A Phase III Study Comparing Combined External Beam Radiation and Transperineal Interstitial Permanent Brachytherapy With Brachytherapy Alone for Selected Patients With Intermediate Risk Prostatic Carcinoma
Phase: PHASE3
Conditions: Prostate Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY (12/17/14) 
 
RTOG 0232 
 
A PHASE III STUDY COMPARING COMBINED EXTERNAL BEAM RADIATION AND 
TRANSPERINEAL INTERSTITIAL PERMANENT BRACHYTHERAPY WITH BRACHYTHERAPY 
ALONE FOR SELECTED PATIENTS WITH INTERMEDIATE RISK PROSTATIC CARCINOMA 
 
 
Study Chairs (10/2/15) 
Pathology 
Mahul Amin, M.D. 
(310) 423-6631 
FAX# (310) 423-0170 
aminm@cshs.org   
 
Radiation Oncology 
Brad R. Prestidge, M.D. 
Bon Secours Cancer Institute 
DePaul Medical Center 
155 Kingsley Rd., #100 
Norfolk, VA 23505 
(757) 278-2200 
FAX# (757) 889-5022 
brad@prestidgemd.com 
 
Outcomes 
Deborah Watkins Bruner, R.N., Ph.D. 
(404) 712-9695 
FAX# 404-727-8514 
deborah.w.bruner@emory.edu  
 
Urology 
Martin G. Sanda, MD 
 404-778-6874 
FAX# (404) 778-0993 
msanda@emory.edu 
 
Economics 
Alan Hartford, M.D., Ph.D.  
(617) 638-7070 
FAX# (617) 638-7037 
alan_hartford@hotmail.com   
 
Physics/Quality 
Assurance 
William Bice, Ph.D.  
(925) 330-4392 
FAX# (925) 952-2907 
bice@prodigy.net 
 
CTSU (RTOG 0232)   
Westat 
CTSU Data Operations Center 
1441 W. Montgomery Avenue 
Rockville, M.D. 20850-2062 
(888) 462-3009  
FAX# 888-691-8039 
 
 
 
 
 
 
Credentialing 
Jeff Michalski, M.D. (ITC)  
(314) 362-8566  
FAX# (314) 362-8521 
Michalski@radonc.wustl.edu  
 
Geoffrey Ibbott, Ph.D (RPC) 
(713) 745-8989 
FAX# (713) 794-1364 
gibbott@mdanderson.org 
 
Activation Date: 
June 11, 2003 
 
Version Date: 
December 17, 2014 
Includes Amendments 1-7 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 8 
October 2, 2015 
TBD 
Amendment 7 
December 17, 2014 
2/2/2015 
Update 
May 1, 2014 
May 1, 2014 
Closure 
February 8, 2012 
February 8, 2012 
Update 
September 27, 2011 
September 27, 2011 
Amendment 6 
September 6, 2011 
September 27, 2011 
Amendment 5 
March 29, 2010 
April 8, 2010 
Update 
September 23, 2008 
September 23, 2008 
Amendment 4 with Update 
January 11, 2008 
April 3, 2008 
Amendment 3 
January 24, 2007 
May 22, 2007 
Update 
February 16, 2006 
February 16, 2006 
Amendment 2 
October 11, 2005 
October 27, 2005 
Amendment 1 
February 15, 2005 
March 3, 2005 
1 
 

Update 
December 16, 2003 
December 16, 2003 
Update 
September 10, 2003 
September 10, 2003 
Activation 
January 22, 2003 
June 11, 2003 
 
 
 
 
RTOG 0232 (continued) 
 
NRG Oncology(12/17/14) 
(215) 574-3189 
(800) 227-5463 Ext. 4189 
 
INSTITUTION MUST BE PRE-CREDENTIALED (See Section 5.0) (10/11/05) 
 
 
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. 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU) [1/24/07] 
 
Institutions not aligned with the NRG Oncology will participate through the CTSU mechanism as outlined below 
and detailed in the CTSU logistical appendix. 
 
• 
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 http://members.ctsu.org 
 
• 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU logistical 
appendix for specific instructions and documents to be submitted.  
 
• 
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for specific 
instructions and forms to be submitted. 
 
• 
Data management will be performed by NRG Oncology. Case report forms (with the exception of patient 
enrollment forms), clinical reports, and transmittals must be sent to NRG Oncology unless otherwise 
directed by the protocol. Do not send study data or case report forms to CTSU Data Operations.  
 
• 
Data query and delinquency reports will be sent directly to the enrolling site by NRG Oncology.  Please 
send query responses and delinquent data to the NRG Oncology and do not copy the CTSU Data 
Operations. Each site should have a designated CTSU Administrator and Data Administrator and must keep 
their CTEP AMS account contact information current. This will ensure timely communication between the 
clinical site and NRG Oncology. 
2 
 

INDEX 
 
 
 
Schema 
 
Eligibility Check 
 1.0 
Introduction 
 2.0 
Objectives 
 3.0 
Patient Selection 
 4.0 
Pretreatment Evaluations 
 5.0 
Registration Procedures 
 6.0 
Radiation Therapy 
 7.0 
Drug Therapy 
 8.0 
Surgery 
 9.0 
Other Therapy 
10.0 
Pathology 
11.0 
Patient Assessments 
12.0 
Data Collection 
13.0 
Statistical Considerations 
 
References 
 
Appendix IA, IB, IC 
- Sample Study, Tissue, and Cost-Analysis Consent Forms 
Appendix II 
 
- Performance Status 
Appendix III 
 
- Staging System 
Appendix IV 
 
- Toxicity Criteria 
Appendix V 
 
- Gleason Classification 
Appendix VI 
 
- AUA Voiding Symptom Questionnaire 
Appendix VII 
 
- RTOG Permanent Prostate Implant QA Guidelines 
Appendix VIII 
 
- Post Implant Data Form 
Appendix IX 
 
- Scoring Instructions for EPIC 
Appendix X 
 
- EPIC Questionnaire 
Appendix XI 
 
- EQ 5D 
Appendix XII 
 
- Utilization of Sexual Medications/Devices (10/11/05) 
Appendix XIII 
 
- CTSU Participation Procedures (10/11/05) 
 
 
 
 
3 
 

NRG ONCOLOGY(12/17/14) 
 
RTOG 0232 
 
A PHASE III STUDY COMPARING COMBINED EXTERNAL BEAM RADIATION AND 
TRANSPERINEAL INTERSTITIAL PERMANENT BRACHYTHERAPY WITH 
BRACHYTHERAPY ALONE FOR SELECTED PATIENTS WITH INTERMEDIATE RISK 
PROSTATIC CARCINOMA 
 
SCHEMA  
 
 
S 
 
T 
 
R 
 
A 
 
T 
 
I 
 
F 
 
Y 
 
Stage 
1. T1c 
2. T2a – T2b 
Gleason Score 
1. ≤ 6 
2. 7 
 
PSA 
1. 0 - < 10 
2. 10-20 
 
Neoadjuvant 
Hormonal 
Therapy 
1. No 
2. Yes 
 
 
R 
 
E 
 
C 
 
0 
 
R 
 
D 
 
 
 
Isotope 
 
1. I-125 
2. Pd-103 
 
R 
 
A 
 
N 
 
D 
 
O 
 
M 
 
I 
 
Z 
 
E 
 
Arm 1: 45 Gy EBRT 
Partial pelvis (1.8 Gy/fraction M-F for 
five weeks) followed 2-4 weeks later 
by Pd-103 (100 Gy) or I-125 (110 
Gy)* 
 
or 
 
 
Arm 2 Pd-103 (125 Gy) or I-125 
(145 Gy)* 
* 
Protocol treatment must begin within four weeks after study entry. 
 
 
 
Institution must be pre-credentialed by the Radiological Physics Center (RPC) for prostate brachytherapy  
and the institution must demonstrate the ability to perform electronic data submission to the Image-
Guided Therapy Center (ITC). (See Section 5.0 for details) 
 
Eligibility:  (See Section 3.0 for details)  
- 
Histologically confirmed, locally confined adenocarcinoma of the prostate; 
- 
Clinical stages T1c - T2b (AJCC 6th Edition, see Appendix III); 
- 
Zubrod Performance Scale 0-1; 
- 
Patients must be ≥ 18 years of age; 
- 
Combined Gleason score 7 if PSA  < 10, combined Gleason score < 7 if PSA 10 - 20; 
- 
PSA must be ≤ 20 ng/mL, before hormone therapy, if given (if Gleason score 2-6, then PSA must be ≥  10 
ng/mL); 
- 
Prostate volume by TRUS ≤ 60 cc; 
- 
No prior chemotherapy or pelvic radiation; no prior TURP, cryosurgery, TUNA, TUMT or radical surgery for 
carcinoma of the prostate;  
- 
No previous hormonal therapy beginning < 2 months or > 6 months prior to registration; 
- 
No distant metastases, no clinically or pathologically involved lymph nodes; 
- 
No significant obstructive symptoms; AUA score must be ≤ 15 (alpha blockers allowed); 
- 
No hip prosthesis; 
- 
No major medical or psychiatric illness; 
- 
Signed study-specific informed consent form prior to study entry. 
 
4 
 

Required Sample Size: 586 
5 
 

RTOG Institution #  
 
 
RTOG 0232 
 
ELIGIBILITY CHECKLIST (6/11/03, 2/15/05, 10/11/05) 
Case #   
 
 
(page 1 of 3) 
 
 
______(Y) 
1. Is there histologically confirmed, locally confined adenocarcinoma of the prostate? 
 
______(T1c-T2b) 
2. What is the T stage?  (AJCC 6th Edition,  see  Appendix III) 
 
______(N0) 
3. What is the N stage? (2/15/05) 
 
 
______(0-1) 
4. What is the Zubrod performance status? 
 
______(≤20) 
5. What is the PSA level (prehormones if given)?  (If Gleason sum 7, then PSA must be < 10 
ng/mL, conversely, if PSA is ≥  10 (but ≤  20), then Gleason sum must be < 7). 
 
______(N) 
6. Has the patient had prior pelvic radiation? (2/15/05) 
 
______(N) 
7. Has the patient had prior chemotherapy for prostate cancer? (2/15/05) 
 
______(Y/N) 
8. Has the patient had any prior hormone therapy? 
 
 
 
 
_____ (Y) If yes, did it begin within 2-6 months prior to study entry? 
 
______(Y/N) 
9. Has the patient used a 5-alpha reductase inhibitor? (10/11/05) 
 
 
 
 
_____(Y) If yes, has it been discontinued? (10/11/05) 
 
______(N) 
10. Has the patient had prior radical surgery for prostate carcinoma? (10/11/05) 
 
______(N) 
11. Is there evidence of distant metastases? (10/11/05) 
 
______(Y/N) 
12. Has the patient had previous or concurrent cancer other than basal cell or squamous cell 
skin cancer or in situ at another site? (10/11/05) 
 
______If yes, has the patient been disease free for at least 5 years? 
 
______(N) 
 
13. Are there any major medical or psychiatric illnesses that would prevent completion of 
treatment or interfere with follow-up? (10/11/05) 
 
______(N) 
14. Has the patient had a prior TURP, cryosurgery, TUNA or TUMT? (10/11/05) 
 
______(N) 
15. Is the PSA > 20? (10/11/05) 
 
______(N) 
16. Is the Gleason sum > 7? (10/11/05) 
 
______(Y) 
17. Has the patient had TRUS mapping done and is prostate volume ≤ 60 cc? (10/11/05) 
 
______(Y) 
18. Has patient filled out AUA voiding questionnaire and is the score ≤ 15? (10/11/05) 
 
______(N) 
19. Has the patient had a hip replacement? (10/11/05) 
 
______(Y) 
20. Is the patient at least 18 years of age? (10/11/05) 
6 
 

RTOG Institution #  
 
 
RTOG 0232 
 
 
ELIGIBILITY CHECKLIST (6/11/03, 2/15/05, 10/11/05, 2/16/06) 
Case #   
 
 
 
        (page 2 of 3) 
 
The following questions will be asked at Study Registration: 
 
____________         1.  Name of institutional person registering this case? 
 
____________(Y)    2.  Has the Eligibility Checklist (above) been completed? 
 
____________(Y)    3.  Is the patient eligible for this study? 
 
____________         4.  Date the study-specific Consent Form was signed?  (must be prior to study entry) 
 
____________         5.  Patient's Initials 
 
____________         6.  Verifying Physician 
 
____________         7.  Patient's ID Number 
 
____________       8.  Date of Birth 
 
____________         9.  Race 
 
____________        10.  Ethnic Category (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
 
____________        11.  Patient's Country of Residence 
 
____________        12.  Zip Code 
 
____________        13.  Patient's Insurance Status 
 
____________  14.  Will any component of the patient's care be given at a military or VA facility? 
 
____________        15.  Is the patient going to receive 3D CRT or IMRT if randomized to receive external beam 
radiation therapy (Arm 1)? (10/11/05) 
 
____________        16.   Tissue/Blood Used for Research in Current Study 
 
____________        17. Tissue/Blood Kept for Cancer Research 
 
____________        18.   Tissue/Blood Kept for Medical Research 
 
____________        19.   Allow contact for future research 
 
____________        20. Medicare data to be used for research in the current study? (2/16/06) 
 
 
__________________ Social Security number (2/16/06) 
 
____________        21.   T Stage 1) T1c vs. 2) T2a - T2b  (AJCC 6th Edition, see Appendix III) 
 
____________        22. Combined Gleason Score of Tumor 1) 2-6 vs. 2)  7 
 
____________      23. PSA  1)  0 - < 10 vs. 2)  10-20 
 
 ____________       24.   Neoadjuvant hormone therapy 1) No vs. 2) Yes 
 
____________      25. Is the patient going to receive Isotope 1)  I-125 or 2)  Pd-103? 
7 
 

 
____________        26. Treatment Start Date 
   
RTOG Institution #  
 
 
RTOG 0232 
 
ELIGIBILITY CHECKLIST (6/11/03) 
Case #   
 
 
(page 3 of 3) 
 
 
___________      
27.   Treatment Assignment 
 
 
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/RTOG audit. 
 
Completed by 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
8 
 

1.0 
INTRODUCTION 
1.1 
Background (1/11/08) 
Approximately 60% to 70% of the men with newly diagnosed adenocarcinoma of the prostate 
present with organ-confined disease.  Conventional treatment options that should be discussed 
with each patient in this category include radical prostatectomy, external beam radiation therapy, 
interstitial brachytherapy and watchful waiting, according to the NCI Consensus Conference in 
1988.1   
 
The use of brachytherapy as the sole modality of treatment for early-stage prostate cancer has 
gained popularity over the past decade due to the advent of the transrectal ultrasound-guided 
technique and the favorable reports of imaged-based brachytherapy with Isotopes Iodine-125 (I-
125) and Palladium 103 (Pd-103).  At the same time, dose escalation 3-dimensional conformal 
radiation therapy (3D CRT) has revealed promising results, especially for patients with early-
stage disease.2-4 The notion of stratifying patients into risk groups according to stage, Gleason 
score and PSA has become helpful for the purpose of comparing outcomes for various modalities 
of therapy.5-14 The definition of "low risk" most often includes those patients with a Gleason sum 
of 6 or less, PSA of 10 or less and patients with stage T2a or less disease.  "Intermediate risk" 
patients generally have up to Gleason 7 disease with a PSA up to 20 and palpable tumor to stage 
T2b.  "High risk" patients generally either have a Gleason score of 8 or above, a PSA above 20 or 
advanced disease on digital exam beyond T2b.  Zelefsky et al4 reported five-year actuarial PSA 
relapse-free survival rate of 85% for low risk patients, 65% for intermediate risk and 35% for high 
risk patients, when treated with 3DCRT.  When their analysis was limited to those of patients who 
received greater than 75.6 Gy, the four-year results reported were 95%, 79% and 60% for the 
low, intermediate and high risk groups, respectively.  Similarly, the five-year PSA control 
outcomes reported by Blasko et al6 for their Pd-103 monotherapy patients were 94%, 82% and 
65% for low, intermediate and high risk categories.  Given the excellent results with either single 
modality for the low risk patient, the challenge to improve on results clearly must be concentrated 
on those categorized in the intermediate and high risk groups. (2/15/05) 
 
The role of brachytherapy as monotherapy for high grade disease is controversial in patients with 
Gleason score 7 to 10 disease which brings a high rate of relapse regardless of the treatment 
approach.  In the series reported by Blasko et al6, 91 patients presented with Gleason 7 or 
greater disease and PSA less than 10; these patients were treated with Pd-103 alone and 
achieved a five-year rate of PSA control of 80%.  Wallner, et al.15 used I-125 monotherapy for a 
similar group of 20 patients with Gleason score of 7 and PSA under 10 and found a control rate of 
70%. In contrast, the Seattle group recently reviewed their long term combined radiation 
experience and found 90% and 80% biochemical control rates at 5 and 15 years, respectively, 
among patients with intermediate risk disease.62  
 
To date, there is no evidence of superiority of one isotope over the other, and in fact, Cha et al.16 
recently compared their I-125 and Pd-103 experience using a matched-pair analysis and were 
unable to demonstrate any statistically significant difference in outcomes of all patients with 
Gleason scores between 2 and 8.  Therefore, it appears reasonable, based on clinical 
observation, to use either isotope as monotherapy.   
 
Some have argued that the combination of external beam radiotherapy with interstitial brachytherapy 
boost may allow for improved outcome in these categories relative to either single modality alone 
particularly for those intermediate risk patients at increased risk for extracapsular spread of disease 
9,14  However, the addition of two modalities of radiation carries the potential risk of increased side 
effects and complications, including bowel and bladder toxicity, sexual difficulties, and an overall 
decrease in the patient’s quality of life.  In addition, the cost of such combination therapy is perhaps 
the highest for any form of treatment for prostate cancer, with published data suggesting Medicare 
patients incur average costs (including six months of follow-up) of more than $15,000 for prostate 
brachytherapy alone, over $19,000 for radical prostatectomy, but more than $24,000 for patients 
undergoing both brachytherapy and external beam therapy.17  These differences are consistent with 
some individual institution-specific data that estimated significant differences in cost between 
prostatectomy and brachytherapy patients, although other investigators did not find significant 
9 
 

differences in charges between the two procedures.18-20  It is expected that reimbursement for such 
combined therapy may become increasingly more difficult in the absence of scientific trials 
demonstrating a benefit for such aggressive therapy. 
 
These studies illustrate, however, the importance of collecting cost data, not just for the peri-
operative period, but also for an extended follow-up period.  If indeed there is a difference in failure-
free survival between the two study arms, such that patients undergoing combined radiation 
modalities have a hypothesized reduction of 33% in the yearly PSA failure rate as compared with 
those receiving brachytherapy alone, then the combined-modality arm may prove to be less costly 
with the inclusion of long-term follow-up cost data.  PSA failures may result in higher utilization of 
medical care, including androgen suppression therapy, palliative treatments of metastatic disease, 
surgical procedures due to advancing local disease, or other procedures or medical interventions.  
Furthermore, disease recurrence may be associated with worsening symptoms, psychological 
implications, and overall decreased quality of life.  Hence, even in the absence of a survival 
advantage, combined modality treatment may offer an improvement in quality-adjusted survival, or 
an advantage in overall costs.  Since no such differences in costs have been linked with outcomes 
on an individual patient level, in the absence of scientific trials demonstrating a benefit for the more 
aggressive therapy, and in the absence of better understanding of the comparative costs and quality 
of life outcomes associated with such treatment, justification for the more aggressive combined 
modality therapy may not be seen as adequate from societal or payor perspectives. 
 
As most patients with intermediate risk prostate cancers survive in the first 5-10 years after 
intervention, the morbidity associated with therapy for early stage prostate cancer is a pivotal 
component of patient outcome. Although traditional, physician-reported toxicity data are a useful 
component for evaluating treatment-related morbidity, it has been shown that patient-report data 
(collected via standardized questionnaires) are more sensitive than physician reports to the full 
severity and broad range of therapy effects on patient Health-Related Quality of Life (HRQOL), 
particularly among men with prostate cancer.21 Attention to this paradigm, for example, recently 
led to evidence of superior HRQOL outcome after 3D-CRT compared to conventional external 
beam radiation for localized prostate cancer.22 Two HRQOL instruments (EORTC-QLQC30-
Prostate Module and Expanded Prostate Cancer Index Composite [EPIC]) have been validated 
for use in subjects undergoing brachytherapy with or without external radiation;23,24 other 
instruments (UCLA-PCI and AUA-SI) have also been applied to evaluate HRQOL effects of 
brachytherapy,  though these lack sensitivity to urinary irritative symptoms and hematochezia.25,26 
These studies showed that HRQOL domains impacted by prostate brachytherapy include urinary 
irritative, bowel, sexual, and (to a lesser extent) urinary incontinence.21,27-30  When neoadjuvant 
hormonal therapy is used, a distinct domain representing vitality and hormonal functioning can be 
impacted also.29 However, neither randomized or prospective studies have been conducted to 
determine whether combining prostate brachytherapy with external radiation leads to different 
HRQOL outcome than prostate brachytherapy alone.  To address this question, this trial will 
compare the treatment arms for differences in HRQOL outcome (as measured by change over 
time in EPIC urinary-irritative, urinary-incontinence, bowel, and sexual domains). 
 
 
The previous experience of the RTOG 98-05 included a Phase II trial in looking at the feasibility of 
I-125 interstitial brachytherapy as monotherapy for low risk patients in an effort to document both 
the feasibility with regard to standardization and quality assurance measures as well as toxicity.  
This was followed by RTOG P-0019, which evaluated patients with intermediate risk, clinically 
localized adenocarcinoma of the prostate and treated them with 45 Gy external beam 
radiotherapy followed two to six weeks later by permanent I-125 brachytherapy to a minimum 
peripheral dose of 108 Gy.  The current trial is intended to evaluate the role of external beam 
radiotherapy with interstitial implant compared to interstitial implant alone for selected patients 
with intermediate risk prostatic carcinoma, including either combined Gleason 7 disease with a 
PSA under 10, or combined Gleason scores less than 7 with a PSA between 10-20.   
 
10 
 

2.0 
OBJECTIVES (1/11/08) 
2.1 
Primary Objective 
2.1.1 
To determine whether combined external beam radiation (EBRT) and transperineal interstitial 
permanent brachytherapy will result in better freedom from progression (FFP) for 5 years 
compared to brachytherapy alone among selected patients with intermediate risk prostatic 
carcinoma.   
2.2 
Secondary Objectives 
2.2.1 
To compare EBRT in addition to transperineal interstitial brachytherapy versus interstitial 
brachytherapy alone as related to: (a) biochemical failure, (b) biochemical failure by the 
Phoenix definition, (c) disease-specific survival, (d) local progression, (e) distant metastases 
and (f) overall survival. 
2.2.2 
To evaluate differences in toxicity and quality of life between EBRT and transperineal interstitial 
brachytherapy arm and interstitial   brachytherapy alone arm. 
2.2.3       Feasibility of collecting Medicare data in large NRG Oncology prostate trial for cost effectiveness 
and cost utility analysis of combined radiation therapy. 
 
