A Phase III Surgical Trial to Evaluate the Benefit of a Standard Versus an Extended Pelvic Lymphadenectomy Performed at Time of Radical Cystectomy for Muscle Invasive Urothelial Cancer
Phase: NA
Conditions: Bladder Cancer
Sponsor: SWOG Cancer Research Network

 
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PRIVILEGED COMMUNICATION 
Sent for IRB Review July 15, 2011 
FOR INVESTIGATIONAL USE ONLY 
Activated August 1, 2011 
 
 
SWOG 
 
TITLE 
A PHASE III SURGICAL TRIAL TO EVALUATE THE BENEFIT OF A STANDARD VERSUS AN 
EXTENDED PELVIC LYMPHADENECTOMY PERFORMED AT TIME OF RADICAL CYSTECTOMY 
FOR MUSCLE INVASIVE UROTHELIAL CANCER. 
 
NCT #01224665 
 
STUDY CHAIRS: 
 
Seth P. Lerner, M.D. (Urology) 
Ajjai Alva, M.D. (Medical Oncology) 
Scott Department of Urology 
Hematology/Oncology 
Baylor College of Medicine 
University of Michigan 
6620 Main St., Suite 1325 
1500 E. Medical Center Dr., MEDINN C351 
Houston, TX 77030 
Ann Arbor, MI 48109 
Phone: 713/798-6841 
Phone:  734/936-0091 
FAX: 713/798-5553 
FAX: 734/647-8792 
E-mail: slerner@bcm.edu 
E-mail: ajjai@med.umich.edu 
 
Theresa M. Koppie, M.D.  
Rick Bangs (Patient Advocate) 
 (Urology & Translational Medicine) 
1698 Snowden C ircle 
OHSU Division of Urology 
Rochester Hills, MI  48306 
3303 SW Bond Avenue 
Phone:  248/377-4290 
Mail Code CH1OU 
FAX:  248/813-6898 
Portland, OR 97239 
E-mail:  chezrick@comcast.net 
Phone:  503/346-1500 
 
FAX: 503/346-1501 
 
E-mail:  koppie@ohsu.edu 
 
 
Robert S. Svatek, M.D. (Urology) 
Francisco G. LaRosa, M.D. (Pathology) 
University of Texas Health Science Center San Antonio University of Colorado AMC 
Department of Urology 
Dept of Pathology, MS 8104 
7703 Floyd Curl Drive 
12800 E. 19th Avenue, Rm L18-5103 
San Antonio, TX 78229-3900 
Aurora, CO, 80045 
Phone:  210/602-3116 
Phone:  303/724-3782 
FAX:  210/567-6868 
Fax:  303/724-3781 
E-mail: svatek@uthscsa.edu 
E-mail:  francisco.larosa@ucdenver.edu 
 
Sumanta K. Pal, M.D. (Translational Medicine) 
BIOSTATISTICIANS: 
City of Hope Medical Center 
 
Dept. Of Medical Oncology 
Cathy M. Tangen, Dr.P.H. (Biostatistics) 
1500 E. Duarte Rd. 
Hongli Li, M.S. 
Duarte, CA 91010 
SWOG Statistical Center 
Phone:  626/256-4673 
Fred Hutchinson Cancer Research Center 
Fax:  626/301-8233 
1100 Fairview Avenue North, M3-C102 
E-mail:  spal@coh.org 
P.O. Box 19024 
 
Seattle, WA  98109-1024 
 
Phone: 206/667-4623 
 
FAX:  206/667-4408 
 
E-mail: ctangen@fhcrc.org 
 
E-mail:  hongli@fhcrc.org 

 
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ALLIANCE STUDY CHAIR: 
NCIC-CTG (BLC.1) STUDY CHAIR: 
 
 
Adam S. Kibel, M.D. 
Wassim Kassouf, M.D. 
Dana Farber Cancer Institute 
McGill University Health Center 
E-mail:  akibel@partners.org 
E-mail:  wassim.kassouf@muhc.mcgill.ca 
 
 
ECOG-ACRIN STUDY CHAIR: 
 
 
Daniel J. Canter, M.D. 
 
Urologic Institute of Southeastern Pennsylvania 
Fox Chase Cancer Center 
E-MAIL:  CANTERDA@EINSTEIN.EDU  
 
 
PARTICIPANTS 
 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) SURGEONS WHO HAVE BEEN 
APPROVED VIA THE STUDY-SPECIFIC CREDENTIALING PROCESS OUTLINED IN SECTION 
12.1 (see list on S1011 protocol abstract page on http://swog.org).” 
 
SWOG/SWOG 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
 
NCIC-CTG/NCIC Clinical Trials Group 
 
 
 
 
 

 
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TABLE OF CONTENTS 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective ............................................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Translational Medicine Objectives ................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 7 
3.0 
DRUG INFORMATION .................................................................................................................. 12 
4.0 
STAGING CRITERIA (AJCC SEVENTH EDITION, 2010) ............................................................ 12 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 12 
5.1 
Disease-related Criteria (Step 1) ................................................................................................... 13 
5.2 
Prior Therapy Criteria ..................................................................................................................... 13 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 14 
5.4 
Specimen Submission Criteria ....................................................................................................... 14 
5.5 
Regulatory Criteria ......................................................................................................................... 14 
5.6 
Disease-related Criteria (Step 2) ................................................................................................... 15 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 15 
7.0 
TREATMENT PLAN ...................................................................................................................... 15 
7.1 
Timing of Randomization ............................................................................................................... 15 
7.2 
Treatment ....................................................................................................................................... 15 
7.3 
Adherence to Recommendations for Adjuvant Chemotherapy...................................................... 16 
7.4 
Submission of Lymph Nodes ......................................................................................................... 16 
7.5 
Criteria for Removal from Protocol Treatment ............................................................................... 16 
7.6 
Discontinuation of Treatment ......................................................................................................... 16 
7.7 
Follow-Up Period ............................................................................................................................ 16 
8.0 
DOSE MODIFICATIONS ............................................................................................................... 16 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 17 
8.2 
Dose Modifications ......................................................................................................................... 17 
8.3 
Dose Modifications Contacts ......................................................................................................... 17 
8.4 
Adverse Event Reporting ............................................................................................................... 17 
9.0 
STUDY CALENDAR ...................................................................................................................... 18 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS................................................. 20 
10.1 
Measurability of lesions .................................................................................................................. 20 
10.2 
Recurrence ..................................................................................................................................... 20 
10.3 
Disease-Free Survival .................................................................................................................... 21 
10.4 
Overall Survival .............................................................................................................................. 21 
10.5 
Performance Status ....................................................................................................................... 21 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 21 
11.1 
Accrual Goal ................................................................................................................................... 21 
11.2 
Analysis of Primary Endpoint ......................................................................................................... 22 
11.3 
Analysis of Surgical Endpoints ....................................................................................................... 23 
11.4 
Analysis of Translational Medicine Endpoints ............................................................................... 23 
11.5 
Data and Safety Monitoring Committee Oversight ........................................................................ 24 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 25 
12.1 
Surgeon Credentialing ................................................................................................................... 25 
12.2 
Surgery Review .............................................................................................................................. 25 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 26 
13.1 
Registration Timing ........................................................................................................................ 26 
13.2 
Investigator/Site Registration ......................................................................................................... 26 
13.3 
OPEN Registration Requirements ................................................................................................. 26 
13.4 
Registration Procedures................................................................................................................. 27 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 28 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 29 
14.1 
Data Submission Requirement ...................................................................................................... 29 

 
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14.2 
Master Forms ................................................................................................................................. 29 
14.3 
Data Submission Procedures ........................................................................................................ 29 
14.4 
Data Submission Overview and Timepoints .................................................................................. 30 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 31 
15.1 
Specimen Submission Timepoints ................................................................................................. 31 
15.2 
Specimen Submission Instructions ................................................................................................ 32 
15.3  
Specimen Collection Kits ............................................................................................................... 32 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 32 
16.1 
Adverse Event Reporting Requirements........................................................................................ 32 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 35 
18.0 
APPENDIX ..................................................................................................................................... 37 
18.1 
Determination of Expedited Adverse Event Reporting Requirements ........................................... 38 
18.2 
Translational Medicine Background and Methods ......................................................................... 40 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site 
registration documents: 
For patient 
enrollments:  
Submit study data  directly to the Lead 
Cooperative Group unless otherwise specified 
in the protocol:  
 
CTSU Regulatory Office 
1818 Market Street,  
Suite 1100 
Philadelphia, PA 19103 
 
Phone:  1-866-651-CTSU 
Fax:  215-569-0206 
 
Please refer to the 
patient enrollment 
section for 
instructions on using 
the OPEN system. 
 
Online Data Submission:  Institutions participating 
through CTSU are required to submit and amend 
their data electronically via Online Data 
Submission.  Access the SWOG Workbench 
using your CTSU User ID and password at the 
following url: 
 
https://crawb.crab.org/TXWB/ctsulogon.aspx 
 
Exceptions:  Data items that are not available for 
online submission (operative and pathology 
reports, patient completed forms, scan reports, 
etc.) may be submitted by FAX at 800/892-4007. 
 
Do not submit study data or forms to CTSU Data 
Operations. Do not copy the CTSU on data 
submissions.   
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
 
CTSU sites must follow procedures outlined in the protocol for Site Registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For treatment-related questions, contact the Study PI of the Coordinating Group. (Dr. Seth P. 
Lerner at 713/798-6841). 
 
For eligibility or data submission questions, contact the SWOG Data Operations Center at 
206/652-2267. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU 
Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ 
website https://www.ctsu.org 
The CTSU Web site is located at   https://www.ctsu.org 
 

 
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SCHEMA 
 
NOTE:  Participation in this study is limited to pre-approved, credentialed surgeons (see S1011 
protocol abstract page on http://swog.org for list of pre-approved, credentialed surgeons and 
Section 12.1 for credentialing process). 
 
Patients with 
T2-T4a 
Urothelial Carcinoma 
of the Bladder 
 
 
 
 
Consent 
Step 1, Registration 
 
 
 
 
Intraoperative Assessment Of 
Gross Nodal Involvement Above 
The Bifurcation Of The Common 
Iliac Vessels 
 
 
 
 
Step 2, Randomization 
 
 
 
 
 
 
 
 
Arm 1: 
Arm 2 
Standard Pelvic Lymph Node Dissection ** 
Extended Pelvic Lymph Node Dissection ** 
 
 
 
 
 
 
 
Follow-Up 
6 years 
 
 
 
 
 
** For patients who did not receive neoadjuvant chemotherapy, post operative adjuvant 
chemotherapy for pT any, N+ or pT3-4, N0 is strongly recommended but not required and will be 
left up to the treating physician.  We strongly encourage patient evaluation for adjuvant 
chemotherapy in a multidisciplinary session with the treating urologic surgeon and GU medical 
oncologist coordinating decision making and administration of chemotherapy. 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To compare disease-free survival (DFS) in patients undergoing radical 
cystectomy for muscle-invasive urothelial carcinoma of the bladder (UCB) treated 
with radical cystectomy and extended pelvic lymph node dissection (PLND) 
compared to radical cystectomy and standard pelvic lymphadenectomy. 
 
1.2 
Secondary Objectives 
 
a. 
To compare overall survival (OS) in patients randomized to extended PLND 
versus those randomized to standard pelvic lymphadenectomy. 
 
b. 
To evaluate operative time, whether or not nerve sparing was performed, intra-
operative, peri-operative and 90 day morbidity and mortality, length of hospital 
stay, histology (pure urothelial versus mixed), lymph node counts and lymph 
node density, adjuvant chemotherapy received, and local and retroperitoneal soft 
tissue recurrence in patients randomized to extended PLND versus those 
randomized to standard pelvic lymphadenectomy.  Proximal extent of node 
dissection in those patients randomized to extended PLND will be evaluated as 
well. 
 
1.3 
Translational Medicine Objectives 
 
a. 
To bank paraffin embedded blocks or slides of the primary tumor for future 
translational medicine studies including markers of epithelial and mesenchymal 
transition and correlate these findings with pathologic T stage and node 
metastasis as well as DFS and OS. 
 
b. 
To determine the prognostic value of several putative markers of the pre-
metastatic niche in muscle-invasive bladder cancer, including (1) extent of 
neutrophil infiltration, (2) phosphorylated signal transducer and activator of 
transcription 3 (pSTAT3) expression, (3) vascular endothelial growth factor 1 
(VEGFR1) expression, and (4) macrophage infiltration. 
 
c. 
To evaluate whether the prevalence of the pre-metastatic niche is different 
amongst patients that received neoadjuvant chemotherapy as compared to those 
who did not. 
 
 
2.0 
BACKGROUND 
 
Despite the fact that pelvic lymphadenectomy is performed at the time of radical cystectomy for 
urothelial carcinoma of the bladder (UCB), there are no data from randomized clinical trials, which 
define an association between the extent of the lymphadenectomy and disease progression or 
survival.  There is considerable debate regarding the degree of improvement in outcome gained 
with a more extensive lymphadenectomy for patients undergoing cystectomy for bladder cancer.  
This is exemplified by the large degree of variability in the extent of dissection and number of 
nodes removed by urologists.  The extent of nodal dissection promoted by many academic 
centers involves an extended dissection with the upper limit designated by the aortic bifurcation 
or the inferior mesenteric artery (IMA).  (1,2,3,4,5)  The average number of lymph nodes 
removed at these centers is 20-30 lymph nodes.  In fact, it is has been proposed that a minimum 
number of lymph nodes (~25) be utilized for quality assurance purposes for patients undergoing 
this operation.  (6)  However, in a large multi-institutional trial evaluating the role of neoadjuvant 
chemotherapy, 9% of patients at major academic centers had no lymph node dissection and 37% 
underwent a limited dissection (obturator nodes only).  (7)  Moreover, population-based data from 
the SEER program cancer registry demonstrates a pervasive lack of enthusiasm for an extended 

 
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lymph node dissection with 40% of patients having no lymph nodes recovered during cystectomy.  
(8)  As more attention has been applied to this important quality measure in recent years there 
has been a modest increase in the number of nodes removed and a decrease in the percent of 
patients with no node dissection at all.  (9)  
 
Data from several retrospective series and one prospective non-randomized cohort suggest that 
patients undergoing an extended pelvic lymphadenectomy may derive a survival benefit 
compared to those undergoing a limited pelvic node dissection.  (10)  However, conclusions 
drawn from these studies are subject to significant biases inherent in observational studies of 
surgical procedures.  In addition, there is no prospective data regarding the morbidity as a result 
of the extent of the nodal dissection.  We acknowledge that there is a potential for an increase in 
post-operative morbidity associated with an extended node dissection (possibly related to 
increased operative time and/or blood loss) that could outweigh any derived benefit.  This 
provides further support for the importance of studying this dilemma in a randomized controlled 
trial (RCT).  In addition, the importance of a RCT to address the extent of nodal dissection in 
bladder cancer is reflected in the experience of our surgical colleagues in gastric and pancreas 
cancer. 
 
