A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy With or Without Short-Term Androgen Deprivation Therapy for Patients With Intermediate-Risk Prostate Cancer
Phase: PHASE3
Conditions: Prostate Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 0815 
 
(ClinicalTrials.gov NCT #: 00936390) 
 
 
A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF DOSE-
ESCALATED RADIOTHERAPY WITH OR WITHOUT SHORT-TERM 
ANDROGEN DEPRIVATION THERAPY FOR PATIENTS WITH 
INTERMEDIATE-RISK PROSTATE CANCER 
 
Amendment 4:  April 21, 2015 

 
1 
 
 
RTOG 0815, Version Date April 21, 2015 
 
NRG ONCOLOGY 
 
RTOG 0815 
 
A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF DOSE-ESCALATED 
RADIOTHERAPY WITH OR WITHOUT SHORT-TERM ANDROGEN DEPRIVATION 
THERAPY FOR PATIENTS WITH INTERMEDIATE-RISK PROSTATE CANCER 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the National 
Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network of NCTN 
organizations: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Medical Research Group, and SWOG. 
 
Study Chairs (5/23/12) 
Principal Investigator/Radiation Oncology 
Alvaro A. Martinez, MD, FACR 
21st Century Oncology of Michigan 
A Division of Michigan Healthcare Professionals 
St. Joseph Mercy Hospital Campus 
70 Fulton Street 
Pontiac, MI 48341 
Phone: 248-553-0606/Fax: 248-338-0663 
E-mail: Alvaro.Martinez@rtsx.com 
External Beam Radiotherapy Co-Chair 
Daniel J. Krauss, MD 
William Beaumont Hospital 
Department of Radiation Oncology 
3601 W. Thirteen Mile Road 
Royal Oak, MI  48009 
Phone: 248-551-3576/Fax: 248-551-0089 
E-mail: dkrauss@beaumont.edu 
Low Dose Rate Brachytherapy Co-Chair 
Gerard Morton, MD 
Toronto-Sunnybrook Regional Cancer Center 
Department of Radiation Oncology 
2075 Bayview Ave. 
Toronto, ON M4N 3M5    CANADA 
Phone: 416-480-6165/Fax: 416-480-6002 
E-Mail: gerard.morton@sunnybrook.ca 
Medical Physics Co-Chair 
Di Yan, PhD 
William Beaumont Hospital 
3601 W. Thirteen Mile Road 
Royal Oak, MI  48009 
Phone: 248-551-6589/Fax: 248-551-3784 
E-mail: dyan@beaumont.edu 
 
Outcomes/Utility Co-Chair 
Deborah Watkins Bruner, PhD, RN, FAAN 
Emory University 
Nell Hodgson Woodruff School of Nursing 
1520 Clifton Road, Room 232 
Atlanta, GA 30322 
Phone: 404-712-9695/Fax: 404-727-8514 
E-mail: deborah.w.bruner@emory.edu 
Quality of Life Co-Chair 
Benjamin Movsas, MD 
Henry Ford Health System 
2799 W. Grand Boulevard 
Detroit, MI 48202 
Phone: 313-916-5188/Fax: 313-916-3235 
E-mail: bmovsas1@hfhs.org 
Fatigue Co-Chair 
Mohamed Elshaikh, MD 
Henry Ford Health System 
Department of Radiation Oncology 
2799 W. Grand Boulevard 
Detroit, MI 48202 
Phone: 313-916-3779/Fax: 313-916- 3235 
E-mail: MELSHAI1@hfhs.org 
Translational Research Co-Chair 
Deborah Citrin, MD 
Radiation Oncology Branch 
National Cancer Institute 
10 CRC, B2-3500 
10 Center Drive 
Bethesda, MD 20892 
Phone: 301-496-5457/Fax: 301-480-5439 
E-mail: citrind@mail.nih.gov 
Senior Statistician 
Chen Hu, PhD 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
Phone: 215-940-8842/Fax: 215-928-0153 
E-mail: huc@nrgoncology.org 
 
 
 
 
 
(RTOG 0815 details continued on next page) 
 

 
2 
 
 
RTOG 0815, Version Date April 21, 2015 
 
NRG ONCOLOGY 
 
RTOG 0815 
 
A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF DOSE-ESCALATED 
RADIOTHERAPY WITH OR WITHOUT SHORT-TERM ANDROGEN DEPRIVATION 
THERAPY FOR PATIENTS WITH INTERMEDIATE-RISK PROSTATE CANCER 
 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure 
- 
March 7, 2016 
Amendment 4 
April 21, 2015 
June 8, 2015 
Update 
April 29, 2014 
April 29, 2014 
Update 
November 14, 2013 
November 14, 2013 
Amendment 3 
May 23, 2012 
August 2, 2012 
Update 
January 11, 2011 
January 11, 2011 
Amendment 2 
December10, 2010 
January 11, 2011 
Amendment 1 
August 17, 2010 
January 11, 2011 
Update 
September 17, 2009 
September 17, 2009 
Update 
September 14, 2009 
September 14, 2009 
Activation 
September 14, 2009 
September 14, 2009 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
Bicalutamide 
Commercial 
N/A 
N/A 
Flutamide 
Commercial 
N/A 
N/A 
Leuprolide  
Commercial 
N/A 
N/A 
Goserelin 
Commercial 
N/A 
N/A 
Buserelin* 
Commercial  
N/A 
N/A 
Triptorelin 
Commercial 
N/A 
N/A 
Degarelix 
Commercial 
N/A 
N/A 
*Buserelin is not commercially available in the United States. 
 
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. 

 
3 
 
 
RTOG 0815, Version Date April 21, 2015 
 
NRG ONCOLOGY 
 
RTOG 0815 
 
A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF DOSE-ESCALATED 
RADIOTHERAPY WITH OR WITHOUT SHORT-TERM ANDROGEN DEPRIVATION 
THERAPY FOR PATIENTS WITH INTERMEDIATE-RISK PROSTATE CANCER 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION (4/21/15) 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  
directly to the Lead 
Cooperative Group 
unless otherwise 
specified in the 
protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-CTSU 
Fax: 215-569-0206 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient enrollment 
section (Section 5.0) for instructions on 
using the OPEN system, which can be 
accessed at 
https://www.ctsu.org/OPEN_SYSTEM/  
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. 
   
The study protocol and all related forms and 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 Program - Identity 
and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM 
username and password. 
For patient eligibility: Contact the NRG Oncology Research Associate for Protocol, Data 
Management section at 215-574-3214. 
For treatment-related questions: Correspond by e-mail (preferred) or by phone with the study chair 
designated on the protocol cover page. 
For questions unrelated to patient eligibility, treatment, or 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.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
 

 
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RTOG 0815, Version Date April 21, 2015 
 
TABLE OF CONTENTS 
 
 
SCHEMA ....................................................................................................................................................................6 
1.0 
INTRODUCTION ......................................................................................................................................... 11 
1.1 
Background and Rationale ...................................................................................................................... 11 
1.2 
The Influence of Short-Term Androgen Deprivation Therapy on Health-Related Quality of Life (HRQOL), 
Fatigue, and Quality-Adjusted Survival (QAS) in Patients With Intermediate-Risk Prostate Cancer Receiving 
Dose-Escalated Radiotherapy ............................................................................................................................. 12 
1.3  
Correlation of Circulating Proinflammatory Cytokines to Fatigue in Patients Undergoing Radiotherapy 
for Prostate Cancer .............................................................................................................................................. 14 
2.0 
OBJECTIVES .............................................................................................................................................. 15 
2.1 
Primary..................................................................................................................................................... 15 
2.2 
Secondary ................................................................................................................................................ 16 
3.0 
PATIENT SELECTION ................................................................................................................................ 16 
3.1 
Conditions for Patient Eligibility ............................................................................................................... 16 
3.2 
Conditions for Patient Ineligibility ............................................................................................................. 17 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT .................................................................................. 17 
4.1 
Required Evaluations/Management ........................................................................................................ 18 
4.2 
Highly Recommended Evaluations/Management ................................................................................... 18 
5.0 
REGISTRATION PROCEDURES ............................................................................................................... 18 
Access requirements for OPEN and TRIAD ........................................................................................................ 18 
5.1 
Pre-Registration Requirements for IMRT Treatment Approach .............................................................. 18 
5.2 
Pre-Registration Requirements for 3DCRT Treatment Approach ........................................................... 18 
5.3 
Pre-Registration Requirements for Brachytherapy Treatment Approach ................................................ 19 
5.4 
Digital RT Data Submission to NRG Oncology Using TRIAD ................................................................. 19 
5.5 
Regulatory Pre-Registration Requirements ............................................................................................. 20 
5.6 
Registration .............................................................................................................................................. 21 
6.0 
RADIATION THERAPY ............................................................................................................................... 22 
6.1 
Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT ..................................................... 22 
6.2 
Technical Factors .................................................................................................................................... 23 
6.3 
EBRT Localization, Simulation, and Immobilization ................................................................................ 23 
6.4 
Treatment Planning/Target Volumes ....................................................................................................... 23 
6.5 
Critical Structures .................................................................................................................................... 24 
6.6 
Treatment Verification .............................................................................................................................. 25 
6.7 
Quality Assurance .................................................................................................................................... 25 
6.8  
Dose Specifications/Technical Considerations: LDR Brachytherapy Boost ............................................ 26 
6.9  
Dose Specifications/Technical Considerations: HDR Brachytherapy Boost ........................................... 27 
6.10 
Radiation Quality Assurance Reviews ..................................................................................................... 29 
6.11 
Radiation Adverse Events ....................................................................................................................... 29 
6.12 
Radiation Adverse Event Reporting ........................................................................................................ 29 
7.0 
DRUG THERAPY ........................................................................................................................................ 29 
7.1 
Anti-Androgen Therapy: Casodex (Bicalutamide) ................................................................................... 29 
7.2  
Anti-Androgen Therapy: Eulexin (Flutamide) .......................................................................................... 30 
7.3  
LHRH Agonist (Antagonist) Therapy (leuprolide, goserelin, buserelin, triptorelin, degarelix) ................. 31 
7.4 
Modality Review ....................................................................................................................................... 31 
7.5 
Adverse Events ........................................................................................................................................ 32 
7.6 
CTEP-AERS Expedited Reporting Requirements ................................................................................... 33 
8.0 
SURGERY ................................................................................................................................................... 35 
9.0 
OTHER THERAPY ...................................................................................................................................... 35 
9.1 
Permitted Supportive Therapy ................................................................................................................. 35 
10.0 
TISSUE/SPECIMEN SUBMISSION ............................................................................................................ 35 
10.1 
Tissue/Specimen Submission ................................................................................................................. 35 
10.2 
Specimen Collection for Tissue Banking and Translational Research (Recommended) ........................ 35 
10.3 
Reimbursement ....................................................................................................................................... 37 

 
5 
 
 
RTOG 0815, Version Date April 21, 2015 
 
10.4 
Confidentiality/Storage............................................................................................................................. 37 
11.0 
 PATIENT ASSESSMENTS......................................................................................................................... 37 
11.1 
Study Parameters .................................................................................................................................... 37 
11.2 
Measurement of Response ..................................................................................................................... 38 
11.3 
Criteria for Discontinuation of Protocol Treatment .................................................................................. 38 
11.4  
Health-Related Quality of Life (HRQOL) ............................................................................................. 38 
12.0 
DATA COLLECTION ................................................................................................................................... 39 
12.1 
Summary of Data Submission ................................................................................................................. 40 
12.2 
Summary of Dosimetry Digital Data Submission ..................................................................................... 40 
13.0 
STATISTICAL CONSIDERATIONS ............................................................................................................ 41 
13.1 
Study Endpoints ....................................................................................................................................... 41 
13.2 
Sample Size ............................................................................................................................................. 42 
13.3  
Accrual and Duration ........................................................................................................................... 42 
13.4  
Analysis Plan ....................................................................................................................................... 42 
13.5 
Gender and Minorities ............................................................................................................................. 47 
REFERENCES ........................................................................................................................................................ 49 
APPENDIX I ............................................................................................................................................................. 53 
APPENDIX II ............................................................................................................................................................ 56 
APPENDIX III ........................................................................................................................................................... 57 
APPENDIX IV .......................................................................................................................................................... 60 
 

 
6 
 
 
RTOG 0815, Version Date April 21, 2015 
 
NRG ONCOLOGY 
 
RTOG 0815 
 
A Phase III Prospective Randomized Trial of Dose-Escalated Radiotherapy With or Without Short-Term 
Androgen Deprivation Therapy for Patients With Intermediate-Risk Prostate Cancer 
 
SCHEMA 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
Number of Risk Factors* 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm 1 
1. One risk factor 
Dose-escalated RT alone 
2. Two or 3 risk factors 
 
 
Comorbidity Status 
1. ACE-27** grade ≥ 2  
2. ACE-27 grade < 2 
 
RT Modality 
Arm 2 
1. Dose-escalated EBRT 
Dose-escalated RT combined with short-  
2. EBRT + LDR brachytherapy boost 
term (6 months) androgen blockade (LHRH 
3. EBRT + HDR brachytherapy boost 
agonist + antiandrogen) 
 
 
 
 
*Intermediate risk factors: Gleason Score 7***; PSA >10 but ≤20; T-Stage T2b-T2c. Patients with 
all three intermediate risk factors and ≥ 50% of their sampled biopsy cores involved will not be 
eligible for this study. Note: The percentage of biopsy cores involved will only be considered 
with respect to eligibility for those patients with all 3 of the above risk factors (i.e., patients with 
one or two of the above risk factors are eligible irrespective of the percentage of biopsy cores 
involved). 
 
**The “untreated malignancy” section of the ACE-27 form is to be disregarded with respect to 
the patient’s newly diagnosed, untreated prostate cancer. 
 
***Patients with Gleason score > 8, PSA > 20, or clinical stage > T2c are ineligible for this study. 
 
See pre-registration requirements in Section 5.0.  
 
Note: To be used on this protocol, low-dose rate brachytherapy sources must be listed on the joint RPC/AAPM 
source registry at http://rpc.mdanderson.org/rpc. Select “Brachy Sources/Source Registry”. 
 
Note: As this protocol allows for treatment with exclusively EBRT or EBRT + brachytherapy (at the discretion of 
the treating physician), this must be specified at the time of study enrollment. Should a patient who was originally 
intended to receive brachytherapy be found, post-enrollment, to be a poor brachytherapy candidate based on 
transrectal ultrasound examination, he will no longer be eligible for participation in this study. Therefore, it is 
strongly recommended to obtain ultrasound assessment of prospective brachytherapy patients before 
enrollment on this study.  
 
Patient Population:  (See Section 3.0 for Eligibility) [11/14/13] 
Clinically localized, lymph node negative adenocarcinoma of the prostate diagnosed within 6 months* prior to 
registration at intermediate risk for recurrence as determined by harboring one or more of the following 
intermediate-risk features: Gleason Score 7; PSA >10 but ≤20; Clinical Stage T2b-T2c.  
 
*Patients previously diagnosed with low risk (Gleason score ≤ 6, clinical stage < T2a, and PSA < 10) prostate 
cancer undergoing active surveillance who are re-biopsied and found to have intermediate risk disease according 
to the protocol criteria are eligible for enrollment within 6 months of the repeat biopsy procedure  
 
Required Sample Size: 1520 

 
7 
 
 
RTOG 0815, Version Date April 21, 2015 
 
  
 
 
NRG Oncology Institution #   
 
RTOG  0815 
 
 
 
ELIGIBILITY CHECKLIST (5/23/12)  
Case #  
 
 
 
     (page 1 of 4) 
 
1. ______ (Y) Is there pathologic (histological) proven diagnosis of intermediate risk prostatic adenocarcinoma within 
180 days prior to registration? 
2. ______ (Y) Is the patient’s prostate cancer considered at intermediate risk for recurrence by presenting with one or 
more of the following: 
____ (N/Y) Gleason Score 7 
____ (N/Y) PSA > 10 but ≤ 20 
____ (N/Y) T-Stage: T2b-T2c 
3. ______ (Y/NA) Does the patient have clinically negative (N0) lymph nodes as defined by pelvic +/- abdominal CT or 
MRI, nodal sampling, or dissection within 60 days prior to registration? 
4. ______ (Y/N/NA) Is there no evidence of bone metastases (M0) on a bone scan performed 60 days prior to 
registration? 
 
5. ______ (Y) Has the patient had a history/physical examination within 60 days of registration to include the following:  
 
digital rectal examination of the prostate 
 
formal comorbidity assessment via the ACE-27 
6. ______ (Y) Is Zubrod Performance Status 0-1? 
7. ______ (Y) Is the patient ≥ 18 years old? 
8.______ (Y) Has the baseline serum PSA value been performed with an FDA-approved assay (e.g., Abbott, Hybritech) 
 within 60 days prior to registration? 
9.   ______ (Y/NA) For patients undergoing brachytherapy, has the CBC/differential been obtained within 60 days prior to  
 
 
registration with adequate bone marrow function defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3 
 
Platelets ≥ 100,000 cells/mm3 
 
Hemoglobin (HGB) ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve HGB 
≥ 8.0 g/dl is acceptable)?  
10. ______ (N) Does the patient have any of the following risk factors:  
 
Gleason Score ≥ 8 
 
PSA > 20 
 
T-Stage: ≥T3?  
11. ______ (N/NA) If the patient has three intermediate risk factors, are ≥50% of the number of biopsy cores positive for  
 
 
 
cancer? 
12. ______ (N) Does the patient have prior history of invasive (carcinoma in situ is allowed) malignancy (except non- 
melanomatous skin cancer) or hematological (e.g., leukemia, lymphoma, myeloma) malignancy unless 
disease free for a minimum of 5 years? 
(Continued on the next page) 

 
8 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
 
 
NRG Oncology Institution #   
 
RTOG  0815 
 
 
 
ELIGIBILITY CHECKLIST (12/10/10) 
Case #  
 
 
 
     (page 2 of 4) 
 
13. ______ (N) Has the patient had prior radical surgery (prostatectomy), high-intensity focused ultrasound (HIFU), or  
 
cryosurgery for prostate cancer? 
14. ______ (N) Has the patient received prior hormonal therapy, such as LHRH agonists (e.g. goserelin, leuprolide),  
 
antiandrogens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or bilateral orchiectomy? 
15. ______ (N) Has the patient used finasteride within 30 days prior to registration? 
16. ______ (N) Has the patient used dutasteride within 90 days prior to registration? 
17. ______ (N) Has the patient received prior or concurrent cytotoxic chemotherapy for prostate cancer (prior  
chemotherapy for a different cancer is permitted)? 
 