2.2.4        Prospectively collect diagnostic biopsy samples for future biomarker analyses. 
 
3.0 
PATIENT SELECTION  
3.1 
Conditions for Patient Eligibility: 
3.1.1 
Histologically confirmed adenocarcinoma of the prostate, clinical stage T1c - T2b (AJCC 6th 
Edition, see Appendix III), N0, M0. Lymph node evaluation by either CT, MRI, or node 
dissection is required. (2/15/05) 
3.1.2 
Zubrod performance status 0-1. 
3.1.3 
Patient must be ≥ 18 years of age. 
3.1.4 
Patients with intermediate risk prostate cancer as determined by one of the following 
combinations: 
Gleason < 7, PSA must be 10-20; Gleason 7, PSA must be < 10. 
3.1.5 
Prostate specific antigen (PSA) prior to study entry (and prior to any hormone treatment if 
given) must be ≤ 20 ng/ml.  
3.1.6 
Neoadjuvant hormonal therapy beginning 2-6 months prior to registration is acceptable. The 
use of 5-alpha reductase inhibitors (for example, finasteride) is allowed prior to registration but 
should be discontinued before registration. (10/11/05) 
3.1.7 
Prostate volumes by TRUS  ≤ 60 cc. 
3.1.8 
AUA voiding symptom scores ≤ 15 (alpha blockers allowed); this is completed by the patient. 
3.1.9 
   Patients must sign a study-specific informed consent form prior to study entry. 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Stage < T1c, T2c, T3 or T4 disease (AJCC 6th Edition, see Appendix III). 
3.2.2 
Lymph node involvement (N1). 
3.2.3 
Evidence of distant metastases (M1). 
3.2.4 
Radical surgery for carcinoma of the prostate, prior pelvic radiation, prior chemotherapy for 
prostate cancer, prior TURP, prior cryosurgery, TUNA, TUMT of the prostate. (2/15/05) 
3.2.5 
Previous hormonal therapy beginning < 2 months or > 6 months prior to registration. The use of 
hormones should not be a planned component of therapy. 
3.2.6 
Previous or concurrent cancers other than basal, in situ, or squamous cell skin cancers unless 
disease-free for ≥ 5 years. 
3.2.7 
Major medical or psychiatric illness, which in the investigator's opinion, would prevent 
completion of treatment and would interfere with follow-up. 
3.2.8 
Hip prosthesis. 
 
4.0 
PRE-TREATMENT EVALUATION 
 
Protocol treatment must begin within four weeks after study entry. 
4.1 
History and physical (to include tumor measurements and DRE) and Zubrod performance status 
(Appendix II). 
4.2 
Histological evaluation of prostate biopsy with assignment of a Gleason score to the biopsy 
material.  
4.3 
Laboratory evaluations to include CBC, platelets, BUN, creatinine, free prostate specific antigen 
(PSA) if available, and PSA.  PSA must be done: 
11 
 

• 
 Within 60 days prior to study entry and prior to prostate biopsy or  
• 
 Within 60 days prior to study entry and at least 10 days after prostate biopsy or 
• 
For patients receiving neoadjuvant hormone therapy, PSA must be done within 60 days 
prior to initiation of hormones. 
Note: PSA obtained > 60 days prior to study entry and/or within 10 days following prostate 
biopsy must not be used for study entry PSA (for those patients not on hormones). 
4.4 
Transrectal ultrasound volume study of the prostate prior to the planned external beam radiation 
therapy.  Patients will be placed in a dorsal lithotomy position with care taken to ensure that the 
patient's spine is centered on the table and that the elevation of the legs is symmetric and can 
reliably be reproduced during the brachytherapy procedure. Transrectal ultrasonography will be 
performed.  Images should be obtained at 5 mm intervals, beginning at the base of the prostate, 
with contouring of the prostatic capsule at each axial image.  A volumetric estimate based on a 
height-, width-, and length-derived formula obtained by the urologist at the time of biopsy may be 
used provided it is less than 50 cc and the investigator is confident in the accuracy of such 
measurement. (10/11/05)  
4.5 
Flexible cystoscopy, if advised by the urologist, may be performed to check for urethral strictures. 
4.6 
Lymph node evaluation must be performed by at least one of the following:  CT or MRI of pelvis, 
or exploratory laparotomy or laparoscopy with lymph node biopsy (sampling). (2/15/05) 
4.7 
AUA Symptom Score completed by the patient (Appendix VI). 
4.8 
EPIC Questionnaire completed by the patient (Appendix X). 
4.9 
EQ5D Questionnaire completed by the patient (Appendix XI).  
4.10 
Utilization of Sexual Medications/Devices completed by the patient (Appendix XII) (10/11/05). 
 
5.0 
REGISTRATION PROCEDURES 
5.1 
Pre-Registration Requirements (10/11/05) 
5.1.1 
Brachytherapy (10/11/05) 
Institutions must be pre-credentialed by the Radiological Physics Center (RPC) prior to 
registering any cases to this study.  The credentialing materials may be found on the RPC 
website at http://rpc.mdanderson.org under the “credentialing” tab. (10/11/05) 
5.1.1.1 
If an institution was credentialed for either of the two previous RTOG prostate brachytherapy 
trials (RTOG 98-05, RTOG P-0019), they do not have to be re-credentialed for this trial if the 
radiation oncologist and physicist are the same as on the approved credentialing request, and 
the institution is using the same I-125 seed model and planning system as on the approved 
credentialing request. (Please note that RTOG 98-05 and RTOG P-0019 only permitted the use 
of I-125.  Thus, if an institution wishes to use Pd-103 and has been previously credentialed for 
I-125, they must complete the RPC’s physics credentialing for this source.)  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, the 
Credentialing Questionnaire, and the Reference Cases.  A change in either the treatment 
planning computer or brachytherapy source model will require resubmission of only the 
Reference Cases. (10/11/05) 
5.1.2 
3D-CRT and IMRT (10/11/05) (2/16/06) 
Only institutions that have met the technology requirements and that have provided the baseline 
physics information that is described in 3D-CRT Quality Assurance Guidelines or the IMRT 
Quality Assurance Guidelines (see ATC website at http://atc.wustl.edu) may enter patients on this 
study. (10/11/05) 
5.1.2.1 
For those institutions wishing to use 3D-CRT techniques, the 3D Questionnaire (one per 
institution, see http://atc.wustl.edu) is to be sent to the Washington University Image-Guided 
Therapy Center (ITC) for review prior to entering any cases. Upon review and successful 
completion of "Dry-Run" or “Benchmark” QA test (See http://atc.wustl.edu), the ITC will notify 
both the registering institution and RTOG Headquarters that the institution is eligible to enter 
patients onto this study. Institutions that have previously enrolled patients on RTOG 94-06 may 
enroll patients on this study without further credentialing by the ITC. (10/11/05) (2/16/06) 
5.1.2.2 
Institutions or investigators anticipating the use of IMRT on this study must complete a new 
IMRT Facility Questionnaire. A copy of the IMRT Facility Questionnaire may be obtained only 
via the ITC website at http://itc.wustl.edu. The IMRT Facility Questionnaire requests information 
regarding the training and experience of the IMRT team, IMRT treatment planning and 
12 
 

treatment equipment, and in-house QA procedures.  All institutions must also successfully 
complete an IMRT “dry-run” or benchmark case with the ITC.  In addition, an IMRT phantom 
study or benchmark case with the RPC (see http://rpc.mdanderson.org) must be successfully 
completed if the institution has not previously met this credentialing requirement on another 
RTOG IMRT study, such as RTOG 0126, 0022, or 0225. (10/11/05) (2/16/06) 
5.1.3 
All institutions must demonstrate the ability to perform electronic data submission to the Image-
Guided Therapy Center (ITC) prior to enrolling patients on this study. Additional information can 
be found on the ITC web site at http://itc.wustl.edu. 
5.2 
Registration (10/11/05) 
Patients can be registered only after eligibility criteria are met.   
 
Institutions must have an RTOG user name and password to register patients on the RTOG web 
site. To get a user name and password: 
 
The Investigator must have completed Human Subjects Training and been issued a 
certificate (Training is available via 
http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp). 
 
The 
institution 
must 
complete 
the 
Password 
Authorization 
Form 
at 
http://www.rtog.org/LinkClick.aspx?fileticket=-BXerpBu5AQ%3d&tabid=219, and fax it 
to 215-923-1737.  RTOG Headquarters requires 3-4 days to process requests and 
issue user names/passwords to institutions. 
 
An institution can register the patient by logging onto the RTOG web site (www.rtog.org), going 
to “Data Center Login" and selecting the link for new patient registrations.  The system triggers 
a program to verify that all regulatory requirements (OHRP assurance, IRB approval) have 
been met by the institution. The registration screens begin by asking for the date on which the 
eligibility checklist was completed, the identification of the person who completed the checklist, 
whether the patient was found to be eligible on the basis of the checklist, and the date the 
study-specific informed consent form was signed. 
 
Once the system has verified that the patient is eligible and that the institution has met 
regulatory requirements, it assigns a patient-specific case number. The system then moves to a 
screen that confirms that the patient has been successfully enrolled.  This screen can be 
printed so that the registering site will have a copy of the registration for the patient’s record.  
Two e-mails are generated and sent to the registering site:  the Confirmation of Eligibility and 
the patient-specific calendar. The system creates a case file in the study’s database at the 
DMC (Data Management Center) and generates a data submission calendar listing all data 
forms, images, and reports and the dates on which they are due.  
 
 
If the patient is ineligible or the institution has not met regulatory requirements, the system 
switches to a screen that includes a brief explanation for the failure to register the patient.  This 
screen can be printed. 
 
In the event that the RTOG web registration site is not accessible, participating sites can 
register a patient by calling RTOG Headquarters at (215) 574-3191. 
  
 
6.0 
RADIATION THERAPY 
6.1 
External Beam Radiation Therapy (Arm 1 only; IMRT is allowed on this protocol) (10/11/05) 
 
Protocol treatment must begin within four weeks after study entry. (2/15/05) 
6.1.1 
Non-IMRT external beam radiotherapy (10/11/05) 
6.1.1.1 
Physical Factors. Megavoltage equipment is required with photon energies ≥ 6 MV.  The 
minimum source to axis distance is 100 cm.  A minimum of four field arrangements (AP:PA:R:L) 
is required.  Greater than four fields are permitted.  3DCRT is permitted, but not required. 
(10/11/05) 
6.1.1.2 
Target Volume. In order to evaluate the adequacy of the field margins, the submitted simulator 
films must contain contrast material in the bladder and/or urethra and the rectum.  A retrograde 
urethrogram is highly recommended.  If targeting is performed from a CT scan and the bladder, 
13 
 

urethra and rectum are outlined on the CT scan and displayed on a digitally reconstructed 
radiograph (DRR), the use of contrast is not required.  Patients will be treated to a CTV that 
includes the prostate and seminal vesicles.  The PTV is equal to the prostate and seminal 
vesicles with a minimum 1 cm margin except posteriorly where it may be less.  The PTV must 
receive at least 95% of the prescribed dose. (2/15/05) (10/11/05) 
6.1.1.3 
Doses. The prostate and seminal vesicles will receive a dose of 45 Gy from the external beam 
portion of the treatment.  Daily doses will be 1.8 Gy given 5 times per week.  The prescribed 
dose will be defined at the ICRU reference point.  The permitted dose variation will be ≤  5%. A 
variation acceptable for the external beam treatment is defined as a dose variation between > 
5% and ≤  10%. A deviation unacceptable is a dose variation > 10%. (10/11/05) 
6.1.1.4 
Copies of simulation films of each field and initial port films, the monitor unit calculation form, 
isodose distribution, treatment prescription, and treatment chart will be sent to NRG Oncology 
only if requested.  Beam verification (port) films must be obtained for each field at least every 2 
weeks during treatment and when any adjustments are made.  Port films of each field will be 
submitted to the NRG Oncology only if specifically requested. (10/11/05) 
6.1.2 
IMRT External Beam Radiotherapy (10/11/05): 
6.1.2.1 
Physical Factors. Megavoltage equipment is required with photon energies ≥ 6 MV. 
(10/11/05) 
6.1.2.2 
Target Volume. In order to evaluate the adequacy of the field margins, the submitted 
simulator films must contain contrast material in the bladder and/or urethra and the rectum.  
A retrograde urethrogram is highly recommended.  If targeting is performed from a CT scan 
and the bladder, urethra and rectum are outlined on the CT scan and displayed on a digitally 
reconstructed radiograph (DRR), the use of contrast is not required.  Patients will be treated 
to a target volume that includes the prostate and seminal vesicles.  PTV is equal to the 
prostate and seminal vesicles with a minimum 0.5 to 1 cm margin.  The PTV must receive at 
least 95% of the prescribed dose. (10/11/05) 
6.1.2.3 
Doses. The prostate and seminal vesicles will receive a dose of 45 Gy from the external 
beam portion of the treatment.  Daily doses will be 1.8 Gy given 5 times per week.  The 
prescribed dose will be defined at the ICRU reference point (defined in accordance with 
ICRU Report 62).  The minimum dose to 98% of the PTV is 45 Gy; the minimum dose 
encompassing the CTV is 45 Gy; the maximum dose to the < 2% of the PTV is < 48.1 Gy 
(no variation), < 49.5 Gy (minor variation) or > 49.5 Gy (major variation). (10/11/05) 
6.1.2.4 
First day orthogonal isocenter verification films, or images, must be obtained.  If 
modifications are made in field shaping or design, orthogonal isocenter verification films, or 
images, are required on the first day’s treatment of that field.  Thereafter, weekly verification 
films or images of orthogonal view are required.  The intensity profiles of each beam must 
be independently verified and compared to the planned field intensity. (10/11/05) 
6.1.2.5 
Credentialing requirements and QA guidelines for institutions planning to participate in this 
study using IMRT can be found at the ATC website http://atc.wustl.edu.  (10/11/05) (2/16/06) 
6.1.3 
External Beam Radiation Toxicity.  All patients will be seen weekly by their radiation oncologist 
during external beam radiation therapy.  Any observations regarding radiation reactions will be 
recorded.  The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting beginning April 1, 2010.  The CTCAE version 4.0 is located on the 
CTEP website at (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
(10/11/05) (3/29/10) 
6.2 
Brachytherapy 
6.2.1 
Timing.  Brachytherapy will be performed 2-4 weeks following completion of external beam 
radiotherapy (Arm 1) or within 4 weeks of study entry (Arm 2). 
6.2.2 
Treatment Volumes: 
6.2.2.1 
Clinical Target Volume.  The CTV is the pre-implant TRUS definition of the prostate. 
6.2.2.2 
Planning Target Volume.  The PTV is an enlargement of the CTV.  (2/15/05) 
6.2.2.2.1 
Laterally the PTV may be extended 2 to 3 mm on each axial slice of the TRUS. 
6.2.2.2.2 
Anteriorly the PTV may be extended 2 to 3 mm on each axial slice of the TRUS. 
6.2.2.2.3 
Posteriorly the CTV and the PTV should have the same border. 
6.2.2.2.4 
In the cranial and caudad directions, the CTV may be extended up to 5 mm. 
6.2.2.3 
Evaluation Target Volume.  The ETV is the post implant CT definition of the prostate. 
14 
 

6.2.3 
Preplan.  The number of slices will be recorded.  Slice spacing will be 5 mm.  The planimetric 
volume of the prostate will be the CTV.  Interoperative preplanning is allowed. 
6.2.4 
Implant Procedure: 
6.2.4.1 
Urethra.  A method of visualizing the urethra will be used during the implant, either a Foley 
catheter or aerated gel. 
6.2.4.2 
Records.  Seed locations, given as a template location and retraction, shall be recorded 
during the procedure.  The location of anchoring devices should also be recorded.  If a 
preplan was generated, this information may be annotated directly on the preplan. 
6.2.4.3 
Radiation Safety.  Federal and state requirements shall be followed and appropriate records 
maintained. 
6.2.5 
Seed Calibration and Handling.  Iodine-125 or Palladium-103 seeds may be used.  The sources 
will be received and inventoried in accordance with state and federal regulations.  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.  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.31 
6.2.5.1 
Assay performed by a third party, such as a third party vendor, is allowed as long as the 
assay fulfills the requirements listed in Section 6.2.5. (2/15/05) 
6.2.6 
Source Strength.  For Iodine-125, the allowable source strength for each seed is 0.277 U to 
.548 U (NIST 99 or later).  For Palladium-103 sources, this is 1.29 U to 2.61 U (NIST 99 or 
later). (2/15/05) 
6.2.7 
Brachytherapy Dosimetry.  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 
Group43 and subsequent published AAPM Subcommittee Reports.31,32,58-61  The AAPM’s 
recommendations for Pd-103 dose specifications and prescription are being followed. 
6.2.8 
Prescribed Dose.  The prescription doses for Iodine-125 are 145 Gy and 110 Gy for 
monotherapy and boost implants, respectively.  For Palladium-103 this is 125 Gy and 100 Gy 
for monotherapy and boost implants. The prescription dose minimum peripheral dose (mPD) is 
intended to be delivered to the CTV and is the reference dose for the implant.   
 
 
Procedure 
Dose I-125 
Dose Pd-103 
Boost Therapy 
110 Gy 
100 Gy 
Monotherapy 
145 Gy 
125 Gy 
 
6.2.9 
Post Implant Dosimetric Analysis.  A CT scan will be performed 3 to 5 weeks following the 
implant.  The patient will be scanned in a supine position.  IV and/or bladder contrast may be 
used.  Abutting slices of 3 mm or less will be acquired from 2 cm cephalad to the base of the 
gland to 2 cm caudad to the apex.  All of the seeds used in the implant should be encompassed 
in the scan.  The ETV shall be determined from this scan, as shall the location of the urethra 
and the rectum.  These are the critical structures for this protocol.  Due to the difficulty in CT 
visualization of the urethra, Foley catheterization is recommended. If catheterization is not 
performed, the urethra will not be contoured. The urethra and the rectum contours are to be 
drawn as the outer surface of the Foley catheter and rectal walls, respectively.  The CT scan 
will be used to create a post-implant treatment plan (post plan).  An AP or anterior oblique 
pelvic radiograph will be used to verify the number of sources and this will be recorded on the 
T5 form. A PA and lateral chest x-ray will be obtained to document any pulmonary source 
migration. 
6.2.9.1 
Planning System Calculation Requirements: 
6.2.9.1.1 
The planning system will be able to perform structure-based analysis from axial image 
sets.  This shall include isodose display and generation of Dose-Volume Histograms 
(DVH). 
6.2.9.1.2 
The calculation grid should be set no larger than (2mm x 2mm x the axial slice width). 
6.2.9.1.3 
The planning system shall be capable of transmitting data via DICOM RT to the ITC 
electronically. Please see Appendix VII. 
15 
 

6.2.9.2 
Reporting.  Guidelines established by the American Brachytherapy Society33 are to be 
followed.  DVH-based analysis must be used in the post plan 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. 
6.2.9.2.1 
Coverage.  V100, V90, V80, D90. 
6.2.9.2.2 
Uniformity.  V150. 
6.2.9.2.3 
Urethra.  The maximum dose to the urethra and volume of urethra (in cm3) that received 
more than 200% of the prescription dose [U200(cc)]. 
6.2.9.2.4 
Rectum.  The outer rectal wall will be contoured behind every axial slice of the prostate.  
The maximum dose to the rectum and the volume of the rectum (in cm3) that received 
more than 100% of the prescription dose [R100(cc)]. 
6.2.10 
Post-Implant Confirmation.  Following implantation, cystoscopy may be performed to retrieve 
any seeds from the bladder or the urethral wall.  An x-ray film will be taken post-implant to verify 
seed position. 
6.2.11 
Post-Operative Care.  A Foley catheter may be left indwelling until the patient recovers fully 
from anesthesia.  If the patient has significant symptoms of prostatism, the catheter may be left 
in place for several days as needed. 
6.2.12 
Evaluation Criteria: 
6.2.12.1 
Per protocol:  D90 for the ETV is greater than 90% of the prescription dose but less than 
130% of the prescription dose. 
6.2.12.2 
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. 
6.2.12.3 
Deviation unacceptable:  D90 for the ETV is less than 80% of the prescription dose. 
6.2.13 
Dosimetric Data to be Submitted to the ITC: 
6.2.13.1 
Copies of pre-implant TRUS images with CTV and PTV annotated. 
6.2.13.2 
A copy of the implant record generated during the procedure. 
6.2.13.3 
A copy of the film taken after the procedure and a copy of the film or scout taken during the 
post implant CT. 
6.2.13.4 
A copy of the post implant CT scan, ETV and urethra and rectum delineation and dosimetry 
calculations (must be submitted electronically). 
6.2.13.5 
A copy of the post implant dosimetry report the (T5 Form, Appendix VIII) that contains the 
information required in paragraph 6.2.9 above. 
6.3 
Radiation Toxicity (3/29/10)  
6.3.1 
All patients will be seen weekly by their radiation oncologist during radiation therapy. Any 
observations regarding radiation reactions will be recorded and should include attention toward 
the following potential side effects: 
6.3.1.1 
Small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal urgency, 
proctitis, or hematochezia 
6.3.1.2 
Bladder complications including urinary frequency/urgency, dysuria, hematuria, urinary tract 
infection, and incontinence 
6.3.1.3 
Radiation dermatitis 
6.3.2 
Clinical discretion may be exercised to treat side effects from radiation therapy. Rectal side 
effects such as diarrhea may be treated with drugs such as Diphenoxylate or Loperamide or 
similar drugs. Bladder or rectal spasms can be treated with anticholinergic or Tolterodine. 
Bladder irritation can be managed with Phenazopyridine and/or an alpha blocker. Erectile 
dysfunction can be treated with Sildenafil. 
6.3.3 
Acute toxicity monitoring: Beginning April 1, 2010, acute (≤ 180 days from RT start) side effects 
of radiation therapy will be documented using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. The CTCAE version 4.0 is located on the CTEP website 
at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
6.3.4 
Late toxicity monitoring: All late (> 180 days from RT start) side effects will be evaluated and 
graded according to the RTOG/EORTC Late Radiation Morbidity Scoring Scheme (Appendix 
IV). 
6.4 
Radiation Adverse Event Reporting (10/2/15) 
6.4.1 
Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting Requirements 
16 
 

 
Adverse events (AEs) as defined in the tables below and all serious adverse events 
(SAEs) will be reported to the Cancer Therapy Evaluation Program (CTEP) via the CTEP 
Adverse Event Reporting System (CTEP-AERS) application as directed in this section. 
 
 
Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite). [CTEP, NCI Guidelines: 
Expedited Adverse Event Reporting Requirements.] 
 
 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes: 
 Death; 
 A life-threatening adverse experience; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect. 
 
 
Important medical events that do not result in death, are not life threatening, or do not 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. 
 
Pharmaceutically supported studies will require additional reporting over and above that which 
is required by CTEP.  
 
SAEs (more than 30 days after last treatment) attributed to the protocol treatment (possible, 
probable, or definite) should be reported via CTEP-AERS. 
 
 
Note: All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. “On study” is 
defined as during or within 30 days of completing protocol treatment. 
 
 
CTEP-AERS REPORTING REQUIREMENTS  
 
 
CTEP-AERS provides a radiation therapy (RT)-only pathway for events experienced involving 
RT only, both with and without a drug component arm. Events that occur on the RT-only arm of 
a study with a drug component must be reported for purposes of comparison. Events that occur 
on an RT-only study without a drug component also must be reported. Events involving RT-only 
must be reported via the CTEP-AERS RT-only pathway. 
 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for AE reporting beginning April 1, 2010. The CTCAE version 4.0 is located on the CTEP 
website 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) that meet the criteria defined 
above experienced by patients accrued to this protocol must be reported to CTEP as 
indicated in the following tables using the CTEP-AERS application. CTEP-AERS can be 
accessed via the CTEP web site  
(https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613). Use the patient’s 
case number without any leading zeros as the patient ID when reporting via CTEP-AERS. In 
order to ensure consistent data capture, AEs and SAEs reported using CTEP-AERS must also 
be reported to NRG Oncology on the appropriate case report form (see Section 12.1). In 
addition, sites must submit CRFs in a timely manner after CTEP-AERS submissions. 
 
