is a nonsteroidal antiandrogen that is metabolized into a hydroxylated derivative, which effectively competes with the hydrotestosterone for androgen receptor sites.  
7.3.2 Administration The drug is administered orally at a dose of 250 mg (two 125-mg capsules) three times a day for a total daily dose of 750 mg. Flutamide will begin between two weeks to one day prior to starting LHRH agonist injection and will continue throughout radiotherapy. Administration will be suspended only if there is an apparent or suspected reaction to the drug. See Section 7.3.4.  
Flutamide will be terminated on the last day of radiotherapy. During radiotherapy interruptions, flutamide will be continued.  
7.3.3 Adverse Events Consult the package insert for comprehensive adverse event information. The reported side effects of treatment include diarrhea and anemia. A high percentage of patients treated with flutamide alone developed gynecomastia within 2 to 8 months. There have been post-marketing reports of hospitalization, and, rarely, death due to liver failure in patients taking flutamide.  
Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy, and death related to acute hepatic failure. The hepatic injury was reversible after prompt discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide. Other side effects include impotence and loss of libido, fatigue, and rarely photosensitivity.  
7.3.4 Dose Modifications If gastrointestinal disturbances (cramps, diarrhea) occur prior to initiation of radiotherapy, flutamide will be withheld until the side effects subside; the drug will then be reintroduced at a dose of 250 mg/day and increased (at 3-day intervals) to 500 mg/day and then to 750 mg/day as tolerated. If gastrointestinal disturbances occur after administration of radiotherapy, it might be difficult to identify their cause. However, if severity of diarrhea exceeds the level commonly observed during pelvic irradiation, the toxicity will be ascribed to flutamide and the drug will be permanently discontinued. AST or ALT will be measured pretreatment, then about every other month during oral antiandrogen therapy. If AST or ALT increases ≥ 2 x upper institutional limit of normal, flutamide must be discontinued.  
7.3.5 Storage Flutamide should be stored at temperatures ranging from 20-30 °C and protected from excessive moisture.  
7.3.6 Supply
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commercially available

7.4 Casodex (bicalutamide)
7.4.1 Description Bicalutamide is a nonsteroidal antiandrogen, which has no androgenic or progestational properties. The chemical name is propanamide, N-[4-cyano-3(trifluoromethyl)phenyl]- 3- [(4fluorophenyl)sulphonyl]- 2- hydroxy- 2- methyl, (+,-). Bicalutamide is a racemic mixture with the antiandrogen activity residing exclusively in the (-) or R-enantiomer. Bicalutamide has a long halflife compatible with once-daily dosing. Bicalutamide is well tolerated and has good response rates in phase II trials.  
7.4.2 Administration Bicalutamide is administered orally at a dose of one 50 mg tablet per day. Bicalutamide will be started from two weeks to one day prior to LHRH administration and continued throughout radiotherapy. Administration will be suspended only if there is an apparent or suspected reaction to the drug. **Bicalutamide will be terminated on the last day of radiotherapy.** During radiotherapy interruptions, bicalutamide will be continued.  
7.4.3 Adverse Events Consult the package insert for comprehensive toxicity information. In animal experiments, birth defects (abnormal genitalia, hypospadias) were found in male offspring from female animals dosed with bicalutamide during pregnancy. Although offspring from male animals dosed with bicalutamide did not show any birth defects, patients enrolled in this trial are advised not to cause pregnancy nor donate sperm while receiving protocol therapy or during the first 3 months after cessation of therapy. The use of barrier contraceptives is advised. The most frequent adverse events reported among subjects receiving bicalutamide therapy are breast tenderness, breast swelling, and hot flashes. When bicalutamide 50 mg was given in combination with an LHRH analog, the LHRH analog adverse event profile predominated with a high incidence of hot flashes
(53%) and relatively low incidences of gynecomastia (4.7%) and breast pain (3.2%). Other side effects include impotence and loss of libido, fatigue, and rarely photosensitivity and diarrhea.  
7.4.4 Dose Modifications Bicalutamide should be discontinued in instances of chemical liver toxicity. AST or ALT will be measured pretreatment and then every other month during antiandrogen therapy. If the AST or ALT rises ≥ 2 x the institutional upper limit of normal, bicalutamide must discontinued.  
7.4.5 Storage Bicalutamide should be stored in a dry place at room temperature between 68-77°F.  
7.4.6 Supply Commercially available 7.5 Criteria for Discontinuation of Protocol Treatment **(1/8/09)**
Protocol treatment may be discontinued for any of the following reasons:
- Progression of disease;
- Unacceptable adverse events at the discretion of the treating physician(s);
- A delay in protocol treatment > 8 weeks.  
If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol.  
7.6 **Modality Review**
The Principal Investigator/Radiation Oncologist, Alan Pollack, MD, PhD and the Urology Co-Chair, Leonard G. Gomella, MD will perform a Hormone Delivery Quality Review by sampling of patients who receive or are to receive hormone therapy in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of hormone therapy treatment data as specified in Section 12.1. The scoring mechanism is: **Per Protocol/Acceptable** Variation, Not Per Protocol, and Not Evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year.  
7.7 Adverse Events **(15-Jan-2019)**
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web site
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)
All adverse events (AEs) as defined in the table below (7.8) will be reported via the CTEP-AERS
(CTEP Adverse Event Reporting System) application accessed via the CTEP web site
(https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613).  
Serious adverse events (SAEs) as defined in the table below (7.8) will be reported via CTEPAERS.
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in order to ensure consistent

