Radical Cystectomy Compared With Chemoradiation for Muscle Invasive Bladder Cancer: A Pilot, Randomized-Controlled Non-Inferiority Trial
Phase: NA
Conditions: Muscle Invasive Bladder Cancer
Sponsor: The University of Texas Health Science Center at San Antonio

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
1 
  
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: RADICAL CYSTECTOMY COMPARED WITH 
CHEMORADIATION FOR MUSCLE INVASIVE BLADDER CANCER: A PILOT 
RANDOMIZED CONTROLLED NON-INFERIORITY TRIAL 
 
 
NCT number: NCT02716896 
 
IRB Approval Date: 09/19/2017 
 
Unique Protocol ID: HSC2015-620H 
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
2 
 
RADICAL CYSTECTOMY COMPARED WITH CHEMORADIATION FOR MUSCLE INVASIVE 
BLADDER CANCER: A PILOT RANDOMIZED CONTROLLED NON-INFERIORITY TRIAL 
 
PI: PRINCIPAL INVESTIGATOR 
DHARAM KAUSHIK MD 
ASSISTANT PROFESSOR 
DEPARTMENT OF UROLOGY 
UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER 
7703 FLOYD CURL DRIVE 
SAN ANTONIO, TX 78229-3900 
PHONE: 210-296-7355 
FAX: 210-567-6868 
 
Co-Investigator: 
YUSHENG FENG PHD 
PROFESSOR, MECHANICAL AND BIOMEDICAL ENGINEERING, 
DEPARTMENT OF MECHANICAL ENGINEERING 
DIRECTOR, CENTER FOR SIMULATION, VISUALIZATION  
AND REAL-TIME PREDICTION 
THE UNIVERSITY OF TEXAS AT SAN ANTONIO 
 SAN ANTONIO, TX 78249 
 
Co-investigator: 
ZHENG SHI MD, PHD 
ASSISTANT PROFESSOR 
DEPARTMENT OF RADIATION ONCOLOGY 
CANCER THERAPY AND RESEARCH CENTER 
7979 WURZBACH ROAD, SAN ANTONIO, TX 78229 
 
Faculty Advisor And Co-Investigator 
ROBERT SVATEK MD, MS 
ASSOCIATE PROFESSOR 
DEPARTMENT OF UROLOGY 
UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER 
7703 FLOYD CURL DRIVE 
SAN ANTONIO, TX 78229-3900 
PHONE: 210-296-7355 
FAX: 210-567-6868 
 
CTMS# 15-2105 (number assigned at the time of CTMS entry) 
 
IND#: IND Exempt 
PROTOCOL V. 1.5 
 
DATE: 09/19/2017 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
3 
TABLE OF CONTENTS 
Study Synopsis/Schematics  
 
 
 
 
 
 
 
3 
 
Background and Rationale 
 
 
 
 
 
 
 
 
4 
 
Preliminary Data 
 
 
 
 
 
 
 
 
 
6 
 
Hypothesis and Specific Aims 
 
 
 
 
 
 
 
7 
 
Study Design  
 
 
 
 
 
 
 
 
 
8 
 
Study Enrollment/Withdrawal  
 
 
 
 
 
 
 
9 
 
Inclusion Criteria 
 
 
 
 
 
 
 
 
9 
 
Exclusion Criteria 
 
 
 
 
 
 
 
 
9 
 
Randomization Procedure 
 
 
 
 
 
 
 
9 
 
Participant Withdrawal 
 
 
 
 
 
 
 
9 
 
Schedule of Events 
 
 
 
 
 
 
 
 
 
10 
 
Screening 
 
 
 
 
 
 
 
 
 
10 
 
Baseline Study Visit  
 
 
 
 
 
 
 
11 
 
Treatment Groups 
 
 
 
 
 
 
 
 
11 
 
Post-treatment Study Visits  
 
 
 
 
 
 
12 
 
Study Withdrawal Visit 
 
 
 
 
 
 
 
12 
 
Unexpected Study Visit 
 
 
 
 
 
 
 
12 
 
Study Calendar 
 
 
 
 
 
 
 
 
 
13 
 
Data Collection and Study Evaluations 
 
 
 
 
 
 
14 
 
Data Safety and Monitoring Plan 
 
 
 
 
 
 
 
16 
 
Statistical Considerations 
 
 
 
 
 
 
 
 
21 
 
References 
 
 
 
 
 
 
 
 
 
 
22 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
4 
STUDY SYNOPSIS:  Radical cystectomy vs. Chemoradiation Study Chart 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: 
Qualified T2, T3, T4a patients who are radical cystectomy and chemoradiation candidates 
Post-TURBT follow-up (SOC); Study Randomization (Research); 
Blood work (SOC and Research)*; Study Questionnaires (Research) 
Post treatment Q 3-months follow-ups 
(~ 3, 6, 9, and 12 ± 1 month visits) up 
to one year, and then Q6-months 
follow-ups up to two years (i.e.~ 18, 
24, 30, and 36± 1 month visits)  (SOC)*: 
• 
Imaging study (SOC) 
• 
Blood work (SOC and Research) 
• 
Study Questionnaires (Research) 
• 
Cystoscopy (SOC)** 
Determination of Eligibility 
Radical Cystectomy ± Neoadjuvant chemotherapy (SOC); 
Tissue Sample (Research)* 
Radiation and medical oncology consults;  Induction Chemoradiotherapy 
(approximately starts within 8 weeks (≤ 8 weeks) of the TURBT) 
Radical Cystectomy Arm 
Chemoradiation Arm 
TURBT (SOC); Tissue sample (SOC and Research)* 
Post-Induction Response Evaluation with Cystoscopy and biopsy 
(~3-4 weeks following Induction Chemoradiotherapy) 
Tumor Response T0, Ta, Tcis - At 
site distant from original tumor 
Consolidation Chemoradiotherapy Starts 7‐
14 days following Post‐Induction TURBT 
Post‐Consolidation Response Evaluation (8‐10 weeks 
following Consolidation Chemoradiotherapy) 
 
 
Tumor Response ≥ T1 - On re‐biopsy, the tumor 
persists and invades into or beyond the lamina propria 
 
Radical Cystectomy; tissue sample 
(Research) * 
~3‐8 weeks following Post‐Induction TURBT 
Informed consent 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
5 
RC=Radical Cystectomy 
SOC = Standard of Care 
TURBT = Transurethral resection of bladder tumor 
*= optional study, “GU Tissue Bank HSC20050234H” 
**Post-treatment cystoscopy is SOC for chemoradiation patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
6 
1. BACKGROUND AND SIGNIFICANCE 
 