 
 
18. ______ (N) Has the patient received prior radiotherapy, including brachytherapy, to the region of the study cancer that  
would result in overlap of radiation therapy fields? 
19. ______ (N) Is there prior history of a TURP for patients receiving brachytherapy? 
20. ______ (N) Does the patient have any of the following conditions: 
 
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 (COPD) exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 days of registration 
 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects 
 
AIDS (based on current CDC definition) 
21. ______ (N) Is the patient sexually active with a woman of childbearing potential and not willing/able to use medically  
 
acceptable forms of contraception (e.g., surgical, barrier, medicinal)?  
  

 
9 
 
 
RTOG 0815, Version Date April 21, 2015 
 
NRG Oncology Institution #   
 
RTOG  0815 
 
 
 
ELIGIBILITY CHECKLIST (11/14/13)  
Case #  
 
 
 
     (page 3 of 4)  
 
The following questions will be asked at Study Registration:  
 
IMRT/BRACHYTHERAPY CREDENTIALING IS REQUIRED BEFORE REGISTRATION 
 
 
         
1. 
Institutional person randomizing case 
 
                  (Y) 2. 
Has the Eligibility Checklist (above) been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date Informed Consent Signed 
 
 
         
5. 
Patient’s 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 a VA or military hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization Date 
 
              (Y/N) 18. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 19.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, Alzheimer's 
disease, and heart disease)?   
 
 
 
 
 
 
 
 
 
 
(Continued on the next page) 
  
 

 
10 
 
 
RTOG 0815, Version Date April 21, 2015 
 
NRG Oncology Institution #   
 
RTOG  0815 
 
 
 
ELIGIBILITY CHECKLIST (11/14/13) 
Case #  
 
 
     
 (page 4 of 4)  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's disease, or 
heart disease)?  
 
              (Y/N) 22. 
Have you obtained the patient's consent to allow someone from this institution to contact  
him or her in the future to take part in more research?  
 
                
23. 
Number of risk factors: 
 
 
 
 
1. One risk factor 
 
 
 
 
2. Two or 3 risk factors 
 
 
               
24. 
Comorbidity status: 
 
 
 
1. ACE-27 >grade 2 
 
 
 
2. ACE-27 <grade 2 
 
                
25. 
Radiation Therapy modality: 
1. Dose-escalated EBRT 
2. EBRT + LDR brachytherapy boost 
3. EBRT + HDR brachytherapy boost 
 
              (N/Y) 26. 
IMRT 
 
 
 
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 
 
 
 
 
 

 
11 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
1.0 INTRODUCTION 
1.1 
Background and Rationale (12/10/10) 
Androgen-deprivation therapy (ADT) is a well-recognized treatment for prostate cancer1,2 and has been 
shown, as an adjunct to radiotherapy (RT), in multiple prospective randomized trials, to improve clinical 
outcomes including biochemical, local, and distant disease control as well as disease-free and overall 
survival.3-9 The majority of studies in which these benefits have been demonstrated included patients with 
high-risk, locally advanced, or, in some cases, node-positive disease. The most significant findings 
produced by these clinical trials for high-risk patients are as follows: (1) patients in this population 
receiving ADT have improved outcomes over those not receiving ADT, and (2) long-term (2-3 years) ADT 
is superior to short-term (4 months) ADT.  
 
The mechanism of benefit of ADT in these patients remains unclear, but several potential explanations 
exist. First, although ADT is not regarded as a curative modality by itself, it may have the potential to 
eradicate subclinical, microscopic distant disease. Second, there may exist a synergistic relationship 
between RT and concurrent administration of ADT such that the response of local-regional disease, 
particularly that in the pelvic lymph nodes that typically receive significantly lower doses than those 
received by the prostate, is enhanced.10 Finally, the benefits of ADT in these patients may simply be a 
manifestation of compensating for what, in a percentage of patients, would be suboptimal definitive local 
therapy in the form of “standard-dose” (65-70 Gy) RT. 
 
This current RTOG phase III, prospective, randomized trial is designed primarily to define the magnitude 
of benefit for adding ADT to dose-escalated RT specifically in the treatment of intermediate-risk prostate 
cancer. The study will allow this to be accomplished on several levels. For purposes of eligibility for this 
particular study, 3 intermediate-risk features have been identified: T2b-T2c disease, PSA >10 but ≤20, 
and Gleason score of 7. One or more of these risk features associated with a newly diagnosed prostate 
cancer connotes clinicopathologic eligibility for this study. Patients with all 3 of these risk factors who 
additionally present with ≥ 50% of their sampled biopsy cores positive are believed to be at high risk for 
systemic progression and are excluded from this study. 
 
This study population represents a heterogeneous group, albeit all intermediate-risk by conventional 
criteria, and bias will be minimized by stratifying patients according to whether they harbor a single vs. 
multiple intermediate risk factors. While it is acknowledged that potential sources of bias (e.g., Gleason 7, 
3+4 vs 4+311-14) are not directly accounted for, this schema is the most optimal and practical method for 
potentially identifying which patients from this heterogeneous group stand to benefit from the addition of 
short-term ADT. In addition, by stratifying according to the multiple forms of dose escalation permitted on 
this study (external beam radiotherapy [EBRT], low dose rate [LDR] brachytherapy boost, and high dose 
rate [HDR] brachytherapy boost), it is hoped that differences in terms of the interaction of ADT with 
various radiotherapeutic techniques may be better understood. That is, is the lack of benefit with ADT 
suggested in prior brachytherapy series15-17 a patient selection, biologic, or technical phenomenon? Is it 
simply a dose escalation phenomenon? By allowing both dose-escalated EBRT and brachytherapy in this 
study and stratifying patients accordingly, a greater understanding of this interplay should be elicited. 
Finally, a stratification variable will be added to account for patients’ pre-existing comorbidity.  The Adult 
Comorbidity Evaluation 27 (ACE-27)18-20 will be used to describe any such conditions at levels of none, 
minimal, moderate, or severe with corresponding grades of 0,1,2,3, or 4, respectively, at the time of study 
entry.  Prior prospective data have suggested minimal or no benefit to the addition of ADT to RT for 
patients with greater than moderate comorbidity on this scale (grade ≥ 2).21 
The role of ADT in the intermediate-risk population is not well defined, with ADT administration based 
largely on old practice patterns, physician bias, and extrapolation of data from studies examining patients 
with different disease characteristics treated with older radiotherapy modalities and lower total doses. No 
prospective, randomized data exist examining the use of ADT exclusively in an intermediate-risk prostate 
cancer setting. Likewise, there are no prospective, randomized data to define the role of ADT in the 
setting of dose-escalated RT for any patient population. The data yielded by this prospective, randomized 
clinical trial should result in a better understanding of the benefits of ADT in the intermediate risk patient 
population treated with a range of contemporary radiotherapeutic options. This will allow for physicians to 
make more informed, objective decisions regarding the use of ADT in this patient population and spare 
the morbidity of such therapy to patient subgroups in which a benefit is not observed. 

 
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Several prospective series have now shown clear benefits in terms of biochemical, local, and distant 
disease control comparing “dose-escalated” to “standard-dose” RT, illustrating the point that RT 
techniques used in earlier randomized studies demonstrating the benefits of ADT in these patients were 
suboptimal by current practice standards. A randomized dose-escalation study from M.D. Anderson has 
demonstrated, at 8 years of follow-up, improvements in biochemical and clinical disease progression 
(including distant metastases) for patients treated to an isocenter dose of 78 Gy vs 70 Gy.22 
Massachusetts General Hospital has published a randomized trial that has demonstrated the benefits of 
delivering doses of 79.2 Gy vs 70.2 Gy while using proton beam therapy as a boost,23 and a randomized 
trial from the Netherlands has demonstrated an improvement in freedom from failure for patients receiving 
78 Gy vs 68 Gy.24 Prospective, nonrandomized dose-escalation data from Memorial Sloan Kettering 
Cancer Center has suggested similar benefits in biochemical and clinical control and, despite the fact that 
this study was not randomized, suggests an advantage in terms of reduction in the risk of distant failure 
irrespective of whether or not short-term androgen deprivation therapy was used.25 These advantages 
conferred by dose escalation have been a result of more sophisticated imaging and treatment planning 
techniques that have resulted in the ability to not only increase dose delivery to the prostate, but also to 
enhance bladder and rectal sparing with a concomitant reduction in the risks of acute and chronic 
toxicity.26 
While the benefits of dose escalation are becoming better defined in the setting of EBRT, this has been a 
relatively recent phenomenon that has yet to be significantly evaluated in the setting of concurrent or 
adjuvant ADT. Dose escalation, however, has been implemented for a longer period of time using 
brachytherapy techniques. It is therefore the brachytherapy series that provide the longest available 
follow-up with respect to the use of ADT in the setting of dose escalation. These series have provided, to 
this point, only retrospective experiences, but multiple large reviews from different institutions have 
suggested an equivocal or, in some cases, detrimental effect from the use of adjuvant ADT with 
brachytherapy (either HDR or LDR).15-17 
Nonetheless, concurrent long-term ADT with RT remains standard treatment for patients with high-risk 
disease, and, more recently, published results of a prospective study that included intermediate-risk 
patients suggest a possible benefit to short-term ADT for this patient subgroup.7 That is, do patients with 
organ-confined prostate cancer harboring moderately aggressive features such as a Gleason score of 7 
or a pretreatment PSA value of 10-20 ng/mL stand to benefit from the addition of ADT to definitive RT? 
The trial by D’Amico et al. focused on the role of short-term (6-month) ADT in conjunction with EBRT and 
suggested benefits in terms of biochemical control, cause-specific survival, and even overall survival. 
Once again, however, ADT was not administered in the setting of dose-escalated RT, and the trial 
included both intermediate- and high-risk patients, thereby leaving many questions unanswered with 
respect to the use of ADT in the setting of intermediate-risk prostate cancer. 
The result of the integration of the above data into clinical practice is a situation in which there have 
evolved two distinct practice “standards” for patients with intermediate risk prostate cancer treated 
primarily with radiotherapy, and those standards are the two randomization arms of this study. There is 
currently evidence supporting treatment with either approach, but the fact remains that ADT remains 
untested in the setting of dose-escalated RT. The question of whether or not the potential implications of 
ADT with respect to quality of life and potential exacerbation of medical comorbidities are outweighed by 
increased cure rates of prostate cancer will remain unanswered until this issue is addressed in 
prospective, randomized fashion. 
 
1.2 
The Influence of Short-Term Androgen Deprivation Therapy on Health-Related Quality of Life 
(HRQOL), Fatigue, and Quality-Adjusted Survival (QAS) in Patients With Intermediate-Risk 
Prostate Cancer Receiving Dose-Escalated Radiotherapy   
1.2.1  
Health-Related Quality of Life (HRQOL) 
Some of the side effects associated with RT and ADT negatively affect HRQOL, and others may 
contribute to increased risks for serious health concerns. Urinary, bowel, and erectile dysfunction are well-
known side effects of pelvic RT. Sexual side effects are the most well recognized adverse effects from 
ADT 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 
ADT, 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 

 
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RTOG 0815, Version Date April 21, 2015 
 
as side effects of ADT. These effects may lead to an exacerbation of potentially more serious conditions, 
such as hypertension, diabetes, and coronary artery disease.27 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 ADT and improve the awareness that they should incorporate into routine 
practice strategies for preventing and managing toxicities.28  
 
ADT 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 flashes and worse overall HRQOL (using the Functional 
Assessment of Cancer Therapy-General [FACT-G] scale) in those patients, compared with patients 
receiving no therapy.29 To address HRQOL, RTOG 0815 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 RT and ADT.29 
1.2.2 
Fatigue 
Fatigue has been described as the most frequent and distressing symptom related to cancer and its 
treatment.30 RT-associated fatigue is a common early side effect reported by 80% of patients during 
treatment.31 There is evidence that cancer-related fatigue (CRF) has profound effects on ability to function 
in usual roles and activities and can linger for months or years after treatment completion.32-35 The high 
prevalence of this symptom in persons treated with RT, as well as its association with poor quality of life, 
mark it as a significant problem that requires further scientific study. 
 
The etiology of fatigue, its correlates, and prevalence in the context of prostate cancer treatment are 
poorly understood. Past research suggests that irradiation of larger volumes was associated with more 
fatigue.34,36,37 Likewise, ADT has been associated with increased fatigue.38,39 Only a few studies have 
examined predictors or correlates of fatigue. In a sample of 28 men receiving EBRT and ADT, Truong35 
found that age, Gleason score, PSA, T-stage, ADT duration, and RT dose and fraction did not predict 
severity of fatigue at the completion of treatment. In contrast, other investigators37 found that post-
treatment fatigue was associated with baseline fatigue, role limitations, treatment type, and treatment 
location. Other fatigue correlates have been proposed: depression, poor sleep quality, and lack of regular 
physical activity.31,40,41 Thus, we plan to address such confounding factors with brief and focused 
questions. Of importance, no studies have compared the severity and correlates of fatigue in men 
receiving RT ± ADT. Also many of the previous studies were secondary analyses or had small subject 
samples. 
 
Because fatigue is a major problem associated with both RT and ADT, it would be informative to examine 
this common symptom in the context of a large clinical trial. The large sample would allow for the 
examination of predictors (demographic and treatment) of fatigue severity as well as the effect of fatigue 
on quality of life. Secondary hypotheses are that higher fatigue severity will be associated with poorer 
overall quality of life and that higher baseline fatigue, poorer performance status, and older age will 
predict higher fatigue severity during, at the end of, and following treatment.  
 
In order to minimize the potential impact of various confounding factors on fatigue, a secondary endpoint 
of this study, the following key information regarding potential confounds will also be collected at the time 
of the PROMIS-fatigue short form (using limited questions to minimize patient burden): 
 
 
Anxiety/depression item in EQ5D 
 
Muscle weakness question (scale of 1-5, from none to very much) 
 
Overall Sleep Quality: Item from Pittsburgh Sleep Quality Index:42 
 
Level of physical activity (per GLTEQ) 
Sleep quality will be measured by 1 item (Q3) of the Pittsburgh Sleep Quality Index (PSQI), a self-rated 
questionnaire which measures sleep quality and disturbances over a 1-week or 1-month time period.42 
The sum of the 19 items yields a global score which has been demonstrated to discriminate good and 
poor sleepers; also, it has good internal consistency (Cronbach’s alpha=0.83), stability (test-retest 

 
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RTOG 0815, Version Date April 21, 2015 
 
reliability=.85, P<.001) and discriminant validity. It has been used in patients with cancer and 
demonstrated sleep problems as expected. 42  
 
Participants’ level of physical activity will be assessed using the Godin Leisure-Time Exercise 
Questionnaire (GLTEQ),43,44 which measures time spent per week in each of light, moderate, and 
vigorous activities. A score can be computed for each level of exercise. A total score is computed by 
summing the three levels weighted by their respective metabolic (MET) equivalents of 3, 5, and 9. The 
GLTEQ has good test-retest reliability and has shown convergent validity with both objective and other 
self-report measures of physical activity.43,44  
 
1.2.3  
Quality-Adjusted Survival and Failure Free Survival 
 
In this study, the addition of short term ADT is hypothesized to improve overall survival (OS), while having 
a negative impact on HRQOL. As these are potentially competing advantages and disadvantages of ADT, 
it is useful to combine these factors into one equation, quality-adjusted life year (QALY). QALYs will be 
used to determine whether the potential benefits of the ADT, in terms of OS, outweigh the potential 
disadvantages of this strategy, in terms of a negative effect on HRQOL, compared to the RT only arm. 
Such a quality adjusted survival (or failure free survival) analysis can be invaluable to future patients 
faced with these treatment options. 
  
 
Quality-adjusted survival and freedom from progression can be defined by the weighted sum of different 
time episodes added up to a total QALY or failure free survival-year [U= sum of quality (qi) of health 
states K times the duration (si) spent in each health state.45  
 
 
 
 
 



K
1
i
i
is
q
 
 
U
 
 
The EQ-5D has been used across numerous disease sites. For example, the EQ-5D mean score for 95 
patients with NSCLC (93% male, mean age 62 years) was 0.58 (SD 0.32) [on a scale of “0” death or 
worst possible health to “1” best possible health].46 The EQ-5D has been used to assess QALYs and the 
economic value of prostate cancer screening,47 and treatment of pain related to prostate cancer 
metastasis.48 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 HRQOL 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 
QALYs to every man with prostate cancer.49 
 
1.3  
Correlation of Circulating Proinflammatory Cytokines to Fatigue in Patients Undergoing 
Radiotherapy for Prostate Cancer (12/10/10) 
As described above, fatigue is a major problem for patients treated with RT and ADT.  A better 
understanding of biologic events correlated with fatigue in patients receiving RT and ADT may provide 
insight into the mechanisms of fatigue in these patients and as a result may provide possible avenues for 
intervention. Pro-inflammatory cytokines have been found to play a role in cancer-related fatigue (CRF) 
and fatigue from other chronic illnesses.50   In this study, we will test the hypothesis that alterations in the 
circulating levels of the proinflammatory cytokines such as TNF alpha, IL-1, IL-1ra, IL-6 and the marker of 
inflammation C-reactive protein during RT for prostate cancer predict the likelihood of developing fatigue 
as measured by the PROMIS instrument. 
  
Pro-inflammatory cytokines have been studied as possible markers of CRF.  The most commonly 
implicated cytokines are IL-1, IL-6, TNF alpha, and IFN alpha.51  The mechanism by which these 
cytokines may cause fatigue or be correlated with fatigue is complex; however, IL-1, IL-6, and TNF alpha 
are known to stimulate the hypothalamic pituitary axis, which is also implicated in CRF.  TNF alpha also 
plays a role in modulating central neurotransmission, another potential central mechanism of CRF.52   
 
 
Because many of the therapies used to treat cancers can induce expression of pro-inflammatory 
cytokines, it is possible that the cytokine release caused by these therapies also correlate with the 
occurrence of CRF.  Several small studies have addressed the issue of cytokine levels and their 
correlation with fatigue in patients receiving RT.  Ahlberg et al. evaluated 15 patients treated with pelvic 
RT to a dose of 46 Gy in 2 Gy fractions after hysterectomy.53 Fatigue was assessed with the 

 
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Multidimensional Fatigue Inventory (MFI-20).  Cytokine levels were assessed before starting RT, after 30 
Gy, and within one week of RT.  Fatigue scores were elevated at 30 Gy and at completion of RT.  IL-1 
remained undetectable at all time points.  TNF alpha and IL-6 were increased in several patients at the 
time points during and at the completion of RT.  IL-6 elevated in nearly half of patients, and levels 
decreased through RT in the remainder with a resultant negative correlation between serum IL-6 and 
fatigue in this small population.  Unfortunately this is a small series of patients in whom surgical therapy 
was the primary therapy, which is known to alter cytokine levels such as IL-6, CRP, and TNF alpha 
postoperatively. 
 