addition, sites must submit CRFs in a timely manner after CTEP-AERS submissions.  
7.7.1 **Adverse Events (AEs)**
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting Requirements. February 29, 2012; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 1800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report must be entered electronically into CTEP-AERS.  
7.7.2 **Serious Adverse Events (SAEs)** - Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in Section 7.8 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-AERS notification are defined in the expedited reporting table in Section 7.8. Contact the CTEP-AERS Help Desk if assistance is required.  
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in any of the following outcomes:
- Death;
- A life-threatening adverse drug experience;
- Inpatient hospitalization or prolongation of existing hospitalization;
- A persistent or significant disability/incapacity;
- A congenital anomaly/birth defect; - Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE, when, based upon medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, any pregnancy, including a male patient's impregnation of his partner, must be reported via CTEP-AERS in an expedited manner.
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7.7.3 acute myeloid leukemia (aml)

AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system within 30 days of AML/MDS diagnosis.
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secondary malignancy

A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
- Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])
- Myelodysplastic syndrome (MDS)
- Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.  
Second Malignancy A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified.
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7.8 ctep-aers expedited reporting requirements

All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1398715802346. Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG
Oncology requirements for expedited adverse event reporting.  
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 1800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report must be entered electronically into CTEP-AERS.  
- CTEP-AERS-24 Hour Notification requires that a 24-hour notification is electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 hour CTEP-AERS notification are defined in the expedited reporting table below.  
- Supporting source document is not mandatory. However, if the CTEP-AERS report indicates in the *Additional Information* section that source documentation will be provided, then it is expected. If supporting source documentation accompanies an CTEP-AERS
report, include the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and fax supporting documentation **to the dedicated SAE FAX, 215-717-**
0990.  
- A serious adverse event that meets expedited reporting criteria outlined in the following table but is assessed by the CTEP-AERS System as "expedited reporting NOT required" must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the "NOT Required" assessment; the CTEP-AERS System allows submission of all reports regardless of the results of the assessment.
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the table below. **Important:** All AEs reported via CTEP-AERS also must be reported on the AE
section of the appropriate case report form (see Section 12.1).  
Phase 2 and 3 Trials Utilizing Agents under a non-CTEP IND: CTEP-AERS Expedited Reporting Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose of the Commercially Available Agents **in this Study (Arms 2 & 3)**
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fda reporting requirements for serious

NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR
312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
| Grade 1          | Grade 2            | Grade 3          | Grade 4 & 5   |            |
|------------------|--------------------|------------------|---------------|------------|
| Hospitalization  | Timeframes         | Timeframes       | Timeframes    | Timeframes |
| Resulting in     |                    |                  |               |            |
| Hospitalization  | 10 Calendar Days   |                  |               |            |
| ≥ 24 hrs         | 24-Hour 5 Calendar |                  |               |            |
| Not resulting in | Days               |                  |               |            |
| Hospitalization  | Not required       | 10 Calendar Days |               |            |
| ≥ 24 hrs         |                    |                  |               |            |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
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expedited ae reporting timelines are

o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:
- All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
- Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
- Grade 3 adverse events 2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period.  
Effective Date: May 5, 2011
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additional instructions or exceptions to