Radical cystectomy is the gold standard treatment for muscle-invasive bladder cancer.  It involves 
removal of the bladder and prostate for men and anterior exenteration (including the bladder, 
uterus, ovaries, and part of the vagina) for women. Patients who were treated with the surgical 
approach report poor overall satisfaction, sexual function, urinary and bowel function, and health-
related quality of life.  The current NCCN (National Comprehensive Cancer Network) Clinical 
Practice Guidelines (version 2.2015) indicates bladder-preserving therapy with cystectomy 
reserved for tumor recurrence represents a safe and effective alternative to immediate radical 
cystectomy for muscle invasive bladder cancer.   
According to the current NCCN guidelines, patients who are not surgical candidates (i.e. those 
with extensive comorbidities and/or poor performance status), chemoradiation can be used as a 
curative treatment regimen. This bladder-sparing therapy consist of (1) maximal transurethral 
resection of bladder tumor (TURBT), (2) induction external-beam radiation therapy with 
concurrent chemotherapy, (3) cystoscopic assessment of treatment response with prompt 
cystectomy for non-responders, and (4) active cystoscopic surveillance with salvage cystectomy 
at the first sign of invasive recurrence. 
Retrospective studies have shown that the majority of chemoradiation patients achieves a clinical 
response and preserves the native bladder in >70% of patients while offering long-term survival 
rates comparable to contemporary cystectomy series. 1, 2  
We hypothesize that chemoradiation is non-inferior to radical cystectomy with regard to quality of 
life and progression free and bladder intact survival.  Short of a randomized trial, any direct 
comparison of chemoradiation to radical cystectomy to address our hypothesis is difficult and 
must account for selection bias and confounding variables resulting from discordance between 
clinical, pathologic staging, functional status and comorbidities.  Our proposed randomized pilot 
non-inferiority study aims to provide feasibility data for a larger randomized clinical non-inferiority 
trial comparing the efficacy and safety of chemoradiation and radical cystectomy.  
Given the potential non-inferiority of chemoradiation relative to radical cystectomy, clinical 
prediction of non-response to chemoradiation in terms of biomarkers would be of interest.  
However, there is paucity of predictive markers that can identify non-responders of 
chemoradiation. If predictive markers could be identified, patients might then be selected for the 
treatment most likely to benefit them, which would have the added advantage of maximizing 
overall cure rates and minimizing poor outcomes. Characterization of the genomic drivers of 
bladder cancer has been proposed for evaluating progression. Immunohistochemistry has been 
utilized with limited accuracy. A number of investigators have queried whether comprehensive 
genomic profiling of cancer-related genes could potentially assist in the selection of targeted 
therapies for patients with radiation refractory bladder cancer.3 As part of our pilot study, we 
propose to perform microarray gene expression profiling using Agilent long oligonucleotide (60 
mers) technology to search for molecular alterations differing between responders and non-
responders of chemoradiation with radical cystectomy as a reference.  

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
7 
1.1. PRELIMINARY DATA 
1.1.1. Data on Chemoradiation: The Kaplan–Meier plot in Figure 1 (copied from 
Reference 1) shows 348 patients with muscle invasive bladder cancer who 
underwent chemoradiation at Massachusetts General Hospital (MGH) by response 
(incomplete, complete).  For clinical stage T2, three-year disease specific survival 
rates were 74% and 50% for patients who were complete and incomplete responders 
respectively.1 The MGH Kaplan Meier curves for disease-specific survival suggest 
that response to chemoradiation may contribute to the non-inferiority of 
chemoradiation relative to radical cystectomy with regard to progression free survival 
in this study [Section 2, Specific Aim 1b].   
 
 
Figure 1: Kaplan Meier plots for disease-specific survival following chemoradiation 
for all stratified by induction response status in the MGH study1. 
1.1.2. Role of genome sequencing:  In a radiotherapy test cohort (n = 201), high tumor 
MRE11 expression (one of the candidate genes in our research) in patients receiving 
radiotherapy (RT) was associated with better cancer-specific survival compared with 
cystectomy [70% versus 55% 3-year cause-specific survival (CSS), P = 0.021]4, 
suggesting  that MRE11 expression may play an important role with regard to 
predicting response to chemoradiation [Section 2, Specific Aim 2a].  Figure 2 shows 
the relevant plots copied from Reference 4. 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
8 
 
Figure 2: Kaplan-Meier CSS curves for low and high MRE11 Radiation Therapy (RT) 
compared to cystectomy  
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
9 
2. HYPOTHESIS AND SPECIFIC AIMS 
Multiple 
prospective 
radiation 
therapy 
protocols 
have 
evaluated 
bladder-preserving 
chemoradiation therapy approach for muscle-invasive bladder cancer (MIBC), with radical 
cystectomy reserved for radiation failure.  Aims of bladder preservation in MIBC are to offer a 
quality-of-life advantage and avoid potential morbidity or mortality of RC without compromising 
oncologic outcomes. Because of lack of level-1 evidence, oncologic equivalence of bladder 
preservation modality treatments compared with RC remains unknown. 
2.1 HYPOTHESIS: 
We hypothesized that chemoradiation is non-inferior to radical cystectomy for treatment of MIBC.  
2.2 SPECIFIC AIMS: 
SPECIFIC AIM  1a To determine and quantify quality of life in patients treated with radical 
cystectomy and chemo radiation therapy 
1b To determine and quantify progression free survival and bladder-intact survival in patients 
treated with radical cystectomy and chemoradiation therapy,  
 SPECIFIC AIM 2a To evaluate genetic markers predicting response to chemoradiation by 
performing tissue RNA microarrays. 
2b To assess the feasibility of conducting an adequately powered non-inferiority trial of the same 
design via recruitment rate, patient adherence to both treatment arm, and attrition.  
2.3 STUDY DESIGN: 
Our study will be a pilot, prospective, single-center, randomized non-inferiority trial comparing 
chemoradiation therapy to radical cystectomy. Patients diagnosed with muscle invasive bladder 
cancer after transurethral resection of bladder tumor and are surgical candidates will be 
randomized to either radical cystectomy (with neoadjuvant chemotherapy if suitable candidate) 
or chemoradiation.  
Both treatment methods are considered “standard of care” recommended by the NCCN Clinical 
Practice Guidelines (http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf) in treating 
muscle invasive bladder cancer.  
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
10 
3. STUDY ENROLLMENT AND WITHDRAWAL 
3.1 Inclusion Criteria: 
3.1.1 Pathologically (histologically) proven diagnosis of primary carcinoma of the bladder 
(transitional cell cancer) within 8 weeks of registration. Operable patients whose tumors are 
primary carcinomas of the bladder and exhibit histologic evidence of muscularis propria invasion 
and are AJCC clinical stages T2-T4a, Nx or N0, M0 
3.1.2 Patients without histologically or cytologically confirmed node metastases or any other 
metastases  
3.1.3 Patients must have an adequately functioning bladder after thorough evaluation by an 
urologist and have undergone as thorough a transurethral resection of the bladder tumor as is 
judged safely possible. 
3.1.4 Patients must be considered able to tolerate systemic chemotherapy combined with pelvic 
radiation therapy, and radical cystectomy. 
3.1.5 History and physical examination including weight, performance status, and body surface 
area within 8 weeks prior to study registration 
3.1.6 Zubrod (ECOG) Performance Status 0-2 
3.1.7 Age ≥ 18; 
3.1.8 CBC/differential obtained no more than 4 weeks prior to registration on study, with 
adequate bone marrow function defined as follows: 
a) WBC ≥ 4000/ml 
b) Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3; 
c) Platelets ≥ 100,000 cells/mm3; 
d) Hemoglobin ≥ 10.0 mg/dl (Note: The use of transfusion or other intervention to achieve 
Hgb ≥ 10.0 g/dl is acceptable.); 
3.1.9 Patient’s comprehensive metabolic panel (CMP) must be done no more than 6 weeks 
prior to informed consent and the CMP levels must be within acceptable institutional limits or to 
the discretion of the treating physician, which may be the principal investigator of the study. 
3.1.10 Serum pregnancy test for female patients of childbearing potential, ≤ 72 hours prior to 
study entry; women of childbearing potential and male participants must practice adequate 
contraception. 
3.1.11 Patient must be able to provide study-specific informed consent prior to study entry 
3.2 Exclusion Criteria: 
3.2.1 Unable and unwilling to provide informed consent 
3.2.2 Evidence of distant metastases or histologically or cytologically proven lymph node 
metastases 
3.2.3 Previous systemic chemotherapy (for any cancer) or pelvic radiation therapy 
3.2.4 A prior or concurrent malignancy of any other site or histology unless the patient has been 
disease-free for ≥ 5 years except for non-melanoma skin cancer and/or stage T1a prostate 
cancer or carcinoma in situ of the uterine cervix 
3.2.5 Patients judged not to be candidates for radical cystectomy; patients with pN+ or T4b 
disease are considered to have unresectable disease 
3.2.6 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; 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
11 
• 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
• 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration; 
• 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, 
however, that laboratory tests for liver function and coagulation parameters are not 
required for entry into this protocol. 
• 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in 
this protocol may be significantly immunosuppressive. Protocol-specific requirements 
may also exclude immuno-compromised patients. 
3.2.7 Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic. 
3.2.8 Is pregnant; women of childbearing potential and male participants unwilling to practice 
adequate contraception. 
 