 
17 
 

 
Any event that meets the above outlined criteria for an SAE but is assessed by the 
CTEP-AERS System as “expedited reporting NOT required” must still be reported for 
safety reasons. Sites must bypass the “NOT Required” assessment and complete and 
submit the report. The CTEP-AERS System allows submission of all reports regardless 
of the results of the assessment. 
 
 
CRITERIA FOR CTEP-AERS REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS THAT OCCUR WITHIN 30 DAYS OF THE DATE OF THE 
LAST PROTOCOL TREATMENT 
 
 
 
 
3 
3 
4 & 5 
4 & 5 
Unexpected 
Expected 
 
Unexpected 
 
Expected 
With 
Hospitalization 
Without 
Hospitalization 
With 
Hospitalization 
Without 
Hospitalization 
Unrelated 
Unlikely 
10 Calendar 
Days 
Not Required 
10 Calendar 
Days 
Not Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
10 Calendar 
Days 
10 Calendar 
Days 
10 Calendar 
Days 
Not Required 
24 Hour: 5 
Calendar 
Days 
10 
Calendar 
Days 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS within 24 
hours of learning of the event followed by a complete CTEP-AERS report within 5 calendar days of the 
initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted within 10 calendar 
days of the investigator learning of the event.  
• 
Any medical event equivalent to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 grade 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must 
be reported regardless of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions.   
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth 
defects must be reported via CTEP-AERS if the event occurs following protocol treatment or procedure. 
• 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration on all 
reports. 
 
 
 
CRITERIA FOR CTEP-AERS REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS THAT OCCUR > 30 DAYS AFTER THE DATE OF THE LAST 
PROTOCOL TREATMENT 
 
 
 
 
3 
3 
4 & 5 
4 & 5 
Unexpected 
Expected 
 
Unexpected 
 
Expected 
With 
Hospitalization 
Without 
Hospitalization 
With 
Hospitalization 
Without 
Hospitalization 
Unrelated 
Unlikely 
Not required 
Not required 
Not required 
Not Required 
Not required 
Not 
required 
Possible 
Probable 
Definite 
10 Calendar 
Days 
Not required 
Not required 
Not Required 
24 Hour: 5 
Calendar 
Days 
10 
Calendar 
Days 
 
NRG ONCOLOGY REPORTING REQUIREMENTS (3/29/10) 
 
CTEP-AERS provides a radiation therapy (RT)-only pathway for events experienced involving RT only, 
both with and without a drug component arm. Events that occur on the RT-only arm of a study with a drug 
18 
 

component must be reported for purposes of comparison. Events that occur on an RT-only study without 
a drug component also must be reported. Events involving RT-only must be reported via the CTEP-AERS 
RT-only pathway. 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting beginning April 1, 2010. The CTCAE version 4.0 is identified and located on the CTEP website 
at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) that meet the criteria defined above 
experienced by patients accrued to this protocol must be reported via CTEP-AERS.  Contact the 
CTEP Help Desk if assistance is required. 
 
If supporting source documentation is requested by NRG Oncology, it must be properly labeled 
with the NRG Oncology study/case numbers and the date of the adverse event and must be faxed 
to the NRG Oncology dedicated AE/SAE FAX, 215-717-0990, before the 5- or 10-calendar-day 
deadline. All forms submitted to NRG ONCOLOGY also must include the NRG ONCOLOGY study/ 
case numbers; non-NRG ONCOLOGY intergroup study and case numbers must be included, when 
applicable. CTEP-AERS Reports are forwarded to NRG ONCOLOGY electronically via the CTEP_AERS 
system. Use the patient’s case number as the patient ID when reporting via CTEP-AERS.  
 
Any late death (more than 30 days after last treatment) attributed to the protocol treatment (possible, 
probable or definite) should be reported via CTEP-AERS within 24 hours of discovery.  An expedited 
report, if applicable, will be required within 5 or 10 calendar days. 
 
6.4.2 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
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 during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS . In addition, secondary 
malignancies following radiation therapy must 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. 
 
7.0 
DRUG THERAPY 
 
Not applicable to this study. 
 
8.0 
SURGERY 
 
Not applicable to this study. 
 
9.0 
OTHER THERAPY 
19 
 

9.1 
Neoadjuvant Hormone Therapy  
 
Neoadjuvant hormone therapy is permitted if initiated between 2-6 months prior to registration. 
The duration may not exceed 6 months. Hormone therapy is not allowed to begin at initiation of or 
during radiation treatment. It is important to document neoadjuvant hormone therapy until its 
completion. Extended use of hormone therapy could confound the effects related to the 
biochemical control and quality of life endpoints. 
 
10.0 
PATHOLOGY (4/3/08) 
 
(FOR PATIENTS WHO HAVE CONSENTED TO PARTICIPATE IN THE TISSUE COMPONENT OF THE STUDY; SEE 
APPENDIX IB) 
10.1 
Central Review 
10.1.1 
The investigators at the treating institutions are strongly encouraged to recruit patient 
participation in the central review component of this trial. Slides/blocks from the pre-treatment 
diagnostic prostatic biopsy will be reviewed to confirm Gleason score and to record other 
histopathologic features, such as the extent of tumor in the biopsies, the number of biopsies 
positive, and mitotic index. 
 
10.2 
Collection of Tissue For Translational Research 
10.2.1 
NRG Oncology has been collecting diagnostic tissue from prostate cancer protocols using the 
original diagnostic material for several years. A number of histologic, cell kinetic/proliferation, 
and molecular markers are under investigation, with several showing promise for the 
stratification of patients in future trials. The results of these ongoing studies will lead to the 
investigation of promising similar or new biomarkers with the goals of 1) identifying factors 
predictive of outcome such that patients may be better stratified in future trials, and 2) 
developing novel treatment strategies which target the molecular abnormalities identified.  A 
final decision on which markers will be studied awaits the results of completed NRG Oncology 
prostate cancer trials that have reached maturity. The trial described here will not be ready for 
biomarker analysis for several years. The goal is to measure approximately ten biomarkers 
using the archived pathologic material.  
 
10.3 
NRG Oncology Biospecimen Bank  
10.3.1 
Rationale 
The purpose of the NRG Oncology Biospecimen Bank is to acquire and maintain high quality 
specimens from NRG Oncology trials, to provide uniform access of such tissues to investigators 
for correlative studies, and to preserve tissue from each block through careful block storage 
and processing.  Correlative studies from these specimens are meant to integrate new research 
findings into future protocol development and to educate NRG Oncology members. 
10.3.2 
Central Pathology Review (strongly encouraged) (2/15/05) 
All consenting patients must have at least one H & E slide from each positive biopsy site 
submitted to the NRG Oncology Biospecimen Bank in order for the case to be evaluable for 
central pathology review. (2/15/05) The following must be provided: 
10.3.2.1 
One H &E stained slide per positive biopsy site; 
10.3.2.2 
A Pathology report documenting that submitted blocks, core, or slides contain tumor; the 
report must include the NRG Oncology protocol number and the patient’s case number. The 
patient’s name and/or other identifying information should be removed from the report; 
10.3.2.3 
A Pathology Submission Form clearly stating that the tissue is being submitted for the 
central review; the form must include the NRG Oncology protocol number and patient’s case 
number.  
10.3.3 
Tissue Banking for Biomarker Studies 
 
The investigators at the treating institutions are strongly encouraged to recruit patient 
participation in the translational research component of this trial. The following must be 
provided in order for the case to be evaluable for the NRG Oncology Biospecimen Bank: 
10.3.3.1 
At least one paraffin-embedded tissue block of the tumor (containing the highest grade of 
tumor if multiple biopsy sites contain cancer), a 2 mm core of tumor from the block, obtained 
with a derm punch or similar device, or 15 unstained slides. Kits for punching blocks can be 
obtained free of charge from the NRG Oncology Biospecimen Bank. Blocks/core/slides must 
20 
 

be clearly labeled with the pathology identification number that agrees with the pathology 
report; 
10.3.3.2 
A Pathology Report documenting that submitted blocks, core, or slides contain tumor; the 
report must include the NRG Oncology protocol number and patient’s case number. The 
patient’s  name or other identifying information should be removed from the report; 
10.3.3.3 
A Pathology Submission Form clearly stating that tissue is being submitted for the NRG 
Oncology Biospecimen Bank; the form must include the NRG Oncology protocol number 
and patient’s case number; 
10.3.3.4 
A copy of the patient’s tissue consent form; the consent form must include the NRG 
Oncology protocol number and the patient’s case number. The patient’s name and/or 
identifying information should be removed from the consent form. 
 
 
 
 
 
 
 
 
 
 
10.3.4 
Submit materials (for central review or tissue banking) to: 
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, DHL, etc.): For Frozen Specimens 
NRG Oncology Biospecimen Bank – San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-RTOG (7864)/FAX 415-476-5271; NRGBB@ucsf.edu 
 
10.4 
Reimbursement 
10.4.1 
NRG Oncology will reimburse pathologists from submitting institutions $200 per case if a block 
or core of material is submitted and $100 per case if unstained slides are submitted. After 
confirmation from the NRG Oncology Biospecimen Bank that appropriate materials have been 
received, NRG Oncology Administration will prepare the proper paperwork and send a check to 
the institution. 
 
10.5 
Confidentiality (See RTOG Patient Tissue Consent Frequently Asked Questions, 
http://www.rtog.org/tissuebank/tissuefaq.html for further details) 
10.5.1 
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 includes only 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. 
10.5.2 
The specimens will be stored for an indefinite period of time. If at any time the patient withdraws 
consent to store and use specimens, the material will be returned to the institution that 
submitted it. 
21 
 

 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters (10/11/05) 
 
Follow upe 
 (Interval in months) 
Parameters 
Pre-treatment 
Weekly During 
RT 
Post-
implant 
4 
6 
9 
12 
18 
24 
History, Physical Exam (DRE) 
X 
Xi 
 
Xi 
X 
X 
X 
X 
X 
Zubrod Performance Status 
X 
X 
 
X 
X 
X 
X 
X 
X 
Tumor Measurement 
X 
 
 
X 
X 
X 
X 
X 
X 
Prostate biopsy with Gleason 
scoref 
X 
 
 
 
 
 
 
 
 
CBC, platelets 
X 
Xd 
 
 
 
 
 
 
 
BUN, creatinine 
X 
 
 
 
 
 
 
 
 
PSA (pre-HT, if given) 
Xa 
 
 
 
X 
 
X 
X 
X 
Free PSA (if available) 
Xc 
 
 
 
 
 
X 
 
X 
TRUS 
X 
 
 
 
 
 
 
 
 
Flexible Cystoscopy 
Xc 
 
 
 
 
 
 
 
 
Lymph node assessment 
Xb 
 
 
 
 
 
 
 
 
Post-Implant prostate CTh 
 
 
X 
 
 
 
 
 
 
Post-Implant pelvic AP or 
anterior oblique X-rayh 
 
 
X 
 
 
 
 
 
 
Post-Implant chest PA and 
lateral X-rayh 
 
 
X 
 
 
 
 
 
 
AUA Symptom Indexg 
X 
 
 
X 
 
 
X 
 
X 
EPIC Questionnaireg 
X 
 
 
X 
 
 
X 
 
X 
EQ5D Questionnaireg 
X 
 
 
X 
 
 
X 
 
X 
Utilization of Sexual 
Medications/Devicesg 
X 
 
 
X 
 
 
X 
 
X 
Toxicity Evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
 
a. PSA must be done: 
• 
Within 60 days prior to study entry and prior to prostate biopsy or  
• 
Within 60 days prior to study entry and at least 10 days after prostate biopsy or 
• 
For patients receiving neoadjuvant hormone therapy, PSA must be done within 60 days prior to 
initiation of hormones.  
Note:  PSA obtained > 60 days prior to study entry and/or within 10 days following prostate biopsy must not 
be used for study entry PSA (for those patients not on hormones). 
b. Diagnostic pelvic CT scan or MRI and/or pelvic lymphadenectomy (2/15/05) 
c. Optional 
d. As indicated 
e. Follow up 3-5 weeks post-implant, then every 4, 6, 9 and 12 months post treatment start for year 1; every 6 
months for four years; then annually for the rest of the patient’s life. (2/15/05) 
f. At time of PSA failure 
 
g. AUA is to be administered prior to registration. EPIC, Utilization of Sexual Medications/Devices, and EQ5D 
are to be administered at baseline (between study entry and treatment start). Then all four at 4, 12, and 24 
months after treatment start (either implant or external beam), then annually thereafter for three years. 
(10/11/05) 
h.  Post-implant prostate CT, pelvic AP or anterior oblique x-ray, as well as chest PA and lateral x-ray to be 
performed 3-5 weeks post-implant. (10/11/05) 
i. DRE is optional. (10/11/05) 
 
11.2 
Follow-up Schedule  
11.2.1 
Initial follow-up visit within 3-5 weeks of implant to coincide with post-implant CT. 
11.2.2 
After initial follow-up visit, follow-up will be done at 4, 6, 9 and 12 months post treatment start. 
11.2.3 
Then, every six months until five years post-implant. 
22 
 

11.2.4 
Then, annually thereafter. 
11.2.5 
A bone scan will be performed on any patient who presents with complaints of bone pain that 
cannot be attributed to any intercurrent disease.  Discretionary plain films may be needed to 
evaluate lesions seen on bone scan to confirm the diagnosis of metastatic disease.   
11.2.6 
HRQOL will be measured by administering EPIC, EQ5D, and AUA-SI at baseline and then at 4, 
12, and 24 months after treatment start, then annually thereafter for three years.  The Utilization 
of Sexual Medications/Devices will be administered to assess utilization of medications and 
devices for erectile dysfunction and effectiveness of such interventions, as reported by patients 
before and after definitive brachytherapy for prostate cancer; this tool also will be administered 
at baseline; at 4, 12, and 24 months after treatment start; then annually thereafter for three 
years. (10/11/05) 
11.2.6.1 
Method for patients to complete/record HRQOL survey responses: The HRQOL instruments 
will be self-administered by the patient at the beginning of each scheduled study clinic visit. 
The patient’s self-reported quality of life will be assessed using the prostate cancer-specific 
EPIC, the EQ5D, and the AUA-SI. In addition, the patient-completed Utilization of Sexual 
Medications/Devices will be collected to provide a context for interpreting the sexual domain 
score of the EPIC questionnaire. The time needed for filling out the questionnaires is 
estimated at 25 to 30 minutes.  The patient will be given the questionnaires directly PRIOR 
to being seen by the physician or nursing staff or having any tests/procedures done at the 
clinic visit.  If the patient does not come in for a clinic visit, then questionnaires should be 
mailed to the patient at the time points indicated. There is a Spanish version of the EPIC 
questionnaire available; there are several official language versions of the EQ-5D available.  
(10/11/05) 
11.2.6.2 
Instructions for Clinical Research Associates (CRAs): The instructions given below (i through 
vii) are intended to serve as a guide for the administration of the HRQOL questionnaires.  
The HRQOL questionnaires will be self-administered by the patient. 
i. 
Following the patient’s check-in at clinic, the patient should be taken to a quiet 
area where he may complete the questionnaire without interruption.  Adequate 
time should be provided to the patient so that the questionnaire can be 
completed at the beginning of the clinic visit. 
ii. 
The patient will be given the questionnaire PRIOR to being seen by the 
physician or nursing staff or having any tests/procedures done at the clinic visit.  
iii. 
The patient should be instructed to read the brief directions at the top of the 
page.  After it has been confirmed that the patient understands the directions, 
he should be encouraged to complete every item in order without skipping any.  
Some patients may feel that a given question is not applicable to them and will 
therefore skip the item altogether.  Patients should be encouraged to circle 
the response that is most applicable.  If, for example, a patient is not 
bothered at all by a particular problem, the patient should circle “no problem”, 
“not at all”, “none of the time”, rarely or never”. 
iv. 
The questionnaires must be completed by the patient alone, without coaching 
or suggestions as to the “correct” answer by health care personnel, relatives, or 
anyone else. 
v. 
The study staff may provide clarification but should not rephrase questions, 
suggest answers, or discuss answers.   
vi. 
The study staff will collect the questionnaires as soon as they have been 
completed, check to see that each question has been answered, and remind 
the patient to answer any questions that may have been missed.  If the patient 
declines to answer some or any of the questions, the study staff should enter 
an explanatory comment on the questionnaires. 
vii. 
The questionnaires should be completed in the clinic at the beginning of the 
visit.  However, if the patient does not come in for a clinic visit, the 
questionnaires should be mailed to the patient at the time points indicated.  
(These patients may not return for follow-up and then the data would be 
23 
 

lost). NOTE:  Varying the environment in which the questionnaires are 
completed by allowing completion at other times than the time of the clinic visit 
introduces unnecessary variables into the study. The information provided by 
the patient in the completed questionnaires is confidential and should not be 
discussed with, or shown to, anyone who is not a member of the study team. 
 
11.3 
Measurement of Effect/Response (1/11/08) 
Prostate tumor dimensions in centimeters should be calculated from physical exam and should 
be recorded at entry to study. 
11.3.1 
No Evidence of Disease (NED):  No clinical evidence of disease on digital rectal examination 
and no PSA failure. 
11.3.2 
Equivocal Disease (ED):  This rating will be assigned under the following circumstances: 
1. If abnormalities are present on the prostate digital rectal examination but are thought to be 
abnormal due to treatment and felt not to represent tumor. 
2. If clinical evidence of residual tumor is present but this has regressed from a previous 
examination (initial registration). 
3. If PSA failure occurs (as described in Section 11.3.5) within 24 months post-implant (due to 
possibility of “PSA bounce”, see 11.3.5.3). 
11.3.3 
Locally Progressive Disease (PD):  This rating will be assigned when there is clinical evidence 
in the prostate gland of disease progression or recurrence.  Only those patients with 
progressive disease on digital rectal examination will be scored as digital examination failure.  
The time of failure will be backdated to the first occurrence of equivocal disease after a prior 
normal examination or to the end of radiation therapy treatment if a normal digital rectal 
examination was never achieved.  Re-biopsy of the suspicious area must be done to document 
disease. 
11.3.4 
Time to BiochemicalFailure:  Biochemical failure as defined below: 
11.3.4.1 
Failure is defined as having three consecutive rises of post-treatment PSA at the specified 
intervals or starting hormones after one or more elevations of post-treatment PSA but before 
three consecutive elevations are documented.  If three consecutive PSA rises occur during 
the first 24 months followed by a subsequent non-hormonal induced PSA decrease, patients 
will not be considered PSA failures. Three consecutive rises with any of the three PSA 
values occurring more than 24 months after the implant procedure will constitute 
biochemical (PSA) failure. Starting hormones for any rise at any time will be considered 
failure. The failure day is the midpoint between the last non-rising PSA and first PSA rise. 
ASTRO consensus guidelines34 of rising PSA will be used.  Every effort should be made to 
withhold further therapy until clinical relapse is evident. 
 
In the case of PSA failure, the site of failure should be ascertained before instituting further 
therapy. This would include bone scan and pelvic CT. Re-biopsy of the prostate should be 
performed to determine local control. Intervention depending upon the site(s) of recurrence 
will be left to the discretion of the individual investigator.  
11.3.4.2 
The sum of the rises in three consecutive rises of post-treatment PSA must exceed 1 ng/mL 
above the nadir.  
11.3.4.3 
As a benign  “spike” or “bounce” in the PSA value has been described in as many as 35% of 
patients 12-36 months following brachytherapy, intervention for a PSA failure should be 
based on a positive re-biopsy at least 24 months post-treatment and/or clinical evidence of 
distant relapse (i.e., bone scan, CT scan, etc).  
11.3.5 Time to Biochemical Failure by the Phoenix Definition  
Failure is defined as having PSA ≥ 2 ng/ml over the nadir PSA after 24 months. In the case 
of PSA failure, the site of failure should be ascertained before instituting further therapy. This 
would include bone scan and pelvic CT. Re-biopsy of the prostate should be performed to 
determine local control. Intervention depending upon the site(s) of recurrence will be left to 
the discretion of the individual investigator.  
11.3.6 
Time to Local Progression:  The time to progression will be measured from the date of 
randomization to the date of documented local progression as determined by clinical exam. 
11.3.6.1 
Clinical criteria for local failure are progression (increase in palpable abnormality) at any 
time, failure of regression of the palpable tumor by two years, and redevelopment of a 
24 
 

palpable abnormality after complete disappearance of previous abnormalities. Needle 
biopsy is recommended.   
11.3.6.2 
Histologic criteria for local failure are presence of prostatic carcinoma upon biopsy and 
positive biopsy of the palpably normal prostate more than two years after the start of 
treatment.   
11.3.7 Time to Distant Failure:  The time to distant failure will be measured from the date of randomization 
to the date of documented metastatic disease determined by radiographic criteria and/or tissue 
confirmation. 
11.3.8 Overall Survival:  The survival time will be measured from the date of randomization to the date of 
death.  All patients will be followed for survival.  Every effort should be made to document the 
cause of death.  Post-mortem examination will be carried out when feasible, and a copy of the 
final autopsy report sent to NRG Oncology. 
11.3.9 Disease-Specific Survival: Disease-specific survival duration will be measured from the date of 
randomization to the date of death due to prostate cancer. Causes of death may require review 
by the study chair or their designee. Death due to prostate cancer will be defined as: 
 
11.3.9.1 
Primary cause of death certified as due to prostate cancer. 
11.3.9.2 
Death in association with any of the following conditions: 
• Further clinical tumor progression occurring after initiation of "salvage" anti-tumor (e.g., 
(androgen suppression) therapy. 
•   A rise (that exceeds 1.0 ng/ml) in the serum PSA level on at least two consecutive 
occasions that occurs during or after "salvage" androgen suppression therapy. 
•   Disease progression in the absence of any anti-tumor therapy.  
11.3.9.3    
Death from a complication of therapy, irrespective of disease status. 
11.4 
Acute vs. Late Toxicity  
11.4.1 
Acute toxicity monitoring: Acute side effects ( ≤ 180 days from RT start) will be documented 
using the using the NCI Common Toxicity Criteria version 2.0.  
11.4.2 
Late toxicity monitoring:   All  late ( > 180 days from RT start) side effects will be evaluated and 
graded according to the RTOG/EORTC Late Radiation Morbidity Scoring Scheme (Appendix 
IV). 
25 
 

 
12.0 
DATA COLLECTION (1/11/08) 
 
NRG Oncology, 1818 Market Street, Suite 1720, Philadelphia, PA 19103, FAX# 215/928-0153 (2/15/05) 
12.1 
Summary of Data Submission (10/11/05) (4/3/08) 
Item 
 
Demographic Form (A5) 
Initial Evaluation Form (I1) 
Pathology Report (P1) 
Slides/Blocks (P2) 
AUA Scoring Form (PQ) 
EPIC (FA) 
EQ5D (QF) 
Utilization of Sexual Medications/Devices 
(SA) 
 
External Beam Dosimetry 
Radiotherapy Form (T1)* 
 
Initial Followup Form (FS) 
 
 
Followup Form (F1) 
 
 
 
 
 
 
 
 
AUA Scoring Form (PQ) 
HRQOL (EPIC [FA], EQ5D [QF], 
Utilization of Sexual Medications/Devices 
[SA]) 
 
Autopsy Report (D3) 
 
Due 
 
Within 2 weeks of study entry 
 
 
 
 
 
 
 
 
 
Within 8 weeks post-implant to NRG Oncology 
 
 
At 6 and 16 weeks after treatment start (EBRT 
Arm 1, implant Arm 2)  
 
At 6, 9 and 12 months post treatment start 
(EBRT Arm 1, implant Arm 2); then q 6 months x 
4 years, then annually.  Also at 
progression/relapse and at death. 
 