All patients must have undergone radical prostatectomy prior to being considered for enrollment in this study. Any type of radical prostatectomy will be permitted, including retropubic, perineal, laparoscopic or robotically assisted. If performed, the number of lymph nodes removed per side of the pelvis and the extent of the pelvic lymph node dissection (obturator vs. extended lymph node dissection) should be noted.
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9.0 other therapy 9.1 permitted

All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication.  
9.1.1 Antidiarrheals Antidiarrheals, such as loperamide hydrochloride or diphenoxylate-atropine, may be used as needed. The amounts of the drug(s) and dates used should be documented as much as possible.  
9.1.2 Antispasmatics Antispasmatics, such as oxybutynin or tolterodine tartrate, may be used as needed. The amounts of the drug(s) and dates used should be documented as much as possible.  
9.1.3 Alpha Blockers Alpha blockers, such as doxazosin mesylate, terazosin hydrochloride or tamsulosin hydrochloride may be used as needed. The amounts of the drug(s) and dates used should be documented as much as possible.  
9.1.4 Analgesics Analgesics is a broad category, including non-narcotic and narcotic agents. The use of nonnarcotic agents, such as acetaminophen, non-steroidal anti-inflammatory agents or phenazopyridine hydrochloride for radiotherapy treatment-related pain should be documented as much as possible. Narcotic use as a consequence of treatment should also be recorded.  
9.1.5 Erectile Dysfunction Erectile dysfunction may be treated with medical management (e.g., phosphodiesterase inhibitors), vacuum pumps or other devices as appropriate. The amounts of the drug(s) used and the dates that medical management or the use of mechanical devices was started should be documented.  
9.2 **Treatment of Patients with Subsequent Disease Progression**
Treatment of patients who have failed salvage radiotherapy therapy by criteria described in Section 11 may receive additional medical or surgical therapies. The selection of these therapies will be left to the discretion of the treating physician.
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10.0 tissue/specimen submission (12/31/14) 10.1

The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through careful block storage and processing. NRG Oncology encourages participants in protocol studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides tissue specimens to investigators for translational research studies. Translational research studies integrate the newest research findings into current protocols to investigate important biologic questions. T
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of tissue banking for biomarker studies (highly recommended but not required).  
(3/31/09) Biomarker studies are being done on all NRG Oncology prostatic cancer protocols using the original diagnostic material. The emphasis has been on proliferation markers (e.g., DNAploidy, Ki-67), apoptotic pathway markers (e.g., p53, MDM2, bcl-2, bax, p16), and angiogenesis markers (e.g., COX-2, VEGF) [See Section 1.4]. These markers have shown promise in predicting prostate cancer patient outcome after definitive radiotherapy. A final decision on which markers will be studied awaits the results of completed NRG Oncology prostate cancer trials that have reached maturity (e.g., 86-10, 92-02, 94-13). The trial described here will not be ready for biomarker analysis for several years, with the exception of the Abeta analysis in serum, which will be conducted in conjunction with cognitive outcomes, for those who participate in the neurocognitive battery testing. The goal is to measure approximately 5-10 biomarkers using the archived pathologic material.
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10.2 specimen collection for tissue