 
Geitnez et al. evaluated cytokine levels in 41 breast cancer patients that had undergone breast 
conserving therapy.  Patients rated fatigue with the Fatigue Assessment Questionnaire and a visual 
analog scale of fatigue intensity before, during, and 2 months after RT; and at long term follow up.54,55 
Serum IL-1 beta, IL-6, and TNF alpha were also measured at these time points.  Fatigue was elevated on 
the visual analogue scale during RT; however, no change was noted on the Fatigue Assessment 
Questionnaire.  IL-1beta, IL-6, and TNF alpha did not change during therapy and did not correlate with 
fatigue. 
 
 
While several of the series that drew negative conclusions above found no increase in inflammatory 
cytokine levels with RT, several series have found striking elevations.  For example, Akmansu et al. found 
significant elevations in serum IL-6 and TNF alpha after five weeks of RT compared to pretreatment levels 
in 34 patients receiving RT for head and neck cancer.56 Greenberg et al. found significant elevations in IL-
1 in the early weeks of RT for prostate cancer in 15 patients which correlated with an increase in 
fatigue.57 Fatigue was assessed daily on a visual analogue scale. Patients were screened for depression 
during this study to rule out depression as a confounding factor.   
 
 
In contrast, the effect of ADT on inflammatory markers is less well known.  Small studies have shown 
altered cytokine expression by prostate tumors after ADT,58 but levels of systemic cytokines after 
hormonal therapy for prostate cancer are not well described.  Fatigue is a well-known complication of 
ADT for prostate cancer.59 The combination of RT and ADT for prostate cancer may result in a more 
persistent and prolonged fatigue compared to the series evaluating fatigue after RT alone, with as many 
as 32% of patients experiencing fatigue at the completion of RT and a substantial number experiencing 
fatigue as late as 6.5 weeks after completion of RT.35 Correlation of inflammatory cytokines to fatigue may 
provide mechanistic information regarding the causes of fatigue in these patients and may provide a 
target for intervention in future studies. 
 
Blood collection is mandatory for patients consenting to the QOL portion of this study and optional for 
other participants. It will be strongly recommended that patients consent to having a tissue block sent for 
storage to the NRG Oncology Biospecimen Bank. Paraffin-embedded tissue blocks of diagnostic prostate 
biopsies will be obtained from participating institutions and banked in the NRG Oncology Biospecimen 
Bank for future translational analyses. Plasma and whole blood may be collected from patients enrolled 
on this protocol before and during protocol therapy and banked for future translational research analyses. 
Specifically, plasma will be collected at baseline and during the last week of RT treatments. Whole blood 
will be collected at baseline only. The tissue specimens will be collected and processed according to the 
NRG Oncology specimen processing guidelines and must be clearly labeled with the patient’s case 
number. Anticipated analyses include correlation of whole genome single nucleotide polymorphisms to 
incidence and severity of toxicity from therapy, and evaluation of circulating markers that may correlate to 
patient reported outcomes. An example of one anticipated analysis is the evaluation of plasma cytokines 
for correlation to fatigue as measured by the PROMIS instrument in patients enrolled on this trial. 
Examples of cytokines that may be tested include CRP, TNF alpha, IL-1, IL-1ra, and IL-6. 
 
2.0 OBJECTIVES 
2.1 
Primary 
To demonstrate an overall survival (OS) advantage for the addition of short-term (6 months) ADT to dose-
escalated RT for patients with intermediate-risk prostate cancer. The events for OS will be defined as 
death due to any cause. 
 
 

 
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2.2 
Secondary (12/10/10) 
2.2.1 
Determine whether the addition of ADT to dose-escalated RT improves clinical failures (local recurrence, 
regional recurrence, or distant metastasis), biochemical failure by the “nadir + 2” (Phoenix) definition60, 
freedom from failure (the first occurrence of clinical failure or biochemical failure by the Phoenix 
definition), rate of salvage ADT, and prostate cancer-specific mortality without resulting in increased non-
prostate cancer-specific mortality over dose-escalated RT alone 
2.2.2 
Estimate the magnitude of benefit of ADT with respect to OS for patients treated with different RT 
modalities (i.e., EBRT alone vs. LDR brachytherapy boost vs. HDR brachytherapy boost) 
2.2.3 
Compare acute and late treatment adverse events for patients receiving vs. not receiving ADT and 
correlate this with the presence or absence of pre-existing comorbidity as documented by the Adult 
Comorbidity Evaluation 27 (ACE-27) assessment.18-20 
2.2.4 
Determine whether HRQOL as measured by the EPIC significantly worsens as a function of treatment 
assignment (i.e., ADT + RT compared to RT alone) 
2.2.5 
Demonstrate that the addition of ADT to dose-escalated RT is associated with higher fatigue severity than 
dose-escalated RT alone by the Patient-Reported Outcome Measurement Information System (PROMIS) 
fatigue domain 
2.2.6 
Demonstrate an incremental gain in OS with more aggressive therapy that outweighs the detriments in 
the primary generic domains of HRQOL (i.e., mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), reported as QALY. 
2.2.7 
Determine whether the PROMIS score change is correlated with plasma cytokine change  
2.2.8 
Collect paraffin-embedded tissue blocks, plasma, and whole blood for future translational research 
analyses 
  
3.0 PATIENT SELECTION 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
3.1 
Conditions for Patient Eligibility (4/21/15) 
For questions concerning eligibility, please contact the study data manager. 
3.1.1 
Pathologically (histologically) proven diagnosis of prostatic adenocarcinoma, at intermediate risk for 
recurrence, within 180 days prior to registration as determined by having one or more of the following 
intermediate-risk features: Gleason Score 7; PSA >10 but ≤20; Clinical Stage T2b-T2c.  
 
Patients previously diagnosed with low risk (Gleason score ≤ 6, clinical stage < T2a, and PSA < 
10) prostate cancer undergoing active surveillance who are re-biopsied and found to have 
intermediate risk disease according to the protocol criteria are eligible for enrollment within 180 
days of the repeat biopsy procedure.  
3.1.2 
Clinically negative lymph nodes as established by imaging (pelvic +/- abdominal CT or MRI), nodal 
sampling, or dissection within 60 days prior to registration, except as noted immediately below: 
 
Patients with a single intermediate risk factor only do not require abdominopelvic imaging, but 
these studies may be obtained at the discretion of the treating physician. Patients with 2 or 3 risk 
factors are required to undergo pelvic +/- abdominal CT or MRI. 
 
Patients with lymph nodes equivocal or questionable by imaging are eligible without biopsy if the 
nodes are ≤1.5 cm; any node larger than this on imaging will require negative biopsy for eligibility. 
3.1.3 
No evidence of bone metastases (M0) on bone scan within 60 days prior to registration. 
 
Bone scan is not required for patients enrolled with a single intermediate risk factor only, but this 
scan may be obtained at the discretion of the treating physician. Patients with 2 or 3 risk factors 
will require a negative bone scan for eligibility. 
 
Equivocal bone scan findings are allowed if plain film x-rays are negative for metastasis. 
3.1.4 
History/physical examination (to include, at a minimum, digital rectal examination of the prostate and 
examination of the skeletal system and abdomen, and formal comorbidity assessment via the ACE-27 
instrument) within 60 days prior to registration. Note: The ACE-27 is posted on the 0815 protocol 
information page on the NRG Oncology/RTOG web site, http://www.rtog.org. Institutions may access a 
web-based Comorbidity Calculator at http://oto2.wustl.edu/clinepi/comorbid.html. 
3.1.5 
Zubrod Performance Status 0-1 
3.1.6 
Age ≥ 18 
3.1.7  
Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech) within 60 
days prior to registration 

 
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RTOG 0815, Version Date April 21, 2015 
 
 
Study entry PSA must not be obtained during the following time frames: (1) 10-day period 
following prostate biopsy; (2) following initiation of ADT; (3) within 30 days after discontinuation of 
finasteride; or (4) within 90 days after discontinuation of dutasteride. 
3.1.8 
For patients undergoing brachytherapy only: CBC/differential obtained within 60 days prior to registration, 
with adequate bone marrow function defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3  
 
Platelets ≥ 100,000 cells/mm3  
 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 
g/dl is acceptable.) 
3.1.9 
Patient must be able to provide study-specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility (12/10/10) 
3.2.1 
Patients with Gleason Score ≥ 8; PSA > 20; OR Clinical Stage ≥ T3 are ineligible for this trial. 
 
Should findings of extracapsular extension or seminal vesicle invasion be noted on prostate MRI, 
this study, if used, will not render patients ineligible for accrual to this protocol. Primary tumor 
staging for eligibility purposes is to be based on palpable or core biopsy evidence only with 
respect to extracapsular extension or seminal vesicle involvement. 
3.2.2 
Patients with all three intermediate risk factors who also have ≥ 50% of the number of their biopsy cores 
positive for cancer are ineligible for this trial. 
3.2.3 
Prior invasive malignancy (except non-melanomatous skin cancer) or hematological (e.g., leukemia, 
lymphoma, myeloma) malignancy unless disease free for a minimum of 5 years (prior diagnoses of 
carcinoma in situ are permitted)  
3.2.4 
Prior radical surgery (prostatectomy), high-intensity focused ultrasound (HIFU) or cryosurgery for prostate 
cancer 
3.2.5 
Prior hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide), antiandrogens (e.g., 
flutamide, bicalutamide), estrogens (e.g., DES), or bilateral orchiectomy 
3.2.6 
Use of finasteride within 30 days prior to registration 
3.2.7 
Use of dutasteride within 90 days prior to registration 
3.2.8 
Prior or concurrent cytotoxic chemotherapy for prostate cancer; prior chemotherapy for a different cancer 
is permitted. 
3.2.9 
Prior RT, including brachytherapy, to the region of the study cancer that would result in overlap of RT 
fields 
 
Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostate 
volume <60 cc, AUA score ≤15 within 60 days of registration, and no history of prior transurethral 
resection of the prostate (TURP); prior TURP is permitted for patients who receive EBRT only) 
3.2.10 Severe, active co-morbidity, defined as follows: 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months 
 
Transmural myocardial infarction within the last 6 months 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration 
 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 days before registration  
 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that 
laboratory tests for liver function and 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. While the treatment employed 
in this study is not significantly immunosuppressive, it is felt that a diagnosis of AIDS associated 
with prostate cancer is likely to impact this study’s primary endpoint of overall survival. Patients 
who are HIV seropositive but do not meet criteria for diagnosis of AIDS are eligible for study 
participation.  
3.2.11 Men who are sexually active with a woman of child-bearing potential and not willing/able to use medically 
acceptable forms of contraception (e.g., surgical, barrier, medicinal) during protocol treatment and during 
the first 3 months after cessation of protocol treatment; this exclusion is necessary because the treatment 
involved in this study may be significantly teratogenic.  
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT  
 

 
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RTOG 0815, Version Date April 21, 2015 
 
Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do not 
affect eligibility.  
 
4.1 
Required Evaluations/Management (4/21/15)  
4.1.1  
AST or ALT <2 x the upper limit of normal 
 
4.1.2 
Alkaline phosphatase 
 
4.1.3 
Serum total testosterone 
4.1.4 
Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostatic volume 
<60 cc and American Urologic Association (AUA) symptom index composite score ≤15. This may be 
performed before or after study enrollment but, ideally, will be performed prior to study enrollment as the 
RT modality (EBRT alone, EBRT + HDR, EBRT + LDR) must be specified at the time of enrollment. If a 
patient is thought to be a poor brachytherapy candidate based on anatomy at the time of ultrasound, he 
may still participate in the study but must receive EBRT only per protocol guidelines. If a patient is 
deemed an inadequate brachytherapy candidate after he has already been enrolled on the protocol, he 
may be switched to EBRT administered per protocol guidelines, but this will result in a protocol deviation. 
 
4.2 
Highly Recommended Evaluations/Management (5/23/12)  
4.2.1 
History of non-protocol lipid lowering therapy (statin drug): including drug name, dose, treatment start and 
end dates (if applicable) 
 
5.0 REGISTRATION PROCEDURES (11/14/13)  
Access requirements for OPEN and TRIAD 
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. 
 
Institutions that have been previously credentialed for prostate 3DCRT or IMRT on prior RTOG/NRG 
Oncology protocols and that have successfully irradiated a phantom and been approved by the Imaging 
and Radiation Oncology Core (IROC) Houston need not perform additional credentialing for RTOG 0815. 
However, respective institutions may only administer treatment for which they have been previously 
credentialed (i.e., an institution credentialed for 3DCRT only may not administer IMRT on this study 
without completing the IMRT credentialing process). Credentialing requirements for IMRT and 3DCRT are 
specified in Sections 5.1 and 5.2 below. 
 
5.1 
Pre-Registration Requirements for IMRT Treatment Approach (11/14/13) 
5.1.1 
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 IROC Houston web site. Visit 
http://irhochouston.mdanderson.org and select “Credentialing” and “Credentialing Status Inquiry”. 
 
 
An IMRT phantom study with IROC Houston must be successfully completed (if the institution has not 
previously met this IMRT 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, IROC 
Houston will notify both the registering institution and NRG Oncology that the institution has met the IMRT 
credentialing requirements. 
5.1.2 
The institution or investigator must either modify their existing Facility Questionnaire on file at NRG 
Oncology or complete the online Facility Questionnaire (available on the IROC Houston web site at 
http://irhochouston.mdanderson.org) and send it to IROC Houston for review prior to entering any cases. 
IROC Houston will notify the institution and NRG Oncology when all requirements have been met and the 
institution is RT credentialed to enter patients onto this study. 
 
5.2 
Pre-Registration Requirements for 3DCRT Treatment Approach (11/14/13) 
5.2.1 
Only institutions that have met the technology requirements and that have provided the baseline physics 
information that are described in 3DCRT Quality Assurance Guidelines may enter patients onto this 
study. 
5.2.2 
The online Facility Questionnaire (one per institution, available on the IROC Houston web site at 
http://irhochouston.mdanderson.org) or a modification to your existing Facility Questionnaire on file is to 

 
19 
 
 
RTOG 0815, Version Date April 21, 2015 
 
be sent to IROC Houston for review prior to entering any cases. IROC Houston will notify the institution 
and NRG Oncology when all requirements have been met and the institution is RT credentialed to enter 
patients onto this study. 
 
5.3 
Pre-Registration Requirements for Brachytherapy Treatment Approach (4/21/15) 
Note: To be used on this protocol, low-dose rate brachytherapy sources must be listed on the 
joint RPC/AAPM source registry at http://rpc.mdanderson.org/rpc. Select “Brachy Sources/Source 
Registry”. 
5.3.1  
Institutions must be pre-credentialed by IROC Houston prior to registering any cases to this study. The 
credentialing materials may be found on the IROC Houston website at http://irochouston.mdanderson.org  
under the “Credentialing” tab. 
 
 
If an institution was credentialed for a previous RTOG prostate brachytherapy trial (98-05, P-0019, 0232, 
or 0526), they do not have to be re-credentialed for RTOG 0815 if the radiation oncologist and physicist 
are the same as on the approved credentialing request, and the institution is using the same seed model 
and planning system as on the approved credentialing request. A change of physician will require 
submission of the Knowledge Assessment Form and Clinical Test Case. A change in physicist will require 
submission of the Knowledge Assessment Form and the Reference Case. A change in either the 
treatment planning computer or brachytherapy source model will require resubmission of only the 
Reference Case.  
5.3.2 
LDR Brachytherapy Credentialing  
In order to use brachytherapy 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 have already been met, are available at the IROC Houston web site, 
http://irochouston.mdanderson.org by selecting “Credentialing” and “RTOG”. 
5.3.3  
HDR Brachytherapy Credentialing   
Only institutions that have completed the Knowledge Assessment Questionnaire, the Facility Inventory, 
and the Benchmark Cases, as described in the NRG Oncology HDR Prostate Implant Quality Assurance 
Guidelines (see IROC Houston web site http://irochouston.mdanderson.org) may enter patients onto this 
study. The sample clinical case with complete post implant data form and other materials are to be sent to 
IROC Houston. Upon review and successful completion, IROC Houston will notify both the registering 
institution and NRG Oncology that the institution has successfully completed this requirement. The IROC 
Houston will then notify the institution and NRG Oncology that all requirements have been met and the 
institution is eligible to enter subsequent patients onto this study. Institutions previously credentialed for 
RTOG 0321 do not have to be re-credentialed for RTOG 0815. 
 
The first five cases from any newly-credentialed institution will be reviewed by the study co-chair for each 
respective RT modality to ensure protocol compliance with respect to target coverage, heterogeneity, and 
normal critical structure dose constraints. Once an institution has demonstrated protocol compliance, 
future cases will be selected randomly for review.  
 
5.4 
Digital RT Data Submission to NRG Oncology Using TRIAD (11/14/13) 
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 Oncology clinical trials a 
secure method to transmit DICOM RT and other objects. TRIAD anonymizes and validates the 
images as they are transferred. 
 
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. 

 
20 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will need to 
have the TRIAD application installed on his/her workstation to be able to submit images. 
TRIAD installation documentation can be found on the NRG Oncology/RTOG website Core 
Lab tab.    
 
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. 
 
5.5 
Regulatory Pre-Registration Requirements (4/21/15)  
5.5.1 
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.  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 re-
registration) 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. 
 
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 enroll 
patients. Study centers can check the status of their registration packets by querying the Regulatory 
Support System (RSS) site registration status page of the CTSU member web site by entering credentials 
at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically load to RSS. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not required 
to submit separate IRB approval documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review.  This information will be provided to the CTSU Regulatory Office from the CIRB at the 
time the site’s Signatory Institution accepts the CIRB approval.  The Signatory site may be contacted by 
the CTSU Regulatory Office or asked to complete information verifying the participating institutions on the 
study.  Other site registration requirements (i.e., laboratory certifications, protocol-specific training 
certifications, or modality credentialing) must be submitted to the CTSU Regulatory Office or compliance 
communicated per protocol instructions. 