Gastrectomy with an extended regional (D2) lymphadenectomy is the standard treatment for 
curable gastric cancer in Asia.  However, because of a 10-30% rate of para-aortic node 
involvement, additional para-aortic nodal dissection (PAND) has been performed in Japan since 
the 1980s for patients with advanced stage disease.  A landmark RCT asked the question of 
whether the addition of PAND to the D2 lymphadenectomy improved survival for patients with 
stage T2-4 tumors.  (11)  The overall incidence of surgery-related complications was 20.9% in the 
D2 lymphadenectomy group and 28.1% in the group assigned to D2 lymphadenectomy plus 
PAND (p = 0.07).  The authors observed no significant differences in recurrence-free or overall 
survival rates between the two groups.  (12) 
 
Similarly, extended lymph node dissections for pancreatic head cancer have been conducted 
since the 1980s.  Several retrospective trials demonstrated improved survival rates for patients 
undergoing extended nodal dissection.  A RCT to assess the difference between a standard and 
extended nodal dissection was initiated but closed after an interim analysis revealed a poorer 
survival and increased morbidity in the extended nodal dissection group.  (13) 
 
An extended node dissection in patients undergoing cystectomy for bladder cancer may offer a 
survival benefit compared to a standard node dissection via more complete tumor eradication, 
improved staging and thus identifying patients who may benefit from adjuvant chemotherapy, or 
other theoretical mechanisms.  In order to optimize the benefits of an extended node dissection 
through improved nodal staging, all patients with node metastasis will be strongly advised to 
receive peri-operative chemotherapy which is currently considered a standard of care in locally 
advanced urothelial bladder cancer.  In addition and in accordance with standard of care, 
chemotherapy will be strongly recommended for patients found to have advanced pathologic 
stage (pT3-T4) at cystectomy.  Failure to include this stipulation in the trial design could result in 
biased administration of adjuvant chemotherapy, influenced by which arm the patient was 
randomized to, and lead to non-informative results. 
 
A poll of centers of excellence suggest that a 10-12% improvement in 3-year DFS (65-67%) for 
patients in extended lymphadenectomy would be meaningful and establish extended node 
dissection as the standard of care in this patient population 
 
Since the introduction of MVAC chemotherapy in the 1980s, little progress has been made in 
improving survival for patients with advanced bladder cancer.  Despite a significant improvement 
in overall survival with administration of peri-operative chemotherapy, the mortality rate for 
patients undergoing radical cystectomy for UCB approaches 50%.  A properly performed lymph 
node dissection may provide a significant improvement in survival for these patients.  Currently 
the boundaries of a pelvic node dissection for patients undergoing radical cystectomy for UCB are 
not clear and the urologic community has failed to define a standard template.  The literature is 
replete with various proposed definitions.  Defining, a standard nodal dissection for this disease is 

 
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critical because the extent of lymph node dissections are increasingly being compromised due to 
the increasing performance demands placed on the surgeon and the widespread utilization of 
robotic laparoscopy for this operation.  Performing an extended lymph node dissection takes 
additional time, especially with a robotic laparoscopic approach.  Retrospective data and expert 
opinion are a poor substitute for level I evidence as demonstrated by the findings of RCTs of 
extended versus standard LND in other solid organ malignancies. 
 
Early reports of radical cystectomy for UCB stressed the high rate of local recurrence that was 
related, in part, to limited or no dissection of the regional lymph nodes.  A greater understanding 
of the pathways by which UCB progressed, locally and regionally, suggested that a more radical 
resection might have therapeutic benefit.  (14)  Jewett hypothesized that 25% to 30% of 
recurrences in pelvic lymph nodes were due to inadequate lymphadenectomy.  In patients 
undergoing radical cystectomy for UCB the involvement of regional lymph nodes varies from 14% 
to 40%, thus it is important to define the extent of lymphadenectomy.  (15,16,17)  Published 
outcomes following attempts at controlling the regional lymphatics for bladder cancer date back to 
1932 when the routine inclusion of a pelvic lymph node dissection at the time of radical 
cystectomy was initiated.  (18) 
 
Controversy regarding the role of lymphadenectomy and the extent of the dissection necessary to 
obtain maximal tumor control has persisted to the present.  Some surgeons recommend that the 
proximal limit of resection be the level of the bifurcation of the common iliac vessels, since 
patients with nodal disease superior to this point are thought to be incurable by radical 
cystectomy.  (19)  In contrast, others advocate an extended lymph node dissection beyond this 
point, citing non-randomized data as supportive of a more extensive dissection for improved 
staging and therapeutic efficacy.  (20,21,22) 
 
Several institutional studies have reported improved outcome in patients undergoing an extended 
lymph node dissection, as defined by the number of lymph nodes identified pathologically.  In a 
study of 447 patients Leissner et al. found a 20% improvement in overall 5- year survival (85% of 
patients, with organ-confined UCB and greater than or equal to 16 lymph nodes resected 
survived 5 years compared to 65% of patients with less than or equal to 15 lymph nodes 
resected).  Control of local disease also was superior in patients having a more extensive, 
compared to a limited nodal resection (17% recurrence compared to 27% recurrence).  (23) 
 
At Memorial Sloan-Kettering Cancer Center (MSKCC) the recent experience with radical 
cystectomy was reviewed to determine the relationship between the extent of lymphadenectomy 
and staging, disease control and prognosis.  (24,25,26)  A total of 322 patients with UCB treated 
by radical cystectomy were reviewed; 258 patients demonstrated no evidence of node 
involvement while 64 patients had regionally involved lymph nodes.  Overall 5-year survival was 
improved in patients with a greater number of lymph nodes examined regardless of the status of 
the nodes.  For the node-negative group 5-year survivals of 80%, 60%, and 20% were observed 
for patients with greater than 8, 4 to 7, and 0 to 3 nodes respectively examined following radical 
cystectomy.  For patients with positive node disease, a 50% versus a 20% 5-year survival was 
seen if greater than versus less than 11 nodes were examined.  Koppie and colleagues evaluated 
over 1,000 consecutive patients from 11 different surgeons with different extents of dissection.  
They observed that the probability of survival continued to rise with increasing numbers of lymph 
nodes removed up to a threshold of 23 nodes.  (27)  
 
Poulsen et al. reported their group’s experience with 194 patients treated by either limited or 
extended lymph node dissection at the time of radical cystectomy.  (28)  These investigators 
found a significantly greater number of nodes were removed with the extended dissection (mean 
25, range 9 to 67) compared to the limited dissection (mean 14, range 5 to 30).  The extended 
dissection identified a larger percentage of patients with nodal metastases (improved staging).  
For patients where the primary UCB was confined to the bladder wall, positive nodes were 
identified in patients having the extended (12.5%) compared to the limited (8.9%) resection.  The 
potential contribution of the extended, compared to limited, dissection to improved cancer control 
was suggested by a recurrence-free survival at 5 years for the subgroups with tumors confined to 
the bladder wall (tumor stage pT2b or less) (85% versus 64%, p < 0.02) and without evidence of 

 
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lymph node metastasis (stage pT3a or less, pN0) (90 % versus 71%, p < 0.02).  Similarly, local 
recurrence rates (2% versus 7%) and distant metastatic risk (10% versus 21%) was improved in 
patients undergoing an extended dissection compared to a limited dissection.  These data were 
corroborated in a recent update of this series which highlighted the fact that one-third of patients 
had nodal metastasis proximal to the anatomical limits of a node dissection limited to the true 
pelvis only.  (29)  In summary these data provide compelling evidence that an extended node 
dissection may provide a survival benefit for patients undergoing radical cystectomy for UCB.  
Nevertheless, the inherent aforementioned biases and lack of a control arm limits the conclusions 
drawn from these studies. 
 
A review of the contemporary cystectomy literature which includes a mix of standard and 
extended node dissection suggests that a reasonable estimate of disease-free and overall 
survival associated with standard node dissection for patients with muscle invasive bladder 
cancer (≥ T2) is 55% at 3 years and 55% at 5 years (Table 1 and 2) respectively. 
 
Table 1.  Percentage 5 year disease-free survival (DFS) by pathologic stage after radical 
cystectomy with and without pelvic lymph node metastasis: selected series reporting DFS 
(2000-2009) 
 
 
No. of 
Selected 
Series 
PTS 
≤P1 
P2a 
P2 
P2b 
P3a 
P3 
P3b 
P4a,b 
N  
neg 
N 
pos 
All 
pts 
Dalbagni, et al 
(2001) 
300 
Not 
reported 
 
 
 
 
 
 
 
 
 
 
Stein, et al 
(2001) 
1054 
80-88 
 
81 
 
68 
 
47 
44 
78 
35 
68 
Madersbacher, 
et al (2003)    
507 
76 
 
74 
 
 
52 
 
36 
--- 
33 
62 
Hautmann, et al 
(2006) 
788 
90 
 
72 
 
 
43 
 
28 
75 
21 
66 
Shariat, et al 
(2006) 
888 
81 
 
72 
 
 
44 
 
28 
80 
35 
58 
Ghoneim, et al 
(2008) 
2720 
82 
75 
 
53 
 
40 
 
29 
62 
27 
56 
Manoharan, et 
al (2009) 
432 
81 
 
70 
 
 
44 
 
16 
72 
29 
64 
Volkmer, et al 
(2009) 
1270 
Not 
reported 
 
 
 
 
 
 
 
 
 
62 
 
Table 2.  Percentage 5 year overall survival (OS) by pathologic stage after radical 
cystectomy with and without pelvic lymph node metastasis: selected series reporting OS 
(2000-2009) 
 
 
No. of 
Selected 
Series 
PTS 
≤P1 
P2a 
P2 
P2b 
P3a 
P3 
P3b 
P4a,b 
N 
neg 
N 
pos 
All 
pts 
Dalbagni, et al 
(2001) 
300 
64 
63 
59 
58 
23 
26 
28 
27 
 
 
45 
Stein, et al 
(2001) 
1054 
74 
 
72 
 
58 
 
38 
33 
69 
31 
66 
Madersbacher, 
et al (2003)    
507 
63 
 
63 
 
NS 
 
 
32 
--- 
26 
59 
Hautmann, et al 
(2006) 
788 
Not 
reported 
 
 
 
 
 
 
 
 
 
58 
Shariat, et al 
(2006) 
888 
Not 
reported 
 
 
 
 
 
 
 
 
 
 
Ghoneim, et al 
(2008) 
2720 
Not 
reported 
 
 
 
 
 
 
 
 
 
 
Manoharan, et 
al (2009) 
432 
79 
 
60 
 
 
43 
 
17 
69 
22 
59 
 

 
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Accrual capability:  The Study Chairs have consulted extensively with the major centers of 
excellence with respect to the overall management of bladder cancer and specifically radical 
cystectomy as well as surgeons experienced with extended pelvic and iliac lymphadenectomy.  
Prior to protocol development, the Study Chairs conducted a survey in order to understand 
practice patterns and willingness and ability to randomize. Commitments were obtained from 
each of the centers and surgeons surveyed to randomize eligible patients (see table below).  The 
Study Chairs polled 15 urologists practicing at 7 high-volume centers regarding their interest in 
participation in this trial.  Each center agreed to participate in the study and reported that their 
anticipated yearly enrollment in this trial would be up to 340-370 patients annually. 
 
Site 
Surgeons 
# patients potentially 
eligible/year 
Baylor College of Medicine 
Amiel, Lerner 
40 
MD Anderson Cancer Center 
Dinney, Grossman, Kamat 
80 
Memorial Sloan-Kettering Cancer Center 
Bochner, Dalbagni 
50 
Oregon Health and Science University  
Koppie 
20-30 
University of Southern California 
Skinner, Daneshmand 
50-70 
University of Texas Southwestern 
Lotan, Raj, Sagalowsky 
50 
Washington University School of Medicine 
Kibel, Grubb 
50 
Total 
15 surgeons 
340-370 year 
 
The size of the eligible population is estimated as 340-370 annually from these centers alone 
before expanding the trial to additional sites.  We anticipate a high acceptance to the trial by 
patients based on experience with similar trial designs in gastric and esophageal cancers.  These 
are data provided by the surgeons at these sites and represent a high-side estimate of annual 
accrual. There is an obvious large pool of patients for accrual and commitments from each of 
these centers to accrue. In order to achieve an accrual rate of 13 patients/month when each of 
these sites has IRB approval we would require approximately one half of the estimated accrual 
capability from these sites only.  Since this survey, we have obtained commitments from BC 
Cancer Agency (Peter Black), Cleveland Clinic (Andrew Stephenson), Rochester (Edward 
Messing), and University of Texas Health Science Center San Antonio (Robert Svatek and Dipen 
Parekh).  These are high volume SWOG sites.  ALLIANCE formally reviewed and unanimously 
approved the trial.  This will facilitate participation from MSKCC and adds vanguard sites at 
University of Chicago (Gary Steinberg and Norm Smith), Ohio State (Kamal Pohar), and UCSF 
(Max Meng).  ECOG-ACRIN has also agreed to participate and sites expressing interest include 
Vanderbilt (Peter Clark, Mike Cookson, Sam Chang) and UT Southwestern.  If we achieve the 
accrual required to meet the vanguard feasibility portion of the trial, then the trial would be 
expanded to other interested centers in SWOG, ALLIANCE and ECOG-ACRIN that meet the 
credentialing requirements.  
 