10.2.1 Sites may submit the following specimens:
(22Jun2017) An H&E stained slide (can be a duplicate cut slide, does not have to be a diagnostic slide) and corresponding paraffin-embedded tissue block of the tumor (preferred) or at least 10 unstained 5 micron sections on positively charged slides. If tumor heterogeneity is observed, the submission of multiple blocks, including tissue from the area having the highest Gleason score, is desirable. **Note:** Tissue block or slides must be clearly labeled with the pathology identification number that corresponds to the Pathology Report.  
The following must be provided in order for the case to be evaluable for the Biospecimen Bank:
- A Pathology Report documenting that the submitted block contains tumor. The report must include the NRG Oncology protocol number and patient's case number. The patient's name and/or other identifying information should be removed from the report.  
The surgical pathology numbers and information must NOT be removed from the report.  
- A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG
Oncology Biospecimen Bank; if for translational research, this should be stated on the form. The form must include the NRG Oncology protocol number and patient's case number.  
Serum, plasma, whole blood, and urine See Appendix IV for the blood and urine collection kits and instructions. **Note**: Kits include a label for shipping.  
The following must be provided in order for the case to be evaluable for the Biospecimen Bank: A
Specimen Transmittal Form (STF) documenting the date of collection of the serum, plasma, whole blood, and/or urine; the NRG Oncology protocol number, the patient's case number, and method of storage, for example, stored at -80° C, must be included.  
Specimen Collection Summary  
| Specimen Collection for Tissue Banking                                                                                                                                                         |                                                                                                              |                                                                                                                       |                                                                                             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|
| Specimens taken from                                                                                                                                                                           | Collected when:                                                                                              | Submitted as:                                                                                                         | Shipped:                                                                                    |
| patient: Representative H&E stained                                                                                                                                                            | Pretreatment                                                                                                 | H&E stained slide                                                                                                     | Slide shipped ambient                                                                       |
| slides of the primary tumor A paraffin-embedded tissue  block or 3mm punches from  block or 10-15 unstained slides  on plus slides of the primary  tumor taken before initiation of  treatment | Pretreatment                                                                                                 | Block or unstained slides or one to two 3mm punch  biopsies from FFPE block                                           | Block or unstained slides  shipped ambient                                                  |
| SERUM: 5-10 mL of whole blood                                                                                                                                                                  | Pretreatment                                                                                                 |                                                                                                                       |                                                                                             |
| in 1 red-top tube and centrifuge                                                                                                                                                               | Week 6 of RT 3, 6, 12 months (±1  month) after end of  RT; then yearly for 6  years (±2 months)              | Frozen serum samples  containing 0.5 mL per  aliquot in 1 mL cryovials  (five )                                       | Serum sent frozen on  dry ice via overnight  carrier                                        |
| PLASMA: 5-10 mL of  anticoagulated whole blood in  EDTA tube #1 (purple/ lavender  top) and centrifuge                                                                                         | Pretreatment Week 6 of RT 3, 6, 12 months (±1  month) after end of  RT; then yearly for 6  years (±2 months) | Frozen plasma samples  containing 0.5 mL per aliquot in 1 mL cryovials (five )                                        | Plasma sent frozen on  dry ice via overnight  carrier                                       |
| DNA: 5-10 mL of anticoagulated  whole blood in EDTA tube #2 (purple/ lavender top) and mix                                                                                                     | Pretreatment                                                                                                 | Frozen whole blood                                                                                                    |                                                                                             |
| Week 6 of RT                                                                                                                                                                                   | samples containing 1 ml per aliquot in 1ml  cryovials (three to five)                                        | Whole blood sent frozen  on dry ice via overnight  carrier                                                            |                                                                                             |
| 10-20 mL clean-catch urine                                                                                                                                                                     | Pretreatment Week 6 of RT and  Post-treatment at Year 5 after end of  RT (±2 months)*                        | One-two 5-10 mL urine  aliquots in 1-2 sterile 15  ml polypropylene  centrifuge tube.  Store frozen at  -20 or 80 C | Urine sent frozen on dry  ice via overnight carrier in batches. Do not ship  in Urine Cups. |  
* Effective with amendment 6, urine will be collected only at year 5 after completion of RT. If sites collected urine at other timepoints (3, 6, and 12 months after RT, and yearly between 12 months and 5 years) prior to this change they should still submit them to the tis sue bank.  
10.2.2 Storage Conditions **(10/22/09)**
Store at-80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:
- Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only).  
OR:
- Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out Monday-Wednesday only).  
OR:
- Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only).
Please indicate on Specimen Transmittal Form the storage conditions used and time stored.  
10.2.3 Submit materials for Tissue Banking as follows:
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank- **San Francisco**
University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, **etc.): For Frozen Specimens**
NRG Oncology Biospecimen Bank- San Francisco University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Questions: 415-476-7864/FAX 415-476-5271; RTOG@ucsf.edu 10.3 Confidentiality/Storage (15-Jan-2019)
10.3.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient's case number only. The NRG Oncology Biospecimen Bank database only includes the following information: the number of specimens received, the date the specimens were received, documentation of material sent to a qualified investigator, type of material sent, and the date the specimens were sent to the investigator. No clinical information is kept in the database.  
10.3.2 Specimens for tissue banking will be stored for an indefinite period of time. If at any time the patient withdraws consent to store and use specimens, the material will be returned to the institution that submitted it.
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11.0 patient assessments 11.1 study