 
21 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
Downloading Site Registration Documents 
Site registration forms may be downloaded from the RTOG 0815 protocol page located on the CTSU 
members’ web site. 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  
 
Click on the (state organization type e.g. P2C, CITN, NCTN Groupname) link to expand, then 
select trial protocol, RTOG-0815  
 
Click on the Site Registration Documents link  
 
Requirements for RTOG 0815 site registration: 
 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB) 
 
CTSU RT Facilities Inventory Form (if applicable) 
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. 
5.5.2 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
Prior to clinical trial commencement, Canadian institutions must complete and fax (215-569-0206) or e-
mail (CTSURegulatory@ctsu.coccg.org) the following forms to the CTSU Regulatory Office: 
 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,  
 
Qualified Investigator Undertaking Form, and  
 
Research Ethics Board Attestation Form. 
5.5.3 
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. 
 
5.6 
Registration (4/21/15) 
5.6.1  
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://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role 

 
22 
 
 
RTOG 0815, Version Date April 21, 2015 
 
on either the LPO or participating organization roster. 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.   
 
6.0 RADIATION THERAPY (4/21/15)  
This trial will not utilize the services of the ITC for dosimetry digital treatment data submission. PRIOR TO 
ENROLLING PATIENTS, please see Section 5.4 for information on installing TRIAD for submission of 
digital RT data. 
 
Protocol treatment must begin within 4 weeks after randomization (administration of either RT 
alone [Arm 1] or RT + ADT [Arm 2]). Patients randomized to receive short-term ADT should begin  
RT 8 weeks after the first LHRH agonist injection. 
 
Note: As this protocol allows for treatment with exclusively EBRT or EBRT + brachytherapy (at the 
discretion of the treating physician) this must be specified at the time of study enrollment. Should a  
patient who was originally intended to receive brachytherapy be found, post-enrollment, to be a  
poor brachytherapy candidate based on transrectal ultrasound examination, he may be switched to external 
beam radiotherapy administered per protocol guidelines, but this will result in a protocol deviation. 
Therefore, it is strongly recommended to obtain ultrasound  
assessment of prospective brachytherapy patients before enrollment on this study.  
 
6.1 
Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT  
6.1.1  
Dose will be normalized such that exactly 98% of the PTV receives the prescription dose and will be 
scored as per protocol. The maximum allowable dose within the PTV is 107% of the prescribed dose to a 
volume that is at least 0.03 cc. The minimum allowable dose within the PTV is >95% of the prescribed 
dose to a volume that is at least 0.03cc.  
6.1.2 
Patients treated entirely via EBRT shall receive prescription doses to the PTV (with the above constraints) 
of 79.2 Gy delivered in 1.8 Gy fractions. All attempts should be made to deliver the PTV dose with the 
above heterogeneity constraints with adherence to the critical structure parameters listed below in Table 
1.  The PTV prescription dose may be reduced by as many as two fractions (total prescription dose of 
75.6 or 77.4 Gy) at the discretion of the treating radiation oncologist only if felt that critical structure dose 
constraints cannot be met for that particular case at a prescription dose of 79.2 Gy. See Section 6.5 
below for specifics regarding when to implement a dose reduction. The final prescription dose will be 
reported specifically to the study coordinator and recorded on a patient-by-patient basis.   
 
 
Table 1.  Critical Structure Dose Constraints 

 
23 
 
 
RTOG 0815, Version Date April 21, 2015 
 
Normal organ 
limit† 
No more than  
15% volume 
receives dose  
that exceeds 
No more than  
25% volume 
receives dose 
that exceeds 
 
No more than 
 35% volume 
receives dose 
that exceeds 
No more than 
50% volume 
receives dose  
that exceeds 
Bladder 
Constraint 
80 Gy 
75 Gy 
70 Gy 
65 Gy 
Rectum 
Constraint 
75 Gy 
70 Gy 
65 Gy 
60 Gy 
Penile Bulb 
Mean dose less than or equal to 52.5 Gy (See Section 6.5) 
†Normal organ limit refers to the volume of that organ that should not exceed the dose limit.   
 
6.2 
Technical Factors 
6.2.1  
RT will be delivered with megavoltage equipment at energies ≥6 MV.  
6.2.2  
Patients who receive brachytherapy as a component of their RT will undergo EBRT implementing either 
3DCRT or IMRT as described. The prostate and seminal vesicles will be treated to a dose of 45 Gy in 1.8 
Gy fractions prescribed to a PTV dose as above.  
 
6.3 
EBRT Localization, Simulation, and Immobilization 
Simulation will be CT-based in all cases. The use of urethral contrast at the time of simulation is 
recommended but not required. Patients will be positioned supine on a flat tabletop with a customized 
thermoplastic immobilization cast or a molded foam cradle for stabilization and setup reproducibility. The 
degree of bladder fullness should be made to duplicate that which is anticipated for daily treatment, i.e., if 
the patient is instructed to maintain a full bladder for treatment, he should be simulated as such 
(especially for cases in which image guidance or adaptive treatments are not implemented). CT images 
should be acquired at a slice thickness of ≤3 mm from the top of the iliac crests superiorly to the perineum 
inferiorly. Target volumes (Section 6.4.1) and normal critical structures (Section 6.4.1) will be defined in 
the slices in which they are visualized. The 3DCRT cases must utilize “beam’s eye view” representations 
to define final beam aperture. 
 
6.4 
Treatment Planning/Target Volumes (11/14/13) 
6.4.1 
The definition of volumes will be in accordance with the ICRU Report #50: Prescribing, Recording, and 
Reporting Photon Beam Therapy.  
 
The Gross Tumor Volume (GTV) is defined by the physician as all known disease as defined by the 
planning CT, urethrogram, and clinical information. If a urethrogram is used, the GTV will encompass a 
volume inferiorly 5 mm superior to the tip of the dye and no less than the entire prostate. Prostate 
dimensions should be defined as visualized on CT scan. 
 
The Clinical Target Volume (CTV) is the GTV plus areas considered to contain microscopic disease, 
delineated by the treating physician, and is defined as follows: 
 
 
 
CTV is the GTV (prostate) plus areas at risk for microscopic disease extension plus the proximal bilateral 
seminal vesicles. Only the proximal 1.0 cm of seminal vesicle tissue adjacent to the prostate shall be 
included in the clinical target volume.61 This 1.0 cm of seminal vesicles refers to both radial (in plane) and 
superior (out of plane) extent. If both prostate and seminal vesicle are visualized in the same CT slice, 
this seminal vesicle tissue will contribute to the 1.0 cm of tissue. 
 
The Planning Target Volume (PTV) will provide a margin around the CTV to compensate for the variability 
of treatment set up and internal organ motion. A range of 5-10 mm around the CTV is required to define 
each respective PTV. Superior and inferior margins (capping) should be 5-10 mm depending on the 
thickness and spacing of the planning CT scan. Careful consideration should be made when defining the 
5-10 mm margin in 3 dimensions.  
 
The ICRU Reference Points are to be located in the central part of the PTV and, secondly, on or near the 
central axis of the beams. Typically these points should be located on the beam axes or at the 
intersection of the beam axes. 
 
Normal Critical Structures to be defined on the treatment planning CT scan will include the following: 
bladder, rectum (from its origin at the rectosigmoid flexure superiorly or the bottom of the SI joints, 
whichever is more inferior to the inferior-most extent of the ischial tuberosities), bilateral femora (to the 
level of ischial tuberosity), penile bulb, and skin. Any small bowel within the primary beam aperture should 

 
24 
 
 
RTOG 0815, Version Date April 21, 2015 
 
be defined as well. All structures will be contoured in their entirety as solid organs. See the NRG 
Oncology/RTOG website (http://www.rtog,org) to view examples of target and normal tissue contours. 
 
The PTV forms the entire target as described. No extension of fields to specifically treat regional lymph 
nodes is permitted. 3D conformal beams will be shaped to include the entire PTV and minimize dose to 
surrounding critical structures as described. Intensity modulated radiotherapy (IMRT) using inverse 
planning is permitted with constraints placed to adhere to critical structure dose limitations as defined 
above. 
 
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. 
 
 
0815 Standard Name 
Description 
EBRT 
GTV 
Gross Target Volume 
CTV 
Clinical Target Volume 
PTV 
Planning Target Volume 
Bladder 
Bladder 
Femur_L 
Left Femoral Head 
Femur_R 
Right Femoral Head 
PenileBulb 
Penile Bulb 
Rectum 
Rectum 
External 
External Patient Contour 
SeminalVesicle 
Seminal Vesicles 
LDR Brachytherapy 
ETV 
 
Rectum 
 
Bladder 
 
HDR Brachytherapy 
CTV 
 
PTV 
 
Prostate 
 
SeminalVesicle 
 
Urethra 
 
Bladder 
 
Rectum 
 
 
6.5 
Critical Structures (12/10/10) 
Critical structure dose constraints shall remain consistent with those represented in prior RTOG 
3DCRT/IMRT prostate protocols (see Table 1 above).  While every effort should be made to deliver 
prescription doses to the PTV as specified while adhering to these constraints, it is recognized that 
certain anatomical factors may prevent this. As mentioned in Section 6.1, a prescription dose reduction to 
a level of 77.4 Gy or 75.6 Gy is permitted if constraints cannot be met at a prescription dose of 79.2 Gy.  
For purposes of compliance, up to a 5% absolute increase in the volume of critical structure receiving 
greater than the specified dose will be considered ”variation acceptable,” e.g. up to 20% of the rectum 
may receive a dose of > 75.6 Gy without a protocol deviation. Any increase in critical structure volume 
greater than 5% receiving more than the specified dose will be considered a “deviation unacceptable.” It 
is at this point that a dose reduction to 77.4 Gy or 75.6 Gy should be implemented. The prescription dose 

 
25 
 
 
RTOG 0815, Version Date April 21, 2015 
 
should be the maximum deliverable up to 79.2 Gy while respecting the critical normal structure 
constraints. Of note, the penile bulb constraint is to be regarded as a guideline, and adherence to this 
should not, in any way, result in a reduction of the prescription dose or compromised dose coverage of 
the target volume. 
 
6.6 
Treatment Verification 
6.6.1 
First day port films or portal images of each field along with orthogonal isocenter verification films (or 
images) must be obtained. If modifications are made in field shaping or design, a port film of each 
modified field along with orthogonal isocenter verification films (or images) is required on the first day’s 
treatment of that field. Thereafter, weekly verification films or images of orthogonal isocenter views 
(anterior to posterior and lateral projection) are required.  
 
 
 
For IMRT the intensity profiles of each beam must be independently verified and compared to the 
planned field intensity. Portal films are not required for IMRT but orthogonal verification films are required, 
just as for 3DCRT. These images are to be archived by the institution for later review if requested by the 
study chair. 
6.6.2 
Daily on-line target localization (kV or MV imaging with fiducials, trans-abdominal ultrasound, or other) or 
off-line adaptive approaches to account for interfraction organ motion and setup variability are permitted 
on this study but not required. The use of image guidance or daily target localization including the specific 
type implemented must be documented by the treating physician and submitted to NRG Oncology using 
the appropriate sections of the Facility Questionnaire. 
6.6.3 
Management of Radiation Dose to the Patient from Daily Localization  
According to the literature, the estimates of patient dose per imaging study for various imaging systems 
vary considerably. The doses are in the range of 0.1 cGy BrainLab’s ExacTrac planar kV-systems and 
can be considered negligible compared with doses from MV portal imaging and kV and MV CT.  The 
doses from helical MV CT scans on a Tomotherapy unit are estimated to be in range from 1 to 3 cGy, 
similar to doses reported for kV cone beam CT on Elekta Synergy machine. The doses for MV cone beam 
CT vary from 1 cGy to 10 cGy depending on the field size. Thus, the doses for 3D imaging systems used 
one time each day are in the range of 0.1 to 10 cGy and can contribute from 0.06 to 6% to a daily dose of 
1.8 Gy.  As a technique of controlling patient dose, it is recommended that a QA procedure be 
established at each institution to verify the accuracy of the image registration software on a daily basis.  
This QA check should be performed by the therapists operating a particular treatment device and is 
aimed at reducing the use of repeat imaging to check that the registration software has functioned 
properly when a shift of patient position is carried out. Additionally, it is not recommended that an 
institution use a daily imaging technique that delivery greater than 3 cGy/dy to the patient.  This limit 
dictates that repeat imaging on a particular day is held to a minimum when systems that deliver up to 3 
cGy per study are used.  
 
6.7 
Quality Assurance (5/23/12)  
6.7.1 
Documentation Requirements 
The institution will archive treatment prescription and verification images for later review by the study chair 
if requested. At least one port film or pretreatment alignment film per field along with the digital 
reconstructed radiographs (DRRs) from the treatment planning program or, alternatively, a simulation 
verification radiograph shall be acquired and kept for evaluation if requested except where geometrically 
impractical. 
6.7.2 
Compliance Criteria 
Cases which meet criteria as stated in Section 6.1.1 will be scored as per protocol. The minimum 
allowable dose within the PTV is >95% of the prescribed dose to a volume that is at least 0.03cc.  Cases 
in which this small volume of at least 0.03cc receives a minimum dose that is <95% but >93% or a 
maximum dose that is >107% and <110% of the prescribed dose will be scored as a variation acceptable. 
Cases in which such a small volume receives less than 93% or >110% of the prescribed dose will be 
scored as a deviation unacceptable. 
 
Acceptable dose heterogeneity will be as follows: This maximum dose volume of the PTV 
must not be shared by a normal critical structure. (Section 6.4.1). The maximum point dose 
to normal critical structures outside the PTV should not exceed the prescription dose. The treating 
physician must carefully consider the tolerance dose/volume to each critical normal structure and 
unspecified tissue.  

 
26 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
6.8  
Dose Specifications/Technical Considerations: LDR Brachytherapy Boost (4/21/15)  
Note: As this protocol allows for treatment with exclusively EBRT or EBRT + brachytherapy (at the 
discretion of the treating physician) this must be specified at the time of study enrollment. Should a 
patient who was originally intended to receive brachytherapy be found, post-enrollment, to be a 
poor brachytherapy candidate based on transrectal ultrasound examination, he may be switched to 
external beam radiotherapy administered per protocol guidelines, but this will result in a protocol 
deviation. Therefore, it is strongly recommended to obtain ultrasound assessment of prospective 
brachytherapy patients before enrollment on this study. 
6.8.1 
LDR, permanent seed, brachytherapy boost is permitted at the discretion of the treating radiation 
oncologist in conjunction with EBRT as described in Section 6.2.2. Implants will only be offered to 
patients with a prostate volume documented to be <60 cc by transrectal ultrasound examination, an AUA 
score ≤15, and no prior history of TURP (Section 3.2.9). The implant may be performed under either 
general or spinal anesthesia and will be performed following the EBRT portion of treatment no more than 
4 weeks following its completion. 
6.8.2 
Preplanning  
This will be carried out prior to the procedure or intraoperatively via transrectal ultrasound examination. 
The prostate will be defined from base to apex in the axial plane at 5 mm slice intervals. The treatment 
length and prostate volume will be recorded. The CTV will consist of the prostate only. The PTV may be 
the same as the CTV or a 2-3 mm margin may be added anteriorly and laterally and up to 5 mm 
craniocaudally at the discretion of the treating physician. 
6.8.3 
Isotope Selection 
Iodine-125 or Palladium-103 seeds may be used. The sources will be received and inventoried in 
accordance with state and federal regulations. If nonsterile loose sources or cartridges are used, at least 
10% of the sources will be assayed in such a manner that direct traceability to either the National Institute 
of Standards and Technology (NIST) or an Accredited Dosimetry Calibration Lab (ADCL) is maintained. 
NIST 1999 standards will be used. If sterile source assemblies or strands are used, alternatively 
nonstranded loose seeds equal to 5% of the total, or five seeds, whichever is fewer, may be ordered and 
assayed. Agreement of the average measured source strength shall agree with that indicated in the 
vendor’s calibration certificate to within 5%. No measured source strengths should fall outside 10% of that 
indicated in the vendor’s calibration certificate. 
 
For I-125, the allowable source strength for each seed is 0.277 U to .650 U (NIST 99 or later). For 
Pd-103 sources, this range is 1.29 U to 2.61 U (NIST 99 or later). 
 
The vendor’s stated source strength shall be used in all dosimetry calculations. Calculations will 
be performed in accordance with NIST 1999 calibration standards, the point source formalism 
described in the report generated by AAPM Task Group 43 and subsequent published AAPM 
Subcommittee Reports. The AAPM’s recommendations for Pd-103 dose specifications and 
prescription are being followed. 
6.8.4  
Prescription Doses 
The prescription dose for permanent seed interstitial boost will be 110 Gy for I-125 and 100 Gy for Pd-
103. Doses will be prescribed as minimal peripheral dose to the PTV. 
6.8.5 
Postimplant Imaging 
A pelvic x-ray with seed count verification will be obtained immediately postimplant. If the seed count 
does not match the number of seeds implanted, PA and lateral chest x-rays will be obtained to rule out 
pulmonary seed migration. CT scan for postimplant dosimetric analysis will be obtained following implant 
completion. Use of a Foley catheter for this test is encouraged for accurate urethral dosimetry but not 
required. This may be obtained immediately postoperative on the day of the implant if desired but no later 
than 5 weeks postimplant. The use of intravesical contrast is encouraged. CT slices should be acquired at 
≤3 mm thickness and should encompass the pelvis from, at minimum, the bottom of the sacroiliac joints 
superiorly to 2 cm caudal to the prostatic apex.  
 
Structures defined will include the prostate, bladder, and rectum. The rectum will be defined from 
the bottom of the sacroiliac joints to the ischial tuberosity and will extend to the outer surface of 
the visualized rectal wall. The postimplant, CT-defined prostate will be defined as the “evaluated 
target volume” (ETV) and will form the basis for dosimetric analysis. 
6.8.6 
Dosimetry 
Postimplant evaluation will be performed on equipment capable of providing structural and volume-based 
dosimetric assessment on both the target and critical structures. Volume acquisition will be based on 

 
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contiguous axial CT slices as described above. Both target volume and critical structures will be 
contoured on each applicable axial slice. Isodose line displays and dose-volume histograms for all 
structures will be generated. 
 
The calculation grid should be set no larger than (2 mm x 2 mm x axial slice width). 
 
The planning system shall be capable of transmitting data via DICOM RT to NRG  
Oncology electronically. 
 
Guidelines established by the American Brachytherapy Society62 are to be followed. DVH-based  
analysis must be used in the postplan evaluation. The following values shall be reported. Vn is 
the percentage of the ETV that received at least n% of the prescription dose. Dm is the minimum 
dose received by m% of the ETV. 
 
Target coverage will be documented in terms of V100, V90, V80, D90. 
 