Inclusion of Women and Minorities: 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below.  Both men and women of all races and ethnic groups are 
eligible for this study. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
10 
43 
53 
Not Hispanic or Latino 
116 
451 
567 
Total Ethnic 
126 
494 
620 
Racial Category 

 
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Ethnic Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
2 
2 
Asian 
2 
9 
11 
Black or African American 
14 
36 
50 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
110 
447 
557 
Racial Category: Total of all Subjects 
 
126 
494 
620 
 
 
3.0 
DRUG INFORMATION 
 
There is no drug information for this study. 
 
 
4.0 
STAGING CRITERIA (AJCC SEVENTH EDITION, 2010) 
 
Primary Tumor (T) 
 
T2 
Tumor invades muscularis propria 
 
pT2a 
Tumor invades superficial muscularis propria (inner half) 
pT2b  Tumor invades deep muscularis propria (outer half) 
 
T3 
Tumor invades perivesical tissue 
 
pT3a 
Microscopically 
pT3b 
Macroscopically (extravesical mass) 
 
T4 
Tumor invades any of the following:  prostatic stroma, seminal vesicles, uterus, vagina, 
pelvic wall, abdominal wall 
 
T4a 
Tumor invades prostatic stroma, uterus, vagina 
T4b 
Tumor invades pelvic wall, abdominal wall 
 
Regional Lymph Nodes (N) 
 
Regional lymph nodes include both primary and secondary drainage regions.  All other nodes 
above the aortic bifurcation are considered distant lymph nodes. 
 
NX 
Lymph nodes cannot be assessed 
N0 
No lymph node metastasis 
N1 
Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external 
iliac, or presacral lymph node) 
N2 
Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, 
external iliac, or presacral lymph node metastasis) 
N3 
LYMPH NODE METASTASIS TO THE COMMON ILIAC LYMPH NODE 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S1011 Prestudy Form and submit to the Data 

 
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Operations Center in Seattle (see Section 14.0).  Any potential eligibility issues should be addressed to 
the Data Operations Center in Seattle at 206/652-2267 prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 28, 56 or 70 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
Step 1 (Registration) 
 
5.1 
Disease-related Criteria (Step 1) 
 
a. 
Patients must have histologically-proven (T2, T3, or T4a) urothelial carcinoma of 
the bladder (UCB) that requires primary radical cystectomy for definitive 
treatment.  Patients must not have clinical stage consistent with a low-risk of 
node metastasis (CIS only, T1).  Patients with a T4b (fixed lesion) are not eligible 
for this study. 
 
NOTE: Patients with predominant urothelial carcinoma with elements of 
adenocarcinoma, squamous cell carcinoma, micropapillary or minor components 
of other rare phenotypes are eligible.  Patients with predominantly small cell, 
squamous cell, or adenocarcinoma histologies are not eligible. Patients with 
other non-urothelial cancers are not eligible (e.g., sarcoma, lymphoepithelial, 
nested variant).   
 
Clinical stage is based on all of the following: TURBT(s) that determined the 
need for cystectomy, bimanual exam and cross sectional imaging. 
 
b. 
There must be plans for the cystectomy and lymph node dissection (LND) to be 
performed within 28 calendar days following registration.  Laparoscopic surgery 
is not allowed. 
 
c. 
Surgery must be planned to be performed by a pre-approved, study-specific 
credentialed surgeon (see Section 12.1 for credentialing process).  The 
registering physician MUST be the pre-approved, credentialed surgeon intended 
to perform the assigned procedure. 
 
d. 
Patients must not have undergone a prior partial cystectomy for invasive bladder 
cancer.  Patients must not have received any prior pelvic surgery that would 
obviate a complete extended lymphadenectomy (e.g. aorto-femoral/iliac bypass) 
or for whom the surgeon feels that their ability to perform a standard or extended 
pelvic node dissection would be compromised. 
 
5.2 
Prior Therapy Criteria 
 
a. 
Prior neoadjuvant chemotherapy for this cancer is permitted however patients 
must have completed treatment within 70 days prior to cystectomy and recovered 
from all associated toxicities at the time of registration. 
 
b. 
Patients must not have received any prior pelvic irradiation. 
 
c. 
Patients must have no evidence of visceral or nodal metastatic disease proximal 
to the common iliac bifurcation on 2 view chest x-ray or CT of the chest and 
abdominal-pelvic imaging with computerized tomography or MRI of the abdomen 
and pelvis.  Chest x-ray or CT of the chest and CT or MRI of the abdomen and 
pelvis must be obtained within 56 days prior to registration.  PET/CT may be 
used as an alternative to CT or MRI or to resolve possible areas of metastases 
seen on cross sectional imaging. 

 
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5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have bilirubin, SGOT, SGPT and alkaline phosphatase values 
within the institutional upper limit of normal (ULN). These laboratory values must 
be obtained within 28 days prior to registration.  Patients with levels of one or 
more of these enzymes greater than IULN may still be enrolled if metastatic 
disease is excluded with appropriate imaging which may include dedicated liver 
imaging, bone scan, PET, CT, MRI, or biopsy when appropriate. 
 
b. 
Patients must have a complete physical examination and medical history within 
28 days prior to registration. 
 
c. 
Choose one of the following 2 o Patients must have a Zubrod performance 
status (see Section 10.5) of 0, 1, or 2 and in the registering physician’s opinion 
be medically suitable to undergo cystectomy.ptions: 
 
d. 
Women must not be pregnant or nursing at the time of radical cystectomy since 
the surgery and prolonged general anesthesia would place the fetus at 
considerable risk for demise.  The prolonged recovery and debility of the patient 
would severely limit the patients’ ability to nurse and care for an infant. 
 
Women of reproductive potential must agree to use an effective contraceptive 
method at the time of radical cystectomy, throughout the surgical recovery 
period, and during post-operative neoadjuvant chemotherapy (if clinically 
indicated).  A woman is considered to be of "reproductive potential" if she has 
had menses at any time in the preceding 12 consecutive months.  In addition to 
routine 
contraceptive 
methods, 
"effective 
contraception" also 
includes 
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-
effect of pregnancy prevention) defined as a hysterectomy, bilateral 
oophorectomy or bilateral tubal ligation.  However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period 
for use of contraceptive measures outlined in the protocol, she is responsible for 
beginning contraceptive measures. 
 
 
e. 
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease-free for 5 
years. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must be offered the opportunity to participate in specimen banking for 
future use to include the translational medicine studies outlined in Section 15.0. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed 
consent in accordance with institutional and federal guidelines. 
 
b. 
As part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions), the treating institution's identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 

 
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Step 2 (Randomization) 
 
Patients must meet all of the criteria in Step 1 above and be registered to the study in order to be eligible 
for Step 2 (Randomization).  Randomization will occur at the time of surgery following complete intra-
abdominal and pelvic exploration ruling out visceral metastatic disease and gross nodal disease in the 
extended template (common iliac, pre-sciatic [fossa of Marseilles], pre-sacral, para-aortic, pre-aortic, pre-
caval, para-caval) nodes. 
 
5.6 
Disease-related Criteria (Step 2) 
 
a. 
Patients must not have intra-operative evidence of pelvic lymph node 
involvement (confirmed by frozen section) at or above the bifurcation of the 
common iliac vessels in any of the extended template.  Rationale:  Failure to 
excise lymph nodes with known cancer involvement would be a substantial 
deviation from standard of care or may be a cause for abandoning the operation 
in favor of systemic chemotherapy. 
 
b. 
Patients must not have intra-operative evidence of T4b disease. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized using a dynamic balancing algorithm (30) with stratification based on:  
 
a. 
Neoadjuvant chemotherapy:  Cisplatin based, vs. Carboplatin based, vs. Other, 
vs. none. 
 
b. 
Clinical stage T2 vs. T3 or T4a.  NOTE:  Clinical stage is based on all of the 
following:  TURBT(s) that determined the need for cystectomy, bimanual exam 
and cross sectional imaging. 
 
c. 
Zubrod performance status: 0-1 vs. 2. 
 
 
7.0 
TREATMENT PLAN 
 
For surgical-related questions, please contact Dr. Seth P. Lerner at 713/798-6841, Dr. Robert 
Svatek at 210/602-3116, or Dr. Theresa Koppie at 503/346-1500.  For chemotherapy-related 
questions, please contact Dr. Ajjai Alva at 734/936-0091. 
 
7.1 
Timing of Randomization 
 
Randomization will be done at the time of surgery after the exploration in order to 
eliminate any bias in interpretation of the findings of the intra-operative exploration and to 
minimize drop-outs due to a positive finding of metastatic disease outside the standard 
node dissection template. After surgical exploration of the abdomen and pelvis and the 
absence of visceral metastatic and gross positive nodes in any of the extended template 
fields, surgery will then proceed according to randomization assignment. 
 
7.2 
Treatment 
 
a. 
Standard Pelvic Lymph Node Dissection 
 
All potential lymph node bearing tissue to include a complete dissection of the 
external and internal iliac and obturator lymph nodes. All potential node bearing 
tissue should be removed within the following boundaries: laterally the 
genitofemoral nerve; distally Cooper’s ligament to include the lymph node of 
Cloquet; proximally the common iliac (CI) bifurcation; medially the bladder to 

 
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include the tissue medial to the hypogastric artery; and posteriorly the floor of the 
obturator fossa with circumferential mobilization of the external iliac artery and 
vein unless contraindicated due to extensive atherosclerotic vascular disease. 
 
b. 
Extended Pelvic Lymph Node Dissection 
 
This includes the standard pelvic lymph node dissection described in Section 
7.2a plus bilateral common iliac nodes to include the node bearing tissue in the 
pre-sciatic region (fossa of Marseilles), pre-sacral nodes including the node 
bearing tissue anterior to the left common iliac vein and medial to the common 
iliac arteries up to the bifurcation of the aorta. The node dissection may be 
extended proximal to the aortic bifurcation up to the inferior mesenteric artery 
(IMA) to include the distal paracaval, pre-caval, pre-aortic and paraortic lymph 
nodes according to surgeon preference. 
 
7.3 
Adherence to Recommendations for Adjuvant Chemotherapy 
 
For patients who did not receive neoadjuvant chemotherapy, post operative adjuvant 
chemotherapy for pT any, N+ or pT3-4, N0 is strongly recommended but not required and 
will be left up to the treating physician.  The Study Chairs will review the records of all 
patients enrolled to assess adherence to this recommendation.  Non-compliance with this 
recommendation will be addressed by inquiry with the site physicians and coordinators. 
 
7.4 
Submission of Lymph Nodes 
 
At a minimum the standard pelvic lymph node dissection will be submitted to the 
institutional pathologist for routine histology in two separate packets labeled left and right 
pelvic. The extended pelvic lymph node will be submitted in a minimum of 3 packets 
labeled left and right common iliac (including the tissue dissected from the fossa or 
Marseilles - also referred to as pre-sciatic) and pre-sacral. If the nodes are dissected from 
the bifurcation of the aorta proximally then these will be submitted as a separate 
packet(s). All of these regions may be submitted in smaller packets (e.g. external iliac, 
obturator, internal iliac) at the surgeons preference.  The S1011 Intra-Op Surgical 
Assessment Form describing the node packet submission to pathology must be 
completed and submitted to the Data Operations Center in Seattle per Section 14.4b. 
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
Intra-operative complication requiring immediate completion or termination of 
surgery such as myocardial infarction or serious vascular injury. 
 
b. 
When the patient is off protocol treatment and S1011 Surgeon’s 90-Day 
Assessment Form Standard Versus Extended LND has been submitted. 
 
c. 
The patient may withdraw from the study at any time for any reason. 
 
7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the study forms. 
 
7.7 
Follow-Up Period 
 
All patients will be followed for recurrence and survival for a maximum of 6 years after 
Step 2, Randomization or until death (whichever occurs first). 
 
 
8.0 
DOSE MODIFICATIONS 
 

 
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8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
Dose Modifications  
 
There are no dosage modifications for this study. 
 
8.3 
Dose Modifications Contacts 
 
For surgical-related questions, please contact Dr. Seth P. Lerner at 713/798-6841, Dr. 
Robert Svatek at 210/602-3116, or Dr. Theresa Koppie at 503/346-1500.  For 
chemotherapy-related questions, please contact Dr. Ajjai Alva at 734/936-0091. 
 
8.4 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair, the NCI via CTEP-AERS, and to the IRB per local IRB requirements. 

 
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9.0 
STUDY CALENDAR 
 
  
Hospitalization 
Year 1 
Year 2 
Year 3 
Year 
4 
Yea
r 5 
Year 
6 
REQUIRED STUDIES 
PRE 
Day of 
Surgery 
Day of 
Discharge 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
Mo 
  
STUD
Y 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
48 
60 
72 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical Exam   
X a 
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
Height, Weight and 
Performance Status 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hospitalization assessment  b 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse Event/Morbidity 
assessment  c 
  
  
 X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
LABORATORY 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bilirubin  
X 
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
SGOT and  SGPT    
X 
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
Alkaline Phosphatase  d 
X 
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
STAGING 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TURBT 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Bimanual Exam 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X-RAYS AND SCANS   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CT or MRI of abdomen and 
pelvis 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
2 view Chest X-ray or CT of 
the Chest 
X 
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
Bone Scan, PET/CT or other 
imaging directed at potential 
visceral or node metastatic 
sites 
X d  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SPECIMEN SUBMISSION  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Two Paraffin Embedded 
Blocks or 10 unstained slides 
from Primary Tumor 
  
X e 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 8 unstained, formalin-fixed 
paraffin embedded (FFPE) 
sections from the left-pelvic 
and right-pelvic lymph nodes 
  
X e 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Calendar continued on next page.  Click here for footnotes. 