11.2 Evaluation During Treatment **(11/23/11)**
Radiotherapy for Arm 1 begins within 6 weeks (+/- 2 weeks) after registration. Radiotherapy for Arms 2 and 3 begins 2 months after the start of STAD (+/- 2 weeks).  
11.2.1 Prior to radiotherapy
- The AUA SI questionnaire should be administered to all patients prior to protocol treatment.  
For patients on Arms 2 and 3, the AUA SI questionnaire should be administered within 2 weeks of starting RT.  
- For all patients, including those on androgen deprivation (Arms 2 and 3), the following lab evaluations should be done within 30 days prior to starting treatment: CBC, AST or ALT, PSA,
and testosterone. For patients on Arms 2 and 3, these same labs should be drawn within 2 weeks of starting RT.  
- **(3/31/09)** The QOL measures (EPIC, HSCL-25, EQ-5D, and Utilization of Sexual Medications and/or Devices), the neurocognitive test battery (HVLT-R, Trail Making Test Parts A & B, and COWAT), and serum for biomarkers, including Beta Amyloid, will be obtained at pretreatment
(baseline), if the patient has consented to participate in these components of the study. **Note**:
Participation in the neurocognitive test battery is optional for the institution as well as the patient. Institutions participating in the neurocognitive test battery must follow the certification process (See Section 11.9.5 and Appendix V).  
11.2.2 During radiotherapy Patients will be seen and evaluated at least weekly during radiation therapy with documentation of performance status and tolerance, including acute reactions.  
- During week 6 of RT, a CBC, AST or ALT, and testosterone should be obtained. - During week 6 of RT, the AUA SI questionnaire should be administered.  
- **(3/31/09)** The QOL measures (EPIC, HSCL-25, EQ-5D, and Utilization of Sexual Medications and/or Devices), the neurocognitive test battery (HVLT-R, Trail Making Test Parts A & B, and COWAT), and serum for Beta Amyloid also should be obtained during week 6 of RT, if the patient has consented to participate in these components of the study. **Note**: Participation in the neurocognitive test battery is optional for the institution as well as the patient. Institutions participating in the neurocognitive test battery must follow the certification process (See Section 11.9.5 and Appendix V).  
- If the patient has consented to participate in the tissue/blood component of the study, blood
(serum, plasma, and whole blood) and urine will be collected during week 6 of RT.  
11.3 Evaluation Following Radiotherapy **(11/16/15)**
11.3.1 At each follow-up visit (3, 6, and 12 months in year 1; q 6 months x 6 years, yearly thereafter unless otherwise indicated; all visits are +/-1month for two years and then +/-2 months thereafter),
the patient will have an interval history, physical examination (including digital rectal examination),
assessment of specific GU and GI toxicity, and the AUA SI questionnaire will be administered.  
11.3.2 The following lab evaluations will be done:
- PSA will be drawn at 1.5 months (+/-2 weeks), 3 months (+/-1 month), 6 months (+/-1 month),
9 months (+/-1 month) and 12 months (+/-1 month) after radiotherapy, at 3 month intervals
(+/-1 month) for the next year. The type of PSA assay (e.g., Abbott) should be recorded on the data forms.  
- If the PSA is ≤ 0.1 ng/mL, PSA will be drawn as described in Section 11.3.2 and at 6-month intervals thereafter (+/-2 months).  
- If the PSA is ≥ 0.2 ng/mL, then PSAs should be obtained at 3-month intervals (+/-1 month)
until the PSA is ≤ 0.1 ng/mL or greater than the nadir+2 ng/mL. If the PSA reverts to undetectable, then the frequency of PSAs will revert to that described in Section 11.3.2. Salvage therapy should **not be initiated prior to the time at which the nadir+2 ng/mL**
endpoint is reached.  
- If the PSA is ≥ 0.2 ng/mL, then follow-up visits should continue at 6-month intervals until the PSA is greater than the nadir+2 ng/mL. Salvage therapy should not be initiated prior to the time at which the nadir+2 ng/mL endpoint is reached.  
- Serum testosterone will be obtained with each PSA measurement. - AST or ALT will be obtained at 1.5 (+/-2 weeks), 3 (+/-1 month), and 6 months (+/-1 month)
after radiotherapy.  
- A CBC will be performed at 3 and 6 months (+/-1 month) after completion of RT.  
11.3.3 The patient should be followed at 3-month intervals (+/-1 month) if ≥ grade 2 GI or GU
complications are present, unless these symptoms have been present for more than 6 months and are not changing.  
11.3.4 A bone scan and CT scan of the abdomen and pelvis will be performed as clinically indicated, such as if the patient develops a PSA recurrence with a doubling time < 10 months or if the patient develops symptoms suggesting the presence of metastatic disease.  
11.3.5 If the patient has consented to participate in the tissue/blood/urine component of the study, specimens are collected after completion of RT per Section 10 and Appendix IV.11.3.6
(3/31/09) If the patient has consented to participate in the QOL and neurocognitive component of the study, the QOL measures (EPIC, HSCL-25, EQ-5D, and Utilization of Sexual Medications and/or Devices) should be obtained at 1 and 5 years post-RT (+/-2 months). The neurocognitive test battery (HVLT-R, Trail Making Test Parts A & B, and the COWAT) should be obtained at 1 and 5 years post-RT (+/-2 months). **Note**: Participation in the neurocognitive test battery is optional for the institution as well as the patient. Institutions participating in the neurocognitive test battery must follow the certification process (See Section 11.9.5 and Appendix V).
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11.4 criteria for freedom from

