Randomized Phase II Trial of Postoperative Adjuvant IMRT Following Cystectomy for pT3/T4 Urothelial Bladder Cancer
Phase: PHASE2
Conditions: Stage III Bladder Cancer, Stage IV Bladder Cancer
Sponsor: NRG Oncology

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NRG ONCOLOGY 
NRG-GU001 
(ClinicalTrials.gov NCT #: NCT02316548) 
 
RANDOMIZED PHASE II TRIAL OF POSTOPERATIVE ADJUVANT IMRT 
FOLLOWING CYSTECTOMY FOR pT3/pT4 UROTHELIAL BLADDER CANCER 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the National 
Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network of NCTN 
organizations: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, and SWOG. 
 
The following NCTN Group Study Champion has been added to this trial: 
SWOG: Seth P. Lerner, MD 
 
Coordinating Center:  
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
Study Team (6/13/16) 
Principal Investigator/Radiation Oncology 
Libni Eapen, MD, FRCPC 
The Ottawa Hospital Cancer Centre 
503 Smyth Road 
Ottawa, Ontario K1H 8L6 
CANADA 
613-737-7700 ext. 70206/Fax: 613-247-3511 
leapen@ottawahospital.on.ca 
Radiation Oncology Co-Chair 
Jason A. Efstathiou, MD, DPhil  
Department of Radiation Oncology  
Massachusetts General Hospital  
100 Blossom Street, Cox 3  
Boston, MA 02114  
617-726-5866/ Fax 617-726-3603 
jefstathiou@partners.org 
Medical Oncology Co-Chair 
Eric Winquist, MD, MSc 
Western University 
London Health Sciences Centre 
790 Commissioners Road East 
London, Ontario N6A 4L6 
CANADA   
519-685-8500/Fax 519-685-8808 
Eric.Winquist@lhsc.on.ca 
Medical Oncology Co-Chair 
William Kevin Kelly, DO 
Thomas Jefferson University 
1025 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-503-4490/Fax: 215-503-7515 
William.Kelly@jefferson.edu 
 
Urology Co-Chair 
Rodney Henry Breau, MSc, MD, FRCSC 
Department of Surgery  
Ottawa Hospital Research Institute  
The Ottawa Hospital/University of Ottawa 
501 Smyth Road, Box 222 
Ottawa, ON K1H 8L6 
613-737-8899 x 7-3019/Fax 613-739-6842 
rbreau@ottawahospital.on.ca 
Urology Co-Chair 
Sia Daneshmand, MD 
USC/Norris Comprehensive Cancer Center 
Institute of Urology 
1441 Eastlake Avenue 
Los Angeles, CA 90089 
503-494-1342 
daneshma@med.usc.edu 
 
Study Team continued on next page 

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NRG ONCOLOGY 
 
NRG-GU001 
 
RANDOMIZED PHASE II TRIAL OF POSTOPERATIVE ADJUVANT IMRT 
FOLLOWING CYSTECTOMY FOR pT3/pT4 UROTHELIAL BLADDER CANCER 
 
Study Team continued 
Medical Physics Co-Chair 
Eric Elder, PhD 
Winship Cancer Institute of Emory University 
1365 Clifton Road, NE, Suite A1232  
Atlanta, GA 30322 
404-778-7339/Fax: 404-778-4139 
 eelder@emory.edu 
Quality Assurance Co-Chair 
John Christodouleas, MD 
Department of Radiation Oncology 
Hospital of the University of Pennsylvania 
Administrative Offices  
The Perelman Center for Advanced Medicine 
3400 Civic Center Boulevard,TRC-2 West 
Philadelphia, PA 19104 
215-662-6568/Fax: 215-349-8975 
christojo@uphs.upenn.edu 
 
Statistician 
Stephanie Pugh, PhD 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-0850/Fax: 215-928-0153 
PughS@NRGOncology.org  
Protocol Administrator 
Beth Goldner 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-940-8870/Fax: 215-928-0153 
goldnerb@nrgoncology.org 
 
Clinical Data Coordinator 
Elaine Motyka-Welsh, RN, MSN, CCRP 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3216 
Motyka-welshe@nrgoncology.org 
Clinical Data Coordinator 
Roseann Bonanni, CTR, CCRP 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3223/Fax: 215-930-8840 
bonannir@nrgoncology.org 
Dosimetrist 
Marsha Radden, RT (R) (T) 
IROC Philadelphia-RT QA Center 
ACR Clinical Research Center 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-2757 
mradden@acr.org 
 
 
 
 
 

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Participating Sites 
 U.S.  
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure/Termination 
- 
February 1, 2017 
Amendment 2 
June 13, 2016 
July 25, 2016 
Amendment 1 
August 7, 2015 
August 31, 2015 
Activation 
January 2, 2015 
February 23, 2015 
 
 
 
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. 

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TABLE OF CONTENTS 
NRG-GU001 ....................................................................................................................................1 
SCHEMA .........................................................................................................................................7 
1. OBJECTIVES ..............................................................................................................................8 
1.1 Primary Objective ......................................................................................................................8 
1.2 Secondary Objectives.................................................................................................................8 
2. BACKGROUND .........................................................................................................................8 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA .........................10 
3.1 
Patient Selection Guidelines ..............................................................................................10 
3.2 
Eligibility Criteria ..............................................................................................................10 
3.3 
Ineligibility Criteria ...........................................................................................................11 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........12 
4.1 
Definition of Disease Assessment .....................................................................................13 
5. TREATMENT PLAN/REGIMEN DESCRIPTION  .................................................................13 
5.1 
All patients will undergo a radical cystectomy . ................................................................14 
5.2 
Radiation Therapy ..............................................................................................................14 
5.3 
General Concomitant Medication and Supportive Care Guidelines ..................................24 
5.4 
Duration of Therapy ...........................................................................................................25 
6. TREATMENT MODIFICATIONS ...........................................................................................25 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................25 
7.1 
Adverse Events ..................................................................................................................25 
7.2 
CTEP-AERS Adverse Event Reporting Requirements .....................................................27 
8. 
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ..............29 
8.1  
Investigator Registration Requirements .............................................................................29 
8.2  
Site Registration Requirements..........................................................................................30 
8.3 
RT-Specific Pre-Registration Requirements......................................................................32 
8.4 
Patient Enrollment .............................................................................................................33 
9. 
DRUG INFORMATION ...................................................................................................34 
10.  
PATHOLOGY/BIOSPECIMEN .......................................................................................34 
11.  
SPECIAL STUDIES (Non-Tissue)....................................................................................34 
12.  
Modality Reviews ..............................................................................................................34 
13.  
ASSESSMENT OF EFFECT DURING TREATMENT ...................................................35 

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13.1  The assessment of treatment effect ....................................................................................35 
13.2  The following lab tests will be done at each visit: CBC and platelet count. .....................35 
14.  
DOCUMENTATION OF CANCER RECURRENCE ......................................................35 
14.1  At each follow up visit the patient will have a history and physical examination .............35 
14.2  The following assessments will be done: CT and/or MRI scan of the pelvis ....................35 
14.3  Criteria for pelvic recurrence. ............................................................................................35 
14.4  Criteria for distant metastases. ...........................................................................................35 
15.  
DATA AND RECORDS ...................................................................................................35 
15.1 
Data Management/Collection ............................................................................................35 
15.2 
Summary of Data Submission ...........................................................................................36 
15.3 
Global Reporting/Monitoring ............................................................................................36 
16. STATISTICAL CONSIDERATIONS ....................................................................................36 
16.1 
Study Design ......................................................................................................................36 
16.2 
Study Endpoints .................................................................................................................36 
16.3 
Primary Objectives Study Design ......................................................................................37 
16.4 
Study Monitoring of Primary Objectives ...........................................................................39 
16.5 
Accrual Considerations ......................................................................................................39 
16.6 
Secondary Elements ...........................................................................................................40 
16.7 
Gender/Ethnicity/Race Distribution...................................................................................42 
REFERENCES ..............................................................................................................................43 
 
 
 

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NRG ONCOLOGY (8/7/15) 
 
NRG-GU001 
Randomized Phase II Trial of Postoperative Adjuvant IMRT Following Cystectomy for 
pT3/pT4 Urothelial Bladder Cancer 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION  
To submit site registration 
documents: 
For patient enrollments: 
Submit study data  
directly to the Lead 
Cooperative Group 
unless otherwise 
specified in the 
protocol: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-CTSU 
Fax: 215-569-0206 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN), which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
-or- https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol 
for further instructions.  
 
 
The most current version of the study protocol and all related forms and documents must be 
downloaded from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org.  Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires user log on with CTEP-IAM username and password. 
For patient eligibility: Contact the NRG Oncology Research Associate for Protocol, Data 
Management section at 215-574-3214. 
For treatment-related questions: Correspond by e-mail (preferred) or by phone with the study chair 
designated on the protocol cover page. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU 
Help Desk by phone or e-mail: CTSU General Information Line – 1-888-823-5923, or 
ctsucontact@westat.com. All calls and correspondence will be triaged to the appropriate CTSU 
representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ 
website   https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU web site is located at https://www.ctsu.org 
 
 

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NRG-GU001 
Randomized Phase II Trial of Postoperative Adjuvant IMRT Following Cystectomy For  
pT3/pT4 Urothelial Bladder Cancer 
SCHEMA (6/13/16) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
PATIENT POPULATION 
Patients with pT3/pT4 pN0-2 urothelial (either pure urothelial or primary urothelial mixed with 
other subtypes) bladder cancer following radical cystectomy.  
 