Dose uniformity will be expressed in terms of V150. 
 
The rectum will be defined from the bottom of the SI joints to the ischial tuberosity. The  
maximum rectal dose as well as the volume and percentage of rectum receiving >100% of the 
prescription dose will be recorded. 
Note: All required LDR Brachytherapy Boost structures must be labeled as listed in the table in Section 
6.4.1 for digital RT data submission. Resubmission of data may be required if labeling of structures does 
not conform to the standard DICOM name listed. 
6.8.7 
Compliance Criteria 
 
Per protocol: D90 for the ETV is greater than 90% of the prescription dose but less than 130% of 
the prescription dose. 
 
Variation acceptable: D90 for the ETV is greater than 80% of the prescription dose, but less than 
90% of the prescription dose, or greater than 130% of the prescription dose. 
 
Deviation unacceptable: D90 for the ETV is less than 80% of the prescription dose. 
6.8.8 
Dosimetric Data to be Submitted to NRG Oncology  
 
Copies of preimplant TRUS images with CTV and PTV annotated 
 
A copy of the implant record generated during the procedure 
 
A copy of the image taken after the procedure and a copy of the image or scout taken during the  
post implant CT 
 
A copy of the postimplant CT scan, ETV and bladder and rectum delineation and dosimetry  
calculations (must be submitted electronically) 
 
A copy of the postimplant dosimetry report that contains the information required in Section 6.8.6  
above. 
6.8.9 
Quality Assurance  
Individual case review will be performed by Dr. Morton, the LDR brachytherapy study co-chair overseeing 
this subgroup of patients enrolled on this protocol, as specified below in Section 6.10. 
 
6.9  
Dose Specifications/Technical Considerations: HDR Brachytherapy Boost (4/21/15)  
Note: As this protocol allows for treatment with exclusively EBRT or EBRT + brachytherapy (at the 
discretion of the treating physician) this must be specified at the time of study enrollment. Should a 
patient who was originally intended to receive brachytherapy be found, post-enrollment, to be a 
poor brachytherapy candidate based on transrectal ultrasound examination, he may be switched to 
external beam radiotherapy administered per protocol guidelines, but this will result in a protocol 
deviation. Therefore, it is strongly recommended to obtain ultrasound assessment of prospective 
brachytherapy patients before enrollment on this study. 
6.9.1 
HDR brachytherapy boost is permitted at the discretion of the treating radiation oncologist in conjunction 
with EBRT as described in Section 6.2.2. Implants will only be offered to patients with a prostate volume 
documented to be <60 cc by transrectal ultrasound examination, AUA symptom index ≤15, and no prior 
history of TURP (Section 3.2.9). HDR treatment will be delivered in 2 fractions separated by a minimum 
time span of 6 hours. This may be done in a single or multiple implant procedures at the discretion of the 
treating physician. The implant(s) may be performed during the EBRT portion of the treatment or within 1 
week prior to its initiation or following its completion. For patients receiving HDR brachytherapy boost who 
are randomized to Arm 2, RT should begin, as for other modalities, 8 weeks following the first LHRH 
administration. The date of HDR brachytherapy implant will constitute the start of RT for those patients 
receiving implants prior to EBRT. 
6.9.2 
All implants will be performed under transrectal ultrasound guidance. Epidural, spinal, or general 
anesthesia may be used. Epidural analgesia may be used for interfraction pain control.  

 
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6.9.3  
At least 14 treatment catheters should be used to ensure adequate target coverage with acceptable dose 
heterogeneity. 
6.9.4  
For patients receiving two fractions in a single implant, fiducial markers identifying the prostatic base and 
apex should be placed at the time of the implant procedure unless previously placed for guidance of 
EBRT.  
6.9.5 
The use of intraoperative cystoscopy is encouraged to ensure the absence of treatment catheters within 
the urethra or bladder. The cystoscope should be retroflexed within the bladder for visualization of the 
bladder neck. Light pressure on the treatment catheters should result in mucosal tenting confirming 
adequate coverage at the prostatic base. 
6.9.6 
For patients undergoing a single implant, a minimum interval of 6 hours will be allotted between fractions. 
If there is significant catheter migration or if the treating physician cannot reproduce the same implant 
geometry, then the implant may be repeated at a later date (without violating Section 6.9.1).  Treatment 
plans for both implants should be submitted to NRG Oncology. 
6.9.7 
Implant Dosimetry (CT-Based) 
 
The treatment planning CT scan must be performed with the patient in the supine position with the Foley 
catheter in place. Metallic obturators or non-CT compatible dummy ribbons must be removed prior to the 
CT scan. The scan must include all of the CTV with at least 9 mm superior and inferior margin, and the 
scan must include the tips of all the implanted catheters. The scan thickness must be ≤0.3 cm and the 
slices must be contiguous. The brachytherapy target volume (Section 6.9.7) and normal critical structures 
(Section 6.9.7) must be outlined on all CT slices. 
 
Dwell Selection and Dwell Time Optimization: Dwell times in positions located outside of the PTV should 
be turned down or off to minimize normal tissue irradiated. A dwell time optimization program based on 
implant geometry or an inverse planning algorithm may be used. Manual optimization is also accepted. 
 
Brachytherapy Target Volume: The CTV is the prostate gland plus any visualized tumor. The PTV is 
equivalent to the CTV. 
 
Brachytherapy Critical Structures: Critical structures to be defined using CT planning include the bladder, 
rectum, and urethra. The outermost extent of the bladder/rectal wall will define those structures. The 
urethra is defined by the outer surface of the Foley catheter.  
 
Critical Structure Dose Limits: The volume of bladder and rectum receiving 75% of the prescription dose 
must be kept to less than 1 cc (V75 <1 cc) and the volume of urethra receiving 125% of the prescription 
dose must be kept to less than 1 cc (V125 <1 cc). Urethral V150 should be 0%. If the dose to normal 
critical structures cannot be kept below the specified level, we recommend readjusting the implant or 
repeating the implant procedure until a more optimal implant is obtained. 
 
Catheter Position Verification: Visual inspection of the catheters prior to delivery of each treatment is 
required. Fluoroscopy or CT also may be used to verify the position of the catheters in relation to the 
Foley catheter balloon and fiducial markers. The physician may adjust the catheters if catheter 
displacement is identified prior to the treatment. If the catheters cannot be satisfactorily repositioned and 
the PTV and normal critical structure DVH parameters are not met with a new plan, then the treatment 
should be postponed until a satisfactory implant is done. If the planning process is repeated, then a 
second set of data should be submitted. 
6.9.8  
Implant Dosimetry (Ultrasound-Based)   
 
Real-time, transrectal ultrasound-based planning is acceptable. The prostate must be defined from base 
to apex in axial slices with a maximum slice thickness ≤0.5 cm. A Foley catheter must be in place for 
definition of the urethra. The slices must include the tips of all the implanted catheters. 
 
Dwell Selection and Dwell Time Optimization: Dwell times in positions located outside of the PTV should 
be turned down or off to minimize normal tissue irradiated. A dwell time optimization program based on 
implant geometry or an inverse planning algorithm may be used. Manual optimization is also accepted. 
 
Brachytherapy Target Volume: The CTV is the prostate gland plus any visualized tumor. The PTV is 
equivalent to the CTV. 
 
Brachytherapy Critical Structures: Critical structures to be defined using ultrasound-based planning 
include the rectum and urethra. The urethra is defined by the outer surface of the Foley catheter. For 
ultrasound-based planning, the urethra will be defined by the Foley catheter in slices extending from the 
base to the prostate apex. The anterior rectal wall must be defined along the length of the prostate.  
 
Critical Structure Dose Limits: Attempts should be made to limit the volume of urethra receiving ≥115% of 
the prescription dose to ≤5%. Up to 10% will be considered variation acceptable. Dose to > 1 cc of the 
anterior rectal wall should not exceed 75% of the prescription dose. 
 
Catheter Position Verification: For the ultrasound-based planning system, the treatment should be 
delivered with the transrectal ultrasound probe in the patient, the same position during the acquisition of 

 
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images used for planning. For the second fraction, a repeat ultrasound plan or a CT-based plan must be 
done prior to delivery of the second fraction.  Alternatively, the ultrasound-based implant and treatment 
may be repeated at a later date (without violating Section 6.9.1). Treatment plans for both implants should 
be submitted to NRG Oncology. 
Note:  All required HDR Brachytherapy Boost structures must be labeled as listed in the table in Section 6.4.1 
for digital RT data submission. Resubmission of data may be required if labeling of structures does not 
conform to the standard DICOM name listed. 
6.9.9 
Compliance Criteria 
A prescription dose of 21 Gy will be delivered to the PTV in two equal fractions of 10.5 Gy. Ninety-five 
percent coverage of the PTV with the prescription dose is considered per protocol, ≥90% but <95% is 
considered variation acceptable, and <90% coverage is considered deviation unacceptable. The first 
fraction of 10.5 Gy will be delivered as soon as possible following completion of the implant procedure 
and treatment planning. Both fractions must be delivered within a single 24-hour period and separated by 
a minimum of 6 hours. Overnight hospital stay is permitted between fractions if necessary. 
6.9.10 Catheter Removal  
After completion of the treatment all catheters will be removed. 
6.9.11  Data Submission 
All data will be digitally submitted to NRG Oncology and include CT data, normal critical structures, all 
PTV contours, and digital DVH data for all normal critical structures, the PTV for dose plan, a copy of the 
daily treatment chart for EBRT and Brachytherapy. 
6.9.12  Quality Assurance  
 
Individual case review will be overseen by Drs. Martinez and Krauss, the study co-chairs overseeing this 
subgroup of patients enrolled on this protocol, as specified in Section 6.10. 
 
6.10 
Radiation Quality Assurance Reviews (12/10/10) 
The study co-chairs for the respective RT modalities offered in this trial will oversee quality assurance 
reviews for patients treated in those respective fashions. RT quality assurance reviews will be ongoing 
and performed remotely. RT quality assurance reviews will be facilitated by IROC Philadelphia and IROC 
Houston. 
 
 
6.11 
Radiation Adverse Events 
6.11.1 All patients will be seen weekly by their treating radiation oncologist while undergoing therapy.  Any 
observations with respect to the following symptoms/side effects will be recorded: 
 
Bowel/rectal irritation manifesting as cramping, diarrhea, urgency, proctitis, or hematochezia 
 
Urinary frequency, urgency, dysuria, hematuria, urinary tract infection, or incontinence 
 
Radiation dermatitis 
 
6.11.2 Clinical discretion may be used in managing radiotherapy-related side effects. Diarrhea/rectal 
frequency/urgency may be managed with diphenoxylate or loperamide. Bladder irritation may be 
mitigated with phenazopyridine. Urinary frequency/urgency can be managed with anticholinergic agents 
or alpha-blockers such as tamsulosin. Erectile dysfunction can be managed with phosphodiesterase 
(PDE) inhibitors such as sildenafil. 
 
6.12 
Radiation Adverse Event Reporting  
See Section 7.5 for additional Adverse Events information and 7.6 for Adverse Event Reporting 
Guidelines. 
 
7.0 DRUG THERAPY (5/23/12) 
Patients randomized to receive short-term androgen deprivation therapy must begin this treatment within 
4 weeks after randomization. Androgen deprivation therapy will consist of “total androgen blockade” 
consisting of both LHRH agonist and anti-androgen (either Casodex or Eulexin) for a total duration of 6 
months. Firmagon (degarelix), an LHRH antagonist with similar androgen suppressive activity is an 
acceptable alternative to LHRH agonist therapy. 
 
7.1 
Anti-Androgen Therapy: Casodex (Bicalutamide)  
For further information, consult the package insert. 
7.1.1 
Timing: Oral anti-androgen therapy will begin within (before, same day as, or after) 10 days of the date of 
the first administration of LHRH agonist for patients randomized to Arm 2 and continued for a total 

 
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duration of 6 months. The total duration of administered anti-androgen therapy must be documented and 
submitted to NRG Oncology. 
7.1.2 
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- [(4-
fluorophenyl)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 half-life 
compatible with once-daily dosing. Bicalutamide is well tolerated and has good response rates in phase II 
trials.63,64 
7.1.3 
Supply:  Commercially available. 
7.1.4 
Storage: Bicalutamide should be stored in a dry place at room temperature between 68°-77°F. 
7.1.5 
Administration: Bicalutamide is administered orally at a dose of one 50 mg tablet per day.  Bicalutamide 
will begin within (before, same day as, or after) 10 days of the date of the first LHRH agonist 
administration, and continue for a total duration of 6 months (i.e. the total duration of planned androgen 
deprivation). Administration will be suspended only if there is an apparent or suspected reaction to the 
drug. During RT interruptions, bicalutamide will be continued. Any treatment interruptions or failure of the 
patient to comply with the prescribed medication schedule must be documented and reported to NRG 
Oncology. 
7.1.6 
Toxicity: 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. 
7.1.7 
Dose Modifications: AST and ALT will be measured pretreatment and then monthly during antiandrogen 
therapy. If the AST or ALT rises to ≥ 2x the institutional upper limit of normal, bicalutamide must be 
discontinued. Elevated AST/ALT values to < 2x the institutional upper limit of normal are subject to dose 
modifications or discontinuation of anti-androgen at the discretion of the treating physician. 
 
7.2  
Anti-Androgen Therapy: Eulexin (Flutamide) 
For further information, consult the package insert. 
7.2.1 
Timing:  See Section 7.1.1. 
 
7.2.2 
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. 
7.2.3 
Supply: Commercially available. 
7.2.4 
Storage: Flutamide should be stored at temperatures ranging from 20-30°C (68-86°F) and protected from 
excessive moisture. 
7.2.5 
Administration: Flutamide 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 within (before, same day as, or after) 10 days of 
with the date of the first LHRH agonist administration (and continue for a total duration of 6 months. 
Administration will be suspended only if there is an apparent or suspected reaction to the drug (See 
Section 7.1.5).  During RT interruptions, flutamide will be continued. Any treatment interruptions or failure 
of the patient to comply with the prescribed medication schedule must be documented and reported to 
NRG Oncology. 
7.2.6 
Toxicity: Consult the package insert for comprehensive toxicity 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. 

 
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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. 
7.2.7 
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 
prostate irradiation, the toxicity will be ascribed to flutamide and the drug will be permanently 
discontinued. AST and ALT will be measured pretreatment, then monthly during oral antiandrogen 
therapy. If AST or ALT increase ≥ 2x the institutional upper limit of normal, flutamide must be 
discontinued. Elevated AST/ALT values to < 2x the institutional upper limit of normal are subject to dose 
modifications or discontinuation of anti-androgen at the discretion of the treating physician. 
 
7.3  
LHRH Agonist (Antagonist) Therapy (leuprolide, goserelin, buserelin, triptorelin, degarelix) 
[5/23/12] 
For additional information, consult the package inserts. 
7.3.1 
Timing: For patients randomized to ADT (Arm 2), the first LHRH administration will occur together with the 
start of anti-androgen treatment (see Sections 7.1.5 or 7.2.5) 8 weeks prior to the start of RT. The total 
duration of LHRH therapy will be 6 months. The total administered duration as well as the specific agent 
used must be documented and submitted to NRG Oncology. 
7.3.2     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. 
 
Firmagon (degarelix) is an LHRH antagonist with similar testosterone-reducing properties to the 
LHRH agonists. Initial loading dose of 240 mg subcutaneous followed by monthly maintenance of 
80 mg subcutaneous for a total of six months is required. 
7.3.3  
Supply: Commercially available. (Note: Buserelin is not commercially available in the United States. It is 
commercially available for use in Canada and other countries.) 
7.3.4 
Storage: LHRH analogs should be stored as directed by the commercial supplier. 
7.3.5 
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), subcutaneous 
injection (Eligard), or insertion of a long-acting cylinder that slowly releases the agent (Viadur). The 
manufacturer’s instructions should be followed. 
7.3.6 
Toxicity: Consult the package inserts for comprehensive toxicity information. Class-related toxicity is 
generally a manifestation of the mechanism of action and related to low testosterone levels. In the 
majority of patients testosterone levels increase above normal in 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, and 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. 
 
7.4 
Modality Review 
All records of ADT administration for patients randomized to Arm 2 should be submitted to NRG 
Oncology. Protocol compliance will be assessed at the NRG Oncology semi-annual meetings by the 
study chair/co-chairs. The recommended ADT duration is six months and will be measured from the day 
of initial LHRH agonist injection until the final day of activity (e.g. 90-day depot injection preparations 
given on day 1 and 91 equal 6 months of ADT).  Likewise, submitted records of anti-androgen therapy 
should reflect their total duration of administration, which should mirror the duration of LHRH agonist 
treatment. 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, 

 
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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.  
 
7.5 
Adverse Events (4/29/14) 
Beginning October 1, 2010, this study will utilize the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for grading of all adverse events. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. All AE reporting on the study case report forms will 
continue to use CTCAE version 3.0. 
  
 
All adverse events (AEs) as defined in the tables below 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 tables below will be reported via CTEP-AERS.  
 
In order to ensure consistent data capture, serious adverse events reported on CTEP-AERS 
reports also must be reported on an NRG Oncology case report form (CRF). In addition, sites must 
submit CRFs in a timely manner after CTEP-AERS submissions. 
7.5.1 
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 the NRG 
Oncology at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is 
restored, an AE report submitted by phone must be entered electronically into CTEP-AERS.  
7.5.2 Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited reporting criteria 
defined in the table in Section 7.6 will be reported via CTEP-AERS.  SAEs that require 24 hour CTEP-
AERS notification are defined in the expedited reporting table in Section 7.6.  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.  
7.5.3 Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) 
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.   
 
7.6 
CTEP-AERS Expedited Reporting Requirements (4/29/14) 
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=1390853489613. 
 
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 NRG 
Oncology at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is 
restored, an AE report submitted by phone must be entered electronically into CTEP-AERS. 
 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 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 NRG Oncology 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). 
 

 
34 
 
 
RTOG 0815, Version Date April 21, 2015 
 
Phase 2 and 3 Trials Utilizing a Commercially Available Agent: CTEP-AERS Expedited Reporting 
Requirements for Adverse Events that Occur within 30 Days1 of the Last Dose of the 
Investigational Agent (Bicalutamide, Flutamide, LHRH Agonists) in this Study 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
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). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
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 
Expedited AE reporting timelines are defined as: 
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. 