3.3 Randomization Procedure 
A total of 30 patients will be randomized to either chemoradiation group (n=15) or radical 
cystectomy (with or without neoadjuvant chemotherapy group, n=15). Permuted block 
randomization process through sequentially numbered, opaque sealed envelopes will be utilized 
in assigning participants into either radical cystectomy or chemoradiation group.  All subjects will 
be randomized in blocks of size 2.  A randomization list containing sequence numbers and 
treatment assignments will be prepared by the statistician and used as the sole basis for 
treatment assignments throughout the study.   
3.4 Participant Withdrawal 
• 
The PI can withdraw participants if the PI determines the participants have sustained any 
injury or complication that prevents them from continuing with the study. 
• 
The PI can withdraw participant if the participant is considered not a candidate for 
chemoradiation treatment after radiation and/or medical oncology consult. 
• 
Participants can voluntarily withdraw from the study at any time. 
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
12 
4. SCHEDULE OF EVENTS 
This study requires a minimum of nine study visits to the MARC, CTRC, and/or UHS.  The 
research staff will try to schedule these study visits at the same time as the patient’s routine follow-
up visits as much as possible to lessen the participant’s burden.  Since this study is a comparison 
of two standard of care treatments, participant will not be limited to receiving treatments (i.e. 
radical cystectomy, radiation, and/or chemotherapy) at UTHSCSA affiliated medical facilities.  If 
participant choose to receive treatment (i.e. radical cystectomy, radiation, and/or chemotherapy) 
outside of UTHSCA affiliated medical facilities and still would like to remain in the study, we will 
request for the participant to release his/her medical records and treatment summaries from 
outside facilities to us after treatment completion.  Participant will return to MARC, CTRC, and/or 
UHS for the routine post-treatment follow-up visits with the treating Urologist.  The specific 
location for the follow-up routine visits will be to the discretion of the treating physician and also 
the participant’s insurance coverage.  A summary of study schedule of events is as follows: 
 
4.1 Screening and enrollment 
Research staff will review clinic schedules to identify potential participants.  Treating 
Physicians/Physician’s Assistant/Nurse Practitioner seeing patients at the MARC Urology Clinics, 
CTRC will also identify study candidates.  Advertising material such as a study flyer will also be 
placed in the Urology clinics to facilitate with participant recruitment.  Potential study candidates 
identified by the research staff and the information regarding study eligibility will be made available 
to the treating physician who provides clinical care and sees the patient in clinic. The treating 
physician, physician assistants (PA), or nurse practitioner (NP) will make initial contact with 
patients whose pre-screening/chart review indicates they may be eligible for study participation.   
Interested participants may also contact the research staff, and if determined possibly eligible for 
study participation, are scheduled for a research appointment. Screening information collected on 
ineligible participants will be shredded at the end of study recruitment.   
Once the patient has been determined to meet pre-screening criteria, potential participants will 
first be approached in their private examination room by their treating medical provider, who may 
also be a research investigator.  If the patient indicates an interest in study participation, he will 
be provided further information about the study, answer questions, and provide a copy of the 
consent form.  The individual will be encouraged to take the consent form home to read and 
discuss with family, friends, or physicians.  If interested, the potential participant will be scheduled 
to come in and sign consent and undergo study assessments.   
The technical aspects of the study will be discussed with potential participants by the Principal 
Investigator, approved research team members and/or by study co-investigators.  Research staff 
members who are IRB approved and designated for that role will conduct the consent process.  
The following consent elements will be discussed:  voluntary nature of participation, purpose of 
the study, study procedures, risks and benefits, the collection of protected health information, 
confidentiality, and participant rights.  The participant will be given a copy of the informed consent 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
13 
to read and consider and ample opportunity will be given to answer any questions.  The participant 
may decline to participate, decide to participate, or take the consent home to think about 
participating.  A copy of the signed consent form will be provided to each participant.   
The potential participant will then be scheduled for a TURBT (transurethral resection of bladder 
tumor) with the treating urologist, which may also be the study’s principal investigator or co- 
investigator.  TURBT is the standard of care which allows the treating urologist to formally access 
the extent of disease progression and also to evaluate whether the candidate can be treated with 
both radical cystectomy and chemoradiation treatment.  Potential participant will be approached 
to store any leftover tissue specimens, not needed for diagnosis, into the “GU Tissue Bank” (IRB 
HSC20050234H).  The tissue collected will be processed per standard of care, and slides or 
tissue blocks may be accessed later for future use in correlative studies.  The leftover specimens 
may be used for future research studies that may include genetic testing related to bladder 
cancer.  This banking portion is optional and not required to be in the main study.  If the participant 
declines to participate in the optional study, any leftover specimens will be permanently de-
identified through the GUTB (05-234H). 
The potential participant will then return to the clinic for a routine follow-up visit to review the 
TURBT results and discuss treatment options with the treating Urologist within 4 weeks post-
TURBT.  Final eligibility will be determined during the TURBT follow-up visit.  If potential 
participant is eligible for the study, randomization will occur.  The following section outlines study 
procedure during the visit. 
4.2 Baseline Visit 
The potential participant will return to the urology clinic to review pathology results and treatment 
options within 4 weeks of TURBT.  This is a routine post-TURBT follow-up visit (i.e. baseline visit).  
If the potential participant is deemed eligible for both radical cystectomy and chemoradiation by 
the treating urologist, the potential participant will then randomized either to radical cystectomy 
arm or chemoradiation arm. 
Each participant will be assigned a unique subject identifier (subject ID) that has no meaning 
external to the study database.  The participant identifiers will be further masked and password 
protected, and stored only on a secure server behind a “firewall”.  Only authorized research study 
members will have access to these identifiers.  A research study file will be kept for each 
participant accrued.  This file will include the participant’s consent, the assigned unique subject 
identifier, and copies of relevant source documents.  All participant records will be securely stored 
in the Urology research offices at the MARC.  A data entry system will be prepared in RedCap for 
the study.  Both the subject identifier, sequence number, and the treatment assignment for each 
patient will be entered into the database together with clinical outcome data collected across visits 
During this visit, the participant will complete a study questionnaire packet, which may include 
and not limited to demographics, medical history; and study questionnaires such as EORTC QLQ 
C30 and FACT-Bl.  In the interest of time, the study questionnaire packet may also be completed 
at participant’s home and return to the study team via mail or email (per participant preference).  
Study team member will strongly encourage participant to complete the study questionnaire at 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
14 
the time of baseline visit.  If the participant completes the questionnaires from home, a study team 
member may follow-up with the participant over the phone, if the completed questionnaires are 
not received within a week of the visit. Two tubes (~ 10 mL or 2 teaspoons each) of research 
blood will also be drawn.  Study team member or clinic staff will record participant’s height, weight, 
and vital signs.  At the completion of the baseline measurements, each participant will be 
randomized to either “Radical Cystectomy” or “Chemoradiation” following a process through 
sequentially numbered, opaque sealed envelopes by an authorized research study member. 
4.3. Required Evaluations/Management (baseline prior to initiation of any protocol treatment) 
 