 
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TREATMENT  
(see Section 7.0 for details) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Surgical assessment of nodal 
dissection  f 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Standard or Extended Pelvic 
Lymph Node Dissection 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Submission of Materials for 
Surgical Review  g    
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adjuvant chemotherapy   h 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found 
in Section 14.0.  
 
a 
Physical exam and medical history must be completed within 28 days prior to registration (see Section 5.3b). 
b   
See  S1011 Surgeons Post-Op Data Form (see protocol abstract page, www.swog.org). 
c  
Morbidity data collected on both S1011 Surgeon’s Post-Op Data Form Standard Versus Extended LND and S1011 Surgeon’s 90-Day 
Assessment Form Standard Versus Extended IND (see protocol abstract page, www.swog.org). 
d  
Bone scan required if patient has an elevated alkaline phosphatase or bone pain. 
e 
For patients who consent to specimen banking, specimens must be collected after completion of the final pathologic evaluation. 
f  
See S1011 Intra-Op Surgical Assessment Form (see protocol abstract page, www.swog.org). 
g  
See Section 12.2 
   
h 
For patients who did not receive neoadjuvant chemotherapy, post operative adjuvant chemotherapy for pTany, N+ or pT3-4, N0 is strongly 
recommended, but not required and will be left up to the treating physician. 
 
 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Measurability of lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 
cm  with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All 
tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by 
scan (CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
1. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 
 
4. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
10.2 
Recurrence 
 

 
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Criteria for recurrence will include measurable disease on cross-sectional imaging or 
plane radiography targeting lung, liver and bone as most common sites for recurrence.  
Bone scintigraphy may be used according to Good Medical Practice.  Local pelvic 
recurrence may be determined by cross-sectional imaging and/or DRE (and confirmed by 
biopsy if indicated).  PET/CT may be used to confirm suspicious abnormalities on other 
imaging modalities. 
 
10.3 
Disease-Free Survival 
 
From date of randomization to date of first documentation of relapse/recurrence or death 
due to any cause.  Patients last known to be alive without report of relapse/recurrence 
are censored at date of last contact. 
 
10.4 
Overall Survival 
 
Measured from date of randomization to date of death from any cause.  Patients known 
to be alive are censored at date of last contact. 
 
10.5 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
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, e.g., light 
housework, office work.   
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual Goal 
 
We anticipate that 113 eligible patients will be randomized per year to this study on a 
group-wide basis.  We will also assume that 10 percent of enrolled patients will be found 
to be clinically or pathologically ineligible and hence, not randomized so our Step 1 
sample size will be inflated to account for this.  Based on an extensive review of the 
contemporary literature (see Section 2.0, Table 1), we estimate that 3-year disease free 
survival (DFS) for patients at increased risk for pelvic and iliac node metastasis 
undergoing a standard pelvic lymphadenectomy is 55%.  A poll of centers of excellence 
suggest that a 10-12% improvement in 3-year DFS (65-67%) for patients in extended 
lymphadenectomy would be meaningful and establish extended node dissection as the 
standard of care in this patient population.  Assuming exponential survival, 5 years of 
patient accrual, 3 additional years of follow-up and a sample size of 564 eligible patients 
(282 per arm), the study has 85% power to detect a 28% reduction in the hazard rate of 
progression or death with extended lymph node dissection compared to  limited 

 
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dissection (hazard ratio 0.72).  This corresponds to an improvement in 3-year DFS from 
55% to 65% or alternatively median DFS would be extended from 3.5 to 4.8 years if the 
DFS distributions are exponential.  We will use a one sided stratified log rank test with α 
= 0.025, and the analysis will be intent-to-treat. 
 
Assuming an ineligibility rate of 10%, total accrual (eligible + ineligible patients) to the 
initial step is expected to be 620 patients. 
 
As a secondary endpoint, overall survival is also of great interest.  If extended lymph 
node dissection is found to be statistically significantly better than standard lymph node 
dissection with respect to DFS, then an analysis of the survival endpoint will follow.  We 
will allow for three more years of follow-up after the primary analysis has been conducted 
to assess potential survival differences.  If we assume that the standard arm has 5-year 
survival of 55% then we will have 83% statistical power to detect a hazard ratio of 0.72 
(55% vs. 65% survival at 5 years) using a one-sided stratified logrank test with 
alpha=0.025. 
 
11.2 
Analysis of Primary Endpoint 
 
The trial will first open to selected sites with high volume cystectomy practices (more than 
30 per year).  Each surgeon will be credentialed for enrolling in this vanguard lead-in 
based on review of case logs, operative and pathology reports as well as photographic 
documentation of competence in performing a pelvic and iliac lymphadenectomy 
including standard pelvic plus bilateral common iliac and pre-sacral nodes.  Rationale:  to 
monitor quality control – a) ability to consistently perform extended node dissection and 
completeness of the standard dissection; b) make necessary modifications to protocol if 
needed; c) to monitor effects of neoadjuvant chemotherapy and consistency of adjuvant 
chemotherapy; d) to monitor any morbidity attributable to extended node dissection. 
 
A first feasibility analysis would be conducted after the first 15 patients have been 
randomized.  This analysis will address the feasibility and measurement quality of the 
video and/or photographic documentation of the nodal dissections at each institution by 
surgeon.  The Study Chairs anticipate that the intra-operative photography will be of 
sufficient quality to credibly demonstrate the expected completeness of the node 
dissection.  The video and/or photographs will be analyzed for compliance with the stated 
boundaries of the nodal dissection and feed-back will be given to each center based on 
this feasibility analysis.  Operative and pathology reports will be analyzed for consistency 
with the photographic documentation. 
 
The second feasibility analysis would be conducted 1 year after all vanguard sites have 
IRB approval of this study at which time it is expected that approximately 100 patients will 
have been enrolled.  If the planned accrual rate of 100 patients is not met, consideration 
will be given to closing the study due to lack of feasibility.  However, this is just a 
guideline and there may be extenuating circumstances related to, for example, delays in 
IRB approval that might also be considered.  If the study does reach this initial accrual 
goal, it would be opened up more broadly to other qualifying centers. 
 
If this trial continues past the two feasibility assessments, three formal interim analyses 
are planned to evaluate the efficacy of extended lymph node dissection.  The first will be 
conducted after 25% of the expected events (relapse or death without relapse) have 
been reported on the control arm.  The second after 50% of the events have occurred on 
the control arm, and the third when 75% of the expected events have occurred on the 
control arm.  See the table for number of events and expected time when events will 
occur.  The interim analyses will be conducted based on the number of events in the 
standard LND arm and not the estimated calendar time.  Estimated number of events in 
the experimental arm are provided for descriptive purposes only.  At each interim 
analysis, evidence suggesting early termination of the trial and a conclusion that the 
extended lymph node dissection is no better than standard dissection would be if the 
alternative hypothesis of a 28% improvement in DFS with the experimental arm is 

 
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rejected at the 0.005 level, using an extension of the logrank test that allows for testing a 
relative risk not equal to 1.  In addition, the null hypothesis of no difference in DFS will be 
tested at the one-sided level of 0.005.  If the decision is to continue the study for the full 
specified period, we estimate the final analysis will occur approximately three years after 
completion of accrual.  The final DFS analysis will be conducted when 184 events have 
been observed on the standard LND arm, using a one-sided stratified logrank test with a 
significance level of 0.022 to account for multiple interim testing. 
 
If the DFS analysis is statistically significant, the survival analysis will follow 
approximately two years later when 166 deaths have occurred on the control arm.  The 
stratified logrank test will be performed at the one-sided 0.025 level. 
 
 
 
 
 
 
 
 
 
 
 
With 282 eligible patients randomized to each arm, estimates of morbidity and toxicity 
frequencies can be estimated to within ± 6% (95% confidence interval). 
 
In addition to formally testing DFS at the interim analyses, the DSMC will also consider 
the secondary endpoints of morbidity (intra-operative and up to 90 days post-operatively) 
and survival. 
 
11.3 
Analysis of Surgical Endpoints 
 
Surgical endpoints in patients randomized to extended PLND versus standard PLND will 
also be of interest, including operative time, whether or not nerve sparing was performed, 
morbidity and mortality (intra-operative, peri-operative, and at 90 days), length of hospital 
stay, underlying histology (pure urothelial versus mixed), lymph node counts and lymph 
node density, and whether adjuvant chemotherapy was received. These will be analyzed 
using generalized linear models, with confidence intervals and tests based on robust 
standard errors. Adjustments will be made for multiple comparisons. In patients 
randomized to the extended PLND arm, the proximal extent of node dissection will be 
analyzed in an exploratory manner. Also, the two arms will be compared for differences in 
time to local recurrence, and the time to retroperitoneal soft tissue recurrence using a log-
rank test. 
 
11.4 
Analysis of Translational Medicine Endpoints 
 
Aim: To identify the relationship between expression of markers of epithelial 
mesenchymal transition in the primary bladder tumor with local tumor stage, the burden 
of lymph node metastases, and the likelihood of disease recurrence among patients 
undergoing cystectomy for muscle invasive bladder cancer. 
 
Tumor marker expression will be measured as a function of proportion of cells staining 
and intensity of staining (IHC studies) and/or relative level of mRNA expression 
(compared to internal controls).  Associations between marker expression and nodal 
status (positive vs negative, low disease burden versus high disease burden), and 
neoadjuvant chemotherapy will be tested using chi square test.  Kaplan Meier estimates 
of survival and DFS based on marker expression will be performed and corresponding 
survival and DFS curves will be compared using log rank testing.  Cox proportional 
hazards regression analysis will be performed to estimate hazard ratios for progression 
free survival.  Those analysis will be repeated, stratified by whether patients received 
Interim 
Analysis 
Anticipated 
Analysis 
Time 
Relative to 
Study 
Activation 
Percent of 
Expected 
Information 
On Control Arm 
# of Events 
in the 
Control Arm 
(Standard 
LND) 
Anticipated # of Events 
on Experimental Arm 
(Extended LND) 
(assuming the 
alternative hypothesis) 
1 
38 months 
25% 
46 
34 
2 
56 months 
50% 
92 
70 
3 
73 months 
75% 
139 
108 

 
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neoadjuvant and adjuvant chemotherapy.  Where associations look different by strata, 
formal tests of interaction will be performed in order to assess markers associated with 
chemoresistance. 
 
If we assume that 70% of patients will have adequate tissue samples available based on 
prior SWOG experience with surgical trials, then we will have 396 samples (198 per arm). 
The following table provides estimate of the minimally detectable hazard ratio for 
disease-free survival for those with the tissue marker of interest vs. those without. These 
calculations assume 5 years of accrual, 3 additional years of follow-up, median DFS of 3-
year in those with the marker, a two-sided alpha=0.05 and 80% statistical power.  Similar 
survival hazard ratios can be detected with two additional years of follow-up.  These 
calculations also assume there is no interaction between the marker of interest and the 
randomized treatment assignment (type of lymph node dissection). 
 
 
Prevalence of Tissue Marker 
 
10% 
20% 
30% 
DFS Hazard Ratio for Those with 
versus Those without the Marker 
of Interest 
1.82 
1.57 
1.50 
 
In some cases, there may be a combination of markers that have a multiplicative effect 
on the risk of relapse or death.  In addition to assessing multivariate proportional hazards 
regression models, we will also develop classification and regression trees to assess 
these potential multiplicative effects among the markers. 
 
Although statistical power is lower, we also would like to evaluate whether some tissue 
markers are predictive of DFS and survival in those who receive neoadjuvant 
chemotherapy compared to those who did not.  In other words, we will evaluate the 
marker by chemotherapy interaction, at least in a preliminary fashion.  If we assume the 
following distribution of a tissue marker and neoadjuvant chemotherapy: 
 
 
Prior 
Exposure 
to 
Neoadjuvant 
chemotherapy 
Tissue Marker Status  
(30% prev.) 
 
Yes 
 
 
No 
 
 
Absent 
35%  
HR = .48 
35%  
HR = 1.0 
Present 
15% 
 
15% 
 
 
(and assume 55% 3-year DFS for those without the marker) and we specify a two-sided 
alpha=0.05 then there will be 80% statistical power to detect a difference in DFS hazard 
ratios of 1.0 for the tissue marker absence vs. presence in those without neoadjuvant 
chemotherapy versus a HR = 0.48 for the tissue marker absence vs. presence in those 
with prior chemotherapy, suggesting a predictive tissue marker for chemotherapy 
resistance. 
 
This analysis assumes that type of nodal surgery does not have an impact, and the 
randomized groups are pooled together. 
 
11.5 
Data and Safety Monitoring Committee Oversight  
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of SWOG, three SWOG members, 
three non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every six months from the SWOG Statistical Center, and will meet at the Group's bi-

 
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annual meetings as necessary.  The Committee will be responsible for decisions 
regarding possible termination and/or early reporting of the study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Surgeon Credentialing 
 
Each surgeon must be pre-approved and credentialed to participate in this study.  
Credentialing will be performed by the Study Chairs and will include: 
 
a. 
Completion of accredited urologic residency training (for all participating 
surgeons); 
 
b. 
Cumulative number of radical cystectomies over past 3 years ≥ 50; 
 
c. 
Number of radical cystectomies performed at your hospital(s) (not necessarily by 
one surgeon) > 30/year; 
 
d. 
De-identified operative and pathology reports from five recent radical 
cystectomies; 
 
e. 
Representative intra-operative photos (or edited video) demonstrating complete 
extended pelvic and iliac lymphadenectomy.  Minimum photos required are right 
and left pelvic and extended LND if this was performed showing right and left CI, 
pre-sacral and proximal limit of dissection. 
 