 
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RTOG 0815, Version Date April 21, 2015 
 
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 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercially Available Agent: 
None 
 
8.0 SURGERY 
Not applicable to this study 
 
9.0 OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
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 
Diarrhea/rectal frequency/urgency may be managed with diphenoxylate or loperamide. Bladder irritation 
may be mitigated with phenazopyridine. Urinary frequency/urgency can be managed with anticholinergic 
agents or alpha-blockers such as tamsulosin. Erectile dysfunction can be managed with 
phosphodiesterase (PDE) inhibitors such as sildenafil. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
Note: Patients must be offered the opportunity to participate in the correlative components of the study, 
such as tissue/specimen submission. If the patient consents to participate in the tissue/specimen 
component of the study, the site is required to submit the patient’s specimens as specified in Section 10.0 
of the protocol. Sites are not permitted to delete the tissue/specimen component from the protocol or from 
the sample consent. 
10.1 
Tissue/Specimen Submission 
The NRG Oncology Biospecimen Bank- San Francisco,  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. The 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. 
The NRG Oncology Biospecimen Bank also collects tissue for Central Review of pathology. Central 
Review of tissue can be for eligibility and/or analysis.  
 
 
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the purpose of tissue 
banking (recommended) and translational research (recommended). 
 
 
10.2 
Specimen Collection for Tissue Banking and Translational Research (Recommended) [5/23/12] 
For patients who previously have consented to participate in the tissue/blood component of the 
study (See Appendix I). Note: Blood collection is mandatory for patients who have provided 
consent for the QOL portion of this study and optional for other participants.  
The following must be provided in order for the case to be evaluable for the Biospecimen Bank:  
10.2.1 One H&E stained slide 

 
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RTOG 0815, Version Date April 21, 2015 
 
10.2.2 A corresponding paraffin-embedded tissue block of the tumor core biopsy, or at least ten 5 micron 
unstained sections on “plus” slides labeled with the surgical pathology number and block ID. Block or 
unstained slides must be clearly labeled with the pathology identification number that corresponds to the 
Pathology Report. 
10.2.3 A Pathology Report documenting that the submitted block or unstained slides contain(s) 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. 
10.2.4 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.  
10.2.5  Plasma and whole blood cells 
 
See Appendix IV for the blood collection kit and instructions. Note: Kit includes a label for shipping. The 
following must be provided in order for the case to be evaluable by the Biospecimen Bank: A Specimen 
Transmittal Form documenting the date of collection of the plasma and whole blood; the NRG Oncology 
protocol number, the patient’s case number, institution name and NRG or NCI ID, time point of study, and 
method of storage, for example, stored at -80° C, must be included. 
10.2.6 Storage Conditions  
Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C 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; Canada: Monday-Tuesday). 
OR: 
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
10.2.7 Specimen Collection Summary 
 
Specimens taken from 
patient: 
Specimens collected 
when: 
Submitted as: 
 
Shipped: 
Representative H&E 
stained slides of the 
primary tumor 
Pretreatment 
H&E stained slide 
Slide shipped ambient 
A paraffin-embedded 
tissue block of the 
primary tumor taken 
before initiation of 
treatment or at least 10 
unstained 5 micron 
sections on “plus” slides 
 
Pretreatment 
Paraffin-embedded 
tissue block or 
unstained slides 
 
 
Block or unstained 
slides shipped ambient 
 
PLASMA: 5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/lavender top) and 
centrifuge 
Pretreatment, during 
the last week of RT 
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
(five to eight) 
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 
samples containing  1 ml 
per aliquot in 1ml cryovials 
(up to five) 
Whole blood sent 
frozen on dry ice via 
overnight carrier 
 
10.2.8 Submit materials for Tissue Banking and Translational Research as follows: 

 
37 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
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 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
 
10.3 
Reimbursement (4/21/15) 
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) Program, NCI 
funds for reimbursement for protocol-specified biospecimen materials will be distributed per the 
requirements/methods specified by the new NCTN Program. This information will be made available with 
the other registration materials in the Oncology Patient Enrollment Network (OPEN) portal system. OPEN 
will serve as the registration system for all patient enrollments onto NCI-sponsored NCTN trials, including 
this study, which will be transitioned into the new Program from the NCI-sponsored Cooperative Group 
Clinical Trials Program.    
 
10.4 
Confidentiality/Storage  
(See the Patient Tissue Consent Frequently Asked Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx for further 
details.) 
10.4.1 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. 
10.4.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, unless the 
patient has consented to storage for future studies. If at any time the patient withdraws consent to store 
and use specimens, the material will be returned to the institution that submitted it. 
 
11.0 PATIENT ASSESSMENTS 
11.1 
Study Parameters (12/10/10) 
See Appendix I for assessments and timeframes. See Sections 11.1.1 to 11.1.6 for details and/or 
exceptions to Appendix I.  
11.1.1 The pelvic +/- abdominal CT or MRI is required for patients with >1 risk factor (Section 3.1.1) and as 
described in Section 3.1.2. 
11.1.2  Transrectal ultrasound is a one-time test that is required only for patients receiving LDR or HDR 
brachytherapy boost as a component of their treatment. This should ideally be performed prior to study 
enrollment as the RT modality (EBRT alone, EBRT + HDR, EBRT + LDR) must be specified at the time of 
enrollment. In the event that transrectal ultrasound is performed post-enrollment and results in a change 
in the RT modality being administered (the patient may be switched to EBRT administered per protocol 
guidelines), this change will result in a protocol deviation. (See last paragraph of Section 11.3) 
11.1.3 The CBC/differential is required only for patients who will receive either LDR or HDR brachytherapy boost 
(must be known at the time of registration). 
11.1.4 See Section 3.1.7 for special circumstances regarding PSA. Also, PSA will be obtained prior to each 
follow-up visit. 
11.1.5  Serum testosterone need only be obtained from patients randomized to receive ADT (Arm 2) at the time 
of study entry (baseline prior to starting ADT), at the start of RT (8 weeks following 1st LHRH agonist 

 
38 
 
 
RTOG 0815, Version Date April 21, 2015 
 
administration)—may be performed in conjunction with timing of AST/ALT/alkaline phosphatase—and 
every 6 months until rising to baseline levels or for 3 years (whichever is sooner).  
11.1.6  Patients receiving anti-androgen therapy (Arm 2) will need monthly liver function testing (AST, ALT, 
alkaline phosphatase) for the duration of that treatment. 
 
11.2 
Measurement of Response 
11.2.1 Overall survival is the primary study endpoint and the event date of overall survival will be the date of 
death due to any cause. 
11.2.2 Biochemical failure is defined as the documented rise of 2 ng/ml above its post-treatment nadir value. 
11.2.3 Local recurrence is defined as the documented local recurrence as follows: Patients with clinical 
(palpable) suspicion of local recurrence following treatment completion should undergo biopsy for 
pathologic confirmation of local recurrence. Once pathologic confirmation is obtained, the event date will 
be the date at which the palpable progression was first identified.  In the event of biochemical failure 
(nadir + 2 ng/ml), metastatic workup including, at minimum, chest x-ray, bone scan, and abdominopelvic 
CT should be obtained to exclude the possibility of distant failure. If negative, prostate biopsy should be 
performed. If positive, biochemical failure will be considered the local recurrence event. 
11.2.4 Regional recurrence is defined as the documented progression in pelvic lymph nodes. If discovered on 
CT of the pelvis prompted by a biochemical failure, then the event date will be the date of documented 
biochemical failure. 
11.2.5 Distant failure is defined as the documented metastatic disease by any method. If diagnosed on 
diagnostic imaging prompted by biochemical failure, then the event date will be the date of biochemical 
progression. 
11.2.6 Freedom from failure is defined as the first event of biochemical failure, local recurrence, regional 
recurrence, or distant metastasis, as described above. 
11.2.7 Prostate cancer specific mortality is defined as a death due to prostate cancer or a complication from 
treatment  
11.2.8 Non-prostate cancer specific mortality is defined as a death without evidence of prostate cancer or a 
complication from treatment. 
11.2.9 Rate of salvage ADT administration is defined as the first administration of subsequent ADT (either LHRH 
agonist or anti-androgen) is given.  
 
11.3 
Criteria for Discontinuation of Protocol Treatment 
Patients who are experiencing excessive adverse events as deemed by their treating physician may be 
discontinued from the initiated protocol treatment. All attempts should be made to manage adverse 
events adequately so as to avoid this circumstance. As specified in Sections 7.1 and 7.2, anti-androgen 
therapy will be withheld if AST/ALT values are elevated to ≥ 2x the institutional upper limit of normal. 
 
Study analysis will be based on “intent to treat.” If protocol treatment is discontinued, follow up and data 
collection will continue as specified in the protocol. 
 
11.4  
Health-Related Quality of Life (HRQOL) (5/23/12) 
Note: The Quality of Life component of this study closed to patient accrual on March 22, 2012. If the 
patient provided consent to participate in the quality of life component of this study prior to closure to new 
patient accrual, the site is required to administer the QOL assessments as specified in Section 11.0 of the 
protocol. Blood collection is mandatory for patients who have provided consent for the QOL 
portion of this study. 
11.4.1  Prostate Cancer-Specific Health-Related Quality of Life: EPIC 
 
The Expanded Prostate Cancer Index Composite (EPIC) is a prostate cancer health-related quality of life 
(HRQOL) patient self-administered instrument that measures a broad spectrum of urinary, bowel, sexual, 
and hormonal symptoms related to RT and ADT.29 Instrument development was based on advice from an 
expert panel and prostate cancer patients, which led to expanding the 20-item University of California-Los 
Angeles Prostate Cancer Index (UCLA-PCI) to the 50-item EPIC. Summary and subscale scores were 
derived by content and factor analyses. Test-retest reliability and internal consistency were high for EPIC 
urinary, bowel, sexual, and hormonal domain summary scores (each r ≥0.80 and Cronbach's alpha ≥0.82) 
and for most domain-specific subscales. Correlations between function and bother subscales within 
domains were high (r >0.60). Correlations between different primary domains were consistently lower, 
indicating that these domains assess distinct HRQOL components. EPIC domains had weak to modest 
correlations with the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12), indicating 

 
39 
 
 
RTOG 0815, Version Date April 21, 2015 
 
rationale for their concurrent use. Moderate agreement was observed between EPIC domains relevant to 
the Functional Assessment of Cancer Therapy Prostate module (FACT-P) and the American Urological 
Association Symptom Index (AUA-SI), providing criterion validity without excessive overlap.65  
 
 
EPIC is a robust prostate cancer HRQOL instrument that measures a broad spectrum of symptoms; 
however, to decrease patient burden we will only use the domains most pertinent to this study: urinary, 
bowel, sexual, and hormonal. The domains were validated separately, and since each domain will be 
used intact, there is no threat to validity. Dutch and Japanese translations of the EPIC are available, and 
a Spanish translation is planned but not yet available.  
11.4.2 Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue Short Form 
 
The PROMIS fatigue measure (7 items) was developed by the Patient-Reported Outcome Measurement 
Information System (PROMIS), part of the NIH Roadmap Initiative, focused on developing a publicly 
available resource of standardized, accurate, and efficient PRO measures of symptoms, distress, and 
functioning. Two content domains of fatigue, experience and impact, were identified by a panel of experts. 
An item pool of 58 fatigue experience and 54 fatigue impact items were developed. The psychometric 
properties of these items were evaluated in a sample of 450 individuals from the general US population 
using classical test theory indices, monotonicity, and scalability. The expert panel selected the 10 best 
items in each domain. These 20 items were presented to a panel of clinical experts. Only one item was 
dropped because of redundancy. A preliminary fatigue short-form measure of 7 items was created using 
items selected for consistency in the response scale, broad coverage across the fatigue continuum (i.e., 
high to low), and good precision of measurement (discrimination function). 
11.4.3 Quality-Adjusted Survival Analysis: EuroQol (EQ-5D) 
 
The EQ-5D is a patient self-administrated questionnaire that takes approximately 5 minutes to 
complete.66 The first part consists of 5 items covering 5 dimensions including: mobility, self care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension can be graded on 3 levels: 1-no 
problems, 2-moderate problems, and 3-extreme problems. Health states are defined by the combination 
of the leveled responses to the 5 dimensions, generating 243 (35) health states to which unconsciousness 
and death are added.67  
 
 
The 5-item index score is transformed into a utility score between 0, “Worst health state,” and 1, “Best 
health state.” The index score can be used in a quality adjusted survival analysis depending on the health 
state(s) of interest.68 For this study we plan to report the multidimensional utilities for comparative 
purposes. The EQ-5D has now been translated into most major languages, with the EuroQol Group 
closely monitoring the translation process; translations can be accessed at www.euroqol.org. 
11.4.4   Pittsburgh Sleep Quality Index (PSQI) 
Sleep quality will be measured by 1 item (Q3) of the Pittsburgh Sleep Quality Index (PSQI), a self-rated 
questionnaire which measures sleep quality and disturbances.42 The Pittsburgh Sleep Quality Index 
(PSQI) was developed to discriminate between good and poor sleepers. The PSQI has good internal 
consistency (Cronbach’s alpha=0.83), stability (test-retest reliability=.85, P<.001) and discriminant 
validity. It has been used in patients with cancer and demonstrated sleep problems as expected.42  
11.4.5   Godin Leisure-Time Exercise Questionnaire (GLTEQ) 
Participants’ level of physical activity will be assessed using the Godin Leisure-Time Exercise                    
Questionnaire (GLTEQ),43,44 which measures time spent per week in each of light, moderate, and 
vigorous activities. A score can be computed for each level of exercise. A total score is computed by 
summing the three levels weighted by their respective metabolic (MET) equivalents of 3, 5, and 9. The 
GLTEQ has good test-retest reliability and has shown convergent validity with both objective and other 
self-report measures of physical activity.43,44 
 
12.0 
DATA COLLECTION 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1720 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 

 
40 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
12.1 
Summary of Data Submission (12/10/10) 
 
 
 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks of study entry 
Initial Evaluation Form (I1) 
 
Pathology Report (P1)  
 
Pathology Material (P2) 
 
 
 
 
 
EPIC (FA) 
PROMIS (HP) 
EQ-5D (QF) 
PSQI/GLTEQ Form (QL) 
 
 
 
Post Treatment Evaluation Form (F0) 
ARM 2 only: At the start of RT and 3 months 
post RT 
 
 
 
 
Follow-up Form (F1) 
 
ARM 1: At 3 months, 6 months, 9 months, and 
12 months after completion of RT, then every 6 
months for 4 years, then annually 
 
 
 
ARM 2: At 6 months, 9 months, and 12 months 
after completion of RT, then every 6 months 
for 4 years, then annually 
 
 
EPIC (FA) 
PROMIS (HP) 
EQ-5D (QF) 
During the last week of RT and at 6 months, 1 
year and 5 years after completion of RT  
PSQI/GLTEQ Form (QL) 
 
 
 
Autopsy Report (D3) 
At the time of death (if available) 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5 for account 
access and installation instructions) [11/14/13] 
 
Preliminary Dosimetry Information  
 
Digital data submission includes the following: 
 
CT dataset with contours for all critical normal structures, GTV, CTV, and 
PTVs 
 
Digital beam geometry for initial and boost beam sets 
 
Doses for initial, boost and composite sets of concurrently treated beams 
 
Digital DVH data for all required critical normal structures, GTV, CTV, and 
PTVs for total dose plan 
 
All required structures MUST be labeled per the table in Section 6.4.1 
 
Upon submission of the digital data via TRIAD, complete an online Digital 
Data Submission Information Form (DDSI)  located on the website at 
http://www.rtog.org/clinicaltrials/protocoltable/studydetails.aspx?study=0815  
 
Note: All simulation and portal films and/or digital film images will be kept by the 
institution and ONLY submitted if requested. 
Within 1 week of 
start of RT 
Final Dosimetry Information 
 
 
 

 
41 
 
 
RTOG 0815, Version Date April 21, 2015 
 
Radiotherapy Form (T1) 
Daily Treatment Record (T5) [copy to HQ] 
Note: T5 submissions for patients receiving brachytherapy must include the 
Complete Daily Treatment Record for both (EBRT) and brachytherapy boost. 
 
LDR Brachytherapy 
Post-implant evaluation CT scan 
Post-implant structure set 
Post-implant plan  
Post-implant dose distribution 
NRG Oncology/RTOG Prostate Brachytherapy Protocol Compliance Form (BC)-
Available on the IROC Houston website, http://rpc.mdanderson.org/rpc 
Radiotherapy Form (T1) – 5 weeks post implant 
 
HDR Brachytherapy 
Implant CT scan 
Implant structure set 
Implant plan  
Implant dose distribution 
NRG Oncology/RTOG Prostate Brachytherapy Protocol Compliance Form (BC)-
Available on the IROC Houston website, http://rpc.mdanderson.org/rpc 
Radiotherapy Form (T1) – 5 weeks post implant 
 
Note: Copies of simulation and port films/images will be submitted to NRG 
Oncology ONLY if specifically requested. 
Within 1 week of 
RT end 
 
 
 
 
 
 
 
 
 
If applicable:   
3-5 weeks post 
implant—Submit 
listed items to 
TRIAD. 
 
12.2.1 Dosimetry Data Submission to IROC Houston (11/14/13) 
Submit to TRIAD; see Section 5.0 for account access and installation instructions. 
Hardcopies should be sent to:  
IROC Houston 
ATTN:  Dosimetry 
8060 El Rio Street 
Houston, TX 77054 
Phone: 713-745-8989; Fax: 713-794-1364 
E-mail: rpc@mdanderson.org 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Endpoints (12/10/10) 
13.1.1  Primary Endpoint 
Overall survival (OS): The failure event for OS will be death due to any cause (See Section 11.2.1).  
13.1.2 Secondary Endpoints 
 
Biochemical failure by the Phoenix (nadir + 2) defintion60 (See Section 11.2.2) 
 
Local recurrence (See Section 11.2.3)  
 
Regional recurrence (See Section 11.2.4) 
 
Distant metastasis (See Section 11.2.5) 
 
Freedom from failure (FFF) (See Section 11.2.6) 
 
Prostate cancer-specific mortality (See Section 11.2.7) 
 
Non-prostate cancer-specific mortality (See Section 11.2.8) 
 
Rate of salvage ADT (See Section 11.2.9) 
 
Rates of OS for patients treated with the 3 different RT modalities in each arm 
 
Incidence of “acute” adverse events (based on CTCAE, v. 3.0): The acute adverse events will be 
the first occurrence of worst severity of the adverse event ≤30 days of the completion of RT. 
 
Time to “late” grade 3+ adverse events (based on CTCAE, v. 3.0): The time of a first late grade 
3+ adverse event, defined as >30 days from the completion of RT. 
 