a) Cystoscopic evaluation by the participating urologic surgeon no more than 6 weeks prior 
to registration will include bimanual examination under anesthesia, as thorough as 
possible, a transurethral resection of the bladder tumor. Patients referred from an outside 
hospital with a muscularis propria-invading bladder tumor will be re-resected by the 
participating urologist. 
b) Radiologic evaluation including chest CT, abdominal and pelvic CT and bone scan no 
more than 6 weeks prior to start of treatment. 
c) Comprehensive metabolic panel (CMP) obtained no more than 4-6 weeks prior to 
registration 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
15 
5. Randomization 
5.1 Radical Cystectomy Arm- Those randomized to “Radical Cystectomy” will be scheduled for 
surgery.  In brief, radical cystectomy is the removal of the entire bladder, nearby lymph nodes 
(lymphadenectomy), part of the urethra, and nearby organs that may contain cancer cells.  In men 
the prostate, the seminal vesicles, and part of the vas deferens are also removed. In women the 
cervix, the uterus, the ovaries, the fallopian tubes, and part of the vagina are also removed.  
Participants in this group may also undergo neoadjuvant chemotherapy prior to the surgery as is 
the current standard of care.  The decision for specific chemotherapy regimen is based on medical 
oncologist’s evaluation. All AE occurring during the study period will be assessed and attribution 
assigned. 
The surgical approach, robotic versus open, is determined by patient and surgeon mutual 
preference.  All urinary diversions will be done via an open incision and the mode of diversion, 
whether intracorporeal or extracorporeal (orthotopic neobladder, continent cutaneous diversion 
or ileal conduit) will be selected by mutual agreement of the surgeon and patient, as is customarily 
done.  The extent of the lymph node dissection will be determined by the surgeon but at minimum 
will include the external iliac, obturator, and hypogastric regions.   
 
Lymph node dissection: Minimum lymph node (men and women) – all potential lymph node 
bearing tissue with the lateral limit the genitofemoral nerve, distally Cooper’s ligament to include 
the lymph node of Cloquet, proximally the crossing of the ureter over the common iliac vessels, 
medially the bladder to include the tissue medial to the hypogastric artery, posteriorly the floor of 
the obturator fossa with circumferential mobilization of the external iliac artery and vein. 
 
5.2 Chemoradiation Arm - Those randomized to chemoradiation will undergo radiation therapy 
concurrently with chemotherapy which serves as radiosensitizer.  The following is a brief outline 
of the radiation therapy.  Specific treatment frequency and dosage will be at the discretion of the 
treating physician/center. 
 
 
Radiaton Therapy  (Protocol treatment must begin within 8 weeks following transurethral 
resection and endoscopic evaluation) 
 
All patients who are randomized to bladder preservation arm will receive the induction 
course of chemoradiation first. This regimen will begin within 8 weeks following the TUR 
and cystoscopic evaluation by the participating urologic surgeon. Patients with a complete 
response to the induction regimen will receive consolidation chemoradiation, starting 7-14 
days after cystoscopic re-evaluation. Ideally, treatment should begin on a Monday for both 
Induction and Consolidation chemoradiation.   
 
 
5.2.1 Dose Specifications  
a) Induction Treatment 
On the induction regimen, radiation treatment is delivered one time per day (QD). For the 
first 10 treatment days, 2 Gy is delivered to the CTVpelvis. Then, 2 Gy is delivered to the 
CTVbladder for the next 4 treatment days, followed by 2 Gy to the CTVboost for the 
remaining 6 treatment days. This induction course will deliver a total of 40 Gy to the 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
16 
CTVboost (20 Gy from the pelvic fields, 8 Gy from the bladder fields and 12 Gy from the 
tumor boost). 
b) Consolidation Treatment 
On the consolidation regimen, radiation treatment is delivered to the CTVpelvis at 2 Gy 
per fraction one time per day (QD) over 12 treatment days for a total of 24Gy. This is the 
same pelvic field that was treated as a component of induction therapy. For patients 
completing both induction and consolidation treatment, the resulting total dose to the 
CTVboost will be 64 Gy over 10 weeks in 32 fractions. The total dose to the CTVpelvis 
will be 44 Gy. 
c) Radiation Dose Prescription 
The dose should be prescribed at the center of each treatment volume (CTVpelvis, 
CTVbladder, CTVboost), or the mid-plane of the patient if only AP/PA beams are used. 
Criteria for dose coverage are specified in Section 4.6.3. 
 
5.2.2 Technical Factors 
The radiation treatment should be with a high energy linear accelerator with photon 
energies ≥6 MV. 
 
5.2.3 Localization, Immobilization and Simulation  
a) 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 body fix and/or 
leg immobilizers. 
b) Simulation 
A planning CT must be obtained with the patient in the supine position. 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. 
 