A completed S1011 Surgeon Credentialing Checklist (available on the S1011 protocol 
abstract page on http://swog.org) plus operative reports, pathology reports, and photo 
documentation must be submitted electronically to the SWOG Genitourinary Protocol 
Coordinator at S1011Credentialing@swog.org for distribution to the Study Chairs.  Within 
two weeks of submission of all credentialing information, the SWOG Operations Office or 
Study Chair will notify the surgeon when approved for participation.  No registration will 
be accepted until the surgeon is credentialed.  Credentialing may be subject to review at 
time of audit.  See also Section 14.0 for on-study data submission requirements. 
 
12.2 
Surgery Review 
 
a. 
All surgeries performed as part of this study will undergo a central surgical 
review.  The goal of this review is to verify that the lymph node dissection was 
done according to the assigned randomization and the criteria specified in 
Section 7.0 of the protocol. 
 
b. 
The following are required to be submitted within 14 days of surgery to the 
SWOG Data Operations Center in Seattle (see Section 14.4b): 
 
1. 
S1011 Intra-Op Surgical Assessment Form Standard versus Extended 
LND; 
 
2. 
Digital image(s) of intra-operative photo(s) showing extent of node 
dissection; 
 
3. 
Copy of the operative report(s); 
 

 
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4. 
Copy of corresponding pathology report(s). 
 
The S1011 Urology Study Chairs will review all these data within 7 days of receipt and 
interact with the surgeons at each site to provide feedback in order to ensure the 
consistency of the extent of node dissection in the two arms. 
 
Independent oversight will be provided by the SWOG Surgery Quality Committee who will 
review these data at least annually and make recommendations for improvement in 
monitoring and data collection as needed. 
 
13.0 
REGISTRATION GUIDELINES 
 
NOTE:  Participation in this study is limited to pre-approved, credentialed surgeons.  The 
SWOG Operations Office or Study Chair will notify each surgeon when approved for 
participation.  The registering physician must be the pre-approved, credentialed surgeon 
intended to perform the assigned procedure. 
 
13.1 
Registration Timing 
 
Patients must be registered prior to surgery (no more than 28 calendar days prior to 
planned surgery). 
 
13.2 
Investigator/Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management Branch, 
CTEP, DCTD, NCI.  These forms are available on the CTSU Web site (enter credentials 
at https://www.ctsu.org; then click on the Register tab) or by calling the PMB at 301/496-
5725 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
 
Each investigator or group of investigators at a clinic site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients.  Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
 
Requirements for site registration: 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Oncology Patient Enrollment Network (OPEN) will also ask additional questions that are 
not present on the SWOG Registration Worksheet.  The individual registering the patient 
must be prepared to provide answers to the following questions: 

 
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a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Cooperative Group Credit 
 
f. 
Credit Investigator 
 
g. 
Patient Initials 
 
h. 
Patient’s Date of Birth 
 
i. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
j. 
Country of Residence 
 
k. 
ZIP Code 
 
l. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
m. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
n. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self-Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
o. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated 
with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient in the Rave database.  OPEN can be accessed 

 
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at https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on 
the SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
 
• 
The study site is listed as “approved” in the CTSU RSS. 
 
c. 
Access requirements for OPEN: 
 
• 
Site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account. This is the same account (user ID and 
password) used for the CTSU members' web site.  
 
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the SWOG or CTSU roster:  
 
1. 
If you are a SWOG member, to perform registrations on SWOG 
protocols you must have an equivalent 'Registrar' role on the 
SWOG roster.  Role assignments are handled through SWOG.  
 
2. 
If you are not a SWOG member, to perform registrations on 
SWOG protocols you must have the role of Registrar on the 
CTSU roster. Site and/or Data Administrators can manage CTSU 
roster roles via the new Site Roles maintenance feature under 
RSS on the CTSU members' web site. This will allow them to 
assign staff the "Registrar" role.  
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ 
side 
of 
the 
CTSU 
website 
at 
https://www.ctsu.org 
or 
at 
https://open.ctsu.org.  For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 

 
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14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
14.3 
Data Submission Procedures 
 
Institutions must submit on-study data electronically via the Web by using the SWOG 
CRA Workbench and follow-up data through the Medidata Rave® clinical data 
management system. 
 
a. 
To access the CRA Workbench for on-study data, go to the SWOG Web site 
(http://swog.org) and logon to the Members Area.  After you have logged on, click 
on the CRA Workbench link to access the home page for CRA Workbench 
website.  Next, click on the Pre-Rave Data Submission link and follow the 
instructions.    
 
To submit data via the web the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
 
3. 
You have an active CTEP-IAM account (check at  
https://ctepcore.nci.nih.gov/iam/index.jsp) 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For other difficulties with the CRA Workbench, please email 
technicalquestion@crab.org. 
 
b. 
To submit follow-up data, access to the trial in Medidata Rave® is granted 
through the iMedidata application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access Rave via iMedidata, 
you 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://ctepcore.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating 
organization roster at the enrolling site. 
 
All users at sites that were approved for registrations in RSS will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users must log into 
the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM 
user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page. Please note, site users will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and 

 
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can be accessed by clicking on the link in the upper right pane of the iMedidata 
screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website 
under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk 
at 888/823-5923 or by e-mail at ctsucontact@westat.com.  
 
You may also access Rave® via the SWOG CRA Workbench on the SWOG 
website (www.swog.org) by clicking the link for Rave Data Submission. 
 
c. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do 
not use a cover sheet for faxed data.  Please make sure that each page of all 
faxed data include the SWOG patient number, study ID and patient initials 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF STEP 1, REGISTRATION: 
 
Submit the following: 
 
S1011 Prestudy Form  
 
Operative Report from TURBT 
 
Pathology Report from TURBT 
 
Radiology reports from cross-sectional imaging performed to determine the pre-
REG clinical T stage, e.g. CT, MRI, or PET/CT. 
 
b. 
WITHIN 14 DAYS OF SURGERY, FOR ALL PATIENTS RECEIVING ON-
STUDY SURGERY: 
 
Submit copies of the following: 
 
S1011 Intra-Op Surgical Assessment Form Standard Versus Extended LND  
 
Intra-Op Photos  
(Note:  The Photo Upload Form is located in the data submission section of the 
SWOG CRA Workbench in the S1011 Reg 2 folder under the ‘Follow Up’ tab.  
Photos should be obtained after the randomization and surgical assessment).   
 
Operative Report from cystectomy 
 
Pathology Report from cystectomy 
 
c. 
IF PATIENT CONSENTED, WITHIN 28 DAYS OF RANDOMIZATION: 
 
Submit specimens as outlined in Section 15.0. 
 
d. 
IF 
PATIENT 
NOT 
ELIGIBLE 
OR 
NOT 
CONTINUING 
TO 
STEP 
2 
RANDOMIZATION, WITHIN 14 DAYS AFTER GOING OFF STUDY: 

 
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S1011 Pre-Randomization Off Study Form  
 
S1011 Intra-Op Surgical Assessment Form Standard Versus Extended LND  
(Note:  No Intra-Op photos are required for patients not going on to Step 2, 
Randomization) 
 
e. 
WITHIN 7 DAYS FROM HOSPITAL DISCHARGE: 
 
S1011 Surgeon’s Post-Op Data Form Standard Versus Extended LND  
 
S1011 Adverse Event Form 
 
f. 
WITHIN 90 DAYS POST-SURGERY 
 
S1011 Surgeon’s 90-Day Assessment Form Standard Versus Extended LND  
 
S1011 Adverse Event Form  
 
g. 
AFTER SURGERY, EVERY THREE MONTHS FOR YEAR ONE; EVERY SIX 
MONTHS FOR YEARS TWO AND THREE; AND ANNUALLY UNTIL SIX 
YEARS AFTER RANDOMIZATION OR UNTIL DEATH: 
 
Submit copies of the S1011 Follow Up Form 
(via the Medidata Rave® clinical data management system) 
 
h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and a final S1011 Follow Up Form. 
(via the Medidata Rave® clinical data management system) 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
Specimens for banking and translational medicine studies (submitted to the SWOG Specimen 
Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201) are optional for the 
patient.  
 
Sites must seek additional patient consent for the future use of paraffin embedded tissue (or 
slides).  If patient consents, specimens must be submitted as described below.  Specimens will 
be banked for future use including exploration of the role of epithelial-to-mesenchymal transition 
in bladder cancer metastasis (see Appendix 18.2 for a description of methods).  The translational 
medicine studies will be performed once funding is obtained. 
 
15.1 
Specimen Submission Timepoints 
 
With patient’s consent, specimens must be submitted at the following times (see Section 
9.0): 
 
Within 28 days of randomization, submit: 
 
a. 
Two paraffin embedded blocks (preferred) or 10 unstained slides from the 
primary tumor (allowed, if the primary tumor blocks will not be released) AND a 
copy of the pathology report  
 
b. 
Eight unstained, 4-micrometer (µm), formalin-fixed, paraffin-embedded (FFPE) 
sections from the “left pelvic” and “right pelvic” lymph node packets 

 
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15.2 
Specimen Submission Instructions  
 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp) or via the link on 
the S1011 protocol abstract page on the SWOG website (www.swog.org).  
 
15.3  
Specimen Collection Kits  
 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents.  Adverse events 
are reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse 
events must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe 

 
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expedited adverse event reporting for this protocol. See also Appendix 18.1 for 
general and background information about expedited reporting. 
 
b. 
Reporting methods 
 
This study requires that expedited adverse event reporting use the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). 
CTEP’s guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically 
via 
the 
CTEP-AERS 
web-based 
application 
located 
at 
http://ctep.cancer.gov. 
 
c. 
When to report an event in an expedited manner 
 
When the adverse event requires expedited reporting per Table 16.1 below, 
submit the report within 10 calendar days of learning of the event. 
 
 
d. 
Other recipients of adverse event reports 
 
The Operations Office will forward reports and documentation to the appropriate 
regulatory agencies as required. 
 
Adverse events determined to be reportable must also be reported according to 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
 
e. 
Expedited reporting for surgery-only protocols 
 
Reporting requirements for surgical treatment are provided in Table 16.1. If there 
is any question about the reportability of an adverse event or if on-line CTEP-
AERS cannot be used, please telephone or email the SAE Program at the 
SWOG Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 

 
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Table 16.1. Expedited reporting requirements for adverse events 
experienced by patients who have received surgery on this study.  
 
 
ATTRIBUTION 
 
Grade 4 
 
Grade 5a 
Unexpected 
Expected 
Unexpected 
 
Expected 
 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted using the NCI 
CTEP-AERS within 10 working days of learning of the event. 
 
a 
This includes all deaths within 30 days of the surgical procedure, regardless 
of attribution. Any death that occurs more than 30 days after the surgical 
procedure and is attributed (possibly, probably, or definitely) to the surgery 
and is not due to cancer recurrence must be reported according to the 
instructions above. 
b 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements. You may, 
however, be asked to submit supporting clinical data to the Operations Office 
in order to complete the evaluation of the event. If requested, the specified 
data should be sent by fax to 210-614-0006.  
 
 
 

 
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17.0 
BIBLIOGRAPHY 
 
1  
Lerner SP, Skinner DG, Lieskovsky G, et al. The rationale for en bloc pelvic lymph node 
dissection for bladder cancer patients with nodal metastases: long-term results. J Urol 149: 758-
64; discussion 64-5, 1993. 
 
2  
Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influence bladder cancer outcomes: 
a cooperative group report. J Clin Oncol 22: 2781-9, 2004. 
 
3  
Poulsen AL, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node 
dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 
160: 2015-9; discussion 20, 1998. 
 
4  
Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can 
make a difference. J Urol 128: 34-6, 1982. 
 
5  
Stein JP, Skinner DG. The role of lymphadenectomy in high-grade invasive bladder cancer. Urol 
Clin North Am 32: 187-97, 2005. 
 
6  
Capitanio U, Suardi N, Shariat SF, et al. Assessing the minimum number of lymph nodes needed 
at radical cystectomy in patients with bladder cancer. BJU international 103: 1359-62, 2009. 
 
7  
Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influence bladder cancer outcomes: 
a cooperative group report. J Clin Oncol 22: 2781-9, 2004. 
 
8  
Konety BR, Joslyn SA. Factors influencing aggressive therapy for bladder cancer: an analysis of 
data from the SEER program. J Urol 170: 1765-71, 2003. 
 
9  
Hellenthal NJ, Ramirez ML, Evans CP, deVere White RW, Koppie TM. Trends in pelvic 
lymphadenectomy at the time of radical cystectomy: 1988 to 2004. J Urol 181: 2490-5, 2009. 
 
10  
Steven K, Poulsen AL. Radical cystectomy and extended pelvic lymphadenectomy: survival of 
patients with lymph node metastasis above the bifurcation of the common iliac vessels treated 
with surgery only. J Urol 178: 1218-23; discussion 23-4, 2007. 
 
11  
Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy alone or with para-aortic nodal 
dissection for gastric cancer. N Engl of Med 359: 453-62, 2008. 
 
12  
Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy alone or with para-aortic nodal 
dissection for gastric cancer. N Engl of Med 359: 453-62, 2008. 
 
13  
Farnell MB, Pearson RK, Sarr MG, et al. A prospective randomized trial comparing standard 
pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in 
resectable pancreatic head adenocarcinoma. Surgery 138: 618-28; discussion 28-30, 2005. 
 
14  
Jewett HJ, Lewis EL. Infiltrating carcinoma of the bladder; curability by total cystectomy. J Urol 
60: 107-18, 1948. 
 
15  
Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can 
make a difference. J Urol 128: 34-6, 1982. 
16  
Smith JA, Jr., Whitmore WF, Jr. Regional lymph node metastasis from bladder cancer. J Urol 
1981;126: 591-3. 
 
17  
Wishnow KI, Johnson DE, Ro JY, Swanson DA, Babaian RJ, von Eschenbach AC. Incidence, 
extent and location of unsuspected pelvic lymph node metastasis in patients undergoing radical 
cystectomy for bladder cancer.  J Urol 137: 408-10, 1987. 

 
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18  
Godard H, Koliopoulos A. La cystectomie totale chez la femme dans le cancer de la vessie. Rev 
Chir 51: 201-3, 1932. 
 