 
 
 
 
At 4, 12, and 24 months post treatment start, 
then annually for three years. 
 
 
 
As applicable. 
* NOTE: Copies of simulation and port films and Isodose Distribution for EBRT including IMRT (Arm 1 
only) will be submitted to NRG Oncology ONLY if specifically requested. (10/11/05) (4/3/08) 
 
 
12.2 
Summary of RT QA Requirements (Image-Guided Therapy Center [ITC]) 
Submit to ITC via ATC website at http://atc.wustl.edu (10/11/05) 
 
12.2.1 
Brachytherapy (10/11/05) 
Final Dosimetry Information (Digital 
Data): 
(Final dosimetry information will be 
based upon the post implant CT study) 
 
Post-Implant Form (Appendix VIII) (T5) 
CT Data 
Contours 
Dose Distributions 
Within 8 weeks post-implant 
 
 
 
 
 
 
 
 
 
26 
 

12.2.2 (4/3/08) 
Final Dosimetry Information: 
 
Copy of Radiotherapy Form (T1) 
COPY TO ITC and NRG 
Oncology HQ 
 
Daily Treatment Record 
COPY TO ITC and NRG 
Oncology HQ 
 
 
Within 1 week of RT end 
 
 
 
 
 
 
 
 
12.2.3 For Mail or Federal Express (10/11/05) 
 
Image-Guided Therapy Center (ITC) 
4511 Forest Park Avenue, Suite 200 
St. Louis, MO  63108 
(314) 747-5414; FAX (314) 747-5423 
 
12.2.4 
To send over Internet or using magnetic tape (10/11/05) 
 
Digital data submission may be accomplished using magnetic tape or the Internet.  For network 
submission, the ftp account assigned to the submitting institution shall be used and e-mail 
identifying the data set(s) being submitted shall be sent to: 
 
itc@castor.wustl.edu 
 
 
For tape submission, please contact the ITC about acceptable tape types and formats. 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Endpoints (1/11/08) 
13.1.1 Primary Endpoint 
Freedom from Progression (FFP): The event for FFP will be the first occurrence of the biochemical 
failure (see Section 11.3.4), clinical failure (local progression or distant metastases) or death due to 
any cause from the start of protocol treatment. Patients who are failure event free with less than 5 
years of follow-up or who receive any secondary salvage therapy (e.g., salvage androgen 
deprivation, vaccine therapy, biologic/small molecule therapy, or chemotherapy) will be censored. 
13.1.2 Secondary Endpoints 
• 
Biochemical  Failure (see Section 11.3.4) 
• 
Biochemical failure by the Phoenix definition (see Section 11.3. 5) 
• 
Disease-Specific Survival (see Section 11.3.9) 
• 
Local Progression (see Section 11.3. 6) 
• 
Distant Metastases (see Section 11.3.7) 
• 
Overall Survival (see Section 11.3.8) 
• 
Incidence of “acute” toxicities (based on CTC, v. 2.0.) 
• 
Time to “late” 3+ toxicities (based on CTC, v. 2.0.) 
• 
Early (4 months after therapy start) and late (2 years after therapy start) HRQOL change in 4 
domains: HRQOL change is defined as HRQOL measured at baseline minus HRQOL 
measured at regular intervals in follow-up. 
• 
Feasibility of collecting Medicare data in large NRG Oncology prostate trial for cost 
effectiveness and cost utility analysis of combined radiation therapy. 
• 
Prospectively collect diagnostic biopsy samples for future biomarker analyses 
 
13.2 
Sample Size (1/11/08) 
13.2.1 Stratification: Patients will be stratified before randomization with respect to Stage (T1c vs. T2a-T2b), 
PSA (0 - <10 vs. 10-20), Gleason score (2-6 vs. 7), and neoadjuvant hormonal therapy (no vs. yes).  
The treatment allocation scheme described by Zelen35 will be used because it balances patient 
27 
 

factors other than institution. Patients will be randomized to external beam radiation (45 Gy dose) 
and brachytherapy [Palladium-103 (100 Gy) or interstitial Iodine-125 (110 Gy)] vs. brachytherapy 
alone [Pd-103 (125 Gy) or I-125 (145 Gy)]. 
13.2.2 Sample Size Derivation:   
The sample size calculation is based on the primary endpoint, freedom from progression (FFP) rate 
by 5 years.  Based on the prior results from Blasko et al6  we project that the rate of 5-year FFP of 
interstitial brachytherapy arm, p1 is 80% and hypothesize a 10% improvement in patients treated in 
EBRT plus interstitial brachytherapy,  i.e., p2=90%. The sample size estimates are based on the 
ability to demonstrate that EBRT plus interstitial brachytherapy will improve a FFP rate at 5 years 
compared to interstitial brachytherapy alone by 10% with an α value of 0.025 (one-sided), statistical 
power of 90%.  Two sample binomial testing is employed and five interim analyses with a final 
analysis are planned for early stopping for the efficacy and futility.  Efficacy testing is based on 
Haybittle-Peto test36,37, interim testing will be done at the significance level of 0.001, while a level of 
0.02 will be used at the final analysis to preserve a 0.025 level. The futility testing is based on the 
Freidlin and Korn38 method at a nominal significance level of 0.0001.  Guarding against an ineligibility 
or lack-of-data rate of up to 10%, the final targeted accrual for this study will be 586 patients.   
 
HRQOL change will also be a secondary objective of this study; however, sample size required 
for adequate power to detect clinically significant HRQOL differences is smaller than that required 
to detect differences in FFP 
 
 
13.2.3 Health Related Quality of Life (HRQOL) using EPIC Patient self-assessment of symptoms will be 
performed using four primary EPIC scales: urinary-irritative, urinary-incontinence, bowel, and 
sexual.  The endpoints for EPIC will be early (4 months after therapy start) and late (2 years after 
therapy start) HRQOL change in the four domains.  The conditions for the HRQOL endpoints are 
as follows: 
• 
A clinically significant difference in HRQOL change is defined as 0.5*standard deviation for 
each of 4 primary EPIC HRQOL endpoints (urinary-irritative, urinary-incontinence, bowel, and 
sexual); 
• 
The observed differences from baseline for each of the four primary EPIC HRQOL scales are 
normally distributed; 
• 
The two-sided level of significance is 0.05.  To maintain this type I error and accommodate 
for four primary HRQOL comparisons (at four months and two years), the level of significance 
is adjusted by the Bonferroni approach and is reduced to 0.0125; 
• 
Statistical power of at least 90%; 
 
HRQOL will be collected on all cases participating in the trial.  Therefore, there will be sufficient 
statistical power to detect a difference in HRQOL between the treatment arms.  In addition, the 
standard error of measurement (SEM) will be used to classify these patients as having 
deteriorated from baseline.39  The endpoint will be the two-year deterioration rate.  Since there 
are four primary domains of EPIC, the type I error will also need to be adjusted.  The Hommel 
method for adjusting the type I error will be utilized.40 This method is dynamic while maintaining a 
pre-specified type I error. The two-sided level of significance is the same as stated above. 
Preliminary analysis of RTOG 98-05 showed a 29% rate of deterioration in the FACT prostate 
component domains. If the percentage of patients that deteriorate using the EPIC domains is the 
same as the FACT prostate component, then 29% of the patients will deteriorate using the EPIC 
scales on the brachytherapy alone arm. We want to be able to detect at an absolute difference of 
14.5% or more (i.e., a relative change of 50% or more) in the 2-year deterioration rate between 
the brachytherapy and external beam radiation arm and brachytherapy alone arm.  If there is 
correlation between the four EPIC domains, then the study will have at least 95% power to detect 
the difference between the treatment arms at the 0.05 (two-sided) level of significance.  If there is 
moderate correlation between the scales, then the significance level will reduce to 0.025.  If the 
four domains have low correlation, then the significance level will be 0.0167. If the domain results 
are completely independent, then the significance level will be reduced to 0.0125.  There will be 
at least 95% power regardless of the correlation among the scales.  As such, this study will have 
at least 95% statistical power to detect a difference in the two-year deterioration rate between the 
treatment arms. 
28 
 

13.2.4 Health Related Quality of Life (QOL) Using EQ5D The EQ 5D is a method for obtaining valuations 
of health-related quality of life (HRQOL) to be used as an adjustment to survival and in the cost-
utility analysis. It is a two-part questionnaire that takes approximately 5 minutes to complete.41  
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 
including:  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.42  The second part is a visual 
analogue scale (VAS) valuing current health state, measured on a 20 cm 10 point-interval scale.  
Worst imaginable health state is scored as 0 at the bottom of the scale and best imaginable 
health state is scored as 100 at the top. Both the 5-item index score and the VAS score are 
transformed into a utility score between 0 “Worst health state” and 1 “Best health state”. Either 
the index score or the VAS score can be used in the quality adjusted survival analysis, or enter 
the cost-utility equation, depending on the health state(s) of interest.43 
 
Quality adjusted survival can be defined by the weighted sum of different time episodes added up to 
a total quality-adjusted survival time [U= sum of quality (qi) of health states K times the duration (si) 
spent in each health state.44 
 
∑
=
=
K
1
i
i
is
q
 
 
U
 
 
13.2.5 Cost Effectiveness/Cost Utility (Pilot)(1/11/08): A pilot study is planned to collect cost data on 
patients who consent to participate.  These data will be used to generate hypotheses regarding 
cost effectiveness and cost utility of the combined radiation treatment.  The data will also be used 
for future studies and analyses.  Patient identifiers (e.g., social security numbers and names) will 
be collected on all cases in which the patients have consented.  These patient identifiers will be 
linked to Medicare claims data, detailing payments associated with the interventions on each arm 
of the trial, as well as with payments associated with longer-term outcomes of treatment, 
including recurrences and complications.  This part of the costs analysis will only include patients 
whose care is reimbursed under the federal Medicare payment system, but will exclude those in 
Medicare HMOs as well as those under alternative federal coverage (including Medicaid, DOD, 
and the VA) as well as those covered by private payers or other payment systems. 
 
These Medicare costs data will be extracted from the Health Care Financing Administration’s 
Medicare Statistical System and National Claims History files, and will include claims data from both 
Medicare Part A and Part B.  These data include Medicare claims for inpatient care in hospitals and 
skilled nursing facilities, home health services, hospice services, physician services, and outpatient 
services.  The total amount Medicare deemed payable will be used as the measure of cost for this 
analysis.  This total includes both the amount paid by Medicare as well as coinsurance deductible 
amounts due from the patient and others.   
 
An adjunct study is being developed that will use a separate methodology for collecting patient-
specific costs data, including detailed billing information from voluntarily participating institutions as 
well as patient-specific diaries, detailing medications, doctors’ visits, hospitalizations, and medical 
interventions.  This separate study may be used to test the generalizability of the Medicare data over 
the larger study population. 
 
The Medicare cost data will enter the numerator and the quality-adjusted survival calculated as 
described in Section 13.2.4 will enter the denominator in the Quality Adjusted Life Year (QALY) 
model, producing a dollar per QALY ratio. The $/QALY is a function of the monetary cost per relative 
value of each health state and its duration. In this way, disparate end points are combined into an 
overall value to the patient as well as a common metric for comparison to any other health care 
intervention. 
 
Cost-utility will be analyzed for planned publication at three time-points:  (1) at time of study closure, 
looking at initial treatment costs and quality of life at one year post-therapy, (2) at five years follow-
29 
 

up; and (3) after all follow-up data are in.  The time horizon for economic data collection will be 
seven-years of follow-up, with the same time points as the quality-of-life assessments.   
 
Patient participation in this component will be limited to non-Canadian institutions.  In the two 
previous brachytherapy trials, RTOG 98-05 and P-0019, 83% of the 101 cases and 79% of the 
138 cases, respectively, came from non-Canadian institutions.  Of the 84 cases registered from 
non-Canadian institutions in RTOG 98-05, 58% paid using Medicare, Medicare and Private 
Insurance, or Medicare and Medicaid.  In RTOG P-0019, 32% used Medicare as their primary 
method of payment. 
 
In this protocol, we project that 80% of the eligible cases will be randomized from non-Canadian 
institutions (N=426).  Due to the recent changes in federal regulations regarding privacy and 
collection of patient identifiers (e.g., HIPAA), we expect 25% of these eligible cases will consent 
to providing their social security number and name for this pilot study (N=107).  Table 3 below 
lists the number of eligible and analyzable cases for the cost effectiveness/cost utility component 
by the percentage paying by Medicare (%=25, 33, and 50). 
 
Table 3. Number of Cases Eligible and Analyzable for Cost Effectiveness/Cost Utility 
Component by the Percentage Paying by Medicare 
Percent Paying by Medicare 
Number Eligible and Analyzable 
25% 
27 
33% 
36 
50% 
54 
 
Thus, we expect between 27 and 54 cases to be eligible and analyzable for this component.  
13.3 
Patient Accrual (1/11/08) 
Based on patient accrual in previous RTOG randomized prostate studies, there will be relatively 
few entries during the initial six months while institutions are obtaining IRB approval. In addition, 
due to the credentialing and data transfer requirements necessary for this protocol, this quiet 
period may be extended up to twelve months.  Therefore, we do not expect to meet our targeted 
monthly accrual until the second year.  Based on the projected accrual rate of 8 cases per month 
based on the past six months accrual, we project the total maximum study duration to be 7.7 years 
from now (January 9, 2008) with 2.7 years of accrual to accrue 254 to have 586 cases and at least 5 
years of follow-up for all the patients.  
 
The RTOG Data Monitoring Committee (DMC) will begin evaluating patient accrual semi-annually 
following the anticipated quiet period. If the average monthly accrual rate for the trial is less than 
20% of the rate projected in the paragraph above (i.e., less than 2 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., less than 4 patients per month), the trial will be placed on probation for six 
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-RTOG institutions 
through CTSU is expected to follow a similar pattern as seen in RTOG. 
 
13.4 
Analysis Plan (1/11/08) 
 
All eligible patients who are randomized to the study will be included in the comparison of 
treatment arms (intent-to-treat analysis). 
13.4.1 Statistical Methods: (1/11/08)   
FFP failure event will be the first occurrence of the biochemical failure (see Section 11.3.4), 
clinical failure (local progression or distant metastases) or death due to any cause from the start 
of protocol treatment. Patients who are failure event free with less than 5 years of follow-up or 
30 
 

who receive any secondary salvage therapy (e.g., salvage androgen deprivation, vaccine 
therapy, biologic/small molecule therapy, or chemotherapy) will be censored. The primary 
endpoint FFP rate by 5 years is defined as the proportion of patients with a FFP failure by 5 years 
from the randomization among all eligible patients at baseline and will be estimated by the 
Kaplan-Meier method.51 The Z-test statistic for the difference between the two rates with the 
standard errors estimated by Greenwood’s method will be used with an overall significance level 
of 0.025. The following test statistics will be used for testing between the twp arms.   
  
∑
∑
=
=
−
+
−
−
=
2
1
1
2
2
1
2
1
2
1
)
(
ˆ
)
(
ˆ
n
i
j
j
j
j
n
i
i
i
i
i
f
r
r
f
p
f
r
r
f
p
p
p
T


 (1) 
 
 
where, 
1p and 
2
p are FFP rate of  EBRT plus brachytherapy arm and brachytherapy only arm, 
respectively, estimated by Kaplan-Meier method, ri is the number of patients who are at risk 
and fi is the number of patients who have FFP events (i=1,2).   
 
The following hypotheses are of interest to be tested, where, p1 and p2,are the rate of 5-year FFP 
of EBRT plus brachytherapy arm and brachytherapy only arm, respectively. 
 H0: p1 ≤ p2    vs.    HA: p1 > p2  
If H0 is rejected, then we conclude that EBRT plus brachytherapy arm is better than 
brachytherapy only arm. If H0 is not rejected, then we conclude that EBRT plus brachytherapy 
arm is not better than brachytherapy only arm. 
 
In addition, univariate and multivariate logistic regression45 will be used to compare the 
treatment differences in the hypothesis.  Odds ratios from univariate and multivariate logistic 
regression and the respective 95% confidence intervals will be computed. Stage (T1c vs. T2a-
T2b), PSA (0 - <10 vs. 10-20), Gleason score (2-6 vs. 7), and neoadjuvant hormonal therapy 
(no vs. yes), age, and race (as appropriate) will be adjusted for in the Multivariate analysis. 
 
 
For the HRQOL endpoint, change in each of 4 HRQOL domains (change from baseline to four 
months after therapy and from baseline to two years after therapy) will be compared between 
arms using the t-test because normal distribution of HRQOL scores is expected based on EPIC 
validation studies. EPIC HRQOL scores will be computed as described.24 The EPIC HRQOL 
domains will also be analyzed using the clinically significant change at two years as defined by 
the SEM.  The percentage of patients on each arm that have deteriorated according to the 
EPIC primary scales will be reported in this study. Any missing HRQOL data will be assumed to 
be missing completely at random (MCAR). Therefore, standard statistical methods will be used 
in all HRQOL analyses. 
 
13.4.2 
Cost Effectiveness/Utility Analysis:  A (Medicare) perspective will be used in this analysis.  
Using the pilot data obtained (from consented patients), differences in charges between the two 
treatments will be assessed using multivariable ordinary least-squares regression.  In addition, 
comparison of charges and outcomes will be reported as the ratio of dollars per life year saved.  
This ratio will be calculated as the difference in the costs between patients treated with 
brachytherapy and those treated with brachytherapy plus external beam radiotherapy divided 
by the difference in the probability of life years saved in these two groups.  Cost-utility 
outcomes will be reported in U.S.$/Quality Adjusted Life Year using the EQ5D five item index 
score and the VAS score for current health. A 3% and 5% discount rate will be used for both 
costs and effects; sensitivity analysis will be undertaken at 1% and 7%.  Sensitivity analysis will 
also be used to determine the relationship between variation in key cost variables and final 
results. We will assume all data are missing completely at random, or at a minimum, missing at 
random and use standard statistical methods for the cost effectiveness/cost utility analyses. 
31 
 

13.4.3 
Interim Analysis to Monitor the Study Progress:  Interim reports with statistical analyses will be 
prepared twice a 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; data quality; compliance rate of treatment 
delivery with the distributions of important prognostic baseline variables; and the frequencies 
and severity of the toxicities by treatment arm. The interim reports will not contain the results 
from the treatment comparisons with respect to the primary endpoint, FFP, or secondary 
endpoints such as biochemical failure. 
13.4.4 
Significance Testing for Early Termination and Reporting: 
13.4.4.1 
Primary Endpoint: Freedom from Progression(1/11/08) 
A group sequential test with five planned interim analyses and a final analysis will be 
performed. The interim analysis will be carried out when the cumulative accrual (patients 
whose follow-up is at least 5 years from the randomization date) are met. At each planned 
interim analysis, the p-value from the Z-test statistics, eq.1, for the difference between the 
two FFP rates assessing treatment efficacy or futility with respect to the primary endpoint will 
be compared to the nominal significance level. The significance level of 0.001, which is 
based on the Haybittle-Peto test36,37, was chosen for efficacy testing.  For the futility testing 
boundary, we will use a less aggressive boundary, Rule C (a level of 0.0001) in Freidlin and 
Korn38.  The following hypotheses are tested. 
H0: p1≤ p2    vs.    HA: p1 > p2 
For efficacy testing, if H0 is rejected, then we conclude that EBRT plus brachytherapy arm is 
better than brachytherapy only arm and report the results (stop accrual if applicable). For 
futility testing, the alternative hypotheses, HA (p1 = p2 + 0.1) will be tested at 0.0001 level 
(the futility nominal significance level).  If we stop the trial for futility, then we will conclude 
that the 5-year FFP of brachytherapy only arm will be better than EBRT plus brachytherapy 
arm and report the results.  Otherwise, we will continue the trial.   
 
Table 12: The Schedule for the Planned Analyses 
Information 
Time 
Estimated 
Analysis Time* 
Cumulative 
Accrual in the Two 
Arms** 
0.17 
6.5 
89 
0.34 
7.4 
177 
0.5 
8.3 
266 
0.67 
9.2 
354 
0.83 
10.2 
443 
1.0 
11.1 
532 
* Time to the interim analysis from the first patient entry without considering ineligibility or 
lack-of-data rate 
 **The number of eligible patients whose follow-up is at least 5 years from the randomization 
date 
 
Based on the results of each interim analysis, the following action will be taken and the 
responsible statistician will recommend to the NRG Oncology 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 NRG Oncology DMC will then make a recommendation about the trial to the 
NRG Oncology Group Chair. 
  
13.4.4.2 
Time to Biochemical Failure-Related Endpoints (1/11/08)  
Biochemical failure (Sections11.3.4 and 11.3.5) will be secondary endpoints of interest and 
will be reported after the primary endpoint result Blasko et al.6 reported their five-year 
biochemical failure-free rate of 82% for palladium-103 monotherapy in intermediate risk 
patients.  In light of the findings in Blasko et al.6, power was calculated for different hazard 
ratios for the analysis of biochemical failure using the estimated sample size. The baseline 
biochemical (failure rate was 0.0389 per year and was assumed to be constant over time. It 
32 
 

was also assumed that the frequency of deaths without a biochemical failure reported was 
2% per year.  This rate was used in Lakatos’ method when calculating the number of 
biochemical failures and statistical power. Table 4 below lists the number of biochemical 
failures and power at the analysis time point for each hazard ratio (Δ=1.3, 1.4, 1.5, and 1.6). 
At the time of the biochemical failure analysis, there will be at least 80% power to detect a 
hazard ratio greater than or equal to 1.5. The nominal significance level at this analysis is 
0.025. The biochemical failure results will be reported following this analysis. Also, 
biochemical failure by the Phoenix definition (PSA ≥ 2 ng/ml over the nadir PSA)46,47,48,49,50 
will be analyzed in a similar fashion.   
 
13.4.4.3   
Time to Failure of Secondary Survival Endpoints (1/11/08) 
The time to failure for secondary endpoints (disease-specific survival, local progression, 
distant metastases, and overall survival) will be measured from the date of randomization to 
the date of the event of interest.  The events for secondary endpoints and time-to-events are 
defined in Sections 11.3. -11.3.9.  The time-to-event distribution of overall survival will be 
estimated using the Kaplan-Meier method51 and the log-rank test49,50 will be used to test 
whether the overall survival rate in the  EBRT and brachytherapy arm is higher than the 
brachytherapy alone arm at the significance level of 0.025.  However, the treatment effect on 
other types of failure may impact the observable measures of disease-specific survival, local 
progression, and distant metastases and competing risks for each endpoint should be 
considered. We will use the cause-specific hazard rate54,55 (the instantaneous rate of cause-
specific mortality in the presence of competing failure types as a function of time) approach 
to consider the competing risk events. Freidlin and Korn38 showed that the cause-specific 
hazard rate approach is better than other approaches, for example, the cumulative incidence 
method,56 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 the  EBRT and brachytherapy arm is higher than the 
brachytherapy alone arm at a significance level of 0.025. In this approach, patients who 
experience other failure first are censored. 
 