The bladder must be voided prior to simulation. Use of IV, bladder or oral contrast is 
optional. Use of a urinary catheter at the time of simulation or cystoscopic placement of 
bladder fiducials prior to simulation is also optional. If bladder contrast is used, a 40-50 ml 
air contrast cystogram is recommended. 
5.2.4 Treatment Planning/Target Volumes 
a) Small Pelvic Fields  
These fields should encompass the entire bladder (CTVbladder), the bladder tumor 
volume (CTVboost), prostate and prostatic urethra (in men), and the regional lymph 
nodes. These lymph nodes include the internal and external iliacs and the obturator lymph 
nodes. All of these structures constitute the CTVpelvis. 
 
Four shaped anterior, posterior and lateral fields will be used. In the cranio-caudal 
dimension, these fields will extend from the lower pole of the obturator foramen to the mid-
sacrum (the anterior aspect of S2-S3 junction). Laterally, the anterior-posterior opposed 
fields will extend 1.5 cm beyond the widest point of the bony margin of the pelvis. For the 
parallel opposed lateral fields, the anterior and posterior field edges will extend 2 cm 
beyond the CTVpelvis. 
 
Field shaping will be used on the anterior-posterior opposed fields to shield the medial 
border of the femoral heads. Shaping will also be employed on the lateral opposed fields 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
17 
inferiorly to shield soft tissue anterior to the pubic symphysis and to block the anal canal 
posteriorly. Superiorly, the lateral fields may include shaping anteriorly to exclude small 
bowel and anterior rectus fascia which lay anterior to the external iliac lymph node chain. 
 
Wedges should be considered in the lateral fields as tissue compensators if there is a 
significant anterior slope. Weighting of the four field arrangement should be considered in 
light of the tumor boost planned such that the final dose to the femoral heads is no more 
than 45 Gy and the final dose to the posterior rectum is no more than 55 Gy. 
 
Anatomic variations in the bladder may necessitate CTV pelvis modifications and deviation 
from the standard protocol defined field borders. Examples include a bladder cystocele 
protruding below the obturator foramen, a bladder diverticulum, bladder herniation through 
the abdominal wall, or a significant post-void residual. For any of these anatomic 
variations, the variation should be encompassed within the defined CTV bladder which in 
turn is used to define the CTV pelvis, and the field edge adjusted to extend 2 cm beyond 
the modified CTV pelvis. 
 
b) Whole Bladder Fields 
The CTVbladder includes the gross tumor volume (GTV) plus the whole bladder volume 
including the bladder wall thickness. This volume is covered using a four-field 
arrangement. Field edges extend 2 cm beyond the CTVbladder. Likewise, field shaping is 
employed to cover the CTVbladder with a 2 cm margin. 
 
c) Tumor Boost Fields 
The gross tumor volume (GTV=CTVboost) is derived from information available from 
bimanual examination, cystoscopic bladder mapping, intraoperative reports and 
radiographic studies.  Close cooperation with the treating urologist is essential. 
Cystoscopically placed fiducial markers may be employed. A variety of field arrangements 
may be considered for treating this volume and efforts should be made to spare uninvolved 
regions of the bladder. Opposed lateral fields are frequently employed for posterior 
lesions. Well lateralized lesions may be amenable to an anterior-posterior field 
arrangement or a wedged pair. Regardless of the chosen field arrangement, the field 
edges should extend 2 cm beyond the defined GTV. The boost field arrangement needs 
to be determined early in the planning process as it may impact field weighting in the other 
phases of treatment such that final doses to the femoral heads and posterior rectum are 
within specified limits. 
 
5.2.5 Critical Structures  
The rectum volume is defined on CT from the anus (at the level of the ischial 
tuberosities) for a length of 15 cm or to the rectosigmoid flexure. A DVH for the rectum, 
bladder, and both femoral heads should be submitted. The following DVH criteria should 
be achieved. 
 
Rectum: 
No more than 50% of the volume above 30 Gy 
No more than 10% of the volume above 55 Gy 
 
Femoral heads: 
No more than 20% of the volume above 50 Gy 
 
5.2.6 Compliance Criteria 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
18 
a) Field Borders 
Variation: Actual field borders and/or PTVs are within 2 cm beyond those stated in the 
protocol and include the target structures described above. 
Deviation: Actual field borders and/or PTVs transect a target structure or are greater 
than 2 cm beyond the borders stated in the protocol. 
 
b) Specified Radiation Dose (Critical structures) 
Variation: Planned dose is within 10% of the specified protocol dose. 
Deviation: Planned dose deviates by more than 10% from the specified protocol dose. 
 
c) Minimum Isodose Coverage (Applies to each CTV independently) 
Generally the minimum dose to any target should be 95 % of the prescription dose to 
that target. To address the single pixel calculation anomalies the D99% is used as the 
dose specifier. 
Per protocol: D99% > 95%. Dose covering 99% of the volume of any target volume is 
no less than 95% of the prescribed dose. 
Variation: D99% < 95% but D99% > 90%. Dose covering 99% of the volume of any 
target 
volume is no less than 90% of the prescribed dose. 
Deviation: D99% < 90%. Target structures coverage falls below 90% of the prescribed 
dose. 
d) Maximum Dose (Applies to each CTV independently) 
Generally the maximum dose to any target should be less than 107% of that target’s 
prescribed dose. 
Per protocol: V107% < 0.12 cc. Less than 0.12 cc of the CTV receives a dose 
exceeding 
107% of the prescribed dose. 
Variation: V107% > 0.12 cc but this dose does not exceed 110% of this dose. 
Deviation: The maximum dose to the 0.12 cc volume does exceed 110% of the 
prescribed dose. 
e) Elapsed Days 
Per protocol: No more than 3 break days 
Variation: 4 to 7 break days 
Deviation: 8 or more break days 
 
5.2.7 Treatment Interruption (12/6/15) 
If a grade 3 hematologic toxicity (ANC or platelets) develops during chemoradiotherapy, 
all treatment (both radiation and chemotherapy) should be discontinued for a minimum 
of 1 week.  
 
Treatment may be resumed when the hematologic toxicity resolves to ≤ grade 2. If these 
laboratory values have not been reached after a 1-week delay, they should be checked 
weekly until they become acceptable. If after 3 weeks the blood counts have not 
recovered, all protocol treatment should be discontinued and the patients should be 
treated on an individual basis. 
 