19  
Wishnow KI, Johnson DE, Ro JY, Swanson DA, Babaian RJ, von Eschenbach AC. Incidence, 
extent and location of unsuspected pelvic lymph node metastasis in patients undergoing radical 
cystectomy for bladder cancer.  J Urol 137: 408-10, 1987. 
 
20  
Poulsen AL, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node 
dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 
160: 2015-9; discussion 20, 1998. 
 
21  
Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can 
make a difference. J Urol 128: 34-6, 1982. 
 
22  
Leissner J, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional 
cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU international 
85: 817-23, 2000. 
 
23  
Leissner J, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional 
cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU international 
85: 817-23, 2000. 
 
24  
Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influence bladder cancer outcomes: 
a cooperative group report. J Clin Oncol 22: 2781-9, 2004. 
 
25  
Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc pelvic lymph node 
dissection on the number of lymph nodes retrieved in cystectomy specimens. J Urol 166: 2295-6, 
2001. 
 
26  
Koppie TM, Vickers AJ, Vora K, Dalbagni G, Bochner BH. Standardization of pelvic 
lymphadenectomy performed at radical cystectomy: can we establish a minimum number of 
lymph nodes that should be removed? Cancer 107: 2368-74, 2006. 
27  
Koppie TM, Vickers AJ, Vora K, Dalbagni G, Bochner BH. Standardization of pelvic 
lymphadenectomy performed at radical cystectomy: can we establish a minimum number of 
lymph nodes that should be removed? Cancer 107: 2368-74, 2006. 
 
28  
Poulsen AL, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node 
dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 
160: 2015-9; discussion 20, 1998. 
 
29  
Steven K, Poulsen AL. Radical cystectomy and extended pelvic lymphadenectomy: survival of 
patients with lymph node metastasis above the bifurcation of the common iliac vessels treated 
with surgery only. J Urol 178: 1218-23; discussion 23-4, 2007. 
 
30  
Pocock SJ, Simon R.  Sequential treatment assignment with balancing for prognostic factors in 
controlled clinical trials.  Biometrics 31:103-115, 1975. 
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
Translational Medicine Background and Methods 
 

 
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18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.0. 
 
All serious adverse events must also be reported to the local Institutional Review Board 
(IRB). Documentation of this reporting should be maintained for possible inspection 
during quality assurance audits. 
 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
When a study includes both investigational and commercial agents, the following rules 
apply. 
• 
Concurrent administration: When an investigational agent(s) is used in 
combination with a commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent(s) and 
a commercial agent(s) on the same study arm, but the commercial agent(s) is 
given for a period of time prior to starting the investigational agent(s), expedited 
reporting of adverse events that occur prior to starting the investigational agent(s) 
would follow the guidelines for commercial agents. Once therapy with the 
investigational agent(s) is initiated, all expedited reporting of adverse events 
should follow the investigational guidelines. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms. All 
appropriate treatment locations should have access to a copy of the CTCAE. 
 
Step 2:  Grade the event using the NCI CTCAE version specified. 
 

 
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Step 3:  Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
Step 4:  Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in  
• 
the current NCI Agent-Specific Adverse Event List (for treatments using agents 
provided under an NCI-held IND); 
• 
the drug package insert (for treatments with commercial agents only); 
• 
Section 3.0 of this protocol. 
 
Step 5:  Review Table 16.1 in the protocol to determine if there are any protocol-specific 
requirements for expedited reporting of specific adverse events that require special 
monitoring.  
 
Step 6:  Determine if the protocol treatment given prior to the adverse event included an 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
NOTE:  If the patient received at least one dose of investigational agent, follow the 
guidelines in Table 16.1. 
 
NOTE:  This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed possibly, probably, or definitely to the agent(s) must be reported according to 
the instructions in Table 16.1. 

 
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18.2 
Translational Medicine Background and Methods 
 
a. 
Translational Medicine:  Exploring role of epithelial-to-mesenchymal transition in 
bladder cancer metastasis. 
 
 
1. 
Background  
 
Despite the clinical importance of metastasis, much remains to be 
learned about the biology of the metastatic process.  The development 
and progression of cancer is a multistep process.  The classical view of 
metastasis is that during tumor progression, cancer cells acquire multiple 
alterations that render them increasingly competent to establish 
metastatic lesions in specific organs. (1) 
 
Epithelial-to-mesenchymal transition (EMT) is a developmental program 
that plays critical roles in wound healing and solid tumor metastasis. (2) 
The process is characterized by loss of adhesion and cell polarity 
accompanied by cellular invasion and migration.  At the molecular level, 
EMT is associated with loss of expression of E-cadherin, adherens 
junction, and cell polarity genes coupled with increased expression of 
matrix metalloproteases and vimentin, as well as elevated expression of 
transcriptional repressors of E-cadherin, such as Twist, Zeb-1, Zeb-2, 
Snail, and Slug.  Members of the miR200 family of micro RNAs also play 
central roles in maintaining the "epithelial" phenotype by directly binding 
to the transcripts encoding Zeb-1 and Zeb-2, therapy suppressing their 
translation and promoting their degradation. (3,4) The TGFB/bone 
morphogenic protein (BMP) cytokines and other paracrine drivers of the 
EMT phenotype act in part by downregulating expression of the miR200 
family and promoting expression of E-cadherin's repressors. (5) 
 
It has recently been demonstrated that Twist, a repressor of CDH1, may 
promote tumor metastasis by silencing Ecadherin expression and 
inducing EMT. (6)  Twist expression has been associated with higher 
stage and grade for patients with bladder cancer.  Moreover, twist 
expression and loss of E Cadherin in the primary bladder tumors have 
been shown to be independent predictors of disease specific survival for 
patients with bladder cancer. (7) It has also been suggested that Twist 
regulates apoptosis through p53 dependent and independent pathways, 
resulting in chemoresistance to cisplatin and microtubule agents such as 
taxanes, which are frequently used in the treatment of advanced bladder 
cancer.  (8) 
 
The p63 proteins were originally cloned due to their homology to p53.  
However, p63 does not appear to function as a classical tumor 
suppressor, since it is rarely genetically inactivated in epithelial 
malignancies.  Recent work suggests that urothelial cancer stem cells 
retain expression of several of the molecular markers that are expressed 
by the normal basal urothelial cells, including p63.  Nonetheless, other 
studies have concluded that p63 is downregulated in muscle-invasive 
tumors, suggesting that it might in fact function as a tumor suppressor to 
inhibit invasion and metastasis. (9) 
 
Activation of the AKT signaling pathway gives cancer cells a proliferative 
and survival advantage. Dysregulation of the AKT pathway is a frequent 
event in cancer and can occur as the result of several mechanisms, but 
is most commonly due to the inactivation of PTEN via deletion and/or 
mutation, or mutation of PIK3CA, the catalytic subunit of the PI3K protein 

 
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complex.  Recent studies have shown that both PIK3CA mutations and 
PTEN deletions are frequent events in bladder cancer, with 25% of 
tumors having PIK3CA mutations, predominantly in the helical domain, 
and 12% having loss of heterozygosity at the PTEN locus. (10) 
Furthermore, at the expression level, 49% of tumors studied showed 
significant down-regulation of PTEN. (11)  Importantly, it has been 
demonstrated in various settings that AKT has a role in EMT, and that 
this mechanism may be mediated by the activity of MMP.  (12,13,14,15) 
 
Another key regulatory checkpoint dysregulated in bladder cancer is the 
RB/p16 axis, which normally controls transit through the G1-S transition.  
Alterations in both the RB or p16INK4A tumor suppressor genes are 
common events in bladder cancer, occurring as mutations and deletions. 
(16) Interestingly, recent studies have found a linkage between RB 
depletion and EMT through deregulation of E-cadherin, suggesting that 
loss of RB not only affects proliferation, but can also aid in the transition 
to a metastatic phenotype through EMT. (17) 
 
It has been demonstrated that loss of E-cadherin expression 
accompanied by increased expression of matrix metallprotease-9 (MMP-
9) was associated with a poor outcome in patients with muscle-invasive 
urothelial cancer. (18)  More recently, two other groups linked EMT to 
poor outcome in patients.  (19,20)  In addition, in other solid tumors EMT 
is associated with "stemness" and drug resistance.  (21,22) 
 
The goal of this correlative study is to explore the role of epithelial 
mesenchymal transition in the process of metastases and disease 
progression for patients undergoing radical cystectomy for bladder 
cancer. 
 
2. 
Specific hypotheses: 
 
Hypothesis:  Epithelial mesenchymal transition drives lymph node 
metastasis and systemic circulation of tumor cells in patients with muscle 
invasive bladder cancer. 
 
Aim a:  To identify the relationship between expression of markers of 
epithelial-mesenchymal transition in the primary bladder tumor with local 
tumor stage, the burden of lymph node metastases, and the likelihood of 
disease progression among patients undergoing cystectomy for muscle 
invasive bladder cancer. 
 
Aim b:  To correlate the expression of markers of epithelial-mesenchymal 
transition in primary bladder tumors. 
 
3. 
Methods and specimen collection 
 
Sample collection:   
After the patient has consented to the S1011 trial, radical cystectomy 
with lymph node dissection will be performed in a carefully controlled 
fashion per study protocol.  Bladder and nodal specimens will be fixed in 
formalin and paraffin embedded according to a study prescribed 
protocol. Two paraffin embedded blocks representative of the primary 
tumor will be sent to the SWOG biorepository, where tissues will be used 
for tissue microarrays and allocated for RNA extraction. (See Section 
15.0) 
 
Immunohistochemistry protocol: 
The following well-characterized antibodies and corresponding final 
working concentrations will be used for this study: E-Cadherin , mAb, 
Zymed,Cat# 13-1700, 1:1000, Twist, rabbit poly Ab, Santa Cruz 

 
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Biotechnology, clone H81, dilution 1:50;  EGFR , mAb, Zymed  28-005, 
dilution 1:10;  Ki67 (MIB-1), mAb, DAKO, M7240, dilution 1:2000;  P53 
(AB-2), mAb, calbiochem, #0P09L, dilution 1:500;  P63(4A4), mAb, 
Santa Cruz, # sc-8431 , dilution 1:500; pAKT(ser 473), rabbit poly, cell 
Signaling, # 3787L, dilution 1:50;  PTEN mAb, Cascade, ABM-2052, 
dilution 1:75;  RB, mAb, QED, #3101-31-7, dilution 1:1000.   
 
An 
avidin-biotin 
peroxidase 
method 
will 
be 
used 
for 
immunohistochemical staining. Briefly, 6-μm whole-mount sections will 
be deparaffinized in xylene and rehydrated in graded alcohol. 
Endogenous peroxidase will be blocked by immersing slides in 0.1% 
PBS/H2O2 for 15 min. For antigen retrieval, slides will be exposed to 
heating in a microwave oven and 0.01 mol/L citric acid (pH 6) for 15 min. 
After cooling to room temperature, appropriate blocking sera will be 
applied for 30-min incubation followed by 4°C overnight incubation with 
primary antibodies. After extensive washing, adequate secondary 
antibodies (biotinylated horse anti-mouse or goat anti-rabbit, 1:500) will 
be applied for 30-min incubation followed by avidin-biotin complex for an 
additional 30 min. Diaminobenzidine will be used as the final chromogen, 
and then the slides will be counterstained with hematoxylin, dehydrated, 
and mounted.  
 
For each molecular marker, expression will be recorded as the 
percentage of tumor cells with positive immunostaining as well as the 
intensity of staining on a scale of 0-2, where 0=no or weak staining, 
1=moderate staining, and 2=strong staining.   
 
The scoring system utilized will be unique to each marker, as staining 
patterns and their significance differ for each antibody.  When possible, a 
composite score will be used for IHC of the proposed EMT markers, so 
that intensity of staining and proportion of staining can be examined 
concurrently.  In other instances, tissue expression will be scored by the 
proportion of cells stained.  In both cases, analysis will be performed with 
the scores as categorical variables.  For example, in our recent 
publication, staining for E-cadherin was categorized as 0 (negative or 
less than 10% moderate to strong membranous staining in tumor cells), 
1 (≥10%, but less than 50% moderate to strong membranous staining), 
or 2 (≥50% moderate to strong membranous staining), whereas Zeb-1 
was categorized as positive (nuclear staining in ≥10% of tumor cells) or 
negative (no nuclear staining or nuclear staining in <10% of tumor cells).  
The following system is commonly used to score EGFR expression in 
bladder tissues:   zero (undetectable staining or membrane staining in 
less than 10% of the tumor cells), +1 (faint, incomplete membrane 
staining in more than 10% of the tumor cells), +2 (weak to moderate, 
complete membrane staining in more than 10% of the tumor cells), and 
+3 (strong, complete membrane staining in more than 10% of the tumor 
cells). EGFR protein expression is then classified as negative (scores 0 
and 1) or positive (scores 2 and 3). 
 
Real-time Reverse Transcriptase PCR analysis:  
RNA isolation: Total RNA from paraffin embedded tissue samples will be 
isolated using RecoverAllTM Total Nucleic Acid Isolation kit for FFPE 
Tissues (Ambion, Inc) according to the manufacturer protocol. RNA 
purity and integrity will be measured by NanoDrop ND-1000 (Thermo 
Scientific, Wilmington, DE) and Agilent Bioanalyzer (Agilent Technology, 
Santa Clara, CA).  EMT markers (E-cadherin, ZEB1, ZEB2, Vimentin, 
MMP2, MMP9 and p63) will be analyzed by real-time PCR.  
 