STRATIFICATION*  
Neoadjuvant preoperative or postoperative adjuvant chemotherapy  
vs.  
No chemotherapy 
 
Pelvic relapse risk category: Intermediate vs. High 
TIMING OF RANDOMIZATION 
Patients who will not receive postoperative adjuvant chemotherapy:  
Within 14 days of registration 
 
Patients who will receive postoperative adjuvant chemotherapy:  
Within 28 days of completion of the chemotherapy 
Arm 1: Standard Arm 
No radiotherapy 
 
Arm 2: Experimental Arm 
Postoperative adjuvant IMRT radiotherapy 50.4Gy 
in 28 fractions 
 
REGISTRATION 
Within 105 days of radical cystectomy 
*Stratification: The administration of even one cycle of chemotherapy will constitute “yes” for either  
neoadjuvant or adjuvant chemotherapy. Intermediate risk= pT3b/pT4a/pT4b  pN0-2 with negative margins and 10 or more 
nodes dissected. High risk = pT3a/pT3b/pT4a/pT4b  pN0-2 with less than 10 nodes dissected and/or with positive 
margins. 

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1. OBJECTIVES 
1.1 Primary Objective 
To evaluate the ability of post-cystectomy adjuvant radiotherapy to safely reduce pelvic 
tumor recurrence, defined as pelvic recurrence-free survival in Section 16.3.2. 
1.2 Secondary Objectives 
Evaluate increase in disease-free survival  
Evaluate toxicity of adjuvant pelvic radiotherapy 
 
2. BACKGROUND (6/13/16) 
Pelvic tumor recurrence following contemporary cystectomy has traditionally been 
considered a relatively infrequent event. Cagiannos and Morash (2009) compiled 8 
institutional series between 1977 and 2006 reporting local recurrence rates ranging from 3.9 
to 29%. These series have underestimated the true risk of pelvic relapse for a variety of 
reasons including: exclusion of patients who have also developed distant metastases, using 
simple numerator/denominator crude risk calculation rather than cumulative incidence rates, 
not calculating risk according to T stage and excluding pelvic relapses if they have not been 
biopsied. Herr (2004), reporting the surgical parameters in the neoadjuvant chemotherapy 
SWOG 8710 trial, demonstrated that despite requiring biopsy confirmation the crude risk of 
developing local recurrence following cystectomy in pT3/4 disease was 32%. 
The 2011 update of the MRC neoadjuvant chemotherapy–cystectomy trial (International 
Collaboration of Trialists) reported a 48% and 49% rate of pelvic recurrence with and 
without neoadjuvant chemotherapy, respectively. In a 2011 Canadian survey of 
contemporary cystectomy, comparably high 48-50% cumulative incidence rates of pelvic 
failure were found. (Eapen) As neither neoadjuvant nor adjuvant chemotherapy reduce pelvic 
failure, locoregional control currently is pursued by optimizing nodal dissection. The well- 
characterized USC experience together with the MSKCC and SWOG 8710 reports 
emphasize the importance of thorough node dissections defined as a minimum of 10-12 
nodes. In a 2012 reanalysis of the USC experience following adequate dissection and 
counting all pelvic failures except those that occur subsequent to the diagnosis of distant 
metastases there is a 24% pelvic recurrence rate. (Daneshmand, MD, oral communication) In 
2014, Christodouleas reported the U Penn and SWOG 8710 pelvic recurrence experience and 
identified low, intermediate, and high risk groups according to stage, extent of node 
dissection and margin status. (Christodouleas 2014) These risk groups experienced 8%, 20% 
and 41% pelvic recurrence rates, respectively. 
In aggregate, this clinical data emphasizes the –to date–neglected problem of significant 
pelvic failure in pT3/4 patients following cystectomy. This pelvic failure can occur alone 
(15-20%) or as is more often the case, in conjunction with distant metastases. As such, it 
constitutes an absolute ceiling on the curability of bladder cancer by surgery and 
chemotherapy, and also can be a source of significant patient morbidity. Thus both the 
approximately 15% of patients with isolated pelvic recurrence in whom cure rates may be 
improved as well as the patients in whom symptoms of pelvic recurrence may be prevented 
(even in the presence of distant metastases) stand to benefit from a reduction in pelvic failure. 
One randomized and several retrospective series of postoperative radiotherapy in squamous 
and transitional bladder cancer suggest superior pelvic control and survival. The hypothesis 

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to be tested is that postoperative IMRT will reduce any pelvic tumor recurrence (occurring 
either in isolation or together with distant metastases) with acceptable toxicity in patients 
with pT3/T4 transitional cell bladder cancer following cystectomy. In 1992, Zaghloul et al 
published the results of a phase III trial of postoperative radiotherapy in squamous cell 
bladder cancer showing reduced pelvic failure. In 1999, Cozzarini from Milan presented their 
retrospective review of postcystectomy radiotherapy. They compared partial/total cystectomy 
alone versus with postoperative radiotherapy of 45-66Gy (median 50.4Gy). Adjuvant RT to 
doses 50.4 Gy or higher was associated with improved survival and improved pelvic control. 
There was an attendant 7% risk of bowel obstruction reported. This trial is important as it 
will be the first prospective randomized trial in Europe and North America to address the 
significant problem of pelvic failure. In this phase II study, with contemporary IMRT, we 
aim to demonstrate the reduction of pelvic recurrence with postoperative radiotherapy in the 
North American context. The IMRT regimen utilized will mirror the radiotherapy delivered 
postoperatively in uterine cancers in RTOG trials. This contemporary radiotherapy 
minimizes both gastrointestinal and pelvic marrow toxicity. The latter is particularly relevant 
in patients who may have received neo or adjuvant chemotherapy and in those patients who 
might need chemotherapy for the palliation of metastatic disease. Using IMRT we can expect 
to achieve this improved pelvic control with certainly no more, and likely less toxicity than 
reported from the Egyptian and European experiences.  (Baumann) The Cairo group has in 
April 2013 published the results of their pre versus postop randomized phase III radiotherapy 
trial demonstrating very low rates of gastrointestinal and surgical serious toxicity with 
50Gy/25 fractions with non IMRT radiotherapy. Stringent collection of all serious bowel 
toxicity encountered will be buttressed by well-defined stopping rules to ensure that we 
identify any clinically significant increase in bowel toxicity that requires surgical correction. 
There is a limited USC experience  with  pelvic radiotherapy in patients who have 
neobladders demonstrating its safety in ten patients (Ballas 2015). Three  patients had Grade 
1 or 2 acute ( diarrhea , proctitis, rectal discomfort)  and no patients had chronic GI toxicity.  
No patient had acute, and  two patients had grade 1 chronic “GU” toxicity (mild nocturnal 
incontinence, some diminished pouch capacity). A larger neobladder irradiation experience 
from France again demonstrating the safety of neobladder irradiation  has not yet been 
published (Sargos, personal communication). Thus we will include patients who, following 
cystectomy, have non-continent diversions (eg, ileal conduits) or continent non-orthotopic 
catheterizable diversions (eg, Indiana pouch ) or continent orthotopic diversions (eg, Studer 
pouch or neobladder ). Potential neobladder irradiation toxicity will be closely  monitored.  
To reconcile the concept of studying radiotherapy in only those patients who have had the 
ideal operation (minimum of ten removed nodes and negative margins) with the reality that 
for 55% of patients these specifics have not been attained with the surgery performed 
currently in North America (AUA 2012), we will study all radical cystectomy pT3/T4 
patients and stratify according to intermediate and high risk failure grouping. In a similar 
vein, we will utilize a pragmatic approach to the issue of adjuvant and neoadjuvant 
chemotherapy balancing the facts that only 8% of patients get neoadjuvant chemotherapy, the 
strong conviction that patients should be considered for postop adjuvant chemotherapy, the 
clinical reality that a substantial proportion of patients get neither neoadjuvant nor adjuvant 
chemotherapy, and finally that when adjuvant chemotherapy is used it is the uniform 
perspective that it should precede any consideration of adjuvant radiation. The lack of impact 
of chemotherapy on pelvic recurrence makes the issue more of the impact on patient 

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selection and radiotherapy efficacy that the administration of adjuvant chemotherapy 
introduces. Specifically, randomization before chemotherapy will likely result in a proportion 
of patients not getting the assigned adjuvant radiotherapy because of chemotherapy toxicity, 
overall treatment, fatigue and early manifestation of some of the 30% of pelvic recurrences 
that occur within 6 months of cystectomy. Thus we will register trial eligible patients within 
105 days post cystectomy and randomize regarding adjuvant radiotherapy at that time for 
patients not getting chemotherapy, but delay that randomization until after chemotherapy in 
patients so treated. However, the pelvic relapse data will be collected in all registered 
patients. This approach to dealing with issues of the surgical quality and chemotherapy 
grounds the study in the reality of contemporary North American management of locally 
advanced bladder cancer and allows the asking of whether adjuvant radiotherapy can usefully 
help the pelvic recurrence problem. 
Given that patients with locally advanced cancer have a high rate of systemic metastases, it is 
important to determine the impact of pelvic radiotherapy not only on pelvic relapse but also 
on overall disease-free survival. We will thus be powering the study looking for a 10% 
increase in DFS, the signal that will warrant proceeding to a confirmatory phase III trial. We 
will proceed to this phase III trial only if our primary pelvic failure and secondary DFS 
endpoints are met with acceptable toxicity. 
 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (via the contact list on the NRG web site). For radiation therapy-related 
eligibility questions, please contact IROC Philadelphia RT (via the contact list on the NRG 
web site). 
 