In addition, the Cox regression model57 will be used to compare the treatment differences. 
Both unadjusted and adjusted hazard ratios and the respective 95% confidence interval will 
be computed.  At least the treatment arm, to Stage (T1c vs. T2a-T2b), PSA (0 - <10 vs. 10-
20), Gleason score (2-6 vs. 7), and neoadjuvant hormonal therapy (no vs. yes), age, and 
race (as appropriate) will be adjusted for in this analysis.   
 
 
 
Table 4. Power of significance testing for early reporting of biochemical failure 
 
∆ 
Biochemical 
Failures 
Power 
1.30 
194 
49.5% 
1.40 
189 
67.8% 
1.50 
184 
81.1% 
1.60 
179 
89.8% 
 
13.4.4.4  Comparison of the Incidence of Acute Toxicity and Time to Late Grade 3+ Toxicity (1/11/08) 
Acute toxicities are scored according to NCI Common Toxicity Criteria version 2.0. and will be 
defined as the worst severity of the adverse event occurring less than or equal to 180 days of 
RT start. Late toxicities are scored according to the RTOG/EORTC Late Radiation Morbidity 
Scoring Scheme (Appendix IV) and will be defined as the worst severity of the adverse event 
occurring more than 180 days of the RT start.   
33 
 

 
Both acute grade 2+ and 3+ toxicity will be examined separately. Univariate logistic regression4 
will be used to model the distribution of acute adverse events.  Multivariate logistic regression 
will be used to model the distribution of acute adverse events, adjusting for covariates. 
Treatment arm, Stage (T1c vs. T2a-T2b), PSA (0 - <10 vs. 10-20), Gleason score (2-6 vs. 7), 
and neoadjuvant hormonal therapy (no vs. yes), and age (as appropriate) will be adjusted for in 
the multivariate analysis.  Both unadjusted and adjusted odds ratios and the respective 95% 
confidence interval will be computed and tested using a one-sided chi-square test with the 
significance level of 0.05.   
 
 
 
The time to late grade 3+ adverse events will be measured from the RT start to the time of the 
worst late grade 3+ adverse event, respectively.  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. The distribution 
of time to late grade 3+ adverse events will be estimated using the Kaplan-Meier method51 and 
tested using a one-sided log-rank test52,53 with the significance level of 0.025.  A multivariate 
Cox regression model57 will be used to compare the treatment differences of time to late 
adverse event.  Both unadjusted and adjusted hazard ratios and the respective 95% confidence 
interval will be computed. Treatment arm, Stage (T1c vs. T2a-T2b), PSA (0 - <10 vs. 10-20), 
Gleason score (2-6 vs. 7), and neoadjuvant hormonal therapy (no vs. yes), age, and race (as 
appropriate) will be adjusted for in this analysis. 
 
13.4.5 
Analysis For Reporting the Initial Treatment Results: (1/11/08) The primary hypothesis of this 
study is whether the addition of external beam radiation to brachytherapy will improve the 
freedom from progression (FFP) by 5 years rate compared to brachytherapy alone.  The final 
analysis will occur after each patient has been potentially followed for a minimum of five years 
for the primary endpoint, FFP  unless the early stopping rule is satisfied. It will include 
tabulation of all cases entered and those excluded from the analyses with the reasons for such 
given; the distribution of the important prognostic baseline variables; and observed results with 
respect to the primary and secondary endpoints. All eligible patients randomized will be 
included in the comparison and will be grouped by assigned treatment in the analysis. Five 
interim analyses and one final analysis will be performed for efficacy and futility of the 
experimental treatment will be carried out as described in Section 13.4.4.1. The Z-test statistics 
for the difference between the two 5 years FFP rates with the standard errors estimated by 
Greenwood’s method, eq. (1), will be used with an overall significance level of 0.025. The 
treatment comparison of biochemical related  failures and secondary survival endpoints will be 
analyzed as described in Sections 13.4.4.2 and 13.4.4.3, respectively, in Section 13. Also, 
where feasible, treatment comparisons with respect to the primary endpoint (freedom from 
progression) and secondary endpoints such as biochemical failure will be compared within 
each ethnic category.  
13.5 
Inclusion of Minorities (1/11/08) 
In conformance with the national Institutes of Health (NIH) Revitalization Act of 1993 with regard 
to inclusion of women and minorities in clinical research, we address this issue here, as we will 
also analyze treatment differences in this male cohort by ethnicity. Based on previous RTOG 
prostate protocol data, we project that 80% of the men in the study are White, 15% are Black or 
African American, 3% are Hispanic, 0.5% are Asian, 0.3% are Pacific Islander, 0.2% are 
American Indian or Alaskan Native, and 1% are others and unknown.  The following table lists the 
projected accrual for each racial group.  Assuming no difference among races with respect to 
overall survival, the statistical power for detecting the hypothesized difference is 83% and 25% for 
white and black, respectively. 
 
Obviously, with 80% and 15% of the available sample being white and African American, 
respectively, univariate comparisons by treatment will not yield sufficient power in most cases. 
The distribution of cases by race (African American vs. Non-African American) and treatment arm 
for the recently completed RTOG prostate trials 92-02 and 94-13 are shown in Table 5.  There 
was no statistical evidence to support a difference in treatment outcome and race in either study 
The change in the relative risk of treatment contributed by the interaction is a factor close to one; 
i.e., the value equal to the eβ, where β is the parameter estimate for the interaction term. [RTOG 
34 
 

94-13:  eβ =1.06, p=0.77 (RT Field) and eβ =1.36,  p=0.12 (HT Timing); RTOG 92-02:  eβ =1.06, 
p=0.75].  Thus, we do not expect to see any evidence of a treatment difference between 
brachytherapy alone and brachytherapy and EBRT in the African American population in the 
current study.  We will, however, include the ethnicity variable in all regressions including the Cox 
model. 
 
Table 5.  Distribution of Race (African American vs. Non-African American) and Treatment Arm in RTOG 
Studies 94-13 and 92-02 
 
 
 
 
Race 
Study 
Treatment Arms* 
N 
African American 
Non-African American 
RTOG 94-13 
 
 
 
 
Radiation Field 
WP RT 
641 
153 (24%) 
488 (76%) 
 
PO RT 
638 
176 (28%) 
462 (72%) 
 
 
 
 
 
Hormone Timing 
NHT 
635 
159 (25%) 
476 (75%) 
 
AHT 
644 
170 (26%) 
474 (74%) 
 
 
 
 
 
RTOG 92-02 
STAD 
761 
92 (12%) 
669 (88%) 
 
LTAD 
753 
105 (14%) 
648 (86%) 
• 
Treatment arms for:  RTOG 94-13: WP RT = Whole Pelvis RT (Radiation Therapy)+Boost and 
TAS (Total Androgen Suppression); PO RT = Prostate Only RT and TAS; NHT= Neoadjuvant 
TAS and RT; and AHT = Adjuvant TAS and RT and RTOG 92-02: STAD = Short-term TAS (4 
months) and RT; and LTAD = Long-term TAS (28 months) and RT. 
 
 
 
 
 
 
 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
N/A 
18 
0 
18 
Not Hispanic or Latino 
N/A 
568 
0 
568 
Ethnic Category: Total of all subjects 
N/A 
586 
0 
586 
Racial Category 
 
American Indian or Alaskan Native 
N/A 
1 
0 
1 
Asian 
N/A 
3 
0 
3 
Black or African American 
N/A 
100 
0 
100 
Native Hawaiian or other Pacific Islander 
N/A 
1 
0 
1 
White 
N/A 
481 
0 
481 
Racial Category: Total of all subjects 
 
586 
0 
586 
 
35 
 

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24. 
Wei JT, Dunn RL, Litwin MS, Sandler HM, and Sanda MG.  Development and validation of the Expanded 
Prostate Cancer Index Composite (EPIC) for comprehensive HRQOL assessment in men with prostate 
cancer. Urology. 2000;56:899-905. 
 
25. 
Litwin MS, et al. The UCLA Prostate Cancer Index: Development, reliability, and validity of a health-related 
quality of life measure. Med Care. 1998;36:1002-1012. 
 
26. 
Barry MJ, Fowler FJ, Jr., O'Leary MP, et al. The American Urological Association symptom index for benign 
prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 
1992;148(5):1549-57; discussion 1564. 
 
27. 
Brandeis JM, Litwin MS, Burnison M, et al. Quality of life outcomes after brachytherapy for early stage 
prostate cancer. J Urol. 2000;163:851-857. 
 
28. 
Davis JW, Kuban DA, Lynch DF, and Schellhammer PF.  QOL after treatment for localized prostate cancer: 
differences based on treatment modality.  J Urol. 2001;166: 947-52. 
 
29. 
Wei JT, Dunn RL, Sandler HM, et al. A comprehensive comparison of health related quality of life following 
contemporary therapies for localized prostate cancer.  J Clin Onc. 2002; 20(2):557-566. 
 
30. 
Talcott JA, Clark JA, Stark PC, Mitchell SP.  Long-term treatment related complications of brachytherapy 
for early stage prostate cancer: a survey of patients previously treated.  J Urol. 2001;166:494-9. 
 
31. 
Williamson J, et al. Dosimetric prerequisites for routine clinical use of new low energy photon interstitial 
brachytherapy sources. Recommendations of the American Association of Physicists in Medicine Radiation 
Therapy Committee. Ad Hoc Subcommittee of the Radiation Therapy Committee. Med Phy. 1998; 25(12): p. 
2269-70. 
 
32. 
Nath R, Anderson LL, Luxton G. et al.  Dosimetry of interstitial Brachytherapy sources:  Recommendations of 
the AAPM Radiation Therapy Committee Task Group No. 43.  American Association of Physicists in 
Medicine. Med Phys. 1995; 22: 209-234. 
 
33. 
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 Oncol Biol Phys.  2000; 
1: 221-230. 
 
37 
 

34. 
ASTRO consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys. 
1997;37:1035-1041. 
35. 
Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 1974;27:365-375. 
 
36. Haybittle,J.L. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 
Oct;44(526):793-7, 1971. 
 
37. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. 
Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction 
and design. Br J Cancer. Dec;34(6):585-612, 1976 
 
38. Freidlin B, Korn EL. Testing treatment effects in the presence of competing risks. Stat Med. 24:1703-1712, 
2005. 
 
 
39. Wyrwich KW, Tierney W, Wolinsky FD. Further Evidence Supporting a SEM-Based Criterion for Identifying 
Meaningful Intra-Individual Changes in Health-Related Quality of Life. J Clin Epidemiol. 1999; 52:861-873. 
 
40. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika. 
1988;75:383-386. 
 
41. Schulz MW, Chen J, Woo HH, et al. A Comparison of Techniques for Eliciting Patient Preferences in Patients 
with Benign Prostatic Hyperplasia. J Urol. 2002 Jul;168(1):155-159. 
 
42. Badia X, Herdman M, Kind P. The influence of ill-health experience on the valuation of health.  
 
43. Wu AW, Jacobson KD, Frick DL, et al. Validity and responsiveness of the EQ5D as a measure of health-related 
quality of life in people enrolled in an AIDS clinical trial. Qual Life Res. 2002 May;11(3):273-82 
 
44. Glasziou, PP, Simes, RJ, Gelber, R.D. Quality Adjusted Survival Analysis.  Stat Med. 1990; 9:  1256-1276. 
 
45. Agresti A. Categorical Data Analysis. New York: Wiley; 1990. 
 
46. 
Vicini FA, Kestin LL, Martinez AA. The correlation of serial prostate specific antigen measurements with 
clinical outcome after external beam radiation therapy of patients for prostate carcinoma. Cancer. 88:2305-
2318, 2000. 
 
47. 
Kestin LL, Vicini FA, Martinez AA. Practical application of biochemical failure definitions: What to do and 
when to do it. Int J Radiat Oncol Biol Phys. 53:304-315, 2002. 
 
48. 
Pickles T, Kim-Sing C, Morris WJ, et al. Evaluation of the Houston biochemical relapse definition in men 
treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time 
bias. Int J Radiat Oncol Biol Phys. 57:11-18, 2003. 
 
49. 
Thames H, Kuban D, Levy L, et al. Comparison of alternative biochemical failure definitions based on clinical 
outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995. Int 
J Radiat Oncol Biol Phys. 57:929-943, 2003. 
 
50. 
Buyyounouski MK, Hanlon AL, Eisenberg DF, et al. Defining biochemical failure after radiotherapy with and 
without androgen deprivation for prostate cancer. Int J Radiat Oncol Biol Phys. 63:1455-1462, 2005. 
 
51. 
Kaplan EL and Meier P: Nonparameteric estimation from incomplete observations. J Amer Statist Assoc. 
1958;53:457-481. 
 
52. 
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer 
Chemother. 1966;Rep 50:163-170. 
 
38 
 

53. 
Kim K, Tsiatis AA. Study duration for clinical trials with survival response and early stopping rule. Biometrics. 
46:81-92, 1990. 
 
54. 
Kalbfleisch JD, Ross LP. The statistical analysis of failure time data. New York: John Wiley & Sons; 1980. 
 
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55. 
Gaynor JJ, Feuer EJ, Tan CC, et al. On the use of cause specific failure and conditional failure probabilities: 
Examples from clinical oncology data. J Amer Statist Assoc. 1993; 88:400-409. 
 
56. 
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist. 
1988;16:1141-1154. 
 
57. 
Cox DR: Regression models and life tables. J Royal Stat Soc. 1972; Series B, vol 34:187-229. 
 
58. 
Recommendations of the American Association of Physicists in Medicine on Pd interstitial source calibration 
and dosimetry:  Implications for dose specifications and prescription:  Medical Physics 27(4), 2000, 634-642. 
 
59. 
Kubo HD, et al. Report of the ad hoc committee of the AAPM Radiation Therapy Committee on 125I sealed 
source Dosimetry.  Int J Radiat Oncol Biol Phys. 1998; 40(3): 697-702. 
 
60. 
Williamson JF, et al. Guidance to Users of Nycomed Amersham and North American Association of 
Physicists in Medicine on 103Pd interstitial source calibration and dosimetry:  Implications for dose 
specification and prescription.  Med Phys. 2000; 27(4): 634-642. 
 
61. 
Williamson JF, et al. Recommendations of the American Association of Physicists in Medicine on 103Pd 
interstitial source calibration and dosimetry:  Implications for dose specification and prescription.  Med Phys. 
2000; 27(4): 634-642. 
 
62. 
Sylvester JE, Grimm, PD, Blasko, JC, et al. 15-year biochemical relapse free survival in clinical stage T1-
T3 prostate cancer following combined external beam radiotherapy and brachytherapy; Seattle 
experience. Int J Radiat Oncol Biol Phys. 2006;67:57-64. 
 
39 
 

 
 
 
 
 
 
 
 
 
 
 
APPENDIX IA    (10/2/15) 
RTOG 0232 
 
INFORMED CONSENT  
FOR 
A PHASE III STUDY COMPARING COMBINED EXTERNAL BEAM RADIATION AND 
TRANSPERINEAL INTERSTITIAL PERMANENT BRACHYTHERAPY WITH 
BRACHYTHERAPY ALONE FOR SELECTED PATIENTS WITH INTERMEDIATE RISK 
PROSTATIC CARCINOMA 
 
This is a clinical trial (a type of research study).  Clinical trials include only 
patients who choose to take part.  Please take your time to make your 
decision. Discuss it with your friends and family.  The National Cancer Institute 
(NCI) booklet, “Taking Part in Clinical Trials: What Cancer Patients Need To 
Know,” is available from your doctor. 
 
You are being asked to take part in this study because you have prostate cancer. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
The purpose of this study is to compare the effects (good and bad) of two different 
radiation treatments in patients with prostate cancer.  The effects of placing small 
radioactive pellets (hereinafter called seeds) inside your prostate (brachytherapy) 
after external radiation therapy will be compared to the effects of using 
brachytherapy alone in patients with prostate cancer.  
 
This research is being done to see which treatment is better.  This study will also 
look at your already biopsied prostate cancer tissue for information that may help to 
predict and treat prostate cancer in the future.  In addition, the study will gather 
information about the effects of the treatment on your quality of life.  A cost 
comparison between the two treatments, including long term costs thereafter, is 
also planned for participants under Medicare.  
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY (1/11/08) 
 
About 586 people in North America will take part in this study. 
40 
 

 
 
  
 
 
  
 
 
 
 
WHAT IS INVOLVED IN THE STUDY?         
SCHEMA  
 
 
S 
 
T 
 
R 
 
A 
 
T 
 
I 
 
F 
 
Y 
 
Stage 
1. T1c 
2. T2a – T2b 
Gleason Score 
1. ≤ 6 
2. 7 
 
PSA 
1. 0 - < 10 
2. 10-20 
 
Neoadjuvant 
Hormonal 
Therapy 
1. No 
2. Yes 
 
 
R 
 
E 
 
C 
 
0 
 
R 
 
D 
 
 
 
Isotope 
 
1. I-125 
2. Pd-103 
 
R 
 
A 
 
N 
 
D 
 
O 
 
M 
 
I 
 
Z 
 
E 
 
Arm 1: 45 Gy EBRT 
Partial pelvis (1.8 Gy/fraction M-F for 
five weeks) followed 2-4 weeks later 
by Pd-103 (100 Gy) or I-125 (110 
Gy)* 
 
or 
 
 
Arm 2 Pd-103 (125 Gy) or I-125 
(145 Gy)* 
 
*PROTOCOL TREATMENT MUST BEGIN WITHIN FOUR WEEKS AFTER STUDY ENTRY. 
 
You will be “randomized” into one of the study groups (arms) described below. 
Randomization means that you are put into a group by chance.  It is like flipping a 
coin.  Which group you are put in is done by a computer.  Neither you nor the 
researcher will choose what group you will be in.  You will have an equal chance of 
being placed in either group. 
Treatment Arm 1:  External Radiation Therapy and then Brachytherapy 
 
External Radiation Therapy: 
If you are randomized to receive this treatment, external radiation therapy to 
your prostate will be given once a day, five days a week, Monday to Friday, for 
five weeks.  External radiation therapy treatments will be given on an 
outpatient basis at your institution.   
 
Brachytherapy (Internal Radiation Therapy):   
Two to four weeks after the completion of external radiation therapy, 
radioactive seeds will be implanted into your prostate.  This procedure is done 
on an outpatient basis under anesthesia at your institution.  Procedures that 
are done to deliver brachytherapy: 
 
• Local or general anesthesia will be given prior to and during the 
procedure. 
41 
 

 
 
 
 
 
• 
With the help of ultrasound, thin needles with radioactive pellets will   
be inserted through the skin between your anus and scrotum into your 
prostate.   
• 
As each seed is placed in the correct position, the needle is pulled out 
leaving the seed in your prostate. 
 
The number of needles and seeds varies depending on the size and shape of your 
prostate. 
 
Treatment Arm 2: Brachytherapy Alone 
 
Brachytherapy (Internal Radiation Therapy):   
 
This is the same as the Brachytherapy described under Arm 1 above, except 
that the radioactive seeds will deliver a somewhat higher dose of radiation. 
 
Treatment Arms 1 and 2:  
 
If you take part in this study, you will have the following tests and procedures: 
 
• 
A physical examination, including a digital rectal exam (DRE): 
o prior to beginning treatment,  
o weekly in Arm 1 during external radiation therapy (NOTE: DRE 
is optional/at study doctor’s discretion);  
o at 4, 6, 9 and 12 months for the first year following treatment, 
(NOTE: at 4 months is DRE optional/at study doctor’s 
discretion); 
o every 6 months for the next four years; 
o and then annually for the rest of your life.   
The follow-up visits generally take 15 to 30 minutes (in addition to time for 
answering questionnaires described below). 
• 
Blood tests prior to beginning treatment; weekly during radiation therapy if 
your doctor feels these tests are needed, and at each follow-up visit (except 
at the 4 and 9 month visits) as described above. 
• 
An ultrasound examination of your prostate prior to brachytherapy.  This is a 
brief, outpatient procedure in which an ultrasound probe is placed into your 
rectum to determine the precise size and shape of your prostate.  This 
procedure determines where each needle and seed will be placed. 
• 
Your doctor may want an examination of your bladder prior to treatment. 
This may include insertion of a small flexible tube through your penis into 
your bladder (cystoscopy). 
• 
CT scan, MRI, or possible removal and biopsy of pelvic lymph glands, if 
indicated, to evaluate your cancer prior to treatment. 
• 
If your disease worsens, your physician may request a needle biopsy of your 
prostate to see how your prostate has responded to treatment.  
42 
 

 
• 
A CT scan of your prostate, a pelvic x-ray, and two chest x-rays 3 to 5 weeks 
following radioactive seeds being implanted. 
• 
You will be asked to complete four questionnaires about your sexual and 
urinary functioning and overall quality of life.  These questionnaires should 
take about 25-30 minutes to complete.  You will be asked to complete these 
forms prior to treatment, at 4 months, 12 months, and 24 months after 
treatment and once a year after that for three years. 
 
HOW LONG WILL I BE IN THE STUDY? 
 
If you receive Treatment 1, you will receive external radiation therapy once a day, 
five days per week for five weeks.  Two to four weeks following radiation therapy, 
the radioactive seeds will be implanted into your prostate.  Follow-up visits will 
continue for the rest of your life according to the above schedule. 
 
If you receive Treatment 2, the radioactive seeds will be permanently implanted 
within 2 to 4 weeks from study enrollment.  Follow-up visits will continue for the rest 
of your life according to the above schedule. 
 
The researcher may decide to discontinue your treatment if it is in your medical 
best interest, your condition worsens, or new information becomes available and 
this information suggests the treatment will be ineffective or unsafe for you.  It is 
unlikely, but the study may be stopped early due to lack of funding or of enough 
participants. 
 
You can stop participating at any time.  However, before you do this, we ask you to 
talk with the researcher and your regular doctor first. 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
While on the study, you are at risk for these side effects.  You should discuss these 
with the researcher and/or your regular doctor.  There also may be other side 
effects that we cannot predict.  Other drugs will be given to make side effects less 
serious and uncomfortable, such as medication to reduce irritation of the bowel, 
rectum, or bladder.  Trouble with erections also can be successfully treated with 
medication in many circumstances.  Many side effects go away shortly after the 
radiation therapy is stopped, but in some cases side effects can be serious or long-
lasting or permanent.  Some side effects do not become apparent for months or 
years after all treatment has been delivered. 
 