 
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Real-time PCR technology (ABI PRISM 7500; Applied Biosystems, 
Foster City, CA) will be used in conjunction with Assays-on-Demand 
(Applied Biosystems). The comparative CT method (1) will be used to 
determine relative gene expression levels for each target gene.  The 
cyclophilin A gene will be used as a internal control to normalize for the 
amount of amplifiable RNA in each reaction. The PCR mixture consisting 
of Taqman Master Mix (without uracil-N-glycosylase), MultiScribe reverse 
transcriptase, RNase inhibitors, and 20 ng (this amount is depends on 
the Standard Curve generated using each set of primers) of total RNA 
will be prepared in a final volume of 25 ul. Thermal cycling will be 
initiated with reverse transcription at 48°C for 30 min and the Taq Gold 
activation step at 95°C for 10 min. The thermal profile for the PCR will be 
95°C for 15 s and 60°C for 1 min. Data will be obtained during 40 cycles 
of amplification. We will use primers/probe sets (Assays-on-Demand) 
which are designed to amplify a shorter amplicon from Applied 
Biosystems to increase the sensitivity of PCR reaction since the integrity 
of RNA from paraffin embedded tissues will be lower relative to RNA 
obtained from fresh frozen tissues.  E-cadherin; Hs00170423_m1, ZEB1; 
Hs00232783_m1, ZEB2; Hs00207691_m1, Vimentin; Hs00185584_m1, 
MMP2; Hs00234422_m1, MMP9; Hs00957562_m1 and Cyclophylin A; 
Hs99999904_m1.  Primers and fluorescent probes for p63 isoforms will 
be designed by Primer Express 3.0 (Applied Biosystems).   
 
For miRNA analysis, total RNA will be reverse transcribed using the 
miRNA-specific TaqMan miRNA Reverse Transcription kits for hsa-miR-
200a, hsa-miR-200b, miR-200c, and miR-429 following the manufacturer 
protocol (Applied Biosystems, Inc.). miRNA expression will be quantified 
using 
commercially 
available 
TaqMan 
miRNA 
assays 
(Applied 
Biosystems, Inc.). Expression will be normalized using TaqMan miRNA 
endogenous control assay RNU24.  Real-time PCR will be carried out on 
an Applied Biosystems ABI PRISM 7500 using TaqMan Universal PCR 
Master Mix, No AmpErase UNG (Applied Biosystems, Inc.). 
 
b. 
Translational Medicine:  Exploring the pre-metastatic niche in muscle-invasive 
bladder cancer 
 
1. 
Background 
 
The ‘seed-and-soil’ hypothesis was proposed by Paget in 1889, and 
suggests that the biological characteristics of certain tissues may foster 
invasion and growth of metastases. (23)  Identification of these 
susceptible areas, termed pre-metastatic niches, has numerous possible 
clinical applications.  For instance, patients with more abundant niches 
may have increased metastatic potential – niche prevalence could 
therefore serve as a personalized supplement to current prognostic 
models. (24)  
 
In bladder cancer, we have generated preliminary data suggesting that 
the pre-metastatic niche may be marked by neutrophils (i.e., CD15+ 
cells). Specifically, we have assessed benign nodal tissue derived from 
20 patients with muscle-invasive bladder cancer. Through an IRB- 
approved protocol (COH IRB 11210), benign lymph node tissue collected 
at the time of cystectomy from a cohort of 20 patients was obtained.  
These patients had (1) a pathologically verified diagnosis of muscle 
invasive disease prior to cystectomy, (2) pT2a-T4N0 disease determined 
at the time of cystectomy, (3) no radiographic evidence of metastasis 
prior to cystectomy, and (4) available paraffin-embedded sections 

 
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encompassing both primary tumor and benign lymph nodes.  From these 
patients, 4 µm sections of benign lymph node tissue were stained with 
monoclonal antibodies directed at VEGFR1 (ImClone Systems) and 
CD15 (a human neutrophil marker; Abcam).  Stained sections for 
pSTAT3 (Santa Cruz Biotechnology) were performed, since recent data 
suggest the potential role of phosphorylated Signal transducer and 
activator of transcription 3 (pSTAT3) in mediating neutrophil recruitment 
to pre-metastatic sites. (25)  Co-localization of VEGFR1 and CD68+ 
macrophages was observed, and sections were stained with a 
monoclonal antibody directed at CD68 (Signet).  Image Pro Plus 
software was used to count positive cells and an average count across 
the 8-100x fields was used for statistical analyses. The median age of 
this cohort was 70 (range, 40-86), and the cohort included a relatively 
balanced number of patients with clinical stage 2 and 3 disease (11 
patients and 9 patients, respectively).  Only 1 patient had received 
neoadjuvant chemotherapy in this cohort, and 2 patients had received 
adjuvant treatment (all 3 patients received cisplatin/gemcitabine as their 
cytotoxic regimen).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A wide spectrum of positive staining was seen for each of the assessed 
biomarkers.  Analyses of overall survival were conducted using the 
Kaplan-Meier method (with the log-rank test) based on subgroups 
characterized by high (above the mean) or low (below the mean) 
biomarker expression.  There was a significant extension of overall 
survival amongst patients with a decreased degree of neutrophilic 
infiltration (P<0.01; Figure 1). Also, lower levels of pSTAT3 were 
associated with improved overall survival (P=0.04; Figure 1).  In contrast, 
no difference in outcome was observed based on VEGFR1 or CD68 
expression above or below median values (P=0.60 and P=0.28, 
respectively).  Also, no difference in survival was observed when 
segregating patients by clinical stage (P=0.73). 
 
2. 
Statistical Plan 
 
The primary endpoint of the clinical study is to determine whether use of 
radical 
cystectomy 
with 
extended 
lymphadenectomy 
yields 
an 
improvement in DFS as compared to radical cystectomy with standard 
lymphadenectomy.  The study uses a historical estimate of 55% 3-year 
DFS in association with standard lymphadenectomy, and suggests that a 
10-12% improvement (i.e., to 65-67%) would be meaningful and 

 
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establish extended lymphadenectomy as a stand of care.  With these 
estimates in mind, assuming exponential survival, 5 years of patient 
accrual, 3 additional years of follow-up and a sample size of 564 eligible 
patients (282 per arm), the study has 85% power to detect a 28% 
reduction in the hazard rate of progression or death with extended 
lymphadenectomy (hazard ratio, 0.72).  Assuming an ineligibility rate of 
10%, total accrual is estimated to be approximately 620 patients. 
 
Several correlative studies have been built into the original protocol.  The 
statistical considerations for the current study are slightly different, as we 
plan to incorporate a testing and validation cohort.  We expect that 395 
patients will have usable lymph node samples as specified in the 
protocol (assuming that tissue is available for 70% of study participants).  
The testing cohort will be comprised of the first half of these patients, or 
approximately 200 patients, and the results from the second 200 patients 
will be used for validating the results. On a case by case basis, some 
patients who are found to be ineligible for the clinical trial due to reasons 
other than pathology may be used for these analyses. 
  
The underlying hypothesis for the correlative studies associated with this 
aim is that biomarker expression levels (i.e., (CD15, pSTAT3, VEGFR1 
and CD68 cell counts in the benign nodal tissue) may predict clinical 
outcome (i.e., DFS).  For each biomarker, recursive partitioning will be 
used to determine the cutoff value of average cell count that maximally 
distinguishes DFS within the training cohort.  These cutoffs will be 
examined in the validation cohort.  
 
Table 1 provides 
an estimate of 
the 
minimally 
detectable 
hazard ratio for 
DFS for those 
with an elevated 
biomarker 
expression level 
(i.e., high CD15 
expression) relative those with a low biomarker expression level.  These 
effect sizes apply equally to the training and validation subsets since the 
sample size will be the same for both. The designation of “high” and 
“low” biomarker expression levels will be based on the cutoffs designated 
in the training cohort.  These calculations assume 5 years of accrual, 3 
additional years of follow-up, median 3-year DFS of 50% in those with 
“high” biomarker expression, a two-sided alpha of 0.05, and 80% 
statistical power. These calculations further assume that there is no 
interaction between the marker of interest and the randomized treatment 
assignment (type of lymph node dissection). Because all currently 
enrolling patients are being offered participation in the banking of their 
lymph node tissue, there will be no loss of sample size for this recently 
activated trial. 
 
In some cases, there may be a combination of biomarkers that have a 
multiplicative effect on the risk of relapse.  Classification and regression 
trees to assess the potential multiplicative effect amongst markers and 
form prognostic groups based on these algorithms will be explored.  
Prognostic models using traditional clinical factors such as clinical stage, 

 
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pathologic stage, age, receipt of neoadjuvant chemotherapy and 
performance status to predict disease-free survival will be developed in 
the training set and the area under the curve (AUC) will be calculated in 
the validation set. (43)  Then, the model that also incorporates markers 
of the pre-metastatic niche (identified in the training set) will also be 
added to the model and the AUC will again be estimated.  A comparison 
of the traditional AUC to the niche AUC will be made to evaluate whether 
these biomarker expression factors contribute to the DFS prognosis in 
this patient population. 
 
Bibliography for 18.2 
 
 
1  
Fidler, I.J., Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. 
Clowes memorial award lecture. Cancer Res 50(19):6130-8, 1990.) 
 
2  
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance 
against the epithelial phenotype? Nat Rev Cancer  7:415-28, 2007. 
 
 
3  
Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to 
mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008. 
 
4  
Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial 
phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 
22:894-907, 2008. 
 
5  
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance 
against the epithelial phenotype? Nat Rev Cancer  7:415-28, 2007. 
 
6  
Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an 
essential role in tumor metastasis. Cell 117:927-39, 2004. 
 
7  
Fondrevelle ME, Kantelip B, Reiter RE, et al. The expression of Twist has an impact on survival in 
human bladder cancer and is influenced by the smoking status. Urol Oncol 27:268-76, 2009. 
 
8  
Kwok WK, Ling MT, Lee TW, et al.  Up-regulation of TWIST in prostate cancer and its implication 
as a therapeutic target.  Cancer Res 65(12):5153-62, 2005. 
 
9  
Urist MJ, Di Como CJ, Lu ML, et al. Loss of p63 expression is associated with tumor progression 
in bladder cancer. Am J Pathol 161:1199-206, 2002. 
 
10  
Platt FM, Hurst CD, Taylor CF, et al.  Spectrum of phosphatidylinositol 3-kinase pathway gene 
alterations in bladder cancer.  Clin Cancer Res 15(19):6008-17, 2009. 
 
11  
Platt FM, Hurst CD, Taylor CF, et al.  Spectrum of phosphatidylinositol 3-kinase pathway gene 
alterations in bladder cancer.  Clin Cancer Res 15(19):6008-17, 2009. 
 
12  
Grille SJ, Bellacosa A, Upson J, et al.. The protein kinase Akt induces epithelial mesenchymal 
transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. 
Cancer Res 63: 2172–2178, 2003. 
 
13  
Larue L, and Bellacosa A, Epithelial-mesenchymal transition in development and cancer: role of 
phosphatidylinositol 3' kinase/AKT pathways, Oncogene 24(50): 7443–7454, 2005. 
 

 
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14  
Onoue T, Uchida D, Begum NM,  et al. Epithelial-mesenchymal transition induced by the stromal 
cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells, Int J Oncol 29: 1133–
1138, 2006. 
 
15  
Kim D, Kim S, Koh H, et al. Akt/PKB promotes cancer cell invasion via increased motility and 
metalloproteinase production, FASEB J 15: 1953–1962, 2001. 
 
16  
Veltman JA, Fridlyand J, Pejavar S, et al.  Array-based comparative genomic hybridization for 
genome-wide screening of DNA copy number in bladder tumors.  Cancer Res 63(11):2872-80, 
2003. 
 
17  
Arima Y, Inoue Y, Shibata T, et al.  Rb depletion results in deregulation of E-cadherin and 
induction of cellular phenotypic changes that are characteristic of the epithelial-to-mesenchymal 
transition.  Cancer Res 68:2104-12, 2008. 
 
18  
Inoue K, Kamada M, Slaton JW, et al. The prognostic value of angiogenesis and metastasis-
related genes for progression of transitional cell carcinoma of the renal pelvis and ureter. Clin 
Cancer Res 8:1863-70, 2002. 
 
19  
Baumgart E, Cohen MS, Silva Neto B, et al. Identification and prognostic significance of an 
epithelial-mesenchymal transition expression profile in human bladder tumors. Clin Cancer Res 
13:1685-94, 2007. 
 
20  
Sayan AE, Griffiths TR, Pal R, et al. SIP1 protein protects cells from DNA damage-induced 
apoptosis and has independent prognostic value in bladder cancer. Proc Natl Acad Sci U S A 
106:14884-9, 2009. 
 
21  
Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with 
properties of stem cells. Cell 2008; 133:704-15. 
 
22  
Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition 
contributes to drug resistance in pancreatic cancer. Cancer Res 69:5820-8, 2009. 
 
23  
Paget S. The distribution of secondary growth in cancer of the breast. Lancet 133:571-3, 1889. 
 
24  
Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285-93, 
2009. 
 
25  
Kujawski M, Kortylewski M, Lee H, et al.  Stat3 mediates myeloid cell–dependent tumor 
angiogenesis in mice. J Clin Invest 118:3367-77, 2008. 
 
 

 
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Informed Consent Model for  S1011 
 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:  
 
This model informed consent form has been reviewed by the DCTD/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  (Institutions 
should attempt to use sections of this document that are in bold type in their entirety.)  Editorial 
changes to these sections may be made as long as they do not change information or intent.  If the 
institutional IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they may be justified in writing by the investigator and approved by the 
IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be forwarded to the SWOG Operations Office for approval before a patient may be 
registered to this study.   
 
Please particularly note that the questions related to banking of specimens for future study 
are in bolded type and may not be changed in any way without prior approval from the 
SWOG Operations Office. 
Readability Statistics:   
 
Flesch Reading Ease  
64.3 (targeted above 55) 
Flesch-Kincaid Grade Level 8.3 (targeted below 8.5) 
 
• 
Instructions and examples for informed consent authors are in [italics].  
• 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
• 
The term "study doctor" has been used throughout the model because the local 
investigator for a cancer treatment trial is a physician.   If this model is used for a 
trial in which the local investigator is not a physician, another appropriate term 
should be used instead of "study doctor".  
• 
The dates of protocol updates in the header and in the text of the consent is for 
reference to this model only and should not be included in the informed consent 
form given to the prospective research participant.  
• 
The local informed consent must state which parties may inspect the research 
records. This includes the NCI, the drug manufacturer for investigational studies, 
any companies or grantors that are providing study support (these will be listed in 
the protocol's model informed consent form) and SWOG.  
 