Comparison of prostate cancer-specific health related quality of life (HRQOL) change as 
measured by the EPIC (urinary, bowel, sexual, and hormonal domain)  

 
42 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
Comparison of fatigue status as measured by the Patient-Reported Outcome Measurement 
Information System (PROMIS) fatigue domain 
 
Assessment and comparison of Quality Adjusted Life Years (QALYs) 
 
Correlation between the fatigue PROMIS score change and plasma cytokine change 
 
Collect paraffin-embedded tissue blocks, plasma and whole blood for future translational research 
analyses 
 
13.2 
Sample Size  
The sample size calculation addresses the specific primary hypothesis that the OS rate at 5 years in Arm 
2 will be better than in Arm 1. Assume an exponential survival distribution for each arm and define λ1 is 
the hazard rate for Arm 1 and λ2 is the hazard rate for Arm 2. (HA: λ1 > λ2 ). 
H0: λ1 ≤ λ2vs.  HA: λ1> λ 2 
 
Based on the prior results from multiple dose-escalation trials in which patients were treated without 
androgen deprivation, we project that the rate of 5-year OS of Arm 1 is 90% (a yearly hazard rate of 
0.0211). The study is designed to show an absolute improvement of 3.3% in the 5-year overall survival 
rate (i.e., a 5-year overall survival rate of 93.3%), which translates to a yearly hazard rate of 0.0139 in 
Arm 2.  An exponential distribution for overall survival distribution was assumed for each arm. Three 
interim analyses and a final analysis are planned for early stopping for the efficacy and futility. The 
efficacy testing is based on the power family of test69 with ∆=0 and the futility testing is based on the 
Freidlin and Korn70 method at a nominal significance level of 0.005. Two hundred twenty deaths are 
required to detect a 34% relative reduction in the yearly death rate with 85% statistical power using a one-
sided log-rank test at the 0.025 significance level. After adjusting the sample size for these interim 
analyses, the sample size per arm for the hypotheses is 684. Guarding against an ineligibility or lack-of-
data rate of up to 10%, the final targeted accrual for this study will be 1520 patients. 
 
13.3  
Accrual and Duration (12/10/10) 
The proposed trial, RTOG 0815, builds on the experience obtained in RTOG 0126. RTOG 0126 involved 
a similar group of patients treated with dose-escalated radiotherapy and accrued 1431 patients over 6 
years at an average rate of 20 cases per month. We are estimating an average of 20 cases per month in 
the new trial. We expect RTOG 0815 to complete accrual in 6.3 years. Based on patient accrual in 
previous NRG Oncology/RTOG randomized prostate studies, there will be relatively few entries during the 
initial 6 months while institutions are obtaining IRB approval. The total duration of the study is expected to 
be 11.3 years from the time the first patient is entered to the final analysis under the null hypothesis, the 
hazard rate of Arm 2 will not be better than that of Arm 1, and a uniform accrual rate of 20 patients per 
month. 
 
 
The NRG Oncology Data Monitoring Committee (DMC) will begin evaluating patient accrual semiannually 
following the anticipated quiet period. In accordance with CTEP policies for slowly accruing trials, if the 
average monthly accrual rate for the trial in the fifth and sixth quarters after study activation (i.e., in 
months 13-18) is less than 20% of the rate projected in the paragraph above (i.e., less than 4 patients per 
month), the study will close to further accrual. If the average monthly accrual rate is greater than 20% but 
less than 50% of projected (i.e., fewer than 10 patients per month), the trial will be placed on probation for 
6 months. If the average monthly accrual rate at the end of the probationary period is less than 50% of 
projected, the study will close to future accrual. The participation of non-NRG Oncology/RTOG institutions 
through CTSU is expected to follow a similar pattern as seen in NRG Oncology/RTOG. 
 
13.4  
Analysis Plan (5/23/12)  
13.4.1 Analysis of the Primary Endpoint 
The primary endpoint is overall survival (OS). The time to failure for overall survival will be measured from 
the date of randomization to the date of documented death due to any cause. The overall survival 
function will be estimated by the Kaplan-Meier method.71 We want to test whether or not the overall 
survival rate in Arm 2 is higher than that of Arm 1. The null and alternative hypotheses are: 
H0: λ1 ≤ λ2vs.  HA: λ1> λ 2 
 
where, λ 1 and λ 2 are yearly death rate for Arm 1 and Arm 2, respectively. We will use the log-rank 
test72,73 with a significance level of 0.025 at the final analysis to test this hypothesis. In addition, the Cox 

 
43 
 
 
RTOG 0815, Version Date April 21, 2015 
 
proportional hazard regression model74 will be used to compare the treatment differences. Both adjusted 
and unadjusted hazard ratios and the respective 95% confidence interval will be computed. The number 
of risk factors (1 vs. 2 or 3), comorbidity status (ACE-27 grade ≥ 2 vs, < 2), and RT modality (EBRT vs. 
EBRT+LDR brachytherapy boost vs. EBRT+HDR brachytherapy boost), age, and race (as appropriate) 
will be adjusted for in this analysis. 
13.4.2  Biochemical Failure by Phoenix Definition and Freedom From Failure 
The freedom from failure (FFF) rate by 5 years is defined as the proportion of patients without events of 
FFF failure by 5 years from randomization among all eligible patients at baseline. The failure events for 
FFF will be the first occurrence of clinical failure (local recurrence, regional recurrence, or distant 
metastasis), biochemical failure by the Phoenix definition (PSA ≥2 ng/ml over the nadir PSA).60 Patients 
who are event free with less than 5 years of follow-up, die due to any cause, or who receive any salvage 
therapy (e.g., salvage androgen deprivation, vaccine therapy, biologic/small molecule therapy, or 
chemotherapy) will be censored. The biochemical failure (BF) rate by 5 years is defined in a similar way; 
the proportion of patients with biochemical failure by 5 years (PSA ≥2 ng/ml over the nadir PSA)60 from 
randomization among all eligible patients at baseline. The salvage ADT is defined as the first 
administration of subsequent ADT (either LHRH agonist or anti-androgen). The rate of salvage ADT is 
defined as the proportion of patients who have salvage ADT by 5 years among all eligible patients at 
baseline. The endpoint FFF rate by 5 years will be estimated by the Kaplan-Meier method71 and the BF 
rate by 5 years will be estimated by cumulative incidence method.75  
 
 
The Z-test statistic for the difference between the 2 rates with the standard errors estimated by 
Greenwood’s method will be used, with a significance level of 0.025. The following test statistics (T.S.) will 
be used for testing between the 2 arms: 
 
 




















2
1
2
1
1
2
2
1
2
1
1
2
1
2
2
1
2
1
2
1
)
(
ˆ
)
(
ˆ
)
(
ˆ
)
(
ˆ
)
1
(
)
1
(
.
.
n
j
j
j
j
j
n
i
i
i
i
i
n
j
j
j
j
j
n
i
i
i
i
i
f
r
r
f
p
f
r
r
f
p
p
p
f
r
r
f
p
f
r
r
f
p
p
p
S
T




 (1) 
 
 
 
 
 
where 
1p and 
2
p are the FFF, BF, or the salvage ADT rate of Arm 1 and Arm 2, respectively, estimated 
by the Kaplan-Meier method or cumulative incidence method, ri is the number of patients who are at risk 
and fi is the number of patients who have FFF, BF, or the salvage ADT failure events (i=1,2).  If H0 is 
rejected, then we conclude that Arm 2 is better than Arm 1. If H0 is not rejected, then we conclude that 
Arm 2 is not better than Arm 1. 
 
 
In addition, logistic regression76 will be used to compare the treatment differences in the hypothesis with 
and without adjustment for at least the following covariates; the number of risk factors (1 vs. 2 or 3), 
comorbidity status (ACE-27 grade ≥ 2 vs, < 2), and RT modality (EBRT vs. EBRT+LDR brachytherapy 
boost vs. EBRT+HDR brachytherapy boost), age, and race (as appropriate). Odds ratios and the 
respective 95% confidence intervals will be computed.  
13.4.3 Time to Failure of Secondary Survival Endpoints 
The time to failure for secondary endpoints (local recurrence, regional recurrence, distant metastasis, 
prostate cancer-specific mortality, non-prostate cancer specific mortality) will be measured from the date 
of randomization to the date of the event of interest. The failure events for the secondary endpoints are 
defined as follows—local recurrence: biopsy-proven failure within the prostate/seminal vesicles; distant 
metastasis: clinical and/or radiographic appearance of disseminated disease; prostate cancer-specific 
mortality: death due to prostate cancer; non-prostate cancer-specific mortality: death in a patient with 
disease clinically controlled. 
 
The treatment effect on these failures may impact the observable measures of outcomes (local 
recurrence, regional recurrence, distant metastasis, prostate cancer-specific mortality, non-prostate 
cancer-specific mortality) and other competing risks may dilute the sensitivity. We will use the cause-
specific hazard rate77,78 (the instantaneous rate of cause-specific mortality in the presence of competing 
failure types as a function of time) approach to consider the competing events. Freidlin and Korn70 
showed that the cause-specific hazard rate approach is better than other approaches, for example, the 

 
44 
 
 
RTOG 0815, Version Date April 21, 2015 
 
cumulative incidence method,75 in most cases. The log-rank test on the times to the specific type of 
failure, which considers the presence of competing events, will be used to test whether the survival rates 
of these secondary endpoints in one arm are higher than that of the other arm for each hypothesis at a 
significance level of 0.025. In this approach, patients who experience other failure first are censored. In 
addition, Fine and Gray’s regression79 will be used for these secondary survival outcomes. Both 
unadjusted and adjusted hazard ratios and the respective 95% confidence interval will be computed. At 
least the treatment arm, the stratification variables (the number of risk factors, comorbidity status, and RT 
modality), age, and race (as appropriate) will be adjusted for in this analysis. 
13.4.4 Estimation of Rates of OS of Patients Treated with the Different RT Modalities 
 
Three different RT modalities are allowed for this trial: EBRT, EBRT+LDR brachytherapy boost, and 
EBRT+HDR brachytherapy boost. The rate of OS for patients treated with an RT modality among three 
modalities is defined as the proportion of patients who are treated with an RT modality and alive at 5 
years from the randomization among all eligible patients treated with the RT modality at baseline. This 
rate will be estimated in each arm separately.  
13.4.5 Comparison of the Incidence of Acute Adverse Events and Time to Late Grade 3+ Adverse Events and 
Correlation with Pre-Existing Comorbidity with Adverse Events 
 
Adverse events are scored according to CTCAE, v. 3.0. An acute adverse event will be defined as the 
first occurrence of worst severity of the adverse event occurring less than or equal to 30 days after the 
completion of RT. Univariate logistic regression76 will be used to model the distribution of acute adverse 
events. Multiple logistic regression76 will be used to model the distribution of acute adverse events 
adjusted for covariates. Both unadjusted and adjusted odds ratios and the respective 95% confidence 
interval will be computed and tested using a one-sided Chi-Square test statistic with the significance level 
of 0.025. Late grade 3+ adverse events will be defined as grade 3+ adverse events occurring more than 
30 days after the completion of RT. The time to late grade 3+ adverse events will be measured from the 
time protocol treatment started to the time of the earliest occurrence of a late grade 3+ adverse event. If 
no such late adverse event is observed until the time of the analysis, the patient will be censored at the 
time of the analysis. Death without late adverse event will be considered as the competing risk for late 
adverse events and the distribution of time to late grade 3+ adverse events will be estimated using the 
cumulative incidence method75 and tested using a one-sided Gray’s test statistic75 with the significance 
level of 0.025. A Fine and Gray’s regression model79 will be used to compare the treatment differences of 
time to late adverse event with and without adjusting for other covariates. Both unadjusted and adjusted 
hazard ratios and the respective 95% confidence interval will be computed. At least the treatment arm, 
the stratification variables (the number of risk factors and RT modality), age, and race (as appropriate) will 
be considered when it is adjusted in the analysis. 
 
The correlation of acute adverse events and the ACE-27 grade (≤ 2 vs. 2) will be calculated by Chi-
square test statistics at the significance level of 0.05. The acute toxicity will be considered in two ways: 1) 
absent or present or 2) ≥ grade 3 or < grade 3. The correlation of late adverse events (≥ grade 3 vs. < 
grade 3) and the ACE-27 grade (≤ 2 vs. 2) will be calculated by Chi-square test statistics at the 
significance level of 0.05. 
13.4.6 Analysis for Endpoints Related to Quality of Life (QOL) 
  
Patient accrual for the QOL measurements will be limited to 200 cases in each arm.  
Quality of life will be assessed via the following instruments: the Expanded Prostate Cancer Index (EPIC), 
the Patient-Reported Outcome Measurement Information System (PROMIS) fatigue domain, and the 
EuroQol (EQ-5D). 
 
Information regarding potential confounds will also be collected in a short form (QL) using limited 
questions to minimize patient burden. This information can be used to evaluate the potential impact of 
these confounding factors on fatigue. Patient responses to the following will be collected in the QL form: 
muscle weakness (one item), overall sleep quality as measured by one item from the Pittsburgh Sleep 
Quality Index (PSQI),42 and level of physical activity as measured by the Godin Leisure-Time Exercise 
Questionnaire (GLTEQ).43,44 Anxiety/depression is also a potential confound with fatigue and patient 
responses to the anxiety/depression item in the EQ-5D can be used. 
 
Protocol-eligible patients will be included in the QOL analysis only if they agree to participate in the QOL 
portion of this study. All the QOL instruments (EPIC, PROMIS fatigue domain, EQ-5D) will be collected on 
all cases participating in this portion of the trial. Patients will complete the EPIC, PROMIS fatigue domain, 
and the EQ-5D at pretreatment (baseline), week 3 of RT, at the last week of RT, and at 6 months, 1 year, 

 
45 
 
 
RTOG 0815, Version Date April 21, 2015 
 
and 5 years after the end of RT. At the same time points, the QL form (i.e., one item from the PSQI, 3 
items from the GLTEQ, and one question regarding general muscle weakness) will be collected. To 
minimize missing QOL data, we have included detailed instructions for collection of QOL and what to do if 
the patient misses a scheduled assessment, and RTOG provides individualized patient calendars 
available to Investigators and Research Associates 24/7 on the NRG Oncology/RTOG web site.  
 
We will describe the distributions of QOL data collection patterns over all collection points in each 
treatment arm. Longitudinal data analysis, specifically the general linear mixed-effect model80 will be 
performed to describe the change trend of the EPIC, PROMIS fatigue domain, and the EQ-5D across the 
2 treatments. The primary objective in HRQOL analysis is to determine the QOL differences. The 
response will be the change of measurement from baseline for each measurement. The model will 
include the baseline and stratification variables (the number of risk factors, comorbidity score, and RT 
modality).  
 
Patient self-assessment of symptoms will be performed using 4 primary EPIC domains: urinary, bowel, 
sexual, and hormonal symptoms. The PROMIS fatigue domain consists of 7 questions to quantify the 
fatigue continuum (i.e., high to low), and good precision of measurement (discrimination function). Each 
question has a 5-point Likert scale (1-never, 2-rarely, 3-sometimes, 4-often, 5-always). The EQ-5D is a 2-
part self-assessment questionnaire and only the first part will be used. This consists of 5 items covering 5 
dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension 
is measured by a 3-point Likert scale (1-no problems, 2-moderate problems, and 3-extreme problems). 
There are 243 (=35) health states. We will transform the 5-item index score into a utility score between 0 
(worst health state) and 1 (best health state) for comparative purposes. We hypothesize that the 
measurements from the EPIC will be worse in Arm 2 than Arm 1 because of the aggressiveness of 
treatment. We also hypothesize that measurements from the PROMIS fatigue domain will be higher in 
Arm 2 than in Arm 1.  
 
To address the non-ignorable missing data caused by censoring survival time, the data analysis also will 
include patients who have not died. To examine trade-offs between survival time and QOL, we will 
combine them for each patient into a single measurement: Quality Adjusted Life Year (QALY). If (and only 
if) the primary endpoint hypothesis is substantiated, we will conduct a cost-utility analysis. The cost-utility 
analysis will not be done until after the primary endpoint results are published. QALY is defined by the 
weighted sum of different time episodes added up to a total quality-adjusted survival time. These health 
state-based methods of quality-adjusted survival analysis are known as the quality-adjusted time without 
symptoms and toxicity method (Q-TwiST).45 
 
 
Q-TwiST = ∑i=1
k qi si 
 
 
where qi is the quality (the utility coefficient) of health state i, si is the duration spent in each health state, 
and k is the number of health states. We will use Glasziou’s multiple health-state (Q-TwiST) models to 
use the repeated measures of EQ-5D. Because Glasziou’s method incorporates longitudinal QOL data 
into an analysis of quality-adjusted survival, the health-stated model must be constructed on the following 
assumptions: 
 
 
A1) QOL is independent from treatment. 
 
A2) A health state is independent from previous states. 
 
A3) Proportionality of quality-adjusted duration and duration of the actual state of health 
 
 
Assumption A1 can be checked by plotting QOL over time according to treatment, and the t test can be 
used to compare the mean QOL scores of each treatment arm. Assumption A2 can be checked by 
comparing the QOL for patient groups in a given health state where the groups are defined by duration of 
previous health state experience using a regression model. Suitable checks for assumption A3 at 
minimum would be a simple plot. If data does not support these assumptions, we will use a method which 
uses the longitudinal QOL data directly. Cost-utility will be analyzed at 2 time points: at 1 year and 5 years 
posttherapy. We will use the 5-item utility score in EQ-5D for the cost-utility analysis. We will use the Z-
test to test the hypothesis that the cost-utility in the 2 treatment arms is the same with a significance level 
of 0.05 and a 2-sided test.  
 