Risks Associated with Implant Therapy 
Very Likely 
• 
Infection that can be treated with antibiotics 
• 
Soreness in the implant area 
• 
Temporary fatigue  
• 
Temporary nausea  
43 
 

 
• 
Temporary diarrhea 
• 
Abdominal cramps 
• 
Bladder irritation with some bleeding 
 
 
 
 
 
 
 
 
 
• 
Inability to achieve an erection 
• 
Urinary tract infection  (UTI) 
 
Less Likely, But Serious 
• 
Injury to the bladder, urethra, bowel or other tissues in your pelvis or abdomen 
• 
Rectal bleeding that requires medication or burning/cutting of tissue or surgery 
to correct 
• 
Intestinal or urinary obstruction 
• 
Inability to control urination  
• 
Movement of a radioactive seed to the lungs 
• 
Serious infection 
• 
Rectal fistula (breakdown of tissue between the urinary tract and rectum) 
 
Risks Associated with External Radiation Therapy 
Very Likely 
• 
Tanning or redness of skin in treatment area 
• 
Rash, itching or peeling of skin 
• 
Temporary hair loss in the treatment area 
• 
Temporary nausea  
• 
Temporary diarrhea 
• 
Abdominal cramps 
• 
Bladder irritation with a stinging sensation 
• 
Frequency or urgency of urination 
• 
Inability to control urination (incontinence) 
• 
Rectal irritation with more frequent bowel movements 
• 
Fatigue 
• 
Urinary Tract Infection (UTI) 
• 
Inability to achieve an erection 
 
Less Likely, But Serious 
• 
Injury to the bladder, urethra, bowel or other tissues in your pelvis or abdomen 
• 
Intestinal or urinary obstruction 
• 
Rarely, rectal bleeding that requires medication or burning/cutting of tissue or 
surgery to correct  
 
 
Risks Associated with External Radiation Therapy AND Seed Implant Therapy: 
• 
Worsening of bowel, bladder or sexual dysfunction problems 
• 
An overall decrease in your quality of life 
 
44 
 

 
Reproductive Risks: 
If you are a man able to father children, the treatment you receive may risk harm to 
an unborn child unless you use a form of birth control approved by your doctor.  If 
you are unwilling to use adequate birth control measures to prevent pregnancy, you 
should not participate in this study.  If you suspect you have caused anyone to 
become pregnant while you are on this study, you must tell your doctor 
immediately. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
If you agree to take part in this study, there may or may not be direct medical 
benefit to you.  We hope the information learned from this study will benefit other 
patients with prostate cancer in the future. 
WHAT OTHER OPTIONS ARE THERE? 
 
Other options that could be considered for your condition instead of this study may 
include the following:  (1) external radiation therapy alone, whether standard,  three 
dimensional conformal, or intensity modulated radiation therapy (IMRT); (2) internal 
radiation therapy (brachytherapy) like this study, or by temporary insertion of 
radioactive rods, called high dose rate therapy; (3) hormone therapy; (4) surgery to 
remove your prostate (radical prostatectomy); (5) watchful waiting with regularly 
scheduled monitoring with digital rectal exams (DRE) and PSA blood draws; or (6) 
no treatment except medications to make you feel better.  With the latter choice, 
your tumor would continue to grow and your disease would likely eventually spread. 
The treatments (1) through (4) could be given either alone or in combination with 
each other. 
 
Your doctor can tell you more about your condition and the possible benefits of the 
different available options. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential.  We cannot 
guarantee absolute confidentiality.  Records of your progress while on the study will 
be kept in a confidential form at this institution and in a computer file at the 
headquarters of NRG Oncology.  Your personal information may be disclosed if 
required by law.  
 
Organizations that may inspect and/or copy your research records for quality 
assurance and data analysis include groups such as the Food and Drug 
Administration (FDA), the National Cancer Institute (NCI) or its authorized 
representatives, the Cancer Trials Support Unit (CTSU), qualified representatives of 
applicable drug manufacturers, and other groups or organizations that have a role 
in this study.   
 
45 
 

 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance 
company.  If you are randomized to receive Treatment 1, the combination of 
external radiation with implant may result in higher costs to you or your insurance 
company than an implant alone.  Please ask about any expected added costs or 
insurance problems. 
In the case of injury or illness resulting from this study, emergency medical 
treatment is available but will be provided at the usual charge.  Although no funds 
have been set aside to compensate you in the event of injury or illness related to 
your treatment or procedures, you do not waive any of your legal rights to 
compensation, if any, by signing this form. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  Medicare should be considered a health insurance provider. 
 
You will receive no payment for taking part in this study. 
 
You may find a National Cancer Institute guide: "Clinical Trials and Insurance 
Coverage - a Resource Guide" helpful in this regard. You may ask your doctor for a 
copy, 
or 
it 
is 
available 
on 
the 
World 
Wide 
Web 
at 
http://www.nci.nih.gov/ClinicalTrials/insurance (and click on printable version). 
 
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
 
 
Taking part in this study is voluntary.  You may choose not to take part or you may 
leave the study at any time.  If you choose to stop participating in the study, you 
should first discuss this with your doctor.  In order to provide important information 
that may add to the analysis of the study, he/she may ask your permission to 
submit follow-up data as it relates to the study.  You may accept or refuse this 
request.  Leaving the study will not result in any penalty or loss of benefits to which 
you are entitled. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be 
reviewing the data from this research throughout the study.  We will tell you about 
the new information from this or other studies that may affect your health, welfare, 
or willingness to stay in this study. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
(This section must be completed) 
 
For information about your disease and research-related injury, you may contact: 
 
46 
 

 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
47 
 

 
 
For information about this study, you may contact: 
 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
 
For information about your rights as a research subject, you may contact: 
(OHRP) suggests that this person not be the investigator or anyone else directly involved with the 
research) 
 
 
 
 
 
 
 
 
Name 
 
 
Telephone Number 
 
You may also call the Project Office of the NCI Central Institutional Review Board (CIRB) at 888-
657-3711 (from the continental US only). 
 
WHERE CAN I GET MORE INFORMATION? 
 
You may call the NCI’s Cancer Information Service at 
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615. 
 
Visit the NCI’s Web sites  
 
for clinical trials information go to  http://cancer.gov/clinicaltrials  
 
for cancer information go to  http://cancer.gov/cancerinformation 
 
CancerFax: Includes NCI information about cancer treatment, screening, 
prevention, and supportive care. To obtain a contents list, dial 301-402-5874 or 
800-624-2511 from a fax machine handset and follow the recorded instructions.  
 
SIGNATURE 
 
I have read all the above, asked questions, and received answers concerning areas I did 
not understand.  I have had the opportunity to take this consent form home for review or 
discussion.   
 
I willingly give my consent to participate in this program.  Upon signing this form I will 
receive a copy.  Upon request, I will also receive a copy of the protocol (full study plan). 
 
___________________________ 
__________________________ __________ 
Patient’s Name  
                            
Signature 
 
       Date 
 
 
___________________________                      ____________________________ __________ 
48 
 

 
Name of Person Obtaining Consent 
 
Signature 
  
Date 
 
49 
 

 
 
APPENDIX IB (2/15/05) 
RTOG 0232 
 
CONSENT FORM FOR USE OF TISSUE FOR RESEARCH 
 
ABOUT USING TISSUE FOR RESEARCH 
 
We would like to keep some of the tissue that remains from the biopsy you underwent in the 
diagnosis of your cancer for future research.  If you agree, this tissue will be kept and may be 
used in research to learn more about cancer and other diseases.  
 
The research that may be done with your tissue is not designed specifically to help you.  It might 
help people who have cancer and other diseases in the future. 
 
All possible methods will be used to ensure your privacy and confidentiality.  Identifying 
information will be taken off anything associated with your tissue before it is given to a researcher.  
Reports about research done with your tissue will not be given to you or your doctor.  These 
reports will not be put in your health record.  The research will not have an effect on your care. 
 
THINGS TO THINK ABOUT 
 
The choice to let us keep the left over tissue for future research is up to you.  No matter what 
you decide to do, it will not affect your care or participation in the primary study. 
 
If you decide now that your tissue can be kept for research, you can change your mind at any 
time.  Just contact us and let us know that you do not want us to use your tissue, and then any 
tissue that remains will no longer be used for research. 
  
In the future, people who do research may need to know more about your health.  While 
__________ (doctor/institution) may give researchers reports about your health, your 
doctor/institution will not give researchers your name, address, phone number, or any other 
information that will let the researchers know who you are. 
 
Sometimes tissue is used for genetic research (about diseases that are passed on in families).  
Even if your tissue is used for this kind of research, the results will not be put in your health 
records. 
 
Your tissue will be used only for research.  However, the research done with your tissue may help 
to develop new products in the future, or your tissue may be used to establish a cell line that 
could be patented and licensed.  If this occurs, you will not be paid for this use. 
 
BENEFITS 
 
The benefits of research using tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them. 
 
 
50 
 

 
 
RISKS 
 
There is a very small chance that information from your health records could be incorrectly 
released.  All possible methods will be used to protect your privacy and ensure confidentiality.  
Unless you have given your specific permission, your _______ (doctor/institution) will not release 
your personal results or information to third parties such as employers or insurers. 
 
In the case of injury or illness resulting from participating in this research, emergency medical 
treatment is available but will be provided at the usual charge.  Although no funds have been set 
aside to compensate you in the event of injury or illness related to your participation in this 
research, you do not waive any of your legal rights to compensation, if any, by signing this form. 
 
MAKING YOUR CHOICE 
 
If you have any questions about the research involving your tissue or about this form, please talk 
to your doctor or nurse, or call the institution’s research review board at _________ (IRB’s phone 
number). 
 
Please read each sentence below and think about your choice.  After reading each sentence, 
circle “Yes” or “No”.  No matter what you decide to do, it will not affect your care or 
participation in the primary study.   
 
1. 
My tissue may be used for the research in the current study. 
 
 
 
Yes                No 
 
2. 
My tissue may be kept for use in research to learn about, prevent, or treat cancer. 
 
 
 
Yes 
No 
 
3. 
My tissue may be kept for use in research to learn about, prevent, or treat other health 
problems (for example:  diabetes, Alzheimer’s disease, or heart disease). 
 
 
 
Yes 
No 
 
4. 
Someone from ______ (doctor’s office/institution) may contact me in the future to ask me 
to take part in more research. 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
 
Participant statement: 
51 
 

 
I have read and received a copy of this consent form. I have been given an opportunity to discuss 
the information with my doctor/nurse, and all of my questions/concerns have been answered to 
my satisfaction. My answers above and my signature below indicate my voluntary participation in 
this research.  
 
 
 
                                                                   
 
  
Patient’s Name  
                                Signature 
 
     Date 
 
 
 
Witness statement: 
I have explained the information in this consent form to the patient and have answered any 
questions raised. I have witnessed the patient’s signature. 
 
 
            
_    _________          
Name of Person Obtaining Consent                    Signature 
 
 Date 
 
 
 
 
 
52 
 

 
 
 
APPENDIX IC (10/2/15) 
RTOG 0232 
CONSENT FORM FOR USE OF COST DATA FOR RESEARCH 
(Limited to Participants Whose Health Care is Covered at Least in Part by Medicare) 
 
 
ABOUT USING COST INFORMATION FOR RESEARCH 
 
In comparing different treatments for prostate cancer, very little is known about long-term costs of 
different kinds of treatment.  This study compares two different kinds of treatment that are 
different in their initial costs.  However, the long-term costs of the two different treatments are not 
known.  Obtaining this information would allow us to study both the cost and the benefits of the 
treatments involved in this study.  This information would help patients; physicians and providers 
make more informed decisions about these therapies in the future. 
 
We would like to obtain information about both the short-term and the long-term costs of 
treatment for your prostate cancer.  To do this, we would like to use computerized information 
from the Medicare system to estimate the costs of your medical care.  You are being asked to 
provide your name and Social Security Number so that we may link your treatment and outcomes 
to the cost data involved in both your treatment and follow-up care.  
 
This information is private and confidential.  We must have your permission to use a personal 
identifier to obtain your specific Medicare information.  The specific information about you that 
is collected will not be given to any other party, including your physician, the hospital, or 
any other third party. These reports will not be put in your health record.  The Medicare 
data will be aggregated with data from all patients participating in this portion of the study, and 
only reported in aggregate form.  No personal identifying information will be made public. 
 
This cost information will be used only for research. 
 
 
THINGS TO THINK ABOUT 
 
The choice to let us have access to your Medicare information is up to you.  No matter what you 
decide to do, it will not affect your care or participation in the primary study. 
 
If you decide now that your Medicare data may be used for research, you can change your mind 
at any time.  Just contact us and let us know that you do not want us to use your information, and 
your information will be removed from the study database. 
 
 
 
 
 
 
 
 
53 
 

 
 
BENEFITS 
 
The benefits of research using costs data include learning how to achieve the most effective 
treatments for cancer while avoiding added costs and decreased quality of life for patients.  This 
information would help patients like you; physicians and providers make more informed decisions 
about these therapies in the future. 
 
RISKS 
 
There is a very small chance that information from your billing information could be incorrectly 
released.  If you give your permission for us to use your Medicare information, that information 
will be furnished to the NRG Oncology directly by Medicare, and will not be made available to any 
third party, including your physician, hospital, employer, or other insurer.  All possible methods 
will be used to protect your privacy and ensure confidentiality.   
 
 
MAKING YOUR CHOICE 
 
If you have any questions about the research involving your cost data or about this form, please 
talk to your doctor or nurse, or call the institution’s research review board at _________ (IRB’s 
phone number). 
 
Please read each sentence below and think about your choice.  After reading each sentence, 
circle “Yes” or “No”.  No matter what you decide to do, it will not affect your care or 
participation in the primary study. 
 
My Medicare data may be used for the research in the current study. 
 
Yes 
 
 
No 
 
Participant statement: 
I have read and received a copy of this consent form.  I have been given an opportunity to discuss the 
information with my doctor/nurse, and all of my questions/concerns have been answered to my 
satisfaction.  My answers above and my signature below indicate my voluntary participation in this 
research.  
 
 
 
                                                            
       
  
Patient’s Name  
                                 Signature 
 
     Date 
 
 
 
Witness statement: 
I have explained the information in this consent form to the patient and have answered any questions 
raised.  I have witnessed the patient’s signature. 
 
 
            
_ 
   _________          
Name of Person Obtaining Consent                    Signature 
 
 Date 
 
 
54 
 

 
APPENDIX II 
 
KARNOFSKY PERFORMANCE SCALE 
 
 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead  
 
 
 
ZUBROD PERFORMANCE SCALE 
 
 
0 
Fully active, able to carry on all predisease activities without restriction 
(Karnofsky 90-100). 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature.  For example, light housework, 
office work (Karnofsky 70-80). 
 
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 (Karnofsky 50-
60). 
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours (Karnofsky 30-40). 
 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair (Karnofsky 10-20). 
 
 
55 
 

 
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) 
 
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). 
56 
 

 
APPENDIX III  (continued) 
 
AJCC STAGING SYSTEM 
PROSTATE, 6th Edition 
 
 
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]) 
 
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 
 
 
N0 
 
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 
57 
 

 
 
 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
APPENDIX IV 
ORGAN TISSUE 
0 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
5 
SKIN 
None 
Slight atrophy; Pigmentation change; 
Some hair loss 
Patch atrophy; Moderate telangiectasia; Total 
hair loss 
Marked atrophy; Gross telangiectasia 
Ulceration 
 
D 
SUBCUTANEOUS 
TISSUE 
None 
Slight induration (fibrosis) and loss of 
subcutaneous fat 
Moderate fibrosis but asymptomatic; Slight 
field contracture; <10% linear reduction 
Severe induration and loss of subcutaneous 
tissue; Field contracture > 10% linear 
measurement 
Necrosis 
E 
A 
T 
MUCOUS 
MEMBRANE 
None 
Slight atrophy and dryness 
Moderate atrophy and telangiectasia; Little 
mucous 
Marked atrophy with complete dryness; Severe 
telangiectasia 
Ulceration 
H 
SALIVARY 
GLANDS 
None Slight dryness of mouth; Good response 
on stimulation 
Moderate dryness of mouth; Poor response 
on stimulation 
Complete dryness of mouth; No response on 
stimulation 
Fibrosis 
D 
I 
SPINAL 
CORD 
None 
Mild L’Hermitte’s syndrome 
Severe L’Hermitte’s syndrome 
Objective neurological findings at or below cord 
level treated 
Mono, para quadriplegia 
R 
E 
BRAIN 
None 
Mild headache; Slight lethargy 
Moderate headache; Great lethargy 
Severe headaches; Severe CNS dysfunction 
(partial loss of power or dyskinesia) 
Seizures or paralysis; Coma C 
T 
L 
EYE 
None 
Asymptomatic cataract; Minor corneal 
ulceration or keratitis 
Symptomatic cataract; Moderate corneal 
ulceration; Minor retinopathy or glaucoma 
Severe keratitis; Severe retinopathy or 
detachment Severe glaucoma 
Panopthalmitis/Blindness 
Y 
 
R 
LARYNX 
None 
Hoarseness; Slight arytenoid edema 
Moderate arytenoid edema; Chondritis 
Severe edema; Severe chondritis 
Necrosis 
E 
L 
A 
LUNG 
None 
Asymptomatic or mild symptoms (dry 
cough); Slight radiographic appearances 
Moderate symptomatic fibrosis or 
pneumonitis (severe cough); Low grade fever; 
Patchy radiographic appearances 
Severe symptomatic fibrosis or pneumonitis; 
Dense radiographic changes 
Severe respiratory 
insufficiency/continuous 
O2/Assisted ventilation 
T 
E 
D 
 
HEART 
None 
Asymptomatic or mild symptoms; 
Transient T wave inversion & ST 
Changes; Sinus tachycardia >110  
(at rest) 
Moderate angina on effort; Mild pericarditis; 
Normal heart size; Persistent abnormal T 
wave and ST changes ; Low ORS 
Severe angina; Pericardial effusion; Constrictive 
pericarditis; Moderate heart failure; Cardiac 
enlargement; EKG abnormalities 
Tamponade/Severe heart 
failure/Severe constrictive 
pericarditis 
T 
O 
 
R 
A 
ESOPHAGUS 
None 
Mild fibrosis; Slight difficulty in 
swallowing solids; No pain on swallowing 
Unable to take solid food normally; 
Swallowing semi-solid food; Dilation may be 
indicated 
Severe fibrosis; Able to swallow only liquids; May 
have pain on swallowing 
Dilation required 
Necrosis/Perforation Fistula 
D 
I 
A 
SMALL/LARGE 
INTESTINE 
None 
Mild diarrhea; Mild cramping; Bowel 
movement 5 times daily Slight rectal 
discharge or bleeding 
Moderate diarrhea and colic; Bowel 
movement >5 times daily; Excessive rectal 
mucus or intermittent bleeding 
Obstruction or bleeding, requiring surgery 
Necrosis/Perforation Fistula 
T 
I 
O 
N 
LIVER 
None 
Mild lassitude; Nausea, dyspepsia; 
Slightly abnormal liver function 
Moderate symptoms; Some abnormal liver; 
function tests; Serum albumin normal 
Disabling hepatitic insufficiency; Liver function 
tests grossly abnormal; Low albumin; Edema or 
ascites 
Necrosis/Hepatic coma or 
encephalopathy 
 
E 
F 
F 
KIDNEY 
None Transient albuminuria; No hypertension; 
Mild impairment of renal function; Urea 
25-35 mg%;Creatinine 1.5-2.0 mg%; 
Creatinine clearance > 75% 
Persistent moderate 
albuminuria (2+); Mild 
hypertension; No related 
anemia; Moderate impairment of renal 
function; Urea > 36-60mg% Creatinine 
clearance (50-74%) 
Severe albuminuria; Severe hypertension 
Persistent anemia (< 10%); Severe renal failure; 
Urea >60 mg% Creatinine >4.0 mg% Creatinine 
clearance < 50% 
Malignant hypotension; Uremic 
coma/Urea > 100% 
E 
C 
T 
S 
BLADDER 
None 
Slight epithelial atrophy; Minor 
telangiectasia (microscopic hematuria) 
Moderate frequency; Generalized 
telangiectasia; Intermittent macroscopic 
hematuria 
Severe frequency & dysuria Severe generalized 
Telangiectasia (often with petechiae); Frequent 
hematuria; Reduction in bladder capacity  
(< 150 cc) 
Necrosis/Contracted bladder 
(capacity < 100 cc); Severe 
hemorrhagic cystitis 
 
 
 
 
BONE 
None 
Asymptomatic; No growth retardation; 
Reduced bone Density 
Moderate pain or tenderness; Growth 
retardation; Irregular bonesclerosis 
Severe pain or tenderness; Complete arrest of 
bone growth; Dense bone sclerosis 
Necrosis/Spontaneous fracture
 
JOINT 
None 
Mild joint stiffness; Slight limitation of 
movement 
Moderate stiffness; Intermittent or moderate 
joint pain; Moderate limitation of movement 
Severe joint stiffness; Pain with severe limitation 
of movement 
Necrosis/Complete fixation 
 
 
58 
 
 

 
APPENDIX V 
 
GLEASON CLASSIFICATION1 
 
Histologic patterns of adenocarcinoma of the prostate 
 
Pattern Margins 
Tumor 
Areas 
Gland 
Pattern 
Gland 
Size 
Gland 
Distribution 
Stromal 
Invasion 
1 
Well defined Single, separate,  
round 
Medium Closely 
packed 
Minimal, 
expansile 
2 
Less definite Single, separate rounded 
but more variable 
Medium Spaced up to 
one gland 
diameter, 
average 
Mild, in larger 
stromal planes 
3 
Poorly 
defined 
Single, separate 
more irregular 
Small 
medium, 
or large 
Spaced more 
than one 
gland 
diameter, 
rarely packed 
Moderate, in 
larger or smaller 
stromal planes 
or  
3 
Poorly 
defined 
Rounded masses of 
cribriform  
or papillary epithelium 
Medium 
or large 
Rounded 
masses with 
smooth sharp 
edges 
Expansile 
masses 
4 
Ragged, 
infiltrating 
Fused glandular  
masses or "hypernephroid
Small 
Fused in 
ragged 
masses 
Marked, through 
smaller planes 
5 
Ragged, 
infiltrating 
Almost absent, few  
tiny glands or signet ring 
Small 
Ragged 
anaplastic 
masses of 
epithelium 
Severe between 
stromal fibers or 
destructive 
or 
5 
Poorly 
defined 
Few small lumina in 
rounded masses of solid 
epithelium central necrosis
Small 
Rounded 
masses and 
cords with 
smooth sharp 
edges 
Expansile 
masses 
 
The Gleason Classification is a system of histologic grading based on over-all pattern of 
tumor growth at relatively low-magnification (40 to 100x).  Five patterns of growth are 
recognized and numbered in order of increasing malignancy.  Because of histologic 
variation in the tumor, two patterns are recorded for each case, a primary or predominate 
pattern and a secondary or lesser pattern. 
 
The Gleason Score is the sum of the primary and secondary pattern, if only one pattern is 
present, the primary and secondary pattern receive the same designation. 
 
(Primary = 2, Secondary = 1, Gleason = 3) 
(Primary = 2. Secondary = 2, Gleason = 4) 
 
1. Gleason, D.F. et al: Prediction of prognosis for prostatic carcinoma by combined 
histologic grading and clinical staging.  J Urol 111:58, 1974. 

 
APPENDIX VI 
RTOG 0232 
 
 
 
 
 
 
 
 
 
ON-STUDY AUA SYMPTOM SCORE (PQ) 
Case   
 
 
PATIENT NAME   
 
 
TOTAL SCORE 
 
 
 
INSTITUTION NAME 
 
 
 
 
 
 
PLEASE FILL OUT THIS SHORT QUESTIONNAIRE TO HELP US FIND OUT MORE ABOUT 
ANY URINARY PROBLEMS YOU MIGHT HAVE. CIRCLE A NUMBER IN EACH COLUMN 
THAT BEST DESCRIBES YOUR SITUATION.  YOU MUST ANSWER ALL QUESTIONS. 
 
 
 
Not at all 
 
Less than 
one 
time in five 
 
Less than  
half the 
time 
 
About 
half 
the time 
 
More than 
Half the time 
 
Almost 
always 
1. Over the past month or so, how 
often have you had a sensation 
of not emptying your bladder 
completely after you finished 
urinating? 
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
2. Over the past month or so, how 
often have you had to urinate 
again, less than two hours after 
you finished urinating? 
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
3. Over the past month or so, how 
often have you found you 
stopped and started again 
several 
times 
when 
you 
urinated? 
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
4. How often do you find it difficult 
to postpone urination? 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
5. Over the past month or so, how 
often have you had a weak 
urinary stream? 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
6. Over the past month or so, 
how often have you had to 
push 
or 
strain 
to 
begin 
urination? 
 