3.1 PATIENT SELECTION GUIDELINES 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential and men who are sexually active should be willing and 
able to use medically acceptable forms of contraception during therapy. 
 
3.2 ELIGIBILITY CRITERIA (6/13/16) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
Prior to Step 1 Registration 
3.2.1 Initial histological diagnosis of muscle invasive urothelial carcinoma  
3.2.2 Patients must have undergone a radical cystectomy (reconstructed urinary diversion may 
be non-continent diversions (eg, ileal conduits) or continent non-orthotopic catheterizable 
diversions (eg, Indiana pouch) or continent orthotopic diversions (eg, Studer pouch or 

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neobladder)for urothelial bladder carcinoma within 105 days prior to registration.  Final 
cystectomy pathology must be either pure urothelial carcinoma or dominant urothelial 
carcinoma with admixture of other histologies excluding small cell variants. 
 Neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy for the 
bladder cancer is permitted; however, all patients, even those who will receive 
adjuvant chemotherapy, must be registered within 105 days after completing 
cystectomy regardless of whether adjuvant chemotherapy has started. Patients 
who will be receiving adjuvant (postoperative) chemotherapy will be randomized 
within 28 days of completing that chemotherapy. 
3.2.3 Patients with the following pTNM stages per the AJCC 7th ed. are eligible: (8/7/15) 
1. pT3apN0;pN1;pN2 provided less than 10 nodes dissected and/or positive surgical 
margins 
2. pT3bpN0;pN1;pN2 
3. pT4apN0;pN1;pN2 
4. pT4bpN0;pN1;pN2 
3.2.4 Appropriate stage for study entry based on the following diagnostic workup: 
 History/physical examination ≤ 45 days prior to registration; 
 CT or MRI or PET-CT that includes chest, abdomen and pelvis should be  
performed for initial radiological staging. This may be performed pre- or post-surgery 
≤ 90 days prior to registration except in patients getting postoperative adjuvant 
chemotherapy, who will require CT, MRI or PET-CT including the chest and 
abdomen and pelvis no more than 30 days prior to registration. Imaging performed 
postoperatively should show no evidence of residual disease. 
3.2.5 Age ≥ 18  
3.2.6 Zubrod Performance Status 0-2 ≤ 45 days prior to registration 
3.2.7 CBC/differential obtained ≤ 14 days prior to registration with adequate bone marrow 
function defined as follows: 
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 
 Platelets ≥ 100,000 cells/mm3  
 Hemoglobin ≥ 8.0g/dl (NOTE: The use of transfusion or other intervention to achieve 
Hgb ≥ 8.0 g/dl is acceptable.) 
3.2.8 The patient must provide study-specific informed consent prior to study entry. 
 
3.3 INELIGIBILITY CRITERIA (6/13/16) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 Definitive clinical or radiologic evidence of metastatic disease; pN3 disease is not 
allowed (positive common iliac node). 
 
3.3.2 Prior invasive solid tumor or hematological malignancy (except non-melanomatous skin 
cancer and incidentally discovered prostate cancer at time of cystoprostatectomy) unless 
disease free for a minimum of 3 years 
3.3.3 Prior radiotherapy to the pelvis 
3.3.4    Patients with a history of inflammatory bowel disease 
3.3.5   Patients who have required any treatment (medical or surgical) for bowel obstruction 
prior to diagnosis of bladder cancer or who have required surgical treatment for bowel 
obstruction after the cystectomy 

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3.3.6 Severe, active co-morbidity defined as follows: 
 Unstable angina and/or congestive heart failure requiring hospitalization within the   
last 6 months; 
 Transmural myocardial infarction within the last 6 months; 
 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of  
registration; 
 Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic  
disease; 
 HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV  
positive are eligible, provided they are under treatment with highly active 
antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 
30 days prior to registration. Note also that HIV testing is not required for eligibility 
for this protocol. 
 Other major medical illness which requires hospitalization or precludes study therapy  
at the time of registration. 
3.3.7 Women who are breastfeeding  
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
(6/13/16) 
 
PRE-TREATMENT ASSESSMENTS 
Assessments 
Prior to Registration 
STEP 1 
 (calendar days) 
Prior to Randomization 
STEP 2 
(calendar days) 
Radical cystectomy 
≤105 days 
 
History/physical exam 
≤45 days 
 
CT or MRI or PET-CT chest, 
abdomen and pelvis 
For patients not receiving 
adjuvant chemotherapy: 
Pre- or post-surgery ≤ 90 days  
 
For patients receiving 
adjuvant chemotherapy:  
One of these scans must be done 
within 30 days prior to 
registration showing no evidence 
of residual disease 
 
Zubrod performance status 
≤45 days 
In patients getting 
postoperative chemotherapy  
≤28 days* 
CBC w/ diff 
≤14 days 
Informed consent 
Prior to registration 
*Prior to randomization these patients need to be reassessed to ensure they meet the criteria to 
proceed to randomization and have recovered from chemotherapy in that their blood work and 
performance status meet the criteria specified in Sections 3.2.6 and 3.2.7. 
 
 
 
 

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ASSESSMENTS DURING TREATMENT 
Assessments 
 
Pertinent history and physical exam 
 
 
 
Weekly during RT 
 
CBC w/ diff  
See Section 6 for dose modifications. 
 
CTCAE toxicity evaluation 
 
 
 
 
ASSESSMENTS IN FOLLOW UP 
Assessments 
Arm 1: From randomization 
Arm 2: From end of radiotherapy 
History and physical* 
*NOTE: Follow up assessments may be performed by 
a radiation, urological, or medical oncologist. As 
possible radiation toxicity is being evaluated the 
involvement of a radiation oncologist is encouraged. 
 
CTCAE toxicity evaluation 
 
 
6 weeks after randomization (Arm 1)  
-OR-  
6 weeks after end of RT (Arm 2) 
 
Then q3 months x 1 year, q4 months 
during year 2, then q6 months x 3 years.  
Then annually for years 5-10; also at 
progression/relapse (Arms 1 and 2) 
 
Abdominal and pelvic CT or MRI or PET-CT 
q6 months for 3 years and subsequently at 
progression/relapse and physician 
discretion 
Chest imaging with Chest x-ray, CT or 
PET-CT 
q6 months for 3 years and subsequently at 
progression/relapse and physician 
discretion 
 
 
4.1 
Definition of Disease Assessment 
Pelvic recurrence is defined as soft tissue tumor recurrence in the pelvis anywhere 
between the L5-S1 disc space superiorly and the pelvic floor inferiorly, taking into 
account distant metastases or death as competing risks. 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION (6/13/16) 
All eligible patients will be registered within 105 days of undergoing cystectomy. Patients 
not receiving postoperative adjuvant chemotherapy will be randomized within 14 days of 

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registration to the standard arm of no further treatment (Arm 1) or the investigational arm of 
pelvic radiotherapy (Arm 2). Patients who do receive postoperative adjuvant chemotherapy 
will be randomized between these same two arms within 28 days after completion of the 
chemotherapy. 
5.1 
All patients will undergo a radical cystectomy (reconstructed urinary diversion may be 
non-continent diversions (eg, ileal conduits) or continent non-orthotopic catheterizable 
diversions (eg, Indiana pouch ) or continent orthotopic diversions (eg, Studer pouch or 
neobladder )  and at least a standard pelvic node dissection as follows: All potential 
lymph node bearing tissue to include a complete dissection of the external and internal 
iliac and obturator lymph nodes. All potential node bearing tissue should be removed 
within the following boundaries: laterally the genitofemoral nerve; distally Cooper’s 
ligament to include the lymph node of Cloquet; proximally the common iliac (CI) 
bifurcation; medially the bladder to include the tissue medial to the hypogastric artery; 
and posteriorly the floor of the obturator fossa with circumferential mobilization of the 
external iliac artery and vein unless contraindicated due to extensive atherosclerotic 
vascular disease. Of note, a more extensive pelvic lymph node dissection is allowed.  A 
standard pelvic node dissection as described above represents a minimum requirement. 
(6/13/16) 
5.1.1 No concurrent chemoradiation: Some patients may get 2-4 cycles of postoperative 
adjuvant chemotherapy, in which case radiotherapy will start within 49 days after the 
chemotherapy is completed, patients have recovered, and provided there is no recurrence 
of the cancer.  
 