"SWOG" must be listed as one of the parties that may inspect the research records 
in all protocol consent forms for which patient registration is being credited to 
SWOG.  This includes consent forms for studies where all patients are registered 
directly through the SWOG Data Operations Office, all intergroup studies for which  
the registration is being credited to SWOG (whether the registration is through the 
SWOG Data Operations Office or directly through the other group), as well as 

 
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consent forms for studies where patients are registered via CTSU and the 
registration is credited to SWOG. 
 
• 
When changes to the protocol require revision of the informed consent document, 
the IRB should have a system that identifies the revised consent document, in order 
to preclude continued use of the older version and to identify file copies.  An 
appropriate method to identify the current version of the consent is for the IRB to 
stamp the final copy of the consent document with the approval date.  The stamped 
consent document is then photocopied for use.  Other systems of identifying the 
current version of the consent such as adding a version or approval date are allowed 
as long as it is possible to determine during an audit that the patient signed the most 
current version of the consent form.  
 
*NOTES FOR LOCAL INVESTIGATORS:  
• 
The goal of the informed consent process is to provide people with sufficient 
information for making informed choices.   The informed consent form provides a 
summary of the clinical study and the individual's rights as a research participant.  It 
serves as a starting point for the necessary exchange of information between the 
investigator and potential research participant.  This model for the informed consent 
form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared 
by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/ 
• 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
• 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is titled: "Taking Part in Cancer 
Treatment Research Studies".  This pamphlet may be ordered on the NCI Web site 
at https://cissecure.nci.nih.gov/ncipubs or call 1-800-4- CANCER (1-800-422-
6237) to request a free copy.  
• 
Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with 
your local IRB regarding review of additional materials. 
 
*These notes for authors and investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant.  
 

 
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S1011, “A Phase III Surgical Trial to Evaluate the Benefit of a Standard 
versus an Extended Pelvic Lymphadenectomy Performed at Time of 
Radical Cystectomy for Muscle Invasive Urothelial Cancer.” 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you.  Clinical trials include only people who choose to take part. Please take your time to make 
your decision about taking part.  You may discuss your decision with your friends and family.  
You can also discuss it with your health care team.  If you have any questions, you can ask your 
study doctor for more explanation.  
 
You are being asked to take part in this study because you have bladder cancer that is confined to 
the bladder but invades into the deep portion of the bladder and requires bladder removal with 
removal of the lymph nodes in your pelvis. 
 
Why is this study being done? 
 
The purpose of this study is to compare the effects, good and/or bad, of performing a 
standard lymph node removal versus an extended lymph node removal.  The extended 
lymph node surgery removes additional lymph nodes that are farther away from the 
bladder than those removed during standard lymph node surgery.  Lymph nodes are 
present throughout the body and function normally to fight infection.  They may also trap 
cancer cells that spread from a tumor.  This is also referred to as metastasis.  It is 
important remove the lymph nodes near the bladder to determine if they contain bladder 
cancer cells that have spread beyond the bladder.  While extended lymph node removal is 
done commonly at some centers it is still considered experimental since we do not know if 
the additional surgery improves outcome. 
 
How many people will take part in the study? 
 
About 620 people will take part in this study.   
 
What will happen if I take part in this research study?   
Before you begin the study …  
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
• History and physical examination 

 
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• Blood tests to evaluate your blood counts, kidney function, liver function, and blood clotting 
time 
• Chest X-ray or CT scan of the chest 
• 
CT scan or MRI of the abdomen and pelvis  
• 
Bone scan if your study doctor thinks its necessary 
• 
A biopsy of your bladder tumor 
• 
A manual exam of your bladder 
 
During the study …  
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures during follow-up as outlined below.  They 
are part of regular cancer care.  
• 
Blood tests to evaluate your blood counts, kidney function, and liver function  
• 
Chest x-ray or CT scan of the chest 
• 
CT scan or MRI of the abdomen and pelvis  
 
You will be "randomized" into one of the study groups described below. Randomization means 
that you are put into a group by chance. A computer program will place you in one of the study 
groups.  This will happen after your surgery has started, so you will not know which kind of 
surgery you have received until after your surgery.  Neither you nor your study doctor can choose 
the group you will be in.  You will have an equal chance of being placed in either group. 
 
If you are in Group 1 (often called "Arm A") you will undergo standard lymph node removal at 
the same time that your bladder is removed.   
 
If you are in Group 2 (often called "Arm B") you will undergo an extended lymph node removal 
surgery at the same time that your bladder is removed.   
 
During the surgery, your surgeon will take photos or video demonstrating the extent of the 
surgery.  The doctors coordinating this study will be reviewing the photo(s) and video to verify 
you received the surgery you were randomized to.  When you are finished with the surgery, your 
study doctor will provide standard cancer care for your stage of cancer.  Your study doctor may 
recommend chemotherapy given through the veins if cancer is found in your lymph nodes or if 
the tumor has spread into the fat surrounding the bladder or into adjacent organs and if you did 
not receive chemotherapy before surgery.  Some patients may have received chemotherapy before 
surgery and may receive additional chemotherapy after surgery, depending on the stage of their 
disease and after discussion with their study doctor.  After surgery, you will undergo routine 
follow-up testing including CT scans or MRIs of your abdomen and pelvis, chest x-rays, and 
blood tests of the liver, kidney and blood to look for cancer recurrence which are part of standard 
cancer care.  These tests will be performed every three months for the first year after your 
surgery, every six months for the second and third years, and then once a year until six years after 
your surgery.  As part of the study, you will be followed for 6 years after the surgery. 
 

 
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How long will I be in the study? 
 
After you are finished undergoing the surgery, the study doctor will ask you to visit the office for 
follow-up exams as noted above for 6 years to make sure the cancer has not returned. 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.   
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
surgery can be evaluated by your study doctor.  Another reason to tell your study doctor that you 
are thinking about stopping is to discuss what follow-up care and testing could be most helpful 
for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
 
You have already been informed of the risks associated with your bladder surgery and 
signed a separate surgical consent.  The following are the risks of participating in this 
study. 
 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects that 
may happen.  Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects.  Many side effects go away soon after the surgery.  In 
some cases, side effects can be serious, long lasting, or may never go away.  There is also a 
risk of death. 
 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects related to the surgery include those which are: 
 
Likely 
• Longer operation time if randomized to extended lymph node removal which has a low 
likelihood of increased risk or side effects 
 
Less Likely   
• Small increase in chance of requiring a blood transfusion 
 
Rare but serious 

 
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• Blood clots in your legs 
• Accumulation of lymphatic fluid in your pelvis 
• Both are risks of the procedure in general and could potentially be slightly higher with 
a more extensive node dissection 
 
Reproductive risks:  You should not become pregnant while on this study. (sentence deleted 
3/29/13) It is important you understand that you need to use birth control while on this 
study.  Check with your study doctor about what kind of birth control methods to use and 
how long to use them.  Some methods might not be approved for use in this study.  
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While study doctors 
hope the extended lymph node surgery will be more useful against cancer compared to the 
standard lymph node surgery, there is no proof of this yet. We do know that the 
information from this study will help study doctors learn more about extended lymph node 
dissection as a treatment for cancer.  This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting no treatment 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• Local Institutional Review Board (IRB)  
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• SWOG 
 

 
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A description of this study will be available on http://www.clinicaltrials.gov, as required by U.S. 
Law.  This web site will not include information that can identify you.  At most, the web site will 
include a summary of the results of the study.  You can search this web site any time. 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .  You 
can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the study 
doctor in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.   
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 

 
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We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study. We will tell you about important new information 
from this or other studies that may affect your health, welfare, or willingness to stay in this study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone 
number).  [Note to Local Investigator: Contact information for patient representatives or other 
individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]    
 
 *You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) 
at 888-657-3711 (from the continental US only).  [*Only applies to sites using the CIRB.] 
 
Please note:  This section of the informed consent form is about additional 
research studies that are being done with people who are taking part in the main 
study.  You may take part in these additional studies if you want to.  You can still 
be a part of the main study even if you say 'no' to taking part in any of these 
additional studies. 
 
You can say "yes" or "no" to the following studies.  Please mark your choice for 
each study.   
 
1. 
Future Contact 
Occasionally, researchers working with SWOG may have another research idea that 
relates to people on a SWOG study.  In some cases, to carry out the new research, we 
would need to contact participants in a particular study.  You can agree or not agree to 
future contact. 
I agree to allow my study doctor, or someone approved by my study doctor, to 
contact me regarding future research involving my participation in this study.  

 
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Consent Form for Use of Specimens for Research 
 
About Using Specimens for Research 
 
You are going to have surgery to remove your bladder and the lymph nodes in your 
pelvis. 
 
If you agree, samples of your tumor tissue and/or lymph nodes will be sent to an outside 
lab to study the biology of your cancer.  The tumor tissue and lymph node samples will be 
taken at the time of your surgery. (3/29/13) (You will not need to have another biopsy or 
surgery for this purpose.)   
We would like to keep some of the specimens that are left over for future research. If you 
agree, these specimens will be kept and may be used in research to learn more about 
cancer and other diseases. Please read the information sheet called "How Are Specimens 
Used for Research" to learn more about specimen research.  
The research that may be done with your specimens is not designed specifically to help 
you. It might help people who have cancer and other diseases in the future.  
Reports about research done with your specimens will not be given to you or your doctor. 
These reports will not be put in your health record. The research will not have an effect 
on your care.  
Things to Think About  
The choice to let us keep the left over specimens for future research is up to you. No 
matter what you decide to do, it will not affect your care.  
If you decide now that your specimens can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your 
specimens. Then any specimens that remain will no longer be used for research.  
In the future, people who do research may need to know more about your health. While 
SWOG may give them reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who 
you are.  
Sometimes specimens are used for genetic research (about diseases that are passed on in 
families). Even if your specimens are used for this kind of research, the results will not be 
put in your health records.  
Your specimens will be used only for research and will not be sold. The research done 
with your specimens may help to develop new products in the future.  
Benefits  
 
Yes 
No 

 
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The benefits of research using specimens include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records. We will do 
our best to make sure that your personal information will be kept private.  The chance that 
this information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice. After reading each 
sentence, circle "Yes" or "No."  If you have any questions, please talk to your doctor or 
nurse, or call our research review board at IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1.  
My specimens may be kept for use in research to learn about, prevent, treat 
or cure cancer.  
Yes 
No 
2.  
My specimens may be kept for use in research about other health problems 
(for example: diabetes, Alzheimer's disease, or heart disease).  
Yes 
No 
3.  
Someone may contact me in the future to ask me to allow other uses of my 
specimens.  
Yes 
No 
If you decide to withdraw your specimens from a SWOG Specimen Repository in 
the future, a written withdrawal of consent should be submitted through your study 
doctor to the SWOG Operations Office.  Please designate in the written withdrawal 
whether you would prefer to have the specimens destroyed or returned to the study 
doctor. 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 

 
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You will get a copy of this form.  If you want more information about this study, ask your 
study doctor. 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this 
form.  I have read it or it has been read to me.  I understand the information and have had 
my questions answered.  I agree to take part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________ 
     
 

 
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Specimen Consent Supplemental Sheets 
 
How are Specimens Used for Research? 
 
Where do specimens come from? 
 
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials.  
People who are trained to handle specimens and protect donors' rights make sure that the highest 
standards of quality control are followed by SWOG.  Your doctor does not work for SWOG, but has 
agreed to help collect specimens from many patients.  Many doctors across the country are helping in the 
same way.   
 
Why do people do research with specimens? 
 
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to 
treat it, and how to cure it.  Research using specimens can also answer other health questions.  Some of 
these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. 
 
What type of research will be done with my specimen? 
 
Many different kinds of studies use specimens.  Some researchers may develop new tests to find 
diseases.  Others may develop new ways to treat or even cure diseases.  In the future, some of the 
research may help to develop new products, such as tests and drugs.  Some research looks at diseases 
that are passed on in families (called genetic research).  Research done with your specimen may look for 
genetic causes and signs of disease. 
 
How do researchers get the specimen? 
 
Researchers from universities, hospitals, and other health organizations conduct research using 
specimens.  They contact SWOG and request samples for their studies.  SWOG reviews the way that 
these studies will be done, and decides if any of the samples can be used. SWOG gets the specimen and 
information about you from your hospital, and sends the specimen samples and some information about 
you to the researcher.  SWOG will not send your name, address, phone number, social security number 
or any other identifying information to the researcher. 
 
Will I find out the results of the research using my specimen? 
 
You will not receive the results of research done with your specimen.  This is because research can take a 
long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, but 
they may be helpful to people like you in the future. 
 
Why do you need information from my health records? 
 
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given to 
the researcher may include your age, sex, race, diagnosis, treatments and family history.  This information 
is collected by your hospital from your health record and sent to SWOG.  If more information is needed, 
SWOG will send it to the researcher. 
 
Will my name be attached to the records that are given to the researcher? 
 
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go the researcher.  The researcher will not know who you are. 
 

 
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How could the records be used in ways that might be harmful to me? 
 
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer).  The results of genetic research may not apply only to you, but to your family 
members too.  For disease caused by gene changes, the information in one person's health record could 
be used against family members. 
 
How am I protected? 
 
SWOG is in charge of making sure that information about you is kept private.  SWOG will take careful 
steps to prevent misuse of records.  Your name, address, phone number and any other identifying 
information will be taken off anything associated with your specimen before it is given to the researcher.  
This would make it very difficult for any research results to be linked to you or your family.  Also, people 
outside the research process will not have access to results about any one person which will help to 
protect your privacy. 
 
What if I have more questions? 
 
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number).