0 
1 
2 
3 
4 
5 
 Not at all Once every  
8 hours 
Once every 
4 hours 
Once 
every 3 
hours 
Once every  
2 hours 
At least once 
every hour 
7. Over the past month or so, how 
often did you most typically get 
up at night to urinate? 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
Total per column 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature 
 
 
 
 
 
 
 
Date This Form was Completed 
 
60  
 

 
APPENDIX VII (2/15/05) 
 
RTOG Permanent Prostate Implant Quality Assurance Guidelines 
 
I. 
Purpose 
 
To establish QA guidelines for the radiation oncologist, physicist, dosimetrists, and research associate.  To 
participate in this protocol, the oncologist/physicist team must attest in writing to the fact that they have 
performed at least 10 such prostate implants prior to entering patients on this protocol. 
 
II. 
Background 
 
The following reports serve as background material for various aspects of this protocol: 
 
1. ICRU Report 58, Dose and Volume Specification for Reporting Interstitial Therapy 
 
2. Comprehensive QA for radiation oncology: Report of AAPM Radiation Therapy Committee Task Group 
40 Medical Physics 21 (4), 1994, 581-618. 
 
3. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy 
Committee Task Group No. 43 Medical Physics 22 (2), 1995, 209 - 234. 
 
4. Recommendations of the American Association of Physicists in Medicine on Pd interstitial source 
calibration and dosimetry:  Implications for dose specifications and prescription:  Medical Physics 27(4), 
2000, 634-642. 
 
III. 
Technology Requirements 
 
Each institution that wishes to participate in the protocol must have the following capabilities: 
a. A source calibration system, modeled after TG 40, with an NIST traceable calibration for I-125 
and Pd-103. 
 
b. A treatment planning system with the following characteristics: 
 
1) 
A seed model whose results agree with the TG-43 data, as specified below. (See RPC web 
site at http://rpc.mdanderson.org) 
2) 
The ability to calculate brachytherapy dose distributions which display contours, which can be 
either CT based or manually entered.  The brachytherapy dose calculational grid must be 2 
mm x 2 mm or smaller.  Manual superposition of the dose distribution over the contour is 
permitted provided that this superposition is based upon the coordinates of the contour and the 
coordinates of the individual seed locations.  
 
3) 
The ability to produce a dose-volume histogram, DVH.  The manual creation of a DVH is 
permitted provided it is based upon the brachytherapy dose calculation grid which must be 2 
mm x 2 mm or smaller.   
c. 
Transrectal ultrasound for pre-implant images 
d. 
CT images for post-implant analysis 
e. 
DICOM RT for electronic data submission and compatible treatment planning software 
 
IV. 
Credentialing 
 
 
1. 
Institutions must be credentialed by the Radiological Physics Center (RPC) prior to registering 
any cases to this study.  The credentialing materials may be found at the RPC web site:  
http://rpc.mdanderson.org under the “credential” tab. 
 
 
2. 
Institutions who have been previously credentialed to participate in RTOG 98-05/RTOG P-0019 
are automatically eligible to participate in this protocol assuming that these institutions have the 
same radiation oncologist and physicist as were on their original credentialing request and that 
the institution is using the same I-125 seed model as was on their original credentialing request 
(Please note that RTOG 98-05 and RTOG P-0019 only permitted the use of I-125.  Thus if an 
 
61  
 

 
institution wishes to use Pd-103 and has been previously credentialed for I-125, they must 
complete the RPC’s physics credentialing for this source.)  In the event that an institution has 
changed physicist or source model, the institution must resubmit to have the new physicist or 
new source credentialed with the RPC.  In the event that the institution has changed radiation 
oncologist, then the institution must resubmit for clinical credentialing with the RPC.  Additional 
information can be found at the RPC’s web site, http://rpc.mdanderson.org.  
 
In addition to the credentialing of the radiation oncologist, the physicist, and the source, 
institutions must also be credentialed through the RTOG Image-guided Therapy Center (ITC).  
The web site is http://itc.wustl.edu. This web site contains a section, which is entitled “Prostate 
Brachy Docs.”  The required information for credentialing can be obtained from this section.  At 
this time, there are at least two commercial planning systems that have capabilities of a digital 
data exchange for prostate implants.  Institutions must become credentialed using the digital 
approach and are encouraged to request this capability from their software vendor is currently 
available. 
 
V. 
Patient Data Review Process 
 
The data for all patients entered onto this protocol will be reviewed by the PI's and other selected reviewers.  
This review will comprise, in part, of: 
 
 
1. An independent definition of the ETV and an independent recalculation of the dose and the 
DVH's. 
 
 
 
62  
 

 
 APPENDIX VIII                                         RTOG 0232 
 
 
RTOG Post-Implant Dosimetry Data Form  (T5)  
Case   
 
 
 
Patient__________________________________/Physician: 
 
 
 
 
 
 
Source:  ____________________________________________ 
 
Doses are based upon TG 43 Dosimetry 
 
Date of Pre-Implant TRUS Study: _________________________ 
 
Number of slices on pre-implant TRUS  _______ 
 
 
TRUS volumes 
 
CTV 
______ cm3 
PTV 
_______ cm3 
 
Date of Implant:    
 
 
Basic Dosimetry Information 
 
 
1. Average activity per seed as measured by institution: 
 
Source Strength: 
_______U 
Date: 
 
 
 
 
2. Midpoint apparent activity stated by the vendor: 
 
Source Strength: 
_______U 
Date: 
 
 
 
 
3. Number of Seeds Used: 
 
 
 
 
4. Number of Needles Used: 
 
 
 
 
5. Prescribed Dose: ___ Gy 
TG 43/NIST 99Dosimetry 
 
 
6. Peripheral Dose:  ___ Gy 
TG 43/NIST 99Dosimetry 
 
Post Implant CT Analysis 
 
Date of Implant 
 
 
 
Date of Post-Implant CT: 
 
 
 
No. of Seeds Counted on Post Implant A/P Radiograph ____________________ 
 
Prostate 
 
Prostate is defined on   _____  slices. 
 
Post-Implant Volume (ETV) as determined from post-implant CT 
________ cm3 
 
V100  _______ %       V90 ________ %      V80 ________ % 
 
V150  _______ %        D90 ________ Gy 
   
Urethra:    Maximum Dose  _________ Gy     U200  ________ cm3 
 
Rectum:    Maximum Dose  _________ Gy     R100  ________ cm3 
 
63  
 

 
 
Appendix IX 
 
Scoring Instructions for the  
Expanded Prostate cancer Index Composite 
(EPIC)* 
 
 
 
 
To request a copy of EPIC or related information, please contact any of the following 
investigators: 
 
 
 
Martin G. Sanda, M.D. (1/11/08) 
330 Brookline Ave – Rabb 440 
Beth Israel Deaconess Medical 
Center 
Boston, MA 02215 
Phone: (617 )667-2960 
Fax: (617) 667-3013 
Email: msanda@bidmc.harvard.edu 
 
 
 
 
 
 
 
 
 
John T. Wei, M.D., M.S. 
University of Michigan  
2916 Taubman Center,  
1500 E. Medical Center Dr., 
Ann Arbor, MI  48109-0330 
Phone: (734) 615-3040  
Fax: (734) 936-9127  
Email: jtwei@umich.edu  
 
 
 
 
 
 
 
 
Mark S. Litwin, M.D., M.P.H. 
UCLA Department of Urology 
Box 951738 
Los Angeles, CA 90095-1738 
Phone: (310) 794-7960 
Fax: (310) 206-5343 
Email: mlitwin@mednet.ucla.edu 
 
 
 
 
 
 
 
* A SAS macro for computing the EPIC scores is available at the EPIC web site: 
http://roadrunner.cancer.med.umich.edu/epic/ 
 
Questions regarding the SAS macro should be addressed to:   
 
Rodney L. Dunn 
UMCCC Biostatistics Unit 
C-344 Med Inn Building 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109-0848 
Phone: (734) 615-1396 
Email: rldunn@umich.edu 
 
 
 
 
The Expanded Prostate cancer Index Composite (EPIC) was developed by researchers at University of Michigan 
and UCLA to measure health related quality of life among men with prostate cancer.1 It represents an adaptation of 
the UCLA Prostate Cancer Index,2 modified to enhance sensitivity to therapy effects by increasing the number of 
prostate-targeted items to 50 (compared to 20 in the original UCLA-PCI).  EPIC has been validated in men with 
localized prostate cancer who underwent surgery, external beam radiation, or brachytherapy with or without the use of 
 
64  
 

 
Pag 
 
 
 
Do Not 
 
 
 
 
 
Mark in 
 
 
 
 
 
This 
 
 
 
 
 
Space 
 
hormonal adjuvants.  EPIC is sensitive to specific HRQOL effects of these therapies and to HRQOL effects of cancer 
progression.3 
 
EPIC assesses the disease-specific aspects of prostate cancer and its therapies and comprises four summary 
domains (Urinary, Bowel, Sexual and Hormonal). Factor analysis supports dividing the Urinary Domain Summary 
Score into two distinct Incontinence and Irritative/Obstructive subscales. In addition, each Domain Summary Score 
has measurable Function Subscale and Bother Subscale components.  Response options for each EPIC item form a 
Likert scale, and multi-item scale scores are transformed linearly to a 0-100 scale (see following page: EPIC scoring), 
with higher scores representing better HRQOL.  A summary of EPIC Summary Score and Subscale characteristics 
are tabulated (from Ref. 1):   
 
 
HRQOL Domain 
Number of 
items 
Mean Score 
(sd) 
Test-retest 
reliability 
Internal 
consistency 
reliability 
II. HRQOL Domain Summary Scores 
 
 
 
 
Urinary 
12 
80.2 (17.5) 
0.88 
0.88 
 
Bowel 
14 
86.6 (15.7) 
0.84 
0.92 
 
Sexual 
13 
33.1 (23.6) 
0.91 
0.93 
 
Hormonal 
11 
86.6 (13.8) 
0.80 
0.82 
III. Domain-Specific HRQOL Subscales 
 
 
 
 
Urinary Subscales 
 
 
 
 
[  
Function 
5 
86.5 (16.7) 
0.83 
0.69 
 
Bother 
7 
75.8 (20.4) 
0.87 
0.85 
[  
Incontinence*  
4 
83.2 (22.9) 
0.87 
0.89 
 
Irritative/Obstructive*  
7 
79.7 (18.5) 
0.85 
0.81 
 
Bowel Subscales 
 
 
 
 
 
 
Function 
7 
87.9 (13.6) 
0.78 
0.75 
 
 
Bother 
7 
85.3 (18.8) 
0.85 
0.90 
 
Sexual Subscales 
 
 
 
 
 
 
Function 
9 
29.5 (24.0) 
0.90 
0.92 
 
 
Bother 
4 
41.1 (30.1) 
0.78 
0.84 
 
Hormonal Subscales 
 
 
 
 
 
 
Function 
5 
84.0 (15.3) 
0.79 
0.51 
 
 
Bother 
6 
88.7 (13.6) 
0.73 
0.73 
 
*A single global urinary bother item, which does not distinguish bother related to incontinence from that 
related to urinary obstruction, is not included in the Urinary Incontinence or Urinary Irritative/Obstructive 
subscales; therefore, 11 urinary items comprise these 2 subscales whereas the Urinary Summary Domain 
includes 12 items. 
 
EPIC can be used alone or combined with other instruments, including the AUA-SI, FACT-P, and  Medical 
Outcomes Study SF-12 or SF-36. Inter-scale correlation between EPIC and these instruments has indicated 
that efficient (yet comprehensive) HRQOL assessment can be achieved by co-administering EPIC with SF-
12.4  Concurrent use of the AUA-SI can also provide useful complementary clinical information.5  The 
following scoring instructions therefore assume that EPIC will be co-administered with SF-12 and the AUA-
SI, with these 3 instruments combined according to the following format: 
 
SF-12 General Health Function Survey (first 12 items):  
 
Items 11-22 
  
EPIC (subsequent 50 items excluding 7 AUA-SI items): 
 
Items 23-34, 42-79 
 
AUA Symptom Index (7 items embedded in EPIC Urinary Section): 
Items 35-41 
 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 
 

 
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Scoring the EPIC  
 
There are 2 steps involved in scoring EPIC: 
Step 1. The response for each item is standardized to a 0 to 100 scale according to the table below. 
 
Item Number 
Item Response Value 
Standardized Value 
23,24,25,42,43,48,56,57,58,60,61, 
1 
0 
62,63,64,69,70,71,72 
2 
25 
 
3 
50 
 
4 
75 
 
5 
100 
26,59 
1 
0 
 
2 
33 
 
3 
67 
 
4 
100 
27 
0 
100 
 
1 
67 
 
2 
33 
 
3 
0 
28,29,30,31,32,33,49,50,51,52,53, 
0 
100 
54,65,66,67,74,75,76,77,78,79 
1 
75 
 
2 
50 
 
3 
25 
 
4 
0 
34,44,45,46,55,68 
1 
100 
 
2 
75 
 
3 
50 
 
4 
25 
 
5 
0 
47 
1 
100 
 
2 
50 
 
3 
0 
73 
1 
0 
 
2 
50 
 
3 
100 
 
4 
50 
 
5 
0 
 
Step 2. Using the item groupings listed below for each HRQOL Domain Summary Score or Subscale score, 
average the standardized values (see Step 1, above) for all items within a group to create the 
summary or subscale score. (If >20% of the items that comprise a domain summary score or 
subscale score are missing a response, the corresponding domain summary or subscale score can 
not be calculated). 
 
To calculate the following HRQOL dom
Summary Score or Subscale Score: 
Determine the average of the 
Standardized Values (see Step 1
above) for the following items: 
Number of non-missing items ne
to compute score (otherwise, se
score to missing) 
HRQOL Domain Summary Scor  
 
Urinary Summary 
23-34 
10 
Bowel Summary 
42-55 
12 
Sexual Summary 
56-68 
11 
Hormonal Summary 
69-79 
9 
Domain-specific HRQOL Subsca
 
 
Urinary Subscales: 
 
 
Function 
23-27 
4 
Bother 
28-34 
6 
Incontinence 
23,26-28 
4 
Irritative/Obstructive 
24,25,29-33 
6 
Bowel Subscales: 
 
 
Function 
42-48 
6 
Bother 
49-55 
6 
Sexual Subscales: 
 
 
Function 
56-64 
8 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 
 

 
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Bother 
65-68 
4 
Hormonal Subscales: 
 
 
Function 
69-73 
4 
Bother 
74-79 
5 
 
Please note: 
 
• 
Item numbers are indicated along the right border of the questionnaire (question numbers on left of questionnaire 
pages are not used for scoring because some questions contain multiple items). 
 
• 
The AUA Symptom Index (AUA-SI) is included to provide a clinical context for EPIC urinary measures. 5 
However, the seven AUA-SI items are not included in the calculation of any EPIC domain scores. For ease of 
reference, scoring instructions for the AUA-SI are provided in the Appendix below.  
 
• 
The Medical Outcomes Study SF-12 is a validated measure of General Health Function developed by RAND.4  
It is intended to be used here to derive 2 summary scores (physical and mental component summaries) relevant 
to general HRQOL status, which provide a context for EPIC score results. The SF-12 items themselves are not 
included in the calculation of any EPIC domain scores. For ease of reference, scoring instructions for the SF-12 
are provided in the Appendix below. 
 
• 
Optional satisfaction and socio-demographic/medical history items (Items 80-117) from the original UCLA-PCI 
can be administered with EPIC. These items are not included in any EPIC domain score calculations. 
 
REFERENCES 
 
 (1)  
Wei JT, Dunn R, Litwin M, Sandler H, Sanda MG. Development and Validation of the Expanded Prostate 
Cancer Index Composite (EPIC) for Comprehensive Assessment of Health-Related Quality of Life in Men 
with Prostate Cancer. Urology 2000; In press.  
 (2)  
Litwin MS, Hays RD, Fink A, Ganz PA, Leake B, Brook RH. The UCLA Prostate Cancer Index: development, 
reliability, and validity of a health-related quality of life measure. Medical Care 1998; 36(7):1002-1012. 
 (3)  
Sanda MG, Dunn RL, Sandler HM, McLaughlin PW, Montie JE, and Wei JT.  Comparison of HRQOL after 
brachytherapy, radical prostatectomy, or external beam radiation for localized prostate cancer.  ASCO 
Proceedings 2000; 19:327a.  
(4)  
Ware JE, Keller SD, Kosinski M. SF- 12: How to Score the SF-12 Physical and Mental Health Summary 
Scales. Second ed. Boston: The Health Institute, New England Medical Center, 1995.  
(5)  
Barry MJ, Fowler FJ, Jr., O'Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK et al. The American 
Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the 
American Urological Association. Journal of Urology 1992; 148(5):1549-57; discussion 1564. 
 
APPENDIX: Scoring the AUA-SI and SF-12 
 
Scoring the AUA Symptom Index: 
 
The sum of the raw values for items 35-41 provides the total AUA symptom score.5 
 
Scoring the Medical Outcomes Study SF-12: 
 
There are 3 steps involved in calculating the SF-12 Physical Component Summary (PCS) and Mental Component 
Summary (MCS) scores. 
 
Step 1. Check for missing or out-of-range values for items 11-22 (SF-12 portion of combined survey).  If any missing 
or out-of-range values are found for those items, the PCS and MCS scores can not be calculated. 
  
Step 2. Convert each item response into both physical and mental standardized values according to the table on the 
following page. 
 
Step 3. Sum the physical standardized values from step 2 across all 12 items and add 56.57706 to create the SF-12 
PCS score.  Sum the mental standardized values in similar fashion and add 60.75781 to create the SF-12 
MCS score. 
 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 
 

 
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Converting SF-12 Item Responses to Physical and Mental Standardized Values: 
 
Item Number 
Item Response V
Physical Standard
Value 
Mental Standardized
11 (General Health) 
1 
0 
0 
 
2 
-1.31872 
-0.06064 
 
3 
-3.02396 
0.03482 
 
4 
-5.56461 
-0.16891 
 
5 
-8.37399 
-1.71175 
12 (Moderate Activities) 
1 
-7.23216 
3.93115 
 
2 
-3.45555 
1.86840 
 
3 
0 
0 
13 (Climbing Several Flights of Stairs) 
1 
-6.24397 
2.68282 
 
2 
-2.73557 
1.43103 
 
3 
0 
0 
14 (Accomplish less than you would like)
1 
-4.61617 
1.44060 
 
2 
0 
0 
15 (Limited in the kind of activities) 
1 
-5.51747 
1.66968 
 
2 
0 
0 
16 (Accomplish less than you would like)
1 
3.04365 
-6.82672 
 
2 
0 
0 
17 (Didn’t do activities as carefully as usua
1 
2.32091 
-5.69921 
 
2 
0 
0 
18 (Pain interferes with normal work) 
1 
0 
0 
 
2 
-3.80130 
0.90384 
 
3 
-6.50522 
1.49384 
 
4 
-8.38063 
1.76691 
 
5 
-11.25544 
1.48619 
19 (Felt calm and peaceful) 
1 
0 
0 
 
2 
0.66514 
-1.94949 
 
3 
1.36689 
-4.09842 
 
4 
2.37241 
-6.31121 
 
5 
2.90426 
-7.92717 
 
6 
3.46638 
-10.19085 
20 (Have a lot of energy) 
1 
0 
0 
 
2 
-0.42251 
-0.92057 
 
3 
-1.14387 
-1.65178 
 
4 
-1.61850 
-3.29805 
 
5 
-2.02168 
-4.88962 
 
6 
-2.44706 
-6.02409 
21 (Felt downhearted and blue) 
1 
4.61446 
-16.15395 
 
2 
3.41593 
-10.77911 
 
3 
2.34247 
-8.09914 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 
 

 
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4 
1.28044 
-4.59055 
 
5 
0.41188 
-1.95934 
 
6 
0 
0 
22 (Health interferes w/social activities
1 
-0.33682 
-6.29724 
 
2 
-0.94342 
-8.26066 
 
3 
-0.18043 
-5.63286 
 
4 
0.11038 
-3.13896 
 
5 
0 
0 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 
 

 
 
APPENDIX X 
 
 
 
 
 
 
 
 
 
 
 
This questionnaire is designed to measure Quality of Life issues in patients with Prostate cancer.  
To help us get the most accurate measurement, it is important that you answer all questions 
honestly and completely. 
 
Remember, as with all medical records, information contained within this survey will remain 
strictly confidential. 
 
 
 
 
 
 
 
 
 
Today's Date (please enter date when survey completed):   Month________Day________Year________ 
 
 
Name (optional):  _________________________________________________ 
 
 
Date of Birth (optional):  Month__________Day___________Year__________ 
 
 
 
EPIC 
 
The Expanded Prostate Cancer Index Composite 
 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 

 
 
 URINARY FUNCTION 
This section is about your urinary habits. Please consider ONLY THE LAST 4 WEEKS. 
 
1. Over the past 4 weeks, how often have you leaked urine? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
23/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
2. Over the past 4 weeks, how often have you urinated blood? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
24/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
3. Over the past 4 weeks, how often have you had pain or burning with urination? 
 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
25/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
4. Which of the following best describes your urinary control during the last 4 weeks? 
 
No urinary control whatsoever........... ............................1 
 
Frequent dribbling.......................................................... 2 
(Circle one number) 
26/ 
 
Occasional dribbling....................................................... 3 
 
Total control................................................................... 4 
 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 

 
 
5. How many pads or adult diapers per day did you 
usually use to control leakage 
 
   during the last 4 weeks? 
 
 
 
None ......................................................................... 
0 
 
 
1 pad per day..........................................................… 
1 
 
 
2 pads per day............................................................ 
2 
(Circle one number) 
 
 
3 or more pads per day............................................... 
3 
 
27/ 
 
 
 
 
6. How big a problem, if any, has each of the following been for you during the last 4 weeks?  
     (Circle one number on each line) 
 
No 
Very Small      Small           Moderate 
   Big 
 
Problem 
Problem 
Problem 
Problem 
Problem 
 
a. 
Dripping or leaking urine …......    0 
1 
    2 
3 
4 
28/ 
 
b. 
Pain or burning on urination..... 
0 
1 
2 
3 
4 
29/ 
 
c. 
Bleeding with urination............. 
0 
1 
2 
3 
4 
30/ 
 
d. 
Weak urine stream  
 
 
or incomplete emptying……….. 
0 
1 
2 
3 
4 
31/ 
 
e. 
Waking up to urinate………….. 
0 
1 
2 
3 
4 
32/ 
        f.     Need to urinate frequently during 
               the day …………………………..    0 
1 
2 
3 
4 
33/ 
                             
7. Overall, how big a problem has your urinary function been for you during the last 4 weeks? 
 
No problem...................................... 1 
 
Very small problem.......................... 2 
 
Small problem.................................. 3 
(Circle one number) 
34/ 
 
Moderate problem........................... 4 
 
Big problem..................................... 5 
 
EPIC 2.2002 
Copyright 2002. The University of Michigan. All rights reserved. 

 
 
BOWEL HABITS 
The next section is about your bowel habits and abdominal pain.  
Please consider ONLY THE LAST 4 WEEKS. 
 