5.2 
Radiation Therapy (6/13/16) 
 
For patients on Arm 2, radiation therapy must begin within 21 days after 
randomization. 
 
NOTE 1: IMRT is required for this protocol. In patients not getting postoperative adjuvant 
chemotherapy the radiation treatment must begin within 140 days after cystectomy. For 
patients getting adjuvant chemotherapy radiation treatment must start within 49  days of 
completing chemotherapy. 
  
NOTE 2: Pre-Treatment reviews are required for the first case for an individual site. Based 
on the results of this case review, the reviewers might request that the second case also be 
selected for pre-treatment review. Please allow 3 business days for this to be completed. 
If a resubmission is required the 3 business day timeline will restart. Treatment cannot 
begin until approval from NRG Oncology has been received at the site. 
 
 
5.2.1 Treatment Technology (8/7/15) 
Photon IMRT with megavoltage equipment capable of delivering static intensity 
modulation with a multileaf collimator or dynamic intensity modulation using a multileaf 
collimator or tomotherapy is required. IMRT should utilize six or more fields with a 
minimum source-axis distance of 100cm except in the case of tomotherapy that uses 
85cm or CyberKnife that uses 80 cm. 6-10 MV energy photon beams should be used. 
VMAT is allowed. Protons are not allowed. 

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5.2.2 Immobilization and Simulation (8/7/15) 
 
Immobilization 
Proper immobilization is required for this protocol but the specific method of 
immobilization is up to the discretion of the treating institution. Patient setup 
reproducibility must be achieved using appropriate clinical devices that might include 
customized torso cradles and/or leg immobilizers.  
 
 
Simulation Imaging  
Patients must be immobilized in the supine position.  
 
To better visualize the pelvic vasculature, IV contrast is recommended but not required since 
some patients may have renal insufficiency.  To better delineate the urinary diversion, oral or 
rectal contrast may be injected into the diversion, but this is also not required.   
 
CT scan thickness should be ≤ 3mm through the region that contains the target volumes 
and the critical structures requiring Dose-Volume histogram analysis. CT scan should 
extend at least 4cm above and below the target volumes. The superior limit of the scan 
will be at least at the L1/2 interspace and the inferior limit will be below the perineum. 
 
5.2.3 Imaging for Structure Definition, Image Registration/Fusion, and Follow-up (8/7/15) 
CT simulation scans with or without intravenous or bowel contrast as described above.    
In the case in which contrast is present in the treatment planning CT, the density of the 
contrast should be overridden to a representative background electron density.  
 
 

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5.2.4 Definition of Target Volumes and Margins (8/7/15) 
NOTE: All structures must be named for digital RT data submission as listed in the table 
below. The structures marked as “Required” in the table must be contoured and submitted 
with the treatment plan. Structures marked as “Required when applicable” must be 
contoured and submitted when applicable. Resubmission of data may be required if 
labeling of structures does not conform to the standard DICOM name listed. Capital 
letters, spacing, and use of underscores must be applied exactly as indicated. 
 
The target volume in patients with positive surgical margins is the cystectomy bed and 
the pelvic lymph nodes.  In patients with negative surgical margins, the target volume is 
the pelvic lymph nodes alone.  The cystectomy bed is omitted in patients with negative 
margins because the risk of cystectomy bed failure is significantly reduced.    
 
 
Standard Name 
 
Description 
 
Validation 
CTV_5040 
CTV_5040 will only 
include the pelvic lymph 
nodes in patients with 
negative surgical margins 
and will include the pelvic 
lymph nodes  plus the 
cystectomy bed in patients 
with positive surgical 
margins. 
 
Required 
CTVn_5040  
The Nodal_CTV includes 
the presacral nodes and the 
bilateral distal common 
iliac, external iliac, internal 
iliac, and obturator nodes 
and can be created from 
the union of three sub-
structures: sacral_nodes, 
iliac_nodes, and 
obturator_nodes.   
Required 
CTVsb_5040  
The cystectomy bed CTV 
is intended to include 
tissue in the pelvis that 
surrounded the intact 
empty bladder and 
proximal vagina or prostate 
preoperatively, and the 
surgical cystectomy bed 
including the anterolateral 
para-rectal tissues.   
Required only for patients with positive surgical 
margins. 
PTV_5040 
PTV to receive 5040 
cGy will be a 
symmetrical expansion 
of 7.0 mm beyond the 
CTV_5040 
 
 
Required 
 

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Detailed Specifications  
 
 
CTV_5040: 
The CTV_5040 will only include the pelvic lymph nodes (CTVn_5040) in patients with 
negative surgical margins and will include the pelvic lymph nodes (CTVn 5040)  plus the 
cystectomy bed (CTVsb_5040) in patients with positive surgical margins. 
 
CTVn_5040: 
The CTVn_5040 includes the presacral nodes and the bilateral distal common iliac, 
external iliac, internal iliac, and obturator nodes and can be created from the union of 
three sub-structures: sacral_nodes, iliac_nodes, and obturator_nodes.  The 
presacral_nodes will extend from L5-S1 to the top of S3 and will include 1.0 – 1.5 cm of 
tissue anterior to the sacrum and between the vessel contours.   The iliac_nodes will be 
derived by contouring the common iliac, external and internal iliac vessels starting 
superiorly at L5-S1. The external iliac vessels will be contoured inferiorly to the top of 
the femoral heads and the internal iliac vessels will be contoured inferiorly until they are 
no longer visible on the CT scan or exit through the true pelvis via the greater sciatic 
notch. The iliac_nodes will be created by expanding the iliac vessels by 7 mm in the 
anterior, posterior and lateral dimensions, but not the superior and inferior dimensions.  
The obturator_nodes will encompass 1.0 cm width of tissue medial to the obturator 
internus muscles extending from the anterior border of the ilium to the posterior border of 
the ilium.  The obturator_nodes will be contoured starting superiorly where the internal 
and external iliac vessel contours stop and extend inferiorly to the top of the symphysis 
pubis.  The CTVn_5040 should be created from the union of the sacral_nodes, 
iliac_nodes, and obturator_nodes, but should be trimmed to not extend outside the true 
pelvis, nor into muscle or bone.   See Figures 1 and 2.  
 
 
 
 

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Cystectomy bed CTV (CTVsb_5040): 
The cystectomy bed CTV is intended to include tissue in the pelvis that surrounded the 
intact empty bladder and proximal vagina or prostate preoperatively, and the surgical 
cystectomy bed including the anterolateral para-rectal tissues.  These contours do not 
intentionally include or exclude surgical clips. In addition, small bowel should not be 
carved out of the CTV.   See Table below for anatomical borders of the cystectomy bed 
clinical target volume. 
 
Table 1.  Anatomical borders of the cystectomy bed clinical target volume 
Superior 
The contour will extend 2 cm superior to the superior aspect of the pubic 
symphysis. 
Anterior 
The contour will extend to the posterior aspect of the pubic rami/symphysis.  
Above and below the pubic symphysis, the contour will stop anteriorly at the 
planes defined by extending lines superiorly (Plane 1 in Figures 3 and 4) and 
inferiorly (Plane 2 in Figures 3 and 4) from the posterior aspect of the symphysis. 
Posterior 
The contours will about the anterior one-third of the external ano-rectal 
circumference without extending into the ano-rectum.  Above the level of the 
rectum, the contour will stop posteriorly at the plane defined by extending a line 
superior from the anterior border of the rectum (Plane 3 in Figures 3 and 4).    
Lateral 
The contour will extend to the medial border of the obturator internus muscles 
bilaterally.  Inferior to the obturator internus muscles, the lateral border of the 
contour will extend to the vaginal wall or the prostate bed.   
Inferior 
The contour will stop 2-3mm (1 CT slice on axial images) above the penile bulb 
for males and 1 cm below the lower pole of the obturator foramen for females. 
 

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PTV_5040: The PTV will be a direct expansion of 7.0 mm beyond the CTV_5040. 
 
5.2.5 Definition of Critical Structures and Margins (6/13/16) 
NOTE: All structures must be named for digital RT data submission as listed in the table 
below.  The structures marked as “Required” in the table must be contoured and 
submitted with the treatment plan. Structures marked as “Required when applicable” 
must be contoured and submitted when applicable.  Resubmission of data will be required 
if labeling of structures does not conform to the standard DICOM name listed.  Capital 
letters, spacing, and use of underscores must be applied exactly as indicated. 
 