For a grade 3 acute colitis, cystitis, or any other grade 3 infield (radiation-related) toxicity 
during any treatment week, treatment should be delayed until the toxicity subsides to the 
grade 2 level. If the delay is greater than 3 weeks, then the patient should be considered 
intolerant of protocol therapy and appropriate off-protocol therapy given. 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
19 
5.2.8 Radiation Adverse Events  
• Genitourinary: Frequency, nocturia, acute or chronic bleeding from the bladder 
mucosal surface, cystitis, ureteral obstruction, erectile dysfunction in men, sterility 
• Gastrointestinal: Rectal irritation, bowel obstruction or bleeding, rectal ulcers, 
hematochezia, fistula formation, colitis, mucous-like stools 
• Dermatologic: Erythema, loss of pubic hair which could be permanent 
• Gynecological: Dyspareunia, ovarian failure and sterility 
• General: Weight loss, fatigue 
 
5.3 DRUG THERAPY 
 
Medical Oncologist will determine the chemotherapy regimen concurrently used with radiation 
as a radiation sensitizer. The following is a list of chemotherapeutic drugs that could be used 
per NCCN guideline:  
Cisplatin 
Cisplatin and 5-FU 
5-FU and Mitomycin 
Cisplatin and Paclitaxel 
Low dose gemcitabine 
 
All AE occur during the study period will be assessed and attribution assigned. 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
20 
6. Post-Induction Response Evaluation (for Chemoradiation Arm only)  
 
Following the completion of induction chemoradiotherapy and the evaluation of response all 
patients must be re-registered via cystoscopy and biopsy. At this time, the response results 
(biopsy results andcytology results) and the second phase of the treatment (i.e. radical 
cystectomy for tumor response T ≥ 1or consolidation chemoradiotherapy for tumor response T0, 
Ta, and Tcis) will be recorded and a new data collection calendar generated.  Details regarding 
“Radical Cystectomy” can be found at Section 5.1.  Details regarding “Consolidation 
Chemoradiotherapy” can be found at Section 5.2.2. 
 
The following information will be supplied: 
• original case number 
• results of evaluation and pathologic T stage 
• treatment start date (radical cystectomy or consolidation chemoradiotherapy) 
 
The treatment option registered and the new data collection calendar will be based on the 
parameters specified by the protocol. If the investigator or the patient deviates from the protocol 
specified treatment, documentation of this and data submission as outlined in our study 
Standard operating procedure. 
 
Patients who have developed distant metastases during the induction phase of treatment and 
who will not continue therapy will remain on the original calendar schedule for continued follow 
up only.  
 
After completing either radical cystectomy or consolidation chemoradiotherapy, all response 
results to the second phase of treatment (i.e., either pathologic staging from the radical 
cystectomy or cystoscopic re-evaluation performed following completion of consolidation 
chemoradiotherapy) will be promptly submitted to Data Management. 
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
21 
7. 1 Post-Treatment Study Visits at 3, 6, 9, 12, 18, 24, 30, and 36 month ± 1 month 
Post-treatment study visits will occur every three months (± 1 month) up to one year and every 
six months (± 1 month) thereafter up to two years (i.e. Months 18, 24, 30, and 36).  These study 
visits will be scheduled during the same time as the participant’s routine visit (i.e. standard of 
care) whenever possible.  If not, study team member will work with participant on a time that is 
convenient.  An imaging study either a CT abdomen and pelvis or MRI of abdomen and pelvis will 
be done as standard of care prior to the routine clinic visit.  The treating physician will assess AE 
and assign attribution.  Research study team member will coordinate with the participant to meet 
either before or after the routine clinic visit.  Participants will be asked to complete study 
questionnaires.  The questionnaires may also be mailed and/or emailed back to the study team if 
they cannot be completed within the allotted study time.  And those randomized to 
“chemoradiation Group” will also undergo routine cystoscopy during these follow-up visits (SOC).   
7.2 Withdraw Visit 
Whenever possible, participant will be scheduled for a withdraw visit if she/he chooses to withdraw 
from the study early or if the PI needs to withdraw the participant from the study.  This is an 
optional visit.  During this visit, participant will be asked to have research blood draw and complete 
study questionnaires.   Reasons for withdraw will also be asked and recorded.  Participant will 
have the choice to partake any or all of the activities during withdraw visit. 
7.3 Unscheduled Visit 
Date and reason for any study-related unscheduled visit will be recorded.   Any medical notes, 
radiographic, and/or lab results related to this study-related unscheduled visit will also be obtained 
and recorded. 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
22 
8.STUDY CALENDAR 
8.1 RADICAL CYSTECTOMY ARM 
 
Initial 
visit 
Pre-Treatment (tx) TURBT 
Baseline  
Treatment Period: Radical Cystectomy 
Post-tx 3 
mon f/u 
± 1 mon 
Post-tx 6 
mon f/u 
± 1 mon  
Post-tx 9 
mon f/u 
± 1 mon  
Post-tx 
12 mon 
f/u ± 1 
mon  
Post-tx 
18 mon 
f/u ± 1 
mon 
Post-tx 
24 mon 
f/u ± 1 
mon 
Post-tx 
30 mon 
f/u ± 1 
mon 
Post-tx 
36 mon 
f/u ± 1 
mon (end 
of study 
visit) 
Study eligibility 
X 
X 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Assessment of 
AE 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
SOC Image 
studies (X-Ray, 
CT, and/or 
MRI) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research blood 
sample 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ht, Wt, and 
Vitals# 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Study 
Questionnaires  
 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
 
Note: 
SOC = Standard of Care 
# information may be extracted from EMR 
*Research study questionnaire may be emailed or mailed per patient’s stated preference 
 
 
8.2 CHEMORADIATION ARM 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
23 
 
Initial 
Visit 
Pre-Treatment (tx) TURBT 
Baseline  
Treatment Period: Chemoradiation  
Post-Induction Response Evaluation with Cystoscopy and biopsy (3-4 weeks 
following Induction Chemoradiotherapy) and second phase of treatment** 
Post-tx 3 
mon f/u 
± 1 mon  
Post-tx 6 
mon f/u 
± 1 mon  
Post-tx 9 
mon f/u 
± 1 mon  
Post-tx 
12 mon 
f/u ± 1 
mon  
Post-tx 
18 mon 
f/u ± 1 
mon 
Post-tx 
24 mon 
f/u ± 1 
mon 
Post-tx 
30 mon 
f/u ± 1 
mon 
Post-tx 36 
mon f/u ± 
1 mon 
(end of 
study 
visit??) 
Study eligibility 
X 
X 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Assessment of 
AE 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
SOC Image 
studies (X-Ray, 
CT, and/or 
MRI) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiation & 
Medical 
Oncology 
Consults (SOC) 
 
 
X 
 
 
 
 
 
 
 
 
Research blood 
sample 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ht, Wt, and 
Vitals# 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Study 
Questionnaires  
 
X 
X 
X 
X 
X 
X* 
X* 
X* 
X* 
Note: 
SOC = Standard of Care 
# information may be extracted from EMR 
*Research study questionnaire may be emailed or mailed per patient’s stated preference 
** Post-treatment cystoscopy is SOC for chemoradiation patients ONLY 
**Pending on the results of post-induction TURBT and response evaluation, participant may receive further treatments.  Details on the second phase of treatment are listed in Section 6 and Study Synopsis. 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
24 
 
9. DATA COLLECTION & STUDY EVALUATIONS 
Medical records will be reviewed prior to “Baseline Study Visit” to confirm study eligibility.  After obtaining 
consent, socio-demographic data will be collected through chart review and interviews. Clinical data that 
will be collected include but not limited to bladder cancer treatment history, tumor characteristics, stage, 
laboratory results, medications and co-morbidity.  
Study team member or clinic staff will measure height, weight, and vital signs at each specific study time 
point.  Research blood will be drawn at each study time point.  Blood and tissue samples may be banked 
under the optional study (HSC20050234H GU Tissue Bank).  For those participants who declined to 
participant in the optional study, any leftover samples will be permanently de-identified through the GU 
Tissue Bank (HSC20050234H) honest broker system.  At the close of this study, all biological materials 
collected will be rolled into HSC20050234 GU Tissue Bank. 
9.1 Feasibility: We will report recruitment, visit dates, adherence, attrition rates and compliance with 
randomization for each arm of the study 
 
9.2 Bladder-intact survival: We will report proportion of patients who failed chemoradiation and required 
salvage cystectomy 
 
9.3 Quality of life: A self-assessment questionnaire using the European Organization for Research and 
Treatment of Cancer (EORTC) QLQ- C30 and FACT-Bladder will be used for QOL assessment at 
baseline, 3, 6, 9 and 12 months.8 
 
9.4 Progression free survival: This will be measured from the date of finishing chemoradiation or radical 
cystectomy to the date of first documentation of progression. Progression will be determined using 
RECIST 1.1 criteria by the treating physician based on radiographic or pathologic evidence of disease 
progression, or death from disease. Any documented recurrence will be considered progression.9 The 
date of progression will be recorded. 
 
9.5  Candidate gene expression analysis: For the participants who have consented to be part of the 
optional study (“GU Tissue Bank HSC20050234H), a microarray analysis will be performed on all 
bladder tumor specimens using Agilent Technologies (Agilent SurePrint G3 Human Gene Expression 
8x60K v2) Microarray. Goal is to study the landscape of 50 important candidate genes, which are 
involved in bladder cancer (for example-BRAF, KRAS, EGFR, FGFR). 
 
 
9.6 Activities of Daily Living (ADL) scores: This will be measured at baseline, and during all subsequent 
follow-up visit (i.e. 3, 6, 9 And 12 months) using Activities of Daily Living QOL Questionnaire using Katz 
Index of Independence in Activities of Daily Living (ADL).10 
 
9.7 Retrospective screening & chart review: We will screen and review charts of “potential participant” 
retrospectively using the latest approved eligibility criteria and study schema to determine: 
1. the number of “would-be potential participants”  
2. the number of those who were initially deemed eligible and was truly eligible after TURBT 
3. the number of those who were initially deemed eligible but was ultimately ineligible after TURBT 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
25 
4. rationale for ineligibility 
 
The retrospective screen & chart review will start from the date when the study was first approved by 
the IRB (i.e. April 15, 2016) until present time.  Data including but not limited to medical record number, 
initials of name, gender, race, ethnicity, TURBT result, age at time of treatment, treatment received, 
date of treatment, eligibility status for the study, and rationale if deemed ineligible, will be captured.  
We do not intend to contact these patients for study enrollment since they would’ve received treatments 
for their diagnosis already.  Our intention for this retrospective data collection is that it will provide 
further insight and information on the potentiality of chemoradiation as treatment modality for patients 
with specific bladder cancer diagnosis.  We need to capture this data in order to represent total 
population of patients screened, thereby determining the denominator of the study population. 
 
9. 8 Outline of Captured Data 
Outcome of Interest 
Measure 
Method of Assessment 
Demographics  
 
Self-report questionnaire 
Health History including height, weight, 
and vital signs 
 
Physical exam, review of EPIC 
 
 
 
Study Processes 
 
 
recruitment rate 
adherence 
attrition 
feasibility 
bladder intact survival 
safety 
 
 
 
 
 
Outcomes of interest 
 
 
Quality of Life 
EORTC 
Self-report questionnaire 
 
FACT-Bl 
Self-report questionnaire 
ADL 
Katz ADL 
Self-report questionnaire 
Progression free survival 
RECIST 1.1 
Physician assessment 
Candidate gene expression 
 
Candidate genes 
Laboratory analysis of blood and 
tissue 
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
26 
10. DATA AND SAFETY MONITORING OVERSIGHT 
A Data and Safety Monitoring Plan (DSMP) is required for all an individual protocols conducted at CTRC. 
All protocols conducted at CTRC are covered under the auspices of the CTRC Institutional Data Safety 
Monitoring Plan.  The scoring algorithm for each questionnaire will be included in the data entry system.    
The CTRC Institutional DSMP global policies provide individual trials with:  
• 
institutional policies and procedures for institutional data safety and monitoring,  
• 
an institutional guide to follow, 
• 
monitoring of protocol accrual by the CTRC Protocol Review Committee, 
• 
review of study forms and orders by the Forms Committee, 
• 
tools for monitoring safety events, 
• 
monitoring of UPIRSO’s by the Director of Quality Assurance and DSMC, 
• 
determining level of risk (Priority of Audit Level Score – PALS) ,  
• 
oversight by the Data Safety Monitoring Committee (DSMC),  and 
• 
verification of protocol adherence via annual audit for all Investigator Initiated Studies by the 
CTRC Quality Assurance Division. 
 
10.1 Monitoring Safety: 
The Principal Investigator will perform primary assessment of adverse events, adverse event trends and 
treatment effects on this study.  The PI will conduct independent quarterly review and report findings to the 
CTRC Data Safety Monitoring Committee (DSMC) and the UTHSCSA IRB.  
Baseline events and adverse events will be captured using the CTRC Master Adverse Events Document 
for each patient using CTCAE V.4.03 for the grading and attribution of adverse events. Usage of the CTRC 
Master Adverse Events Document centrally documents: 
• 
the event and grades, severity, and the seriousness of it,  
• 
if the event was a change from baseline,   
• 
the relationship between the event and study intervention 
• 
if the event was part of the normal disease process, and  
• 
what actions were taken as a result of the event.  
 
 
10.2 Safety Definitions: 
 
For this study, the following safety definitions will be applicable: 
Adverse Event Definition: An adverse event (AE) is defined as any untoward or unfavorable medical 
occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research  For this study, 
all adverse events will be documented starting with the date of study enrollment and ending 30 days after 
the “12 months post-treatment study visit’.  
Serious Adverse Event Definition: is any adverse event that: 
1. results in death; 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
27 
2. is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
3. results in inpatient hospitalization or prolongation of existing hospitalization; 
4. results in a persistent or significant disability/incapacity; 
5. results in a congenital anomaly/birth defect; or 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition  
Unanticipated Problems Involving Risks to Subjects or Others Definition: Unanticipated problem involving 
risk to subjects or others includes any incident, experience or outcome that meets all of the following 
criteria: 
A. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied 
(note: the unfounded classification of a serious adverse event as “anticipated” constitutes serious 
non-compliance); 
B. definitely related or probably related to participation in the research; and 
C. suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized 
 
10.3 Reporting Requirements 
For this study, all Master Adverse Events Documents collected on patients for this protocol will be reviewed 
by the Principal Investigator on a monthly basis to determine if a serious safety problem has emerged that 
result in a change or early termination of a protocol such as: 
• 
dose modification, 
• 
suspending enrollment due to safety or efficacy, or 
• 
termination of the study due to a significant change in risks or benefits.   
 