8. How often have you had rectal urgency (felt like I had to pass stool, but did not) during  
the last 4 weeks? 
 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
42/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
9. How often have you had uncontrolled leakage of stool or feces? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
43/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
10. How often have you had stools (bowel movements) that were loose or liquid  
(no form, watery, mushy) during the last 4 weeks? 
 
 
Never............................................... 1 
 
Rarely.............................................. 2 
 
About half the time........................... 3 
(Circle one number) 
44/ 
 
Usually............................................. 4 
 
Always.............................................. 5 
 
11. How often have you had bloody stools during the last 4 weeks? 
 
Never................................................ 1 
 
Rarely.............................................. 2 
 
About half the time........................... 3 
(Circle one number) 
45/ 
 
Usually............................................. 4 
 
Always.............................................. 5 
 
 
 

 
 
12. How often have your bowel movements been painful during the last 4 weeks? 
 
Never............................................... 1 
 
Rarely.............................................. 2 
 
About half the time........................... 3 
(Circle one number) 
46/ 
 
Usually............................................. 4 
 
Always.............................................. 5 
 
13. How many bowel movements have you had on a typical day during the last 4 weeks? 
 
Two or less..................................... 1 
 
Three to four..................................... 2 
(Circle one number) 
47/ 
 
Five or more..................................... 3 
 
 
14. How often have you had crampy pain in your abdomen, pelvis or rectum during the last 4 weeks? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
48/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
15. How big a problem, if any, has each of the following been for you? (Circle one number on each line) 
 
No       Very Small        Small         Moderate 
   Big 
 
Problem 
Problem 
Problem 
Problem 
Problem 
 
a. Urgency to have  
 
 
a bowel movement  ..................  
0 
1 
2 
3 
4 
49/ 
 
b. Increased frequency of 
 
 
bowel movements.....................   
0 
1 
2 
3 
4 
50/ 
 
c. Watery bowel movements......... 
0 
1 
2 
3 
4 
51/ 
 
d. Losing control of your stools...... 
0 
1 
2 
3 
4 
52/ 
 
e. Bloody stools ............................ 
0 
1 
2 
3 
4 
53/ 
 
f. 
Abdominal/ Pelvic/Rectal pain... 
0 
1 
2 
3 
4 
54/ 
 
16. Overall, how big a problem have your bowel habits been for you during the last 4 weeks? 
 
No problem...................................... 1 
 
Very small problem.......................... 2 
 
Small problem.................................. 3 
(Circle one number) 
55/ 
 
Moderate problem........................... 4 
 
 

 
 
 
Big problem..................................... 5 
 
SEXUAL FUNCTION 
The next section is about your current sexual function and sexual satisfaction. Many of the  
questions are very personal, but they will help us understand the important issues that   
you face every day.  Remember, THIS SURVEY INFORMATION IS COMPLETELY CONFIDENTIAL.   
Please answer honestly about THE LAST 4 WEEKS ONLY. 
 
 
17.  How would you rate each of the following during the last 4 weeks? (Circle one number on each line) 
 
                Very 
       
 
 
Poor 
 
 
  to 
                 Very 
 
 None   Poor    Fair    Good   Good 
 
            a.   Your level of sexual desire?....................................... 
1 
2 
3 
4 
5 
56/ 
            b.   Your ability to have an erection?................................ 
1 
2 
3 
4 
5 
57/ 
            c.   Your ability to reach orgasm (climax)?....................... 
1 
2 
3 
4 
5 
58/ 
 
18. How would you describe the usual QUALITY of your erections during the last 4 weeks? 
 
None at all......................................................................................... 
1 
 
Not firm enough for any sexual activity.............................................. 2 
 
Firm enough for masturbation and foreplay only............................... 3        (Circle one number) 
59/ 
 
Firm enough for intercourse.............................................................. 
4 
 
19. How would you describe the FREQUENCY of your erections during the last 4 weeks? 
 
 
I NEVER had an erection when I wanted one................................... 
1 
 
 
I had an erection LESS THAN HALF the time I wanted one............. 
2 
 
 
I had an erection ABOUT HALF the time I wanted one .................... 3        (Circle one number)  
60/ 
 
 
I had an erection MORE THAN HALF the time I wanted one............ 4 
 
 
I had an erection WHENEVER I wanted one..................................... 5 
 
20. How often have you awakened in the morning or night with an erection during the last 4 weeks? 
 
 
Never …................................................................ 
1 
 
       Less than once a week.......................................... 2 
 
       About once a week................................................ 3 
(Circle one number) 
61/ 
 
       Several times a week.......................…................. 
4 
 
 
Daily………………….........................…................. 5 
 
 
 

 
 
21. During the last 4 weeks, how often did you have any sexual activity? 
 
       Not at all................................................................. 1 
 
       Less than once a week.......................................... 2 
 
       About once a week................................................ 3 
(Circle one number) 
62/ 
 
       Several times a week.......................…................. 
4 
 
 
Daily………………….........................…................. 5 
 
22. During the last 4 weeks, how often did you have sexual intercourse? 
 
 
Not at all................................................................. 1 
 
       Less than once a week.......................................... 2 
 
       About once a week................................................ 3 
(Circle one number) 
63/ 
 
       Several times a week.......................…................. 
4 
 
 
Daily………………….........................…................. 5 
 
23. Overall, how would you rate your ability to function sexually during the last 4 weeks? 
 
Very poor..............................................................  1 
 
Poor......................................................................  2 
 
Fair....................................................................... 
3 
(Circle one number) 
64/ 
 
Good....................................................................  4 
 
Very good.............................................................  5 
 
24. How big a problem during the last 4 weeks, if any, has each of the following been for you?  
(Circle one number on each line) 
 
No       Very Small        Small         Moderate 
  Big 
 
Problem 
Problem 
Problem 
Problem 
Problem 
 
a. Your level of sexual desire........  
0 
1 
2 
3 
4 
65/ 
 
b. Your ability to have an erection.   
0 
1 
2 
3 
4 
66/ 
 
c. Your ability to reach an orgasm. 
0 
1 
2 
3 
4 
67/ 
 
 
 
 

 
 
25. Overall, how big a problem has your sexual function or lack of sexual function been for you  
     during the last 4 weeks? 
 
No problem...........................................................  1 
 
Very small problem...............................................  2 
 
Small problem....................................................... 
3 
(Circle one number) 
68/ 
 
Moderate problem................................................  4 
 
Big problem..........................................................  5 
 
HORMONAL FUNCTION  
The next section is about your hormonal function.  Please consider ONLY THE LAST 4 WEEKS. 
 
26. Over the last 4 weeks, how often have you experienced hot flashes? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
69/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
27. How often have you had breast tenderness during the last 4 weeks? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
70/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
28. During the last 4 weeks, how often have you felt depressed? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
71/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
 
 

 
 
29. During the last 4 weeks, how often have you felt a lack of energy? 
 
More than once a day...................... 1 
 
About once a day............................. 2 
 
More than once a week.................... 3 
(Circle one number) 
72/ 
 
About once a week........................... 4 
 
Rarely or never................................ 5 
 
30. How much change in your weight have you experienced during the last 4 weeks, if any? 
 
Gained 10 pounds or more…………..1 
 
Gained less than 10 pounds …..…….2 
 
No change in weight………. …..…….3 
(Circle one number) 
73/ 
 
Lost less than 10 pounds …..…….….4 
 
Lost 10 pounds or more…….…..……5 
31. How big a problem during the last 4 weeks, if any, has each of the following been for you?  
(Circle one number on each line) 
 
  No 
Very Small 
Small 
Moderate 
Big 
 
Problem 
Problem 
Problem 
Problem 
Problem 
 
a.  Hot flashes………...................... 
0 
1 
2 
3 
4 
74/ 
b.  Breast tenderness/enlargement.. 
0 
1 
2 
3 
4 
75/ 
c.  Loss of Body Hair...….................     0  
1 
2 
3 
4 
76/ 
d.  Feeling depressed..….................     0  
1 
2 
3 
4 
77/ 
e.  Lack of energy........….................     0  
1 
2 
3 
4 
78/ 
f.  Change in body weight  
0 
1 
2 
3 
4 
79/ 
 
Overall Satisfaction  
 
32. Overall, how satisfied are you with the treatment you received for your prostate cancer? 
 
Extremely dissatisfied............................... 1 
 
Dissatisfied............................................... 2 
 
Uncertain.................................................. 3          (Circle one number) 
80/ 
 
Satisfied................................................... 4 
 
Extremely satisfied................................... 5 
THANK YOU VERY MUCH!! 
 
 

 
 
APPENDIX XI 
EQ 5D 
 
By placing a tick in one box in each group, please indicate which 
statement best describes your health today. 
Mobility 
I have no problems in walking about                        
 
 
I have some problems in walking about                                   
I am confined to bed  
 
 
 
 
 
 
 
Self-Care 
I have no problems with self-care  
 
 
 
 
 
I have some problems washing or dressing myself 
 
 
 
I am unable to wash or dress myself 
 
 
 
 
Usual Activities 
I have no problems with performing my usual activities  
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
 
 
 
 
I have moderate pain or discomfort 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
Anxiety/Depression 
I am not anxious or depressed                 
 
 
             
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 
The EQ5D Group. EQ5D- a new facility for the measurement of health-related quality of life.  Health Policy 1990;(16)3:199-208. 
 
 

 
APPENDIX XI 
EQ 5D 
 
The respondent is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most 
appropriate statement in each of the 5 dimensions. This decision results in a one-digit number expressing the 
level selected for that dimension. The digits for five dimensions can be combined in a five-digit number describing 
the respondent’s health state. It should be noted that the numerals 1-3 have no arithmetic properties and should 
not be used as a cardinal score.  
Although self-explanatory instructions are provided within the text, the following guidelines may be helpful.  
A respondent may sometimes find that the number of levels is too limited. For example, for the mobility question, 
a respondent in a wheelchair is not 'confined to bed', but he/she may find 'some problems in walking about' 
appears to under-estimate their level of difficulty. If an administrator is present he/she should stress the 
instruction: please indicate which statements best describe your own health state today'. It is the respondent's 
personal evaluation that is required and on no account should a prompt be given. 
The EQ VAS generates a self-rating of health-related quality of life. It should be used with the 5-digit health state 
classification to build a composite picture of the respondent's health status. The respondent rates his/her health 
state by drawing a line from the box marked "Your health state today" to the appropriate point on the EQ VAS.  
Sometimes, respondents tend to rate their health state by placing a mark on the thermometer instead of drawing 
a line. There is no reason why this could not be interpreted as a valid response.  If the line does not cross the 
thermometer, the value horizontally opposite where the line stops should be taken and not where it would be if 
hypothetically extended. It is important to ensure that the respondent is not prompted in any way by the 
administrator and that it is the respondent's own rating of health-related quality of life that is being recorded. 
 
 
 
 
 

 
 
Note:  This is an example only. 
The actual reproducible visual  
analogue scale is being sent 
to us by the EuroQol Group. 
To help people say 
how good or bad a  
health state is, we have 
drawn a scale 
(rather like a  
thermometer) on which 
the best state you can  
imagine is marked by 
100 and the worst state  
you can imagine is 
marked by 0. 
 
We would like you to 
indicate in this scale 
how good or bad is 
your own health today, 
in your opinion. Please 
do this by drawing a 
line from the box below 
to whichever point on 
the scale indicates how 
good or bad your 
current health is. 
Your own health 
state 
today   
 
 
 

 
APPENDIX XII (10/11/05) 
Utilization of Sexual Medications/Devices 
 
 
 
 
 
 
 
 
 
 
Please indicate your response to each question by clearly marking an “X” through the 
box corresponding to your answer :   X 
The following questions relate to any treatments you may have received to  
assist with your erections. 
 
1.  Do you have a penile prosthesis? 
        
  
 
Yes (1)                    (Skip Questions 2-4) 
 
No (2) 
  
 
 
2.  Have you used any medications or devices to aid or improve erections? 
 
                 
 Yes (1) 
 
          
 No (2)                    (Skip Question 3, answer Question 4) 
 
3.  For each of the following medicines or devices, please indicate (by marking an x in each 
row) 
       Whether or not you have tried it or currently use it to improve your erections: 
 
 
 
Have NOT 
  tried it 
Tried it, but 
was NOT 
HELPFUL 
It HELPED, 
but I am NOT 
using it NOW 
It HELPED, 
and I use it 
SOMETIMES 
It HELPED, 
and I use it 
ALWAYS 
a. Viagra or other pill (name pill if 
     not Viagra): 
   1  
   2  
   3 
   4 
   5 
b.  Muse (intra-urethral alprostadil 
     suppository) 
   1  
   2  
   3 
   4 
   5 
c.  Penile injection therapy 
     (Such as caverject) 
   1  
   2  
   3 
   4 
   5 
d. Vacuum erection device 
      (Such as erect-aid) 
   1  
   2  
   3 
   4 
   5 
e.   Other (name medication/device if 
      not listed) 
   1  
   2  
   3 
   4 
   5 
   
 
(Utilization of Sexual Medications/Devices,  courtesy of M Sanda, D Miller, and J Wei)  
 
This questionnaire is designed to assess the use of erectile aids among patients treated for 
prostate cancer. To help us get the most accurate measurement, please answer all questions 
honestly and completely. You may refuse to answer any questions for any reason. All 
information contained within this survey will remain strictly confidential. Thank you for 
participating and for helping us improve the quality of care for prostate cancer patients. 
Today’s Date (please enter data when survey completed): Month____ Day_____ 
Year_____ 
 
 

 
 
 
4.  How would you describe the usual quality of your erections WITHOUT THE ASSISTANCE of 
medicines or devices DURING THE LAST 4 WEEKS? (Please select only one) 
1  
None at all 
2  
Not firm enough for any sexual activity 
3 
Firm enough for masturbation and foreplay only 
4 
Firm enough for intercourse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Utilization of Sexual Medications/Devices, courtesy of M Sanda, D Miller, and J Wei)  
 
 
 
 

 
APPENDIX XIII (2/15/05, 10/11/05, 1/24/07)(4/3/08) (5/1/14) 
 
CTSU LOGISTICS  
 
ADDRESS AND CONTACT INFORMATION FOR RTOG-0232 
 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly to 
NRG Oncology unless 
otherwise specified in the 
protocol: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone - 1-888-823-5923 
Fax – 215-569-0206 
CTSU Patient Registration 
Voice Mail – 1-888-462-3009 
Fax – 1-888-691-8039  
Hours: 9:00 AM – 5:00 PM Eastern 
Time, Monday – Friday (excluding 
holidays) 
 
[For CTSU patient enrollments that 
must be completed within 
approximately one hour, or other 
extenuating circumstances, call 
301-704-2376.  Please use the      
1-888-462-3009 number for ALL 
other CTSU patient enrollments.] 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA  19103 
 
Please do not submit study 
data or forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions.   
For patient eligibility questions: 
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. 
The CTSU Public Web site is located at: www.ctsu.org  
The CTSU Registered Member Web site is located at: http://members.ctsu.org 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES 
 
REGISTRATION/RANDOMIZATION 
 
Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU.  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, CTEP, DCTD, NCI.  These forms are available on the CTSU 
registered member Web site or by calling the PMB at 301-496-5725 Monday through Friday between 8:30 a.m. and 
4:30 p.m. Eastern time. 
 
Each CTSU 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 at http://members.ctsu.org  
 
 

 
APPENDIX XIII (Continued) 
 
All forms and documents associated with this study can be downloaded from the RTOG-0232 Web page on the 
CTSU registered member Web site (http://members.ctsu.org).  Patients can be registered only after pre-treatment 
evaluation is complete, all eligibility criteria have been met, and the study site is listed as ‘approved’ in the CTSU 
RSS. 
 
Requirements for RTOG-0232 site registration: 
• 
All patients MUST be treated with either 3DCRT or IMRT on this trial and all institutions must be pre-
credentialed. Credentialing requirements for 3DCRT and IMRT Treatment Approach are outlined in Section 
5.1 of the protocol and on the Advanced Technology Consortium (ATC) web site at http://atc.wustl.edu. 
Submission of digital data to the Image-Guided Therapy Center (ITC) requires advanced request for an FTP 
account with the ITC (itc@castor.wustl.edu). The ITC will notify the registering institution when that institution 
is eligible to enter patients on study. The status of the credentialing review will be reflected on the RSS Site 
Registration Status screen http://members.ctsu.org/rss/ 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
• 
CTSU RT Facilities Inventory Form  
 
Note: Per NCI policy all institutions that participate on protocols with a radiation therapy component must 
participate in the Radiological Physics Center (RPC) monitoring program.  For sites enrolling through the 
CTSU an RT Facilities Inventory From 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. 
 
Pre-study requirements for patient enrollment on RTOG-0232 
• 
Patient must meet all inclusion criteria, and no exclusion criteria should apply. 
• 
Patient has signed and dated all applicable consents and authorization forms. 
• 
All baseline laboratory tests and prestudy evaluations performed within the time period specified in the 
protocol.  
 
CTSU Procedures for Patient Enrollment 
 
1. Contact the CTSU Patient Registration Office by calling 1-888-462-3009. Leave a voicemail to alert the CTSU 
Patient Registrar that an enrollment is forthcoming. For immediate registration needs, e.g. within one hour, call 
the registrar cell phone at 1-301-704-2376. 
 
2. Complete the following forms: 
 
• 
CTSU Patient Enrollment Transmittal Form 
• 
RTOG-0232 Eligibility Checklist 
 
3. Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of 9:00 a.m. and 5:00 
p.m., Mon-Fri, Eastern Time (excluding holidays); however, please be aware that NRG Oncology registration 
hours end at 4:30 pm Eastern Time. The CTSU registrar will check the investigator and site information to ensure 
that all regulatory requirements have been met. The registrar will also check that forms are complete and follow-
up with the site to resolve any discrepancies. 
 
4. Once investigator eligibility is confirmed and enrollment documents are reviewed for compliance, the CTSU 
registrar will contact NRG Oncology within the confines of NRG Oncology’s registration hours to obtain 
assignment of a treatment arm and assignment of a unique patient ID (to be used on all future forms and 
correspondence). The CTSU registrar will confirm registration by fax.  
 
Study treatment must begin within 4 weeks of patient registration. 
 
 

 
APPENDIX XIII (Continued) 
 
DATA SUBMISSION AND RECONCILIATION 
 
1. All case report forms (CRFs) and transmittals associated with this study must be downloaded from the RTOG-0232 
web page located on the CTSU registered member Web site (http://members.ctsu.org). Sites must use the current 
form versions and adhere to the instructions and submission schedule outlined in the protocol.  
 
2. Submit all completed CRFs (with the exception of patient enrollment forms), clinical reports, and transmittals to 
NRG Oncology unless an alternate location is specified in the protocol. Do not send study data to the CTSU. See the 
Special Materials or Substudies section below for submission of dosimetry data.  
 
3. NRG Oncology will send query notices and delinquency reports to the site for reconciliation. Please send query 
responses and delinquent data to NRG Oncology and do not copy CTSU Data Operations. Each clinical site should 
have a designated CTSU Administrator and Data Administrator and must keep their CTEP AMS account contact 
information current. This will ensure timely communication between the clinical site and NRG Oncology. 
 
4. Please affix the NRG Oncology study/case label to all source documentation and redact the patient’s name. 
 
SPECIAL MATERIALS OR SUBSTUDIES 
 
Radiation Therapy (section 6.0) 
Dosimetry data for 3DCRT and IMRT must be submitted to the Image-Guided Therapy Center (ITC), either by 
digital transmission using the ITC-assigned FTP account or tape submission (contact ITC for acceptable tape 
types and format). Hard copy materials accompanying digital data should also be sent directly to the ITC. See 
section 12.2 for a complete inventory of dosimetry items to be submitted.  
 
Tissue/Specimen Submission– strongly encouraged (section 10.0) 
 
1. With patient’s consent, tumor tissue will be collected for central review. A pathology report and RTOG 
Specimen Transmittal Form must accompany specimens in order for the case to be considered evaluable by the 
NRG Oncology Biospecimen Bank – San Francisco.   
 
2. With patient’s consent, tumor tissue will be banked for biomarkers research. Submit specimens, pathology 
report, RTOG Specimen Transmittal Form, and a copy of the patient’s tissue consent form to the NRG Oncology 
Biospecimen Bank – San Francisco.  
 
3. See protocol section 10.0 for detailed instructions on collection, preparation, and shipment of samples.  
All reports must include the protocol number and patient’s case number (or NRG Oncology label attached). 
Surgical pathology numbers and information must not be removed from the report; however, the patient’s name 
and/or other identifying information should be redacted. Do not send specimens, forms, reports, or transmittals to 
the CTSU.     
 
4. CTSU clinical sites qualify for specimen reimbursement in the amounts stated in section 10.4 of the protocol. 
Payments will be made in accordance with NRG Oncology’s pathology payment cycle and forwarded to the 
enrolling sites by the Cooperative Group credited with the accrual. 
 
SERIOUS ADVERSE EVENT (SAE) REPORTING  
 
1. CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) regarding 
documentation and submission of adverse events.  Local IRBs must be informed of all reportable serious adverse 
reactions.  
 
2. CTSU sites will assess and report adverse events according to the guidelines and timelines specified in the 
protocol. You may navigate to the CTEP Adverse Event Reporting System (CTEP-AERS) from either the Adverse 
Events tab of the CTSU member homepage (http://members.ctsu.org) or by selecting Adverse Event Reporting 
Forms from the document center drop down list on the RTOG-0232 web page.  
 
 

 
APPENDIX XIII (Continued) 
 
3. Do not send adverse event reports to the CTSU. 
 
4. Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, or ALL via the NCI/CTEP AML-
MDS Report Form in lieu of CTEP-AERS. Submit the completed form and supporting documentation as outlined in 
the protocol.   
 
DRUG PROCUREMENT  
Not applicable to this study. 
 
REGULATORY AND MONITORING 
 
Study Audit 
 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 and HHS 45 CFR 46] 
and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program (CTEP) Clinical Trials Monitoring Branch 
(CTMB) guidelines for the conduct of clinical trials and study data validity, all protocols approved by NCI/CTEP that 
have patient enrollment through the CTSU are subject to audit. 
 
Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a Cooperative Group 
or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will become the responsibility of the 
Group receiving credit for the enrollment. For CTSU Independent Clinical Research Sites (CICRS), the CTSU will 
coordinate the entire audit process. 
 
For patients enrolled through the CTSU, you may request the accrual be credited to any Group for which you have an 
affiliation provided that Group has an active clinical trials program for the primary disease type being addressed by the 
protocol. (e.g., NSABP members may only request credit for protocols pertaining to breast or colorectal cancers).  
Registrations to protocols for other disease sites may still take place through CTSU without receiving credit for your 
NSABP activities.  Per capita reimbursement will be issued directly from CTSU. 
 
Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site 
preparation, on-site procedures for review and assessment, and results reporting and follow-up are available for 
download from the CTSU Operations Manual located on the CTSU Member Web site. 
 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
 
The HIPAA Privacy Rule establishes the conditions under which protected health information may be used or 
disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced in HHS 45 
CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA Authorization 
Form located on the CTSU website.  
 
The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to release 
Protected Health Information is NOT required from patients enrolled in clinical trials at non-US sites. 
 
Clinical Data Update System (CDUS) Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative CDUS data will 
be submitted quarterly to CTEP by electronic means. The sponsoring Group fulfills this reporting obligation by 
electronically transmitting to CTEP the CDUS data collected from the study