 
 
 
Standard Name 
 
Description 
 
Validation 
BowelSpace 
Bowel space will include 
the small bowel, cecum, 
ascending colon, transverse 
colon and sigmoid colon in 
one bowel bag contour 
 
Required 
Rectum 
Rectum 
 
 
Required 
Bone_Pelvic 
Pelvic bones near PTV 
 
 
Required 
UreterDivert 
 
See description below 
Required 
Bag_Ostomy 
External ostomy bag 
Optional 
 
 
Detailed Specifications 
BowelSpace:  
Superiorly, the Bowel_space contour will start 3 cm above the superior extent of the 
CTVn_5040.  Inferiorly, the contour will be discontinued on the CT slice where no 
portion of small bowel or colon is visible. The contours will include the volume 

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surrounding loops of bowel out to the edge of the peritoneum as bowel may occupy this 
space at any time during the course of treatment. BowelSpace will include the entire 
small bowel, cecum, ascending colon, transverse colon and sigmoid colon in one bowel 
bag contour. See Figure 2. 
 
Rectum:  
The Rectum contour will include the rectum and anal canal and will be contoured on 
every slice from the rectosigmoid junction superiorly to the level of the ischial 
tuberosities inferiorly. 
 
Bone_Pelvic:  
A structure named Bone_Pelvic will be created to track radiation plan parameters that 
may be associated with changes in bone marrow reserve or insufficiency fractions.  It is 
recommend that hot spots be avoided in the Bone_Pelvic when possible.  Contour the 
pelvic bones starting superiorly 1 cm above the superior extent of the CTVn_5040 
extending inferiorly to 1 cm inferior to the inferior limit of the CTVsb_5040.  The pelvic 
bones can be auto-contoured using a CT density-based algorithm.  See Figure 2. 
 
UreterDivert:   
It is recommended that the urinary diversion be contoured so treatment planners can 
avoid bringing beams directly through this structure when possible.   Determining which 
tissues are included in the UreterDivert contour depends on the type of diversion that the 
patient has had.  If the patient has had a non-continent diversion with a bowel conduit 
(e.g. ileal conduit), the contour will include the stoma and the visible portion of the bowel 
conduit.  If the patient has had a continent non-orthotopic catheterizable diversion (e.g. 
Indiana pouch), the contour will include the stoma, bowel conduit and internal urine 
reservoir.  If the patient has had a continent orthotopic diversion (e.g. Studer pouch or 
neobladder ), the contour will include the bowel reservoir. For some patients, some of the 
tissues of the urinary diversion may not be fully captured in the CT simulation so only a 
portion will be contoured. 
 
Bag_Ostomy: 
For patients who have had a non-continent urinary diversion, it is recommended that the 
external ostomy bag be contoured so treatment planners can avoid bringing beams 
directly through this structure when possible.  Bag_Ostomy structure should be created 
by contouring the entire external urine reservoir that is visible on the CT simulation.  
 
5.2.6 Dose Prescription 
NOTE: The information provided in this section can be used for adjusting the dose 
constraints for treatment planning purposes. This table together with the planning priority 
table should be used during dose optimization. It is important to remember that ideal 
plans might not be achievable in all cases. Thus, the Compliance Criteria table could be 
different than the information given here. Cases will be scored using the Compliance 
Criteria table. 
 
Target Standard 
Name 
Dose (Gy) 
Fraction 
Size (Gy) 
# of fractions 
Dose 
Specification 

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Technique 
PTV_5040 
50.4 
1.8 
28 
97% of the PTV 
will receive 
50.4Gy in 28 
fractions 
 
5.2.7 Compliance Criteria (6/13/16) 
The compliance criteria listed here will be used to score each case. Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be 
different than the prescription table. The Per Protocol and Variation Acceptable 
categories are both considered to be acceptable. The Per Protocol cases can be viewed as 
ideal plans, and the Variation Acceptable category can include more challenging plans 
that do not fall at or near the ideal results. A final category, called Deviation 
Unacceptable, results when cases do not meet the requirements for either Per Protocol or 
Variation Acceptable. Plans falling in this category are considered to be suboptimal and 
additional treatment planning optimization is recommended. 
 
Normalization of Dose: The plan is normalized such that 97% of the PTV_5040 volume 
receives prescription dose of 50.4 Gy. 
 
NOTE: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met. 
 
Target Volume Constraints and Compliance Criteria 
 
Name of 
Structure 
Dosimetric Parameter 
Per Protocol 
Variation 
Acceptable 
PTV_5040 
 
D97%(Gy) 
50.4 
49 to 52 
Dmin(Gy) 
>48 
46 to 48 
Dmax(Gy) 
<56 
56 to 58 
Per protocol range is excluded from that of variation acceptable 
 
Normal Structure Constraints and Compliance Criteria 
 
Name of 
Structure 
Dosimetric 
Parameter 
Per Protocol 
Variation 
Acceptable 
BowelSpace 
V40Gy(%) 
<30 
30 to 50 
Rectum 
V45Gy (%) 
<70 
70 to 80 
 
Recommended dose acceptance criteria for other normal tissue, but not to be used for plan 
score. 
 
Structure 
Recommended dose acceptance criteria 
 Bone_Pelvic 
Per protocol: V15Gy < 90% 
 
Delivery Compliance Criteria 
 

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Per Protocol 
Variation Acceptable 
Overall Treatment Time 
44 days 
≥45 days and ≤ 58 days 
Interruptions 
1 to 7 days 
≥ 8days and ≤ 14 days 
 
5.2.8  Treatment Planning Priorities and Instructions (8/7/15) 
 
Critical Structure and Target priorities must be listed in order of decreasing importance. 
 
1. BowelSpace  
2. PTV_5040 
3. Rectum 
4. Bone_Pelvic 
 
5.2.9  Dose Calculations (8/7/15) 
 
Required Algorithms 
 
Acceptable choices of algorithm are listed at: 
http://irochouston.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%
20-%20algorithm%20list%20updated.pdf.  Any dose calculation algorithm used for this 
study must be listed as one of the acceptable algorithms by IROC Houston. 
 
 
 
 
Primary Dataset for Dose Calculation 
 
The primary dataset for dose calculation must be a free breathing CT without contrast.  In 
the case in which contrast is present in the treatment planning CT, the density of the 
contrast should be overridden to a representative background electron density. 
 
 
Dose Matrix Resolution 
 
Dose grid size should be ≤ 3 mm in all directions. 
 
5.2.10  Daily Treatment Localization/IGRT 
Daily IGRT images should be obtained to ensure proper alignment of the isocenter of the 
simulated fields. These IGRT images may include 1) CBCT with Megavoltage (MV) or 
kilovoltage (kV) x-ray; or 2) paired kV 2D images. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
The two likely side effects during radiotherapy are radiation enteritis (small 
bowel/rectum) and perineal skin reaction. Enteritis manifesting as diarrhea may be treated 
with antidiarrheals such as Imodium and Lomotil. Enteritis manifesting as ileus or bowel 
obstruction will require strong consideration of radiotherapy interruption and/or stoppage 
with other supportive measures as required. Skin toxicity can be managed with topical 
application of barrier or steroid creams. 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
 Antiemetics 
 Anticoagulants 
 Antidiarrheals 

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 Analgesics 
 Hematopoietic Growth Factors 
 Nutritional supplementation 
 
5.4 
Duration of Therapy (6/13/16) 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 Disease progression; 
 Intercurrent illness that prevents further administration of treatment; 
 Unacceptable adverse event(s), including the following: 
o CTCAE Grade 2-4 bowel obstruction during the course of radiation treatment 
o CTCAE Grade 2-4 neutropenia, thrombocytopenia, or anemia during the course 
of radiation treatment that involves more than a 3-week interruption of 
radiotherapy; 
o Any grade AE that requires surgical intervention or revision of the neobladder 
 Patient declines further treatment as per study protocol; or 
 General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
Patients who develop CTCAE Grade 2-4 small and/or large bowel obstruction during the 
course of radiation treatments must have the radiotherapy stopped and NOT resumed. 
Patients who develop CTCAE Grade 2-4 neutrophil and/or platelet hematological toxicity 
should have the radiotherapy held till parameters recover to the following values:  
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 
 Platelets ≥ 100,000 cells/mm3    
If this involves more than a 3-week interruption radiotherapy should be stopped. 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Adverse Events 
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4 for adverse event (AE) reporting. The CTCAE version 4 is identified 
and located on the CTEP web site 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. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below 
will be reported via the CTEP Adverse Event Reporting System (CTEP-AERS) 
application accessed via the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865).  
7.1.1 
Adverse Events (AEs)  
Definition of an AE: Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
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(investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements.; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]  
7.1.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet 
expedited reporting criteria defined in the table in Section 7.2 will be reported via 
CTEP-AERS. SAEs that require 24 hour CTEP-AERS notification are defined in the 
expedited reporting table in Section 7.2.  Contact the CTEP-AERS Help Desk if 
assistance is required. 
 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose 
that results in any of the following outcomes: 
 Death; 
 A life-threatening adverse drug experience; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect; 
 Important medical events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE, when, 
based upon medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  
7.1.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to 
treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the 
CTEP-AERS system within 30 days of AML/MDS diagnosis. 
 
 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event: 
 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
 
 
 
 
Second Malignancy  

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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. 
 
7.2 
CTEP-AERS Adverse Event Reporting Requirements 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting 
System, accessed via the CTEP web site, 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865. 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and 
satisfies NRG requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Oncology Office at 1-800-227-5463, ext. 4189, for instances when 
Internet fails. Once internet connectivity is restored, an AE report submitted by phone 
must be entered electronically into CTEP-AERS. 
 
 CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour 
notification is electronically submitted within 24 hours of learning of the 
adverse event. Each CTEP-AERS 24-hour notification must be followed by a 
CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 
hour CTEP-AERS notification are defined in the expedited reporting table 
below. 
 Supporting source document is not mandatory.  However, if the CTEP-AERS 
report indicates in the Additional Information section that source 
documentation will be provided, then it is expected.  If supporting source 
documentation accompanies a CTEP-AERS report, include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page, 
and fax supporting documentation to the NRG Oncology dedicated SAE 
FAX, 215-717-0990. 
 A serious adverse event that meets expedited reporting criteria outlined in the 
following table but is assessed by the CTEP-AERS System as “expedited 
reporting NOT required” must still be reported to fulfill NRG Oncology safety 
reporting obligations. Sites must bypass the “NOT Required” assessment; the 
CTEP-AERS System allows submission of all reports regardless of the results 
of the assessment.  
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the 
table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE 
section of the appropriate case report form (see Section 15.2). 
 

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Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur within 30 Days of the Last Administration of the Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of commercially available 
agent /intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials 

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For Arm 1, expedited adverse event reporting is not applicable; routine adverse event 
reporting on the case report form fulfills safety reporting requirements for all adverse 
events. 
  
8. REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES 
Access requirements for OPEN, Medidata Rave, and TRIAD 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity 
and Access Management (IAM) account.  
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all 
physicians involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all 
staff involved in the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-
IAM application to register (both initial registration and annual re-registration) with CTEP 
and to obtain a user account.  
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures below for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.)  
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer 
Trials Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
 
8.1  
Investigator Registration Requirements  
8.1.1 Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Lead Protocol Organization.  Food and Drug Administration (FDA) 
regulations and National Cancer Institute (NCI) policy require all investigators 
participating in any NCI-sponsored clinical trial to register and to renew their registration 
annually. Registration requires the submission of: 
 a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
 a current Curriculum Vitae (CV) 
 a completed and signed Supplemental Investigator Data Form (IDF) 
 a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
 

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8.2  
Site Registration Requirements 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU members’ website by entering credentials 
at https://www.ctsu.org.  For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
 
Sites participating in the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing, or amendment review.  This information will be provided to 
the CTSU Regulatory Office from the CIRB at the time the site’s Signatory Institution 
accepts the CIRB approval.  The Signatory site may be contacted by the CTSU 
Regulatory Office or asked to complete information verifying the participating 
institutions on the study.  Other site registration requirements (i.e., laboratory 
certifications, protocol-specific training certifications, or modality credentialing) must be 
submitted to the CTSU Regulatory Office or compliance communicated per protocol 
instructions. 
 
Downloading Site Registration Documents   
Site registration forms may be downloaded from the NRG-GU001 protocol page located 
on the CTSU members’ website. 
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
 Click on the Protocols tab in the upper left of your screen 
 Click on the NRG Oncology link to expand, then select trial protocol NRG-
GU001 
 Click on the Site Registration Documents link 
 
Requirements for NRG-GU001 Site Registration 
 CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via 
the NCI CIRB)  
 IRB Approval Letter (for sites not participating via the NCI CIRB) 
 IRB/REB Approved Informed Consent (English and native language versions*) 
*NOTE: Institutions must provide certification/verification of IRB/REB consent 
translation to NRG Headquarters (described below). 
 IRB/REB registration number renewal information as appropriate. 
 CTSU RT Facilities Inventory Form 
NOTE:  Per NCI policy all institutions that participate on protocols with a 
radiation therapy component must participate in the Imaging and Radiation 
Oncology Core (IROC) Houston QA program.  If this form has been previously 

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submitted to CTSU it does not need to be resubmitted unless updates have 
occurred at the RT facility. 
 
Submitting Regulatory Documents  
Submit completed forms along with a copy of your IRB Approval and Informed Consent 
to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU 
RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (NOTE: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
 Click on the Regulatory tab at the top of your screen 
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
Non-English Speaking Canadian and International Institutions: 
 
Translation of documents is critical. The institution is responsible for all translation costs. 
All regulatory documents, including the IRB/REB approved consent, must be provided in 
English and in the native language. Certification of the translation is optimal but due to 
the prohibitive costs involved NRG will accept, at a minimum, a verified translation. A 
verified translation consists of the actual REB approved consent document in English and 
in the native language, along with a cover letter on organizational/letterhead stationery 
that includes the professional title, credentials, and signature of the translator as well as 
signed documentation of the review and verification of the translation by a neutral third 
party. The professional title and credentials of the neutral third party translator must be 
specified as well. 
 
8.2.1 Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS (8/7/15) 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Headquarters to receive approval to 
participate 
in 
this 
trial. 
For 
more 
details 
see 
link 
below: 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx.  
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to 
enrolling patients to this study. 
 

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8.3 
RT-Specific Pre-Registration Requirements 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, the Imaging and Radiation 
Oncology Core (IROC) Houston will notify your institution when all credentialing 
requirements have been met and the institution is RT credentialed to enter patients onto 
this study.   
 
 
8.3.1 Digital RT Data Submission to NRG Oncology Using TRIAD 
TRIAD is the image exchange application used by NRG Oncology. TRIAD 
provides sites participating in NRG clinical trials a secure method to transmit 
RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions: http://irochouston.mdanderson.org 
 
Treatment 
Modality 
Key Information  
 
IMRT 
Facility 
Questionnaire 
X 
The IROC Houston electronic facility questionnaire (FQ) should be 
completed or updated with the most recent information about your 
institution. To access this FQ go to 
http://irochouston.mdanderson.org/questionnaires 
Credentialing 
Status Inquiry 
Form 
X 
To determine whether your institution needs to complete any further 
credentialing requirements, please complete the “Credentialing Status 
Inquiry Form” found under credentialing on the IROC Houston QA 
Center website (http://irochouston.mdanderson.org 
Phantom 
Irradiation 
X 
An IROC Houston anthropomorphic phantom must be successfully 
completed (if the institution has not previously met this credentialing 
requirement).  Instructions for requesting and irradiating the phantom 
are available on the IROC Houston website 
(http://irochouston.mdanderson.org) 
Pre-Treatment 
Review 
X 
For the first case for an individual site. Based on the results of this 
case review, the reviewers might request that the second case also be 
selected for pre-treatment review. Patient cases must be submitted 
through TRIAD and a DDSI form must be completed. Please allow 3 
business days for this to be completed. If a resubmission is required 
the 3 business day timeline will restart. Treatment cannot begin until 
approval from NRG Oncology has been issued to the institution. 
Credentialing Issued to: 
Institution 
X 
IROC Houston QA Center will notify the institution and NRG 
Headquarters that all desired credentialing requirements have been 
met. 

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DICOM RT and other objects.  TRIAD anonymizes and validates the images as 
they are transferred. 
 
TRIAD Access Requirements 
 Site physics staff who will submit images through TRIAD will need to be 
registered with The Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account. Please refer to 
the beginning of Section 8 for instructions on how to request a CTEP-IAM 
account. 
 To submit images, the site physics user must have been assigned the 'TRIAD site 
user' role on the relevant Group or CTSU roster. NRG users should contact your 
site Lead RA to be added to your site roster.  Users from other cooperative groups 
should follow their procedures for assignment of roster roles. 
 RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations 
When a user applies for a CTEP-IAM account with proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to 
be able to submit images. TRIAD installation documentation can be found on 
the NRG Oncology website Core Lab tab.    
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
8.4 
Patient Enrollment 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
8.4.1 Oncology Patient Enrollment Network (OPEN) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. All site staff will use OPEN to enroll patients to this study. It is 
integrated with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 All eligibility criteria have been met within the protocol stated timeframes. 

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 All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
NOTE:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your records.  
 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the 
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration 
system (e.g. drug shipment and confirmation of registration) will occur.  
 
9. 
DRUG INFORMATION  
Not applicable for this study. 
 
10.  
PATHOLOGY/BIOSPECIMEN 
Not applicable for this study. 
 
11.  
SPECIAL STUDIES (NON-TISSUE) 
Not applicable for this study. 
 
12.  
MODALITY REVIEWS 
Radiation Therapy Quality Assurance Reviews  
One of a 5 person team of radiation oncologists led by the Principal Investigator, Libni 
Eapen, MD, will perform RT Quality Assurance Reviews after cases enrolled have been 
received at IROC Philadelphia RT. The first case from each site will have a pre-treatment 
review and treatment cannot be started until the case is approved. Based on the results of 
this case review, the reviewers might request that the second case also be selected for pre-
treatment review. Three business days are required for this review to be completed once 
complete data is received. Resubmissions will restart the 3 business day clock. The site 
will be notified by the Imaging and Radiation Oncology Core (IROC) Philadelphia RT on 
the status of the review. The RTQA reviews will be ongoing, and will be facilitated by 
IROC Philadelphia RT. 
 
The goal of the review is to evaluate protocol compliance.  The review process is 
contingent on timely submission of radiotherapy treatment data as specified in Section 
15.2. The scoring mechanism is: Per Protocol, Variation Acceptable, and Deviation 
Unacceptable. 
 
 

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13.  
ASSESSMENT OF EFFECT DURING TREATMENT 
13.1  The assessment of treatment effect is solely related to the documentation of radiation 
associated toxicity. At each visit the history and physical examination and blood test will 
document any hematological, GI, GU (genital/urethral), or pelvic soft tissue toxicity. 
13.2  The following lab tests will be done at each visit: CBC and platelet count. 
 
14.  
DOCUMENTATION OF CANCER RECURRENCE AND OTHER CANCER 
EVENTS 
14.1  At each follow up visit the patient will have a history and physical examination and 
recent imaging reports will be reviewed to determine the presence of pelvic tumor 
recurrence, distant metastases, or both. 
14.2  The following assessments will be done: CT and/or MRI scan of the pelvis will be 
performed every 6 months after treatment. Additional imaging will be performed as the 
clinical situation warrants. 
14.3  Criteria for pelvic recurrence: The primary endpoint is pelvic recurrence, which is 
defined as any pelvic soft tissue and/or nodal recurrence (measuring at least 1cm in linear 
dimension) between the L5-S1 interspace and the pelvic floor and/or tumor documented 
at urethroscopy. Ninety-five percent of the pelvic failures will be demonstrated on pelvic 
imaging. Biopsy confirmation is NOT required. 
14.4  Criteria for distant metastases: Distant metastases will be any hematogenous metastases 
and/or lymph node metastases above the L5-S1 interspace, documented by imaging (CT 
and/or MRI and/or bone scans). 
 
15.  
DATA AND RECORDS 
15.1 
Data Management/Collection 
Data collection for this study will be done exclusively through Medidata Rave®. Access 
to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS (Regulatory Support System). To access iMedidata/Rave, the 
site user must have an active CTEP-IAM account and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization 
rosters at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata 
(iMedidata-Notification@mdsol.com) to activate their account. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and will be listed in the 
upper right pane of the iMedidata screen. 
  
Users that have not previously activated their iMedidata/Rave accounts also will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 

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on iMedidata/Rave is available on the CTSU website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
15.2 
Summary of Data Submission (8/7/15) 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7 for information about expedited and routine 
reporting.   
 
Summary of Data Submission: Refer to the CTSU members website. 
 
 
Digital Data Submission Requirements 
 
Summary of Dosimetry Digital Data Submission  
Submit Digital RT Data via TRIAD; see Section 8.3.1 for TRIAD account access and 
installation instructions.  
 
15.3 
Global Reporting/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. 
Reports are due January 31, April 30, July 31, and October 31. 
 
16. STATISTICAL CONSIDERATIONS 
16.1 
Study Design 
16.1.1 Stratification 
Patients will be stratified before randomization with respect to neoadjuvant/adjuvant 
chemotherapy (yes vs. no) and pelvic relapse risk category (intermediate vs. high). The 
administration of even one cycle of chemotherapy will constitute “yes” for either 
neoadjuvant or adjuvant chemotherapy. The treatment allocation scheme described by 
Zelen (1974) will be used because it balances patient factors other than institution.  
16.1.2 Randomization (8/7/15) 
Patients will be randomized in a 1:1 allocation scheme to the standard arm (ARM 1, No 
RT) or to the experimental arm (ARM 2, Post-op adjuvant IMRT of 50.4 Gy in 28 
fractions) after surgery and completion of adjuvant chemotherapy (if given). In patients 
getting postoperative adjuvant chemotherapy, randomization will occur following 
completion of the chemotherapy. 
16.1.3 Total Accrual 
185 patients 
16.1.4  Justification of Design 
 
A randomized phase II design is used to isolate the effect of radiation therapy. 
 
16.2 
Study Endpoints 
16.2.1 Primary Endpoint 
 
Pelvic recurrence-free survival 

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16.2.2 Secondary Endpoints 
 
Disease-free survival, toxicity 
 
16.3 
Primary Objectives Study Design 
16.3.1 Primary Hypothesis and Endpoints 
Hypothesis: Postoperative adjuvant radiotherapy following radical cystectomy will 
reduce pelvic recurrence. 
Endpoint: Pelvic recurrence-free survival 
16.3.2 Definitions of Primary Endpoint and How This Will Be Analyzed 
The primary endpoint is pelvic recurrence-free survival (PRFS), defined as time free of 
pelvic recurrence or death, with patients who experience distant metastasis censored at 
the time of occurrence. Pelvic recurrence is specifically defined as soft tissue and /or 
lymph node tumor recurrence in the pelvis anywhere between the L5-S1 disc space 
superiorly and the pelvic floor inferiorly. This will be determined on the basis of pelvic 
imaging (CT or MRI scan demonstrating soft tissue or nodal recurrence at least 1cm in 
linear dimension) or urethroscopy. Biopsy is not required. 
 
For the definitive analysis at the specified event information, IMRT will be tested in 
terms of a difference in cause-specific-hazards (Kalbfleisch & Prentice 1980; Gaynor et 
al. 1993) for PRFS using the log-rank test. The cumulative incidence of PRFS in the 
presence of competing risks will be computed via cumulative incidence curves (Gaynor). 
We also may test for differences in cumulative incidence of PRFS using Gray’s test 
(Gray 1988), as comparison of both the cause-specific hazards and cumulative incidence 
is relevant to fully interpreting the potential benefit of the intervention (Freidlin & Korn 
2005, Dignam & Kocherginsky 2008). The Cox (1972) proportional hazards model also 
may be used for multivariable analysis of the PRFS cause-specific hazard including 
additional covariates such as stratification factors and any other relevant covariates. We 
may similarly explore the treatment effect on the subdistribution hazard scale (Fine & 
Gray 1999). 
16.3.3 Reporting the Initial Treatment Analysis 
The analysis reporting the treatment results will be carried out after the criteria for early 
stopping/reporting are met. Three interim analyses and one final analysis will be 
performed for efficacy and futility of the experimental treatment and will be carried out 
as described in Section 16.4.1. It will include tabulation of all cases entered and those 
excluded from the analyses; the distribution of the important prognostic baseline 
variables; safety treatments; treatment compliance; and observed results with respect to 
the primary and secondary endpoints will be shown. All eligible patients randomized will 
be included in the comparison and will be grouped by assigned treatment in the analysis 
(intent-to-treat analysis). In addition, exploratory analyses of treatment comparisons of 
the primary and secondary survival endpoints will be tested using the Cox and/or Fine 
and Gray’s proportional hazard model that includes treatment arms, the stratification 
factors, and any other appropriate covariates. 
16.3.4 Sample Size and Power Calculations  
The sample size calculation addresses the specific primary hypothesis that the PRFS 
failure rate at 2 years in Arm 2 (postoperative IMRT) will be better than in Arm 1. 
Assume an exponential survival distribution for each arm and define λ1 is the hazard rate 

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for Arm 1 and λ2 is the hazard rate for Arm 2. (HA: λ1 > λ2). 
 
H0: λ1 ≤ λ2 
vs. HA: λ1> λ 2 
 
We project that the proportion failing for the PRFS endpoint in Arm 1 at 2 years is 30% 
(a 70% PRFS percentage with a yearly hazard rate of 0.178). The study is designed to 
show an absolute reduction of 15% in the 2-year PR proportion to 15%, which translates 
to 85% PRFS and a yearly hazard rate of 0.081 in Arm 2. Forty-seven pelvic recurrences 
and/or deaths are required to detect this 54% relative reduction in the yearly death rate 
with 90% statistical power using a one-sided log-rank test (Mantel 1966) at the 0.10 
significance level. At the planned accrual rate and additional follow-up time of 12 
months, 176 eligible patients would be required. Guarding against an ineligibility or loss 
of patients due to pre-randomization failures of up to 5%, the final targeted accrual for 
this study will be 185 patients. 
 
To assess whether this intervention should advance to phase III evaluation, we also will 
evaluate the effect of radiation therapy on the totality of potential failure events among 
these patients via the disease-free survival (DFS) endpoint, defined as the first occurrence 
of either: pelvic failure, distant metastasis, or death. The disease-free survival proportion 
in the control group is assumed to be 40% (annual failure rate 0.458). With the patient 
sample size fixed at 176 eligible patients, the experimental treatment can be tested for a 
reduction in DFS events by approximately 30% (hazard ratio 0.7025), for a two-year DFS 
proportion of 52.5% (annual failure rate 0.322) with 83% power and one-sided alpha 
0.20. A larger DFS event reduction of 33% could be detected with power 88% (or 
equivalently, 80% power with one-sided alpha 0.12) and for a smaller DFS event 
reduction of 25%, power would approach 75% at alpha 0.20. Thus, this trial will provide 
a reasonably reliable but not definitive test (as appropriate in phase II) for a DFS event 
reduction with the addition of radiation therapy. 
 

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16.4 
Study Monitoring of Primary Objectives 
16.4.1 Interim Feasibility/Futility Analysis Plan 
We will estimate the cumulative incidence of pelvic only or the concurrent pelvic and 
systemic recurrences (PR, for this analysis, deaths and distant metastasis are competing 
risks) for the first 43 patients on the control arm with one year follow up. If the 
cumulative incidence is <14%, the DMC will consider stopping the trial as such a rate 
would generally be inconsistent with the risk-to-benefit ratio needed to justify proceeding 
to a phase III evaluation. Depending on the accrual rate this strategy will result in a 
variable number of patients avoiding being entered on a potentially futile study; for 
example, if the accrual rate is 5 patients per month, about 40 patients would not be 
entered into the study. If the accrual rate is 2.5 patients per month, about 70 patients will 
avoid accrual to the trial. 
16.4.2  Interim Futility Analysis Plan 
An interim analysis for the futility hypothesis that the experimental arm is not as effective 
as or unlikely to be more effective than the standard arm will be performed after 
observation of one-half of the required events (24 for PRFS) has occurred. At the futility 
analysis, we will evaluate PRFS of the experimental (radiation) arm relative to the control 
arm via a hazard ratio. If the observed hazard ratio (experimental/control) is greater than 
or equal to 1.0, then consideration will be given to stopping for futility (i.e., the 
experimental arm will be considered ineffective in this disease population) (see below). If 
the observed hazard ratio of the experimental arm relative to the control arm is less than 
1.0, then the trial will continue to the full target accrual. Under reasonable assumptions, 
termination for futility at the interim analysis using this rule is found to result in minimal 
loss of power (less than 2%) for the primary hypothesis test (Wieand 1994). This same 
evaluation will take place for DFS, and the futility analyses should be able to be 
performed relatively concurrent in calendar time. 
 
If the observed hazard ratio (experimental/control) is ≥ 1.0, a decision about whether to 
terminate accrual will be made after consideration of additional information including 
treatment compliance, follow-up reporting timeliness, and the safety profile of the 
experimental treatment. The independent DMC will review the decision and then make a 
recommendation concerning early stopping to the Group Chair. 
16.4.2 Interim Report to Monitor the Study Progress 
Interim reports with descriptive statistics will be prepared twice per year until the initial 
paper reporting the treatment results has been submitted. In general, the interim reports 
will contain information about the patient accrual rate with a projected completion date 
for the accrual phase, compliance rate of treatment delivery with the distributions of 
important prognostic baseline variables, and the frequencies and severity of the adverse 
event by treatment arm. The interim reports will not contain the results of the treatment 
comparisons with respect to the primary endpoint and secondary endpoints. 
 
16.5 
Accrual Considerations 
16.5.1 Accrual Rate 
Based on typically low accrual for bladder studies, but projecting slightly higher because 
this is a randomized phase II trial, the projected accrual for this trial will be 5 cases per 
month. Based on this assumption, the study is projected to close to accrual approximately 

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36 months from the end period of negligible accrual (first 6 months), with a projection of 
reporting approximately 12-15 months from the end of accrual. 
16.5.2 Accrual Goal 
The final targeted accrual for this study will be 185 patients. 
16.5.3 Study Duration 
 
54 to 57 months 
16.5.4 Estimated Duration for Completion of Primary Endpoint 
36 months from trial activation 
 
 
16.6 
Secondary Elements (6/13/16) 
16.6.1 Secondary Hypotheses and Endpoints  
Hypothesis: Reducing pelvic recurrence will result in improved survival with acceptable 
treatment toxicity. 
Endpoint: Disease-free survival (DFS), toxicity 
16.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
 
Analysis of Secondary Endpoints 
 
DFS, defined as the first occurrence of either: pelvic failure, distant metastasis, or death, 
will be estimated by Kaplan-Meier (Kaplan & Meier 1958) and arms compared using the 
log-rank test (Mantel 1966). Multivariable analysis of DFS including other covariates 
may follow. Cumulative incidence curves for the additional event types other than PRFS 
comprising DFS also may be examined including PR, distant metastasis, etc., with 
interest in whether deaths or distant metastasis failures differ between arms. 
 
 
Treatment Toxicity 
 
Acute (within 90 days of the first day of radiotherapy) and late (any time beyond the 90 
days) radiation bowel toxicity will be scored using CTCAE v4.0 and limited to those AEs 
listed in Section 16.6.3. Very careful attention will be paid to neobladder and  bowel 
complications that require surgical intervention and/or stoppage of radiotherapy. 
Specifically, urinary tract obstruction, urinary retention, urinary fistula, hematuria, 
cystitis noninfective, bladder perforation, and urinary incontinence will be monitored as 
neobladder complications and gastrointestinal adverse events will be assessed for bowel 
complications. 
16.6.3 Interim Safety Monitoring for Bowel Toxicity Requiring Surgery in Arm 2 
We  anticipate that 3-5 % of patients without RT and 5-8% of RT patients will require 
surgery for bowel toxicity and propose close toxicity monitoring with a stopping rule 
calculated to ensure we do not double this risk. Bowel toxicity is defined as the following 
subset of CTCAE v4.0 within 90 days of the first radiotherapy treatment regardless of 
grade and which required surgical intervention: 
 System Organ Class: Gastrointestinal Disorders 
o Abdominal distension, abdominal pain 
o Colitis 
o Colonic fistula, colonic hemorrhage, colonic obstruction, colonic perforation, 
colonic stenosis, colonic ulcer 
o Diarrhea 
o Enterocolitis 

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o Fecal incontinence 
o Gastrointestinal fistula 
o Gastrointestinal pain 
o Ileal fistula, ileal hemorrhage, ileal obstruction, ileal perforation, ileal 
stenosis, ileal ulcer 
o Ileus 
o Jejunal fistula, jejunal hemorrhage, jejunal obstruction jejunal perforation, 
jejunal stenosis, jejunal ulcer 
o Lower gastrointestinal hemorrhage 
o Rectal fistula, rectal hemorrhage, rectal mucositis, rectal necrosis, rectal 
obstruction, rectal pain, rectal perforation, rectal stenosis, rectal ulcer 
o Small intestinal mucositis, small intestinal obstruction, small intestinal 
perforation, small intestinal stenosis, small intestinal ulcer 
o Vomiting 
 
Arm 1 (observation only), will be monitored for bowel toxicity requiring surgery to 
ensure that the anticipated rates are within the expected range. However, for Arm 2, a 
safety rule will be employed. A bowel toxicity rate of ≤ 5% of patients requiring surgery 
is considered acceptable and a rate of 15% is considered unacceptable. The null 
hypothesis is that IMRT post-cystectomy is not tolerable versus the alternative hypothesis 
that IMRT post-cystectomy is tolerable. The following hypothesis will be tested using 
Fleming’s Multiple Testing Procedure (1982) with a significance level of 0.10 and 80% 
statistical power. 
 
H0: p_bts ≥ 0.15 vs. HA: p_bts ≤ 0.05 
 
Active decisions regarding safety of continued accrual will be made sequentially when 
19, 38, and 57 eligible patients have received radiotherapy in Arm 2. We are more 
concerned with a false negative decision (i.e., failing to detect the increase in toxicity if it 
exists) than we are with a false positive decision (i.e., deciding the new regimen is more 
toxic, when in fact it is not). The stopping and continuation rules in Table 14.1 below will 
be applied in three stages to the 57 eligible cases randomized to Arm 2 who received at 
least some RT. If at any stage, we stop and reject the alternative hypothesis and claim that 
the bowel toxicity requiring surgery (any) rate may be greater than or equal to 15%, we 
will temporarily close the study to accrual, gather the relevant source data on the cases 
with bowel toxicity (any), prepare a statistical report summarizing the adverse event 
findings, and present the report to the radiation and medical oncology study chairs for 
review.  
 
Following the study chairs’ review of data, a conference call will be scheduled with the 
study chairs, statistician, and other appropriate NRG Oncology leadership as needed to 
discuss the findings and make a recommendation about the study. Once a 
recommendation is made, the responsible statistician will present the statistical report 
along with the recommendation to the NRG Oncology Data Monitoring Committee 
(DMC) for the Committee’s consideration. The DMC will then make a recommendation 

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about the course of action and future of the study. If at the first or second stage either of 
the stopping rules is not met, we will continue accrual and monitoring for bowel toxicity 
requiring surgery. If we continue until the last stage, we will conclude “tolerability” or 
not.  
Table 16.1 Stopping and Continuation Rules for Bowel Complications 
#analyzable* 
Continue 
Stop and reject HA:p≤0.05 
19 
<3 
≥3 
38 
<4 
≥4 
57 
<5 
≥5 
 
*“Analyzable patients” is defined as eligible patients who received IMRT. 
 
16.7 
Gender/Ethnicity/Race Distribution 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
4 
6 
10 
Not Hispanic or Latino 
28 
147 
175 
Ethnic Category: Total of all subjects 
32 
153 
185 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
2 
2 
Asian 
1 
0 
1 
Black or African American 
4 
4 
8 
Native Hawaiian or other Pacific Islander 
1 
0 
1 
White 
26 
147 
173 
Racial Category: Total of all subjects 
32 
153 
185 
 
 
 

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