The primary endpoint is FFP, which includes biochemical (PSA) failure, clinical failure, and death from any cause.  
11.4.1 Biochemical (PSA) Failure The biochemical failure endpoint is defined according to the proposed new Radiation Therapy Oncology Group/American Society for Therapeutic Radiology and Oncology (RTOG-ASTRO) criteria (see Section 1.3), also known as the Phoenix definition. The Phoenix definition is an increase of the PSA level at least 2 ng/mL above the minimum level reached after therapy.43 Since the patients in this trial are status-post radical prostatectomy, about 70-80% will achieve an undetectable PSA. In these cases, a PSA of 2 ng/mL is evidence of biochemical failure. All PSA
levels done during a follow-up interval will be recorded on the data forms. The initiation of further "salvage" therapy in any form (e.g., androgen deprivation therapy, vaccine therapy, or chemotherapy) after completion of protocol treatment and prior to nadir + 2 ng/mL failure will not be counted as a failure and is strongly discouraged. The success of the trial depends upon allowing the nadir + 2 ng/mL failure criteria to be met before any other therapeutic
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intervention.

11.4.2 Clinical Failure Clinical failure is defined as any evidence of local, regional or distant failure.  
11.4.3 Time to FFP
Time to FFP will be measured from the date of randomization to the date of documented biochemical failure by the Phoenix definition, clinical failure, or death from any cause.  
11.5 **Criteria for Local Failure**
11.5.1 Local Failure Local failure is defined as the development of a new palpable abnormality in the prostate bed after enrollment in the protocol. The presence of a palpable abnormality in the prostate bed prior to randomization is not permitted unless it is biopsy proven to be negative for cancer. Needle biopsy is recommended for any new palpable abnormality. Patients who have a normal exam and no evidence of biochemical failure by the primary endpoint will be considered controlled locally.  
Patients with a new prostatic fossa abnormality and biochemical failure will be considered to have local failure. Patients with a new prostatic fossa abnormality and no evidence of biochemical failure should undergo prostatic fossa biopsy. If salvage therapy is instituted prior to biopsy of a new prostatic fossa abnormality, then these patients will be considered to have had local failure.  
The presence of palpable disease must be recorded on the data collection forms for follow-up evaluations of the patient.  
11.5.2 Biopsy of any new palpable abnormality in the prostatic fossa is recommended to document by histologic criteria the presence of prostatic adenocarcinoma.