 
46 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
To inspect the missing data mechanism, we will use at least a graphical method. A missing completely at 
random (MCAR) mechanism exists when missing values are randomly distributed across all observations. 
A missing at random (MAR) mechanism exists when values are not randomly distributed across all 
observations, rather than one or more sub-samples. If the cause of missing data is MCAR, listwise 
deletion (complete case analysis) will be done. If the MAR assumption is supported by the data, then an 
imputation method such as multiple imputation will be applied to impute missing data. If the MAR 
assumption is not supported by the data, then adjusting for covariates (such as the baseline QOL score) 
might reduce the conditional association between outcomes and missing values. If missing data patterns 
look similar when stratified by such covariate(s), then an analysis that adjusts for such covariate(s) will be 
conducted and an imputation method such as multiple imputation will be applied. If  
  
approximate conditional independence cannot be obtained with any set of covariates, then MNAR 
(missing not at  random) must be addressed by an explicit model for the missing data mechanism and 
then an imputation method such as multiple imputation will be applied. All results from the imputed 
analysis using the multiple imputation will be compared to the complete case analysis results to assess 
any potential biases. We will conduct a sensitivity analysis using various assumptions on the missing data 
to determine what impact missing data and imputation methods have on the study conclusions. 
Imputation methods when prescribed by validated instrument developers will be employed first. Additional 
methods or methods used when none are described for a given instrument may include linear mixed-
effects models to obtain separate estimates for the QOL outcome within strata based on missing data 
patterns.81,82 NRG Oncology recognizes that all options are subject to bias and analysis with more than 
one method for consistency across methods is prudent.  
13.4.7  Correlation Between the Fatigue PROMIS Score Change and Plasma Cytokine Change  
Four hundred patients participating in the QOL portion of this trial will be used for this analysis. The 
analysis will be done in each arm separately to test the prognostic vales of biomarkers. At least the 
following plasma cytokines will be evaluated: CRP, TNF alpha, IL-1, IL-1ra, and IL-6. The highest fatigue 
is typically reported and plasma cytokine levels are known to be altered in the third to fourth week of 
radiation therapy (RT). Therefore, the evaluation time point will be 3 weeks after the start of RT. The 
fatigue PROMIS score change for each item will be calculated by subtracting the fatigue PROMIS score 
at 3 weeks following the start of RT from the baseline score. Similarly, the cytokine change will be 
calculated by subtracting the plasma cytokines measurement at 3 weeks following the start of RT from the 
baseline measurement. The fatigue PROMIS score change ranges from -4 to 4 (1-5 for each item). This 
will be categorized in a meaningful group at the time of analysis. The measure of each cytokine change 
will be a continuous variable. At the least, an Analysis of Variance (ANOVA) will be conducted to see if 
there is a correlation between the fatigue PROMIS score change and plasma cytokine change. Additional 
methods, such as linear mixed-effects, will be used. Additional time points will be tested in a similar way. 
 13.4.8 Collect paraffin-embedded tissue blocks, plasma, and whole blood for future translational research 
analyses 
 
The feasibility of proposed translational studies will be assessed following completion of accrual and 
sample collection. At the time of data maturity of this study, we will propose specific details of the markers 
to be investigated. We will address the assays that will be used and a list of specific correlative aims with 
appropriate statistical considerations. 
13.4.9  Group Sequential Testing for Early Termination and Reporting of Efficacy and Futility 
 
A group sequential test with 3 planned interim analyses and a final analysis will be performed. The interim 
analysis will be carried out when the cumulative deaths are met. At each planned interim analysis, the p-
value from the log-rank test statistic assessing treatment efficacy and futility with respect to the primary 
endpoint, OS, will be compared to the nominal significance level. The efficacy testing is based on the 
power family of test69 with ∆=0 (see Table 2 for nominal significance level for efficacy testing) and for the 
futility testing boundary we will use a less aggressive boundary, Rule C (at a nominal significance level of 
0.005) in Freidlin and Korn.70 The following hypotheses are tested: 
 
H0: λ1 ≤ λ2vs.  HA: λ1> λ 2 
 
 
where λ1 and λ2 are the hazard rate for Arm 1 and Arm 2, respectively. If the H0 is rejected, then we 
conclude that the OS rate of Arm 2 will be better than Arm 1 and stop accrual if applicable.  
 
Table 2: Schedule for the Planned Interim Analysis 
Information 
Estimated Analysis 
Cumulative Number of 
Nominal Significance 

 
47 
 
 
RTOG 0815, Version Date April 21, 2015 
 
Time 
Time* 
Deaths in the  
Two Arms 
Level for 
Efficacy 
(Z-value) 
0.25 
4.7 years 
55 
0.0001 (4.049) 
0.50 
6.8 years  
109 
0.0018 (2.863) 
0.75 
8.9 years 
163 
0.015 (2.338) 
1.00 
11.1 years 
218 
0.025 (2.024) 
*Time to the interim analysis from the first patient entry without considering ineligibility or lack-of-data rate and 
under the null hypothesis 
 
 
For futility testing, the alternative hypotheses, HA (λ1 = λ 2 + 0.0072) will be tested at 0.005 level (the 
futility nominal significance level). If the computed p-value is less than 0.005 then we will consider 
stopping the trial in favor of the H0 and conclude that the overall survival rate of Arm 1 will be better than 
Arm 2. Otherwise, we will continue the trial. 
 
Based on the results of each interim analysis, the following action will be taken and the responsible 
statistician will recommend to the NRG Oncology Data Monitoring Committee (DMC) that the 
randomization be discontinued, if applicable, and the study be considered for early publication. Before 
making such a recommendation, the accrual rate, treatment compliance, safety of the treatments, and the 
importance of the study are taken into consideration along with the p-value. The DMC will then make a 
recommendation about the trial to the appropriate NRG Oncology Leadership as needed. 
13.4.10 Interim Report to Monitor the Study Progress 
 
Interim reports with descriptive statistics will be prepared twice per year until the initial paper reporting the 
treatment results has been submitted. In general, the interim reports will contain information about the 
patient accrual rate with a projected completion date for the accrual phase, compliance rate of treatment 
delivery with the distributions of important prognostic baseline variables, and the frequencies and severity 
of the adverse event by treatment arm. The interim reports will not contain the results of the treatment 
comparisons with respect to the primary endpoint and secondary endpoints.  
 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS 
data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and 
October 31. 
13.4.11 Reporting the Initial Treatment Analysis 
 
The analysis reporting the treatment results will be carried out after the criteria for early stopping/reporting 
are met. Five interim analyses and one final analysis will be performed for efficacy and futility of the 
addition of ADT and will be carried out as described in Section 13.4.9. It will include tabulation of all cases 
entered and those excluded from the analyses; the distribution of the important prognostic baseline 
variables; safety treatments; treatment compliance; and observed results with respect to the primary and 
secondary endpoints will be shown. All eligible patients randomized will be included in the comparison 
and will be grouped by assigned treatment in the analysis (intent-to-treat analysis). In addition, 
exploratory analyses of treatment comparisons of the primary and secondary survival endpoints will be 
tested using the Cox or Fine and Gray’s proportional hazard model that includes treatment arms, the 
stratification factors (the number of risk factors and RT modality), age, and race (as appropriate).  
 
13.5 
Gender and Minorities 
In conformance with the National Institute of Health (NIH) Revitalization Act of 1993 with regard to 
inclusion of women and minorities in clinical research, participation rates of men will be examined in the 
interim analyses. Based on the accrual statistics from RTOG 94-08, we project that 81% of the men in the 
study will be White, 15% will be Black or African American, 3% will be Hispanic, 0.5% will be Asian, 0.3% 
will be Pacific Islander and 0.2% will be American Indian or Alaskan Native. The following table lists the 
projected accrual by race/ethnicity. 
 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 

 
48 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
N/A 
46 
46 
Not Hispanic or Latino 
N/A 
1474 
1474 
Ethnic Category: Total of all subjects 
N/A 
1520 
1520 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
N/A 
49 
49 
Asian 
N/A 
7 
7 
Black or African American 
N/A 
228 
228 
Native Hawaiian or other Pacific Islander 
N/A 
5 
5 
White 
N/A 
1231 
1231 
Racial Category: Total of all subjects 
N/A 
1520 
1520 
 
13.5.1  In the setting of prostate cancer, African American ethnicity has been associated with both increased 
incidence and inferior clinical outcomes. The etiology of this phenomenon remains unclear. As such, no 
specific differences in outcome are hypothesized based on race/ethnicity in this study. Data will be 
collected and available for retrospective outcomes analysis at the time of study conclusion.  

 
49 
 
 
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Quality-of-life Study Group of the Master 2 Project in Pharmacoeconomics. Pharmacoeconomics. 19:855- 
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Roach M, 3rd, Hanks G, Thames H, Jr., et al. Defining biochemical failure following radiotherapy with or 
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Kestin LL, Goldstein NS, Vicini FA, et al. Treatment of prostate cancer with radiotherapy: should the 
entire seminal vesicles be included in the clinical target volume? Int J Rad Oncol Biol Phys. 
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Nag S, Bice W, DeWyngaert K, Prestidge B, et al. The American Brachytherapy Society 
recommendations for permanent prostate Brachytherapy post-implant dosimetric analysis. Int J Radiat 
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Kinnealey, GT, and Furr, BJ. Use of the nonsteroidal anti-androgen Casodex in advanced prostatic 
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Tyrrell, CJ. Tolerability and quality of life aspects with the anti-androgen Casodex (ICI 176,334) as 
monotherapy for prostate cancer. International Casodex Investigators. Eur Urol. 26 Suppl 1:15-9, 1994. 
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Wei JT, Dunn RL, Litwin MS, et al. Development and validation of the expanded prostate cancer index 
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Schulz MW, Chen J, Woo HH, et al. A comparison of techniques for eliciting patient preferences in 
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Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Annual 
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Kalbfleisch JD, Ross LP. The statistical analysis of failure time data. New York: John Wiley & Sons; 1980. 
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Gaynor JJ, Feuer EJ, Tan CC, et al. On the use of cause-specific failure and conditional failure 
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Fine J, Gray RJ: A proportional hazards model for the subdistribution of a competing risk. J Am Stat 
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Verbeke G, Molenberghs G. Linear mixed models for longitudinal data. New York: Springer-Verlag, Inc.; 
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81.  
Donaldson GW, Moinpour CM. Learning to live with missing quality-of-life data in advanced-stage 
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Administration. pp. http://www.qolpro.org/ (accessed Aug. 1, 2006). 
 
 
  

 
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RTOG 0815, Version Date April 21, 2015 
 
APPENDIX I (4/21/15) 
 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS 
(may be required for eligibility) 
 
< 6 months prior to registration 
< 60 days prior to registration 
Elig-related tissue collection 
x 
 
History/physical 
 
x 
CT or MRI abd/pelvis & bone scan 
 
x 
Transrectal ultrasound 
 
For brachy patients only 
Performance status 
 
x 
AUA 
 
For brachy patients only 
(AUA) symptom index 
composite score ≤15 
PSA 
 
x 
CBC w/ diff & ANC 
 
For brachy patients only 
AST, ALT, alk phosphatase 
Pre-treatment 
Serum testosterone 
 
x 
Statin 
x 
QOL Assess. (if patient consents): 
EPIC, PROMIS, EQ-5D,  
PSQI/ GLTEQ 
 
 
Pretreatment 
Tissue for banking (if patient 
consents) 
Blood for banking (if patient 
consents)* 
*Blood collection is mandatory for patients who have provided consent for the QOL portion of the study. 
 
 

 
54 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
APPENDIX I (continued) 
STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT 
 
 
Weekly during 
RT 
Weeks 1 and 5 
of RT 
Week 3 of RT; 
last week of 
RT 
Monthly (Arm 
2 only) 
6-8 weeks 
post RT 
Performance 
status 
 
 
x 
 
 
PSA 
 
 
 
 
x 
CBC w/ diff & 
ANC 
 
x 
 
 
 
AST, ALT, alk 
phosphatase 
 
 
 
See 11.1.5 
 
Serum 
testosterone 
 
See 11.1.5 
 
 
 
Statin 
 
 
 
x 
 
QOL Assess. 
(if patient 
consents): 
EPIC, PROMIS, 
EQ-5D, PSQI/ 
GLTEQ 
 
 
Last week of RT 
 
 
 
Blood for 
banking (if 
patient 
consents)* 
 
 
Last week of RT 
 
 
 
AE evaluation 
x 
 
 
 
 
*Blood collection is mandatory for patients who have provided consent for the QOL portion of the study. 
 
 

 
55 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
APPENDIX I (continued) 
STUDY PARAMETER TABLE: FOLLOW UP ASSESSMENTS 
 
 
ARM 1 
3, 6, 9, and 12 
months 
post RT 
ARM 2 
6, 9, and 12 
months post 
RT 
6 mos, 1 yr, 5 
yrs post RT 
Every 6 
months for 4 
years 
Annually 
Performance 
status 
x 
x 
 
x 
x 
Serum 
testosterone 
See 11.1.5 
 
 
 
Statin 
x 
 
 
 
Tumor response 
eval: physical, 
DRE, PSA 
x 
x 
 
x 
x 
QOL Assess. (if 
patient 
consents): EPIC, 
PROMIS,  
EQ-5D, PSQI/ 
GLTEQ 
 
 
x 
 
 
AE evaluation 
x 
x 
 
x 
x 
 
 

 
56 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
APPENDIX II 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 

 
57 
 
 
RTOG 0815, Version Date April 21, 2015 
 
APPENDIX III 
 
AJCC STAGING SYSTEM 
PROSTATE, 6th Edition 
DEFINITION OF TNM 
 
Primary Tumor, Clinical (T) 
TX  
Primary tumor cannot be assessed 
 
T0  
No evidence of primary tumor 
 
T1  
Clinically inapparent tumor neither palpable or visible by imaging 
T1a  
Tumor incidental histologic finding in 5% or less of tissue resected 
T1b  
Tumor incidental histologic finding in more than 5% of tissue resected 
T1c  
Tumor identified by needle biopsy (e.g., because of elevated PSA) 
 
T2  
Tumor confined with prostate* 
T2a  
Tumor involves one-half of one lobe or less 
T2b  
Tumor involves more than one-half of one lobe but not both lobes 
T2c  
Tumor involves both lobes 
 
T3  
Tumor extends through prostate capsule** 
T3a  
Extracapsular extension (unilateral or bilateral) 
T3b  
Tumor involves the seminal vesicle(s) 
 
T4  
Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external 
sphincter, rectum, levator muscles and/or pelvic wall 
 
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is 
classified as T1c 
 
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3, but 
as T2. 
 
Regional Lymph Nodes (N) 
 
NX  
Regional lymph nodes cannot be assessed 
N0  
No regional lymph node metastasis 
N1  
Metastasis in regional lymph node(s) 
(continued on next page)

 
58 
 
 
RTOG 0815, Version Date April 21, 2015 
 
APPENDIX III (continued) 
AJCC STAGING SYSTEM 
PROSTATE, 6th Edition 
 
Primary Tumor, Pathologic (pT) 
 
pT2*  
Organ confined 
pT2a  Unilateral, involving one-half of one lobe or less 
pT2b  Unilateral, involving more than one-half of one lobe but not both lobes 
pT2c  
Bilateral disease 
 
pT3  
Extraprostatic extension 
pT3a  Extraprostatic extension** 
pT3b  Seminal vesicle invasion 
 
pT4  
Invasion of bladder, rectum 
*Note: There is no pathologic T1 classification 
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease). 
 
Distant Metastasis (M)* 
MX  
Presence of distant metastasis cannot be assessed (not evaluated by any modality) 
M0  
No distant metastasis 
M1  
Distant metastasis 
M1a  
Nonregional lymph node(s) 
M1b  
Bone(s) 
M1c  
Other site(s) with or without bone disease 
 
*Note: When more than one site of metastasis is present, the most advanced category is used; 
pM1c is most advanced. 
 
Histopathologic Grade (G) 
GX  
Grade cannot be assessed 
G1  
Well-differentiated (slight anaplasia [Gleason 2-4]) 
G2  
Moderately differentiated (moderate anaplasia [Gleason 5-6]) 
G3-4  
Poorly undifferentiated or undifferentiated (marked anaplasia [Gleason 7-10]) 
 
(continued on next page)

 
59 
 
 
RTOG 0815, Version Date April 21, 2015 
 
APPENDIX III (continued) 
AJCC STAGING SYSTEM 
PROSTATE, 6th Edition 
 
Stage Grouping 
Stage I   
T1a  
N0  
M0  
G1 
 
Stage II  
T1a  
N0  
M0 
G2, G3-4 
T1b  
N0  
M0  
Any G 
T1c  
N0  
M0  
Any G 
T1  
N0  
M0  
Any G 
T2  
N0  
M0  
Any G 
 
Stage III  
T3  
N0  
M0  
Any G 
 
Stage IV  
T4  
N0  
M0  
Any G 
Any T  N1  
M0  
Any G 
Any T  Any N  M1  
Any G 
 
 
 
 
 
 

 
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RTOG 0815, Version Date April 21, 2015 
 
APPENDIX IV (4/21/15) 
 
APPENDIX FOR NRG ONCOLOGY BIOSPECIMEN COLLECTION: BLOOD COLLECTION KIT 
INSTRUCTIONS 
 
Shipping Instructions: 
US Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
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 or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal Form (STF) has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include date of 
collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the 
container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap 
blocks with bubble wrap. Place padding in top of container so that if you shake the container the blocks 
are not shaking. If you can hear the slides shaking it is likely that they will break during shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal 
Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT 
ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and 
clearly identified. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs). 
There should be plenty of dry ice under and above the specimens. If the volume of specimens is 
greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any 
Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site 
will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped 
Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to delivery delays. 
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80 C until ready 
to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank 
by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271. 
 
(continued on next page)

 
61 
 
 
RTOG 0815, Version Date April 21, 2015 
 
APPENDIX IV 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
This Kit is for collection, processing, storage, and shipping of plasma or whole blood (as specified by the 
protocol): 
 
Kit contents: 
 
One Purple Top EDTA tube for plasma pre-tx (A) 
 
One Purple Top EDTA tube for Whole Blood (B) 
 
Twenty-one (21) 1 ml cryovials 
 
Biohazard bags (3) and Absorbent shipping material (3) 
 
Styrofoam container (inner) and Cardboard shipping (outer) box 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal Form (STF) and Kit Instructions 
 
PREPARATION AND PROCESSING OF  PLASMA AND WHOLE BLOOD: 
(A) Plasma (If requested): Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with the NRG 
Oncology study and case number, collection date, time, and time point, and clearly mark cryovials 
“plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM 
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the STF..  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, 
keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the plasma 
collected (5 to 8) labeled with NRG Oncology study and case numbers, collection date/time, time point 
collected and clearly mark specimen as “plasma”.  Avoid pipetting up the buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the STF. 
 

 
62 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 
 
Label as many 1ml cryovials (up to 5) as necessary for the whole blood collected..Label them with the 
NRG Oncology study and case number, collection date/time, and time point, and clearly mark cryovials 
“blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be 
mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood 
collected (up to 5) labeled with NRG Oncology study and case numbers, collection date/time, time 
point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on STF. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C 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; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent 
thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam 
box. 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard bag.  
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
 
 

 
63 
 
 
RTOG 0815, Version Date April 21, 2015 
 
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail 
NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu