Open Vs Robotic-Assisted Radical Cystectomy: A Randomized Trial
Phase: NA
Conditions: Bladder Cancer Requiring Cystectomy
Sponsor: University of Miami

 
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Open Vs Robotic-Assisted Radical Cystectomy: A 
Randomized Trial 
Protocol Number 36911 
 
 
 
 
Study Principal Investigator 
Dipen J. Parekh, MD 
Professor and Chair, 
Department of Urology, 
University of Miami School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Research Sites: 
 
University of Miami 
The University of Texas Health Science Center at San Antonio 
Vanderbilt University Medical Center  
Mayo Clinic, AZ 
Mayo Clinic, MN 
University of California at Irvine  
Stanford University 
Brigham and Women’s Hospital 
University of Minnesota 
University of Virginia 
University of North Carolina at Chapel Hill 
The Ohio State University 
University of Chicago 
Regents of the University of Michigan 
Loyola University 
 
Data Management and Biostatistics: 
Cancer Research and Biostatics (CRAB), Seattle, WA 
 
 
 

 
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Table of Contents 
 
1. Responsible Entities and Staff……………………………………………………………..4 
 
2. Background and Significance…………………….………………………………...……...6 
 
3. Objectives and Specific Aims……..……………………………………………….….. ….7 
 
4. Experimental Design………………………………………………………………..………8 
 
Inclusion/Exclusion criteria…………………………………………………….…........9 
 
Recruitment and consent procedures……………………..………………………….9 
 
Research Procedures……………………………………………………………….… 9 
 
Clinical Procedures………………………………………….………………………   12 
 
Data Submission Procedures………………………………………………………   14 
 
5.  Statistical Considerations…………………………………………………………………15 
 
6. Human Subjects………………………….………………………………………………..19 
 
  
Compensation……………………………………………………..…………………  19 
 
  
Risks to subject………………………………………………………………….…….19 
 
  
Special precautions……………………………………………………………….…  19 
 
  
Subject Completion and Withdrawal………………………………………………   20 
 
 
      Alternative treatments………………………………………………………………   20 
 
  
Confidentiality…………………………………….………………………………….…20 
 
 
 
     Data Safety Monitoring Committee…………………………………….…………….21 
 
7. Literature Cited………………………………….…………………………………………21 
 
APPENDIX A – ECOG Performance Status Scale………………………………………   23 
 
APPENDIX B – Data Collection Forms……………………………………………………   24 

 
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1.  RESPONSIBLE ENTITIES AND STAFF 
 
Principal Investigator:   
Dipen J. Parekh, MD 
Professor and Chair, 
University of Miami  
 
Co-Investigators: 
 
 
 
 
Daniel A Barocas, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
Vanderbilt University Medical Center 
 
 
 
 
 
Erik Castle, MD 
 
 
 
 
Associate Professor 
 
 
 
 
Mayo Clinic, Scottsdale, AZ 
 
 
 
 
 
 
 
 
 
John Crowley, PhD  
                                           President/CEO 
 
 
 
 
Cancer Research And Biostatistics, Seattle, WA 
 
 
 
 
 
Atreya Dash, MD 
 
 
 
 
Associate Professor  
 
 
 
 
University of Washington 
 
 
 
 
 
Mark Gonzalgo, MD, PhD 
 
 
 
 
Associate Professor 
 
 
 
 
University of Miami 
 
 
 
 
 
 
 
 
 
Adam Kibel, MD 
 
 
 
 
Chair of Urology/Professor 
 
 
 
 
Brigham and Women’s Hospital 
 
 
 
 
 
Badrinath Konety, MD 
 
 
 
 
Professor 
 
 
 
 
University of Minnesota 
 
 
 
 
 
Tracey Krupski, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
University of Virginia 
 
 
 
 
 
Raj Pruthi, MD 
 
 
 
 
Associate Professor 
 
 
 
 
University of North Carolina at Chapel Hill 
 
 
 
 
 
Ahmad Shabsigh, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
The Ohio State University  

 
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Eila Skinner, MD 
 
 
 
 
Chair of Urology/Professor 
 
 
 
 
Stanford University 
 
 
 
 
 
 
 
 
 
Norm Smith, MD 
 
 
 
 
Associate Professor 
 
 
 
 
University of Chicago 
 
 
 
 
 
Robert Svatek, MD 
 
 
 
 
Assistant Professor  
 
 
 
 
The University of Texas Health Science Center at San  
 
 
 
 
Antonio 
 
Matthew Tollefson, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
Mayo Clinic, Rochester, MN 
 
 
 
 
 
Edward Uchio, MD 
 
 
 
 
Associate Professor 
 
 
 
 
University of California at Irvine 
 
 
 
 
 
Alon Weizer, MD 
 
 
 
 
Assistant Professor 
 
 
 
 
Regents of the University of Michigan 
 
 
 
 
 
Michael Woods, MD 
 
 
 
 
Associate Professor 
 
 
 
 
University of North Carolina at Chapel Hill 
 
 
 
 
 
Marcus Quek, MD  
 
 
 
 
Associate Professor 
 
 
 
 
Loyola University 
 
 
Consultants:                     Ian M Thompson, MD 
                                           Professor 
                 
Department of Urology 
                                           The University of Texas Health Science Center at San    
                                           Antonio. 
 
                                           Valerie Lawrence, MD 
                   
Professor 
                                           Internal Medicine 
                                           The University of Texas Health Science Center at San    
                                           Antonio. 
 

 
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                                          Joseph A Smith Jr, MD 
                                          Professor and Chairman, 
                                          Department of Urology, 
                                          Vanderbilt University Medical Center  
 
2.  BACKGROUND AND SIGNIFICANCE 
 
In 2008, approximately 69,000 patients were diagnosed with urinary bladder cancer and 
14,000 patients were expected to die from bladder cancer 1.  Radical cystectomy with 
pelvic lymphadenectomy and urinary diversion is the standard of care for high grade 
carcinoma in situ, high grade recurrent superficial bladder cancer, or tumor invading the 
muscularis propria.  Radical cystectomy with pelvic lymphadenectomy is associated 
with adequate survival outcomes and compares favorably with other treatment 
modalities 2,3.  However, this operation is an extremely complex and involved surgical 
procedure associated with considerable postoperative morbidity 4-6. 
 
Traditionally, an incision is made from just above or at the level of umbilicus to the pubic 
symphysis.  The bladder, prostate gland, and surrounding lymph nodes are removed 
followed by urinary diversion which consists of connecting the urinary tract into a 
segment of intestine7.  The reported major and minor complication rates after open 
radical cystectomy are approximately 13% and 67% 4,5.  More recently, less invasive 
surgical treatments with robot-assisted laparoscopy have been advocated.  Robot 
Assisted Radical Cystectomy (RARC) is one such approach where the radical 
cystectomy and pelvic lymph node dissection are accomplished by a robot assisted 
laparoscopic approach 8.  After the completion of the cystectomy and the lymph node 
dissection, a small periumbilical or infra-umbilical midline incision is made to complete 
the urinary diversion. 
 
In other surgical procedures, such as nephrectomy, minimally invasive approaches 
have been associated with less blood loss, shorter hospital stay, less use of pain 
medication and faster return to preoperative levels of independence9, 10.  One would 
expect that RARC might offer similar advantages over open cystectomy.  Furthermore, 
there is evidence that efforts to compensate for the insensible losses and blood loss 
associated with open surgery may contribute to the high complication rate5. Therefore, 
there is reason to expect that RARC might reduce complication rates compared to open 
cystectomy.  
 
However, RARC is being marketed as superior to the traditional open operation without 
systematic comparative evaluations through randomized trials.  The purported 
advantages of RARC from small-volume, single-institution series are decreased blood 
loss, decreased blood transfusion rates, decreased pain and opioid requirement, earlier 
time to oral intake, decreased hospital stay, fewer wound complications, and expedited 
perioperative and postoperative convalescence and recovery 11-13. Additionally, there 
does not appear to be any compromise in the oncologic outcome as determined by 
pathology of surgical margins and number of pelvic lymph nodes removed 11-13. 
However, despite these advantages, little is known regarding recovery to preoperative 

 
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functional independence with RARC.  Also, RARC is associated with a steep learning 
curve as well as significant cost enhancements.  All outcome studies of RARC are 
either case series reports or comparative studies with major methodological limitations.  
Additionally, all are limited by major selection biases such as patients with more 
favorable oncologic, demographic, and clinical characteristics undergoing the RARC 
compared to the open approach 11,13.  Thus the perception that patient having RARC 
may have a better recovery is potentially due to the bias of preferential patient selection.  
Lastly, comparisons of open and RARC should be cautiously interpreted since they 
have been performed by a variety of surgeons with different training and experience 
levels. 
 
To date, no study has evaluated the outcomes measuring postoperative recovery using 
objective parameters of functional independence in patients undergoing RARC nor 
specifically compared it to outcomes following open cystectomy.  Studies evaluating 
short-term Quality-of-Life (QOL) outcome measures following open cystectomy have not 
been performed yet.  Lawrence et al. conducted a prospective cohort study to 
systematically describe the clinical course and predictors of long-term recovery to 
preoperative levels of functional independence in patients after major elective 
abdominal operations, using both self-report and performance-based instrument14.  
They found that a number of clinical factors independently predicted optimal functional 
recovery.  Serious postoperative complications were consistent independent predictors 
of poorer recovery and longer time to recovery. Poor preoperative physical performance 
status (ECOG scale), serum creatinine > 1.5 mg/dL and albumin < 3 mg/dL 
independently predicted poor recovery at 6 months. However, to our knowledge, no one 
has tested the hypothesis that utilization of the robotic technique would independently 
improve recovery and result in superior short or long-term QOL outcomes. 
 
3.  OBJECTIVES AND SPECIFIC AIMS 
 
Primary End Points 
 
Specific Aim 1 :  
 
 1. Two year progression free survival.  
Specific Aim 2 : 
      1. Serum Hemoglobin, Serum Creatinine and Serum Albumin levels at 
          baseline and in the post operative period at 4-6 weeks, 3 months, 6  months, 12 
months, 24 months, and 36 months. 
 
      2. Quality of Life (QOL) outcomes at baseline and in the post operative period 
          at 3 months and 6 months using the Functional Assessment of Cancer 
          Therapy - Vanderbilt Cystectomy Index  (FACT-VCI) as well as the Short  
          Form 8 (SF-8) Questionnaires. 
 

 
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      3. Compare surrogates of surgical quality by evaluating surgical margin 
          status and number of lymph nodes harvested. 
 
      4. Compare surgical morbidity by evaluating complication rates at 90 days post  
operative using the modified Clavien grading system. 
 
      5. Perioperative measures such as Estimated Blood Loss (EBL), Blood  
          transfusion rates, total intraoperative fluid requirements, total operative  
          time, total postoperative length of hospital stay and analgesic requirement. 
 
6. 3 year progression free survival in 65% of patients. 
 
Specific Aim 3 : 
A.   Patient Reported  Measures of Functional Independence 
1. Activities of Daily Living (ADL) scores at baseline and in the post operative period 
at 4-6 weeks, 3 months, and 6 months.  
 
2. Instrumental Activities of Daily Living (IADL) scores at baseline and in the post 
operative period at 4-6 weeks, 3 months, and 6 months. 
 
      B.  Performance Related Measures of Functional Independence 
1. Hand Grip Strength Test outcomes at baseline and in the post operative period 
4-6 weeks, 3 months, and 6 months. 
 
2. Timed Up and Go Walking Test outcomes at baseline and in the post operative 
period 4-6 weeks, 3 months, and 6 months. 
 
Secondary End Points: 
 
1. Compare fixed and variable costs associated with RARC and ORC operating 
room and hospital component. 
 
4.  EXPERIMENTAL DESIGN 
 
This multi-institutional, randomized trial will enroll approximately 350 participants with 
approximately 175 participants in each arm of the trial at approximately 15 participating 
institutions. This study aims to determine whether Robotic-Assisted Radical Cystectomy 
(RARC) for treatment of bladder cancer provides a non inferior oncologic control 
compared to traditional Open Radical Cystectomy (ORC), as measured by two-year 
progression-free survival.  We propose a multi-institutional approach where participants 
randomized to both groups will have their surgery performed by experienced surgeons 
to eliminate institutional and surgeon bias.  

 
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Inclusion/Exclusion Criteria 
Subject Inclusion Criteria: 
1. Patient must have biopsy proven bladder cancer.  Official pathology report 
reviewed at the participating institution is required. 
2. Bladder cancer must be clinical stage T1-T4, N0-1, M0. (AJCC 7th edition) or 
refractory cis (carcinoma in situ). 
 
Subject Exclusion Criteria: 
1. Inability to give informed consent. 
2. Prior major abdominal and pelvic open surgical procedures that would preclude a 
safe robotic approach, as determined by the treating surgeon. 
3. At the discretion of the treating surgeon, any pre-existing condition such as 
severe chronic obstructive pulmonary disease that precludes a safe initiation or 
maintenance of pneumoperitoneum over a prolonged period of time and during 
surgery. 
4. Age <18 or >99 years. 
5. Pregnancy.   
 
Recruitment and Consent Procedures 
Patients who meet the eligibility criteria will be approached by research staff to 
determine whether they are willing to participate in the study.  To eliminate selection 
bias, any patient who is determined to be a candidate for RARC will be given an option 
to participate in the study. The inclusion of patients eligible for this study will in no way 
compromise the quality of health care they will receive. Prior to study entry, the study 
staff will explain to each potential subject the research objectives, risks and benefits of 
study participation, alternative treatments available, and the subjects’ rights and 
responsibilities.  If the patient agrees to participate, informed consent will be obtained 
and, after consenting, randomization will take place.  Participation in this study will last 
up to approximately 5 years. 
 
Research Procedures 
Randomization 
Eligible, consented patients must be enrolled (i.e., randomized) no more than 60  
days prior to surgery.  This study uses a web-based patient enrollment and  
randomization system, through the data management services of Cancer Research And  
Biostatistics (CRAB).  The patient enrollment/randomization eCRF (electronic Case  
Report Form) is accessed online through the study website at  
https://prodq.crab.org/Parekh/Login.aspx.  Access is protected and available to 
authorized users only.  To request access to this system, or for questions or assistance 
using the website, please contact: WebhelpCRS@crab.org – please specify “Parekh 
Robotic Surgery” in the email subject line. 

 
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Treatment/Intervention Plan: 
Patients taking part in this study will be randomized using a dynamic balancing 
algorithm on type of diversion, within each institution as a block. Surgeons performing 
RARC and/or open radical cystectomy must have performed a minimum total of 10 over 
the past one year.   Surgery must take place within 60 days of randomization.   
 
The surgical approach, robotic versus open, is determined by randomization.  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.   
 
The following surgical templates will be implemented and adherence to these templates 
will be assessed by submission of the Surgeon’s Intra-Op Data Form for all cases to 
CRAB: 
 
Nodal templates (equivalent for robotic and open procedures) 
Minimum LND (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. 
 
Submission and processing of specimens 
The cystectomy specimen (with or without uterus, ovaries, or vaginal cuff in females and 
prostate in males) will be submitted en bloc, processed and assessed in a standardized 
fashion at all the participating institutions for margin status along with histology, size, 
stage, grade and presence/absence of lymphovascular invasion. At a minimum the LND 
will be submitted in two separate packets labeled left and right pelvic. All of these 
regions may be submitted in smaller packets (e.g. external iliac, obturator, internal iliac) 
at the surgeons preference. The standardized Cystectomy Pathology Form will be 
submitted to CRAB. 
 
The perioperative care measures will be performed per institutional standard based on 
each institution’s policy. 
 
Progression free survival: From the date of surgery to the date of first documentation 
of progression or death due to any cause. Patients last known to be alive and 
progression-free are censored at the date of last contact. 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.  All patients will have been followed for at 
least 2 years and 65% of patients will have been followed for 3 years.  

 
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Overall survival: From date of surgery to date of death due to any cause. Patients last 
known to be alive are censored at the date of last contact. 
  
Serum hemoglobin and a comprehensive metabolic panel (CMP) will be measured on 
10 cc of blood obtained by a venipuncture. These laboratory parameters are part of a 
routine preoperative work up and postoperative follow up in patients undergoing radical 
cystectomy and urinary diversion. No extra laboratory tests will be administered to the 
subjects enrolled in this trial. 
 
Pathologic data will be obtained from the pathology reports after surgery with particular 
emphasis on the involvement of surgical margins with cancer, total number of lymph 
nodes harvested and their involvement with cancer as well as the pathologic stage of 
the tumor. All institutions will adopt a standardized procedure to process the cystectomy 
specimens along with the lymph nodes. A standardized form will be used to collect all 
the information pertaining to specimen processing and staging by the participating 
institutions. A copy of the pathologic form will be available in the patients’ clinical 
records. 
 
Perioperative mortality and morbidity will be evaluated using the modified Clavien 
grading system for complications by prospectively recording the intraoperative and post 
operative complications until discharge and by patient interview during post discharge 
period until 4-6 weeks after surgery. The above data will be separately recorded in the 
patient’s clinical records in an inpatient and outpatient setting. 
 
Perioperative measures such as estimated blood loss (EBL), blood transfusion rates, 
total intraoperative fluid requirements, total operative time, total postoperative length of 
hospital stay and analgesic requirement will be prospectively recorded during the 
surgery and the postoperative hospital stay using the anesthesia, operative, nursing and 
inpatient medical records by a research coordinator.  All medications will be converted 
to morphine equivalents by using the online calculator The Clinician’s Ultimate 
Reference found at http://www.globalrph.com/narcoticonv.htm 
 
Costs 
We will obtain fixed and variable operating room costs by assessing amortized cost of 
robotic machine per case, amortized cost of maintenance per case, costs of 
dispensable equipment, cost of OR personnel and anesthesia resources per time. We 
will also obtain fixed and variable hospital costs based on length of stay. The above cost 
data will be collected from each participating center and data will be stored and 
analyzed by CRAB. We hypothesize that costs associated with robotic surgery will be 
no more than 5% of the costs associated with ORC. 
Only research personnel who are approved by the IRBs of the participating institutions 
will have access to study research information. All participating investigators are 
required to undergo and maintain CITI training. 
 
 
 

 
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Clinical Procedures  
Measurements of Study Endpoints  
 
Measurements of the study end points will be conducted according to the following 
Table 1: 
 
Table 1:  Study Calendar 
Assessment 
Baseline 
(Preoperative) 
Hospital 
Discharge 
(±2 weeks) 
4-6 
Weeks 
3 
months 
6 
months 
12 
months 
24 
Months 
36 
Months
Baseline History and 
Physical Exam, 
Consent, Screening, 
ECOG Performance 
Status, TURBT findings 
√ 
 
 
 
 
 
 
 
Randomization 
√ (within 60 
days prior to 
surgery) 
 
 
 
 
 
 
 
Progression Free 
Survival 
 
 
 
 
 
√ 
√ 
√ 
Overall Survival 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
Activities of Daily Living 
(ADL) score 
√ 
 
√ 
(±30 days) 
√ 
(±30 days) 
√ 
(±30 days) 
 
 
 
Instrumental Activities 
of Daily Living (IADL) 
score 
√ 
 
 
√ 
(±30 days) 
√ 
(±30 days) 
√ 
(±30 days) 
 
 
 
Hand Grip Strength 
Test 
√ 
 
√ 
(±30 days) 
√ 
(±30 days) 
√ 
(±30 days) 
 
 
 
Timed Up and Go 
Walking Test 
√ 
 
√ 
(±30 days) 
√ 
(±30 days) 
√ 
(±30 days) 
 
 
 
 
Hemoglobin, BMP, 
serum albumin 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 

 
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Quality of Life 
Questionnaire (QOL) - 
Vanderbilt Cystectomy 
Index and SF8 
√ 
 
 
√ 
(±30 days) 
√ 
(±30 days) 
 
 
 
Obtain Pathology 
Reports for Surgical 
Margin Status and 
Lymph Node Count 
 
 
√ 
 
 
 
 
 
Surgical Complications 
per Modified Clavien 
Classification (AEs)/ 
Serious Adverse Events 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
Postoperative 
Complication Rates 
(Surgeon’s 90-Day Data 
Form) 
 
 
 
√ 
 
 
 
 
Imaging (CT scan /MRI 
/Xray/etc of 
Abdomen/Pelvis/Chest
/etc) 
√ 
 
 
 
 
√ 
√ 
√ 
OR Costs 
Hospital Costs 
 
√ 
 
 
 
 
 
 
Surgeon’s Intra Op 
Data, Cystectomy 
Pathology 
 
Post Op 
 
 
 
 
 
 
Length of Hospital Stay, 
Analgesics, 
Complications 
(Surgeon’s Post Op 
Data Form)  
 
√ 
 
 
 
 
 
 
Target Lesions (Post 
Surgical Disease 
Assessment Form) to 
document cancer 
progression, according 
to local site Standard of 
Care. 
 
 
 
 
√ 
 
√ 
 
√ 
 
√ 
 

 
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Data Submission Procedures  
Data must be submitted according to the following schedule: 
• To perform randomization and obtain subject ID number:  Randomization Form.  
 
• Within 1 week following enrollment:  All of the following forms:  
o Medical History Form 
o Surgical History Form 
o Findings at TURBT Form 
o Hemoglobin, BMP, and Serum Albumin Form 
o Screening Physical Exam and Vital Signs Form 
o Baseline Disease Assessment Form 
o Baseline Vanderbilt Cystectomy Index QOL Questionnaire 
o Baseline SF-8 QOL Questionnaire 
o Baseline Activities of Daily Living QOL Questionnaire 
o Baseline Activities of Instrumental Activities of Daily Living QOL 
Questionnaire 
o Baseline Hand Grip Strength Form 
o Baseline Timed Up and Go Walking Test Form 
 
• Within 1 week of each post-surgery laboratory assessment per Table 1:   
o Hemoglobin, BMP, and Serum Albumin Form 
 
• Within 1 week following surgery:  Surgeon’s Intra-Op Data Form. 
 
• Within 1 week following discharge for surgical hospitalization:   
o Hospital Discharge Visit:  OR and Hospital Costs Reporting Form 
o Surgeon’s Post-Op Data Form 
 
• Within 1 week of each scheduled ADL, IADL, and QOL assessment per Table 1: 
o Vanderbilt Cystectomy Index QOL Questionnaire 
o SF-8 QOL Questionnaire 
o Activities of Daily Living QOL Questionnaire 
o Activities of Instrumental Activities of Daily Living QOL Questionnaire 
o Hand Grip Strength Form 
o Timed Up and Go Walking Test Form 
 
• Within 2 weeks following each scheduled disease assessment/imaging exam per 
Table 1:  Post Surgical Disease Assessment Form. 
 
• Within 4-6 weeks post-op:  Cystectomy Pathology Form 
 
• Within 1 week following 90-days post-op:  Surgeon’s 90-Day Data Form 
 
• Within 1 week following 6-, 12-, 24-, and 36 months post-op (respectively):   

 
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o Post Surgical Disease Assessment 
o Hematology Form 
o Serum Chemistry Form 
 
• Within 1week following each scheduled adverse events evaluation (per Table 1) 
until adverse events have resolved.  Adverse event information is collected on 
the Surgical Complications-Adverse Events Form.  
 
• Within the time frame and per the guidelines specified in section 6:  Serious 
Adverse Events.  Report per the instructions provided in section 6 AND flag as 
“SAE” on the Surgical Complications-Adverse Events Form. 
 
• Within 2 weeks following knowledge of death, if death occurs prior to end of 
study:  Death Report Form. 
 
5. STATISTICAL CONSIDERATIONS  
 
Study Objective and Primary Endpoint 
The primary objective of this study is to compare progression-free survival of RARC 
versus ORC in patients with bladder cancer. More specifically, the primary endpoint for 
this study is progression-free survival at 2 years. This is a non-inferiority comparison, 
i.e. the study will test whether the robotic-assisted cystectomy is, at worst, inferior to the 
open radical cystectomy by a small pre-defined margin. This study will use a centralized 
dynamic allocation procedure to allocate an equal number of patients to each of the 
treatment arms. The procedure will balance the marginal distribution of the stratification 
factors between these two treatments. 
 
Power and Significance 
The margin for this study is 15% which means that RARC would be considered inferior 
if the true progression free survival at two years was more than 15% lower than the 
progression-free survival at two years in the ORC arm. A total of 288 evaluable patients 
(144 patients per arm) yield a study with 80% power and a two-sided significance level, 
alpha, of 5% to correctly reject the null-hypothesis of unacceptable inferiority. These 
calculations are based on the assumption that progression-free survival at two years in 
the patients receiving ORC is approximately 71% and that the rate of progressions at 
two years is binomially distributed2, 17.  Evaluable patients are defined as eligible 
patients who have no major protocol deviations and have 90-day post-surgery follow-up 
data.  Major protocol deviations will be recorded for patients with no surgery given, 
where surgery was started correctly but discontinued before cystectomy was completed; 
or where the patient received a surgery type different from their randomization 
assignment for any reason.  In addition, a major protocol deviation will be recorded if the 
surgery begins as assigned, but the robotic procedure is aborted and an open 
procedure is required to complete the operation. 
 
Stratification Factors 

 
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Because outcomes may vary by type of urinary diversion (ideal conduit or neobladder), 
we will also stratify by the clinical T stage of condition (T1, T2, T3, T4)  and neo 
adjuvant chemotherapy since it directly influences oncologic outcomes.   
 
Accrual and Study Duration 
We anticipate participation of 15 sites and an accrual of approximately 110 eligible 
patients per year. Assuming a maximum drop-out rate of 10%, a total of approximately 
350 patients (approximately 175 patients in each arm) will be accrued to this study. 
Thus approximately 350 patients will be accrued in approximately three years. All 
patients will be followed for at least two years for progression. Based on the accrual 
estimates, after three years of accrual and two additional years of follow-up, 65% of 
patients will have follow up available to evaluate progression free survival at 3 years. 
Thus the study duration is expected to be approximately five years. 
 
Analysis of Primary Endpoint 
 
A one-sided mantel-Haenszel test with half the alpha (0.025) will be used for testing the 
primary non-inferiority hypothesis that compares progression free survival at two years 
in the two treatment arms.   
 
In superiority trials the intent to treat (ITT) population is widely accepted as the analysis 
population for the primary endpoint as it gives the most conservative result of such a 
study. In contrast, for non-inferiority trials the inclusion of ineligible or untreated patients 
or the lack of adherence to the assigned treatment is expected to increase the noise of 
the study and make the two treatment arms look more alike, thus the overall results of 
the study less conservative. Thus we will use the per-protocol (PP) population as the 
analysis population for the primary endpoint. We will also perform a sensitivity analysis 
of the primary endpoint using the ITT population. These two analysis populations are 
defined below. The design and analysis of this trial are based on the SWOG standards 
for noninferiority trials, which are detailed the chapter 12 in the Handbook for Statistics 
in Clinical Oncology, second edition, Chapman & Hall 2006.  
 
Serum hemoglobin, serum creatinine and serum albumin levels will be taken at baseline 
and at a variety of time points post-surgery throughout the study. Linear mixed effects 
will be used to compare these blood levels and their changes over time between the two 
treatment groups.  
 
QOL outcomes will be measured at baseline and in the post-operative period at 3 and 6 
months using the Functional Assessment of Cancer Therapy – Vanderbilt Cystectomy 
Index (FACT-VCI) as well as the Short Form 8 (SF-8) Questionnaires. Simple 
descriptive statistics, such as mean and standard deviation, will be used to summarize 
the FACT-VCI and the SF-8 scores at each time point and for each treatment group.  A 
multivariate linear mixed effects model will then be fitted to each score in this repeated 
measures design. The main effect will be visit (at baseline, 3 and 6 months) and will be 
treated as a categorical variable to accommodate for the non-linear trends. If the exact 
time corresponding to a particular visit differs significantly between patients a variable 

 
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representing the deviation from the visit-specific mean time will be added to the model. 
Standard diagnostic tools will be used will be used to assess model fit.  
Secondary Endpoints 
We will determine whether RARC is superior to ORC in terms of blood loss. More 
specifically, the overall blood loss due to surgery will be compared between the two 
treatment arms. In the ORC group the average blood loss is 575 ml 16. 288 patients 
yield 90% power to detect a difference of blood loss between the two treatment groups 
of 20%. These calculations are based on the assumption that the amount of blood loss 
is normally distributed, that the average blood loss in the open surgery group is 575ml, 
and that the standard deviation of blood loss is 300ml. A one-sided significance level of 
0.025 was used.  
 
We will determine whether RARC is superior to ORC in terms of transfusion rates. The 
transfusion rates (proportion of patients requiring blood transfusions) will be compared 
between the two treatment arms. The transfusion rate for ORC is approximately 
75%(from Table 2, unpublished). 288 patients yield 92% power and a one-sided 
significance level of 0.025 to detect a difference of transfusion rates between arms of at 
least 20%. These calculations are based on the assumption that the transfusion rate is 
binomially distributed. 
 
Table 2 (Preliminary Data from University of Texas Health Sciences Center, San Antonio) 
 
ORC (n=12) RARC(n=12) 
p-value 
Median (IQR) Units of Blood Given 2.5 (1-5) 
0 (0-3) 
0.082 
Transfusion given (%) 
9/12 (75%) 
4/12 (33%) 
0.041 
Median (IQR) LOS (days) 
6.5 (6-8.5) 
6.5 (5-9.5) 
0.554 
LOS  (5 days or less) 
0/12 (0%) 
4/12 (33.3%) 
0.028 
Median No. LNs (IQR) 
19 (6-27) 
10.5 (8.5-17.5) 0.30 
Positive margin 
3/12 (25%) 
0/12 (0%) 
0.064 
All positive margins in the ORC group had pT4 disease. 
Length of hospital stay will be used as a surrogate for recovery after surgery. We will 
determine whether RARC is superior to ORC in terms of length of hospital stay. 
Currently, all of the patients receiving ORC stay in the hospital for more than 5 days 
while 67% of patients in the RARC group stay in the hospital for more than 5 days (from 
Table 3, unpublished). 288 patients yield 97% power and a one-sided significance level 
of 0.025 to detect a difference in percent of patients requiring a hospital stay beyond 5 
days between RARC and ORC arms of at least 20%. These calculations are based on 
the assumption that the percent patients requiring a hospital stay beyond 5 days is 
binomially distributed. 

 
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Table 3 (Preliminary Data for Cost Analyses from University of North Carolina) 
 
 
ORC (n=21) 
RARC (n=20) 
P VALUE 
Age (median) 
70 
70 
 
OR time (mins) 
293 
389 
<0.001 
OR fees (dollars) 
5441 
6202 
<0.00001 
OR disposables 
(dollars) 
2485 
3715 
= 0.0003 
OR capital + 
reusables 
50 
2000 
 
LOS (days) 
6 
4 
=0.02(mann whitney 
U) 
Room and Board 
5954 
3664 
=0.005 (mann 
whitneyU) 
Overall Costs 
19047 
19837 
=0.14(mann whitney 
U) 
 
Hand Grip Strength at 3 months after surgery will be measured as a surrogate for 
recovery after surgery. It was found that only 39% of patients recovered at three months 
after a major abdominal surgery as measured by the Hand Grip Strength14.We will 
compare the proportion of patients recovered as measured by Hand Grip Strength 
between the two treatment arms. We hypothesize that 20% more patients will have 
recovered three months after surgery in the RARC arm compared to the ORC arm. A 
total of 288 patients yield 91% power and a one-sided significance level of 0.025 to 
detect a difference between arms of at least 20%. These calculations are based on the 
assumption that Hand Grip Strength at three months is binomially distributed. 
Surgical margin as a measure for local cancer control will be measured as positive or 
negative for each patient and compared between arms using a Fisher’s exact test. The 
number of nodes resected in each arm will be compared using a t-test. 
 
Progression-free and overall survival will be evaluated using the method of Kaplan 
Meyer and comparisons between arms will be made using the stratified log-rank test.  
 
All efficacy and QL endpoints will be assessed using the PP population. 
 
Analysis Populations: 
 
Per Protocol Population (PP Population): 
 
The per-protocol population includes all patients who have met inclusion/exclusion 
criteria and received the surgery to which they were randomized. This is the primary 
efficacy population. All efficacy and QL endpoints will be assessed using this 
population.  

 
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Intent-to-Treat Population (ITT Population): 
 
The ITT population includes all patients who have been randomized to the trial. Patients 
are assigned to treatment arms based on what they are “randomized” to receive. This is 
the sensitivity analysis population of the primary efficacy endpoint. 
 
6.  HUMAN SUBJECTS 
 
Compensation 
There will be no compensation provided to subjects for participating in the study. 
 
Risks to Subjects 
The only research related risks to subjects are the potential loss of PHI and potential 
mental distress during conduct of questionnaires.  Measures to maintain confidentiality 
are being employed.  For a detailed description, please see the section titled 
“Confidentiality.”  Should patients express discomfort during questionnaires or other 
assessments, they will first be allowed to take a break from questioning.  If distress 
persists, the session will be terminated.  Participants may refuse to answer questions 
which cause them discomfort rather than being withdrawn from the study. 
 
Special Precautions 
Subject data will be examined at each follow up visit and subjects queried for adverse 
events (AE) defined as complications related to the robotic/open cystectomy and/or 
study procedures.  An AE or complication is the appearance of undesirable sign(s), 
symptom(s), or medical condition(s) occurring after a participant signs the informed 
consent and considered to be related to the robotic/open cystectomy and/or study 
procedure. A serious adverse event is any untoward medical occurrence that: 
 
1. Is fatal or life-threatening 
2. Requires hospitalization or prolongation of existing hospitalization  
3. Results in disability/incapacity 
4. Is medically significant in that it may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
 
All AEs or complications will be graded for severity according to the modified Clavien 
grading system.  All adverse events will be reported to the IRB at the time of annual 
review and to the DSMC as described below. 
 
 
The investigator is obligated to assess the relationship between any study-related 
procedure and the occurrence of each SAE.  The investigator will use clinical judgment 
to determine the relationship.  Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 

 
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relationship of the event to any study-related procedure will be considered and 
investigated. 
 
Even in situations when an SAE has occurred and the investigator has incomplete 
information to include in the initial SAE report, the investigator will make an assessment 
of causality for every event prior to reporting it.  The investigator may change his 
opinion of causality in light of follow-up information and amend the SAE case report 
form and report accordingly. 
 
SAEs meeting the IRB definition of Unanticipated Problems Involving Risk to Subjects 
or others (UPIRSO) will be reported to the IRB within 7 days, and within 48 hours if life-
threatening or fatal or will follow the guidelines as required by the local IRBs.  
 
All SAEs will also be reported to the coordinating center office of Dr. Parekh at the 
University of Miami. After completion of review by Dr. Parekh, SAEs will be summarized 
and communicated across sites via the posting to the study website at 
https://prodq.crab.org/Parekh/Login.aspx.  
 
The data will be reviewed on a biweekly basis by the investigators to ensure quality 
control and safety.  During the study when there is a safety evaluation, the investigator 
and/or research staff will be responsible for detecting, documenting and reporting any 
adverse events or serious adverse events to the IRB.   
 
Subject Completion and Withdrawal 
A subject will be considered completed when he/she has completed all follow-up visits 
up to the 24 month evaluation.  A subject may discontinue participation in this study at 
any time at the investigator’s discretion or at the request of the subject.  The reason for 
study withdrawal will be documented in the study related source documentation.   
 
Alternative Treatments 
Subjects who are eligible for the proposed study will be randomized to receive either 
open or robotic-assisted cystectomy.  The alternative to participating in this study would 
be for a subject to choose which surgical technique will be used rather than being 
randomized to one or the other. 
 
Confidentiality  
Maintaining confidentiality of patient-specific information will be top priority throughout 
all phases of the study.  Patient data (PHI) will be compiled in a database and de-
identified upon completion of analysis.  Cases in the database will be identified by 
initials, patient identification number, the year of patient’s birth, and the date of surgery.  
The database will not include information which can be identifiable with the link (or key).  
All electronic data will be stored in a password protected database in accordance with 
institutional computer-security policies.  The identification number is actually a research 
record number that cannot be linked to the subject except by a key. This key will be 
maintained securely by the Principal Investigator. The data will be stored and 
maintained by the CRAB informatics core facility. 

 
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Data Safety Monitoring Committee  
A Data and Safety Monitoring Board will oversee the conduct of the study.  The Board 
consists of 5 voting, independent members:  1 surgeon, 1 medical oncologist, 1 
CCRA/RN, 1 biostatistician, and 1 lay person.  Non-voting members include support 
staff from Cancer Research And Biostatistics (who will prepare the DSMC reports), and 
project faculty (Principal Investigators) as appropriate.  DSMC members receive 
database summaries from CRAB, including adverse events and post surgical 
complications reports, serious adverse event summaries, and other pertinent 
patient/treatment summary information.  Meetings occur every six months, convened via 
teleconference.  The DSMC is responsible for decisions regarding possible termination 
and/or early reporting of the study. 
 
7.  LITERATURE CITED 
 
1. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA: a cancer journal 
for clinicians 2008;58(2):71-96. 
2. 
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(3):666-75. 
3. 
Stein JP, Skinner DG. Results with radical cystectomy for treating bladder 
cancer: a 'reference standard' for high-grade, invasive bladder cancer. BJU international 
2003;92(1):12-7. 
4. 
Cookson MS, Chang SS, Wells N, Parekh DJ, Smith JA, Jr. Complications of 
radical cystectomy for nonmuscle invasive disease: comparison with muscle invasive 
disease. The Journal of urology 2003;169(1):101-4. 
5. 
Shabsigh A, Korets R, Vora KC, et al. Defining Early Morbidity of Radical 
Cystectomy for Patients with Bladder Cancer Using a Standardized Reporting 
Methodology. European urology 2008. 
6. 
Konety BR, Allareddy V, Herr H. Complications after radical cystectomy: analysis 
of population-based data. Urology 2006;68(1):58-64. 
7. 
Stein JP, Skinner DG. Surgical atlas. Radical cystectomy. BJU international 
2004;94(1):197-221. 
8. 
Menon M, Hemal AK, Tewari A, et al. Robot-assisted radical cystectomy and 
urinary diversion in female patients: technique with preservation of the uterus and 
vagina. Journal of the American College of Surgeons 2004;198(3):386-93. 
9. 
Gill IS. Laparoscopic radical nephrectomy for cancer. The Urologic clinics of 
North America 2000;27(4):707-19. 
10. 
Dillenburg W, Poulakis V, Skriapas K, et al. Retroperitoneoscopic versus open 
surgical radical nephrectomy for large renal cell carcinoma in clinical stage cT2 or cT3a: 
quality of life, pain and reconvalescence. European urology 2006;49(2):314-22; 
discussion 22-3. 

 
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11. 
Wang GJ, Barocas DA, Raman JD, Scherr DS. Robotic vs open radical 
cystectomy: prospective comparison of perioperative outcomes and pathological 
measures of early oncological efficacy. BJU international 2008;101(1):89-93. 
12. 
Guru KA, Kim HL, Piacente PM, Mohler JL. Robot-assisted radical cystectomy 
and pelvic lymph node dissection: initial experience at Roswell Park Cancer Institute. 
Urology 2007;69(3):469-74. 
13. 
Dasgupta P, Rimington P, Murphy D, Elhage O, Challacombe B, Khan MS. 
Robotically assisted radical cystectomy. BJU international 2008;101(12):1489-90. 
14. 
Lawrence VA, Hazuda HP, Cornell JE, et al. Functional independence after 
major abdominal surgery in the elderly. Journal of the American College of Surgeons 
2004;199(5):762-72. 
15. 
Fitzmaurice GM LN, Ware JH. . Applied longitudinal analysis. NY. John Wiley & 
Sons 2004. 
16. 
Probstfield JL, Wittes JT, Hunninghake DB. Recruitment in NHLBI population-
based studies and randomized clinical trials: data analysis and survey results. 
Controlled clinical trials 1987;8(4 Suppl):141S-9S. 
17. 
Moyé L. Statistical monitoring of clinical trials:. Fundamentals for investigators 
2006.;NY: Springer. 
 

 
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Appendix A:  ECOG a Performance Status Scale 
 
Grade 
Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair 
5 
Dead 
a As published in Am J Clin Oncol (CCT). 1982;5:649-655. 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX B:  Data Collection Forms 
See Mock-ups of CRAB eCRF webpages