Treatment options in this study are standard of care per NCCN guidelines.   Therefore there are no specific 
end points. 
As per the CTRC DSMP, any protocol modifications, problematic safety reports, unanticipated problems, 
and suspension or early termination of a trial must be reported to all members of the research team.  
Suspension and early termination of a trial must also be reported immediately to the Director of Quality 
Assurance (DQA) who will promptly notify the sponsor and the UTHSCSA IRB.  
The PI will review the Master Adverse Events documents to determine the significance of the reported 
events and will file the Investigator Initiated Study Quarterly DSMC Report Form on a quarterly basis with 
the CTRC DSMC.  The Investigator Initiated Study Quarterly DSMC Report Form includes information on 
adverse events, current dose levels, number of patients enrolled, significant toxicities per the protocol, 
patient status (morbidity and mortality), dose adjustments with observed response, and any interim 
findings.  Any trend consisting of three or more occurrences of the same event will be reported to the CTRC 
DSMP for independent review outside of the quarterly reporting cycle, which begins three months following 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
28 
protocol start up. Conflict of interest is avoided by the independent review of the CTRC DSMC and by 
ongoing independent review of adverse events trends by the Director of Quality Assurance.  
All SAE and UPRISO’s will be reported following CTRC and UTHSCSA institutional guidelines. 
UTHSCSA SAE/UPRISO REPORTING REQUIREMENTS 
Type Event 
Report to 
Timeframe 
All AE, SAE and UPIRSO 
Regulatory Affairs and DQA 
Same as other notification timeframes 
except for SAE/AE which should be 
reported on Monday for the prior week 
SAE 
Clinical Trial Sponsor 
within 24 hours 
AE/SAE 
UTHSCSA IRB 
Annually 
UPIRSO - all 
Clinical Trial Sponsor 
within 24 hours of the PI determining a 
UPIRSO exists 
UPIRSO - life threatening 
UTHSCSA IRB 
within 48 hours of the PI determining a 
UPIRSO exists 
UPIRSO - non-life threatening 
UTHSCSA IRB 
within 7 days of the PI determining a 
UPIRSO exists 
 
AE’s and SAE events that occur during clinical trials with or without an Investigational New Drug (IND) 
application are mandatory reports submitted to FDA via Medwatch FDA F3500A within 15 days for events 
that have at least a possible relationship with the drug. 
10.4 Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at CTRC, the PI has ultimate responsibility for ensuring protocol compliance, 
data accuracy/integrity and responding to recommendations that emanate from monitoring activities.  
Source verification of data will be performed every twelve week. Protocol compliance, data accuracy and 
reporting of events is further ensured by an annual audit conducted by the Data Safety Officer, whose audit 
report is shared with the PI, the research team, and will be reviewed by the CTRC DSMC.  
 
 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
29 
11. STATISTICAL CONSIDERATIONS:  
For this pilot non-inferiority study, we aim to randomize 30 evaluable patients (radical cystectomy: n=15, 
chemoradiation: n=15).   
 
Categorical outcomes will be summarized with frequencies and percentages.  Continuously distributed 
outcomes will be summarized with the sample size, mean, standard deviation, median, minimum and 
maximum.  A consort diagram giving the number patients screened, the number of screen failures, the 
number randomized, the number lost to follow-up by reason, and the number completing the study by 
treatment arm will be created.   In Aim 1a we will test the hypothesis that chemoradiation therapy is non-
inferior to radical cystectomy with regard to change in quality of life at 36 months relative to baseline. In 
Aim 1b, we will test the hypothesis that chemoradiation is non-inferior to radical cystectomy with regard 
progression free survival and bladder intact survival.  With regard to Aim 1a, assuming the 50% (p2) of 
patients randomized to radical cystectomy and 60% (p1) of patients randomized to chemoradiation will 
experience improvement in quality of life at 3 years relative to baseline and a 5% margin () of non-
inferiority, this study would require n=171 subjects per group to attain 80% power for testing Ho: p1-p2 
versus H1: p1-p2> with alpha=5%. The non-inferiority of chemoradiation compared with radical cystectomy 
with regard to changes in quality of life (Aim 1a) will be assessed with Fisher’s exact test.  Progression 
free and bladder-intact survival (Aim 1b) will be summarized by treatment arm with Kaplan-Meier curves 
and supporting tabulations and non-inferiority will be assessed with a logrank test. The significance of 
treatment arm differences with regard to biomarkers (Aim 2a) will be assessed with t-tests or Wilcoxon 
tests.   Pairwise correlations between biomarkers will be displayed overall and by treatment arm.  Logistic 
regression will be used to find a best linear predictor of treatment arm in terms of multiple biomarkers.  
Biomarkers may be log transformed prior to analysis.    Feasibility (Aim 2b) will be assessed with a new 
power and sample size calculation.  If the logistic regression model fails in Aim 2a, random forests will be 
attempted.  If the logrank test fails in Aim 1b, Fisher’s exact test will be used.  R (v3+, Vienna, Austria) or 
SAS (SAS Institute, Cary, North Carolina) software will be used throughout. 
 

 
15-620H, Kaushik, Form BC, 09-19-17, AMD 
30 
  
REFERENCES 
[1] 
Efstathiou JA, Spiegel DY, Shipley WU et al. Long-term outcomes of selective bladder preservation by 
combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol. 2012; 61: 705-11. 
[2] 
Mak RH, Hunt D, Shipley WU et al. Long-term outcomes in patients with muscle-invasive bladder cancer 
after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology 
Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014; 32: 3801-9. 
[3] 
Shariat SF, Tokunaga H, Zhou J et al. p53, p21, pRB, and p16 expression predict clinical outcome in 
cystectomy with bladder cancer. J Clin Oncol. 2004; 22: 1014-24. 
[4] 
Choudhury A, Nelson LD, Teo MT et al. MRE11 expression is predictive of cause-specific survival following 
radical radiotherapy for muscle-invasive bladder cancer. Cancer Res. 2010; 70: 7017-26. 
[5] 
Feng Y, Fuentes D. Model-based planning and real-time predictive control for laser-induced thermal 
therapy. International journal of hyperthermia : the official journal of European Society for Hyperthermic 
Oncology, North American Hyperthermia Group. 2011; 27: 751-61. 
[6] 
Oden JT, Diller KR, Bajaj C et al. Dynamic Data-Driven Finite Element Models for Laser Treatment of 
Cancer. Numerical methods for partial differential equations. 2007; 23: 904-22. 
[7] 
Donat SM, Shabsigh A, Savage C et al. Potential impact of postoperative early complications on the timing 
of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center 
experience. Eur Urol. 2009; 55: 177-85. 
[8] 
Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 
1993; 85: 365-76. 
[9] 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-47. 
[10] 
Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. STUDIES OF ILLNESS IN THE AGED. THE INDEX OF 
ADL: A STANDARDIZED MEASURE OF BIOLOGICAL AND PSYCHOSOCIAL FUNCTION. Jama. 1963; 185: 914-9. 
[11] 
Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the treatment of invasive bladder cancer: long-
term results in 1,054 patients. J Clin Oncol. 2001; 19: 666-75.