A Randomized Phase III Double Blind Clinical Trial Evaluating the Effect of Immune-Enhancing Nutrition on Radical Cystectomy Outcomes
Phase: PHASE3
Conditions: Bladder Carcinoma
Sponsor: SWOG Cancer Research Network

 
 
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PRIVILEGED COMMUNICATION 
 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG CANCER RESEARCH NETWORK 
 
A RANDOMIZED PHASE III DOUBLE-BLIND CLINICAL TRIAL EVALUATING THE EFFECT OF 
IMMUNE-ENHANCING NUTRITION ON RADICAL CYSTECTOMY OUTCOMES (SIMmune) 
TITLE PAGE 
 
NCT # 03757949  
 
STUDY CHAIRS: 
 
Jill Hamilton-Reeves, Ph.D., R.D., C.S.O. 
(Primary Study Chair, Nutritionist)  
University of Kansas Medical Center 
3901 Rainbow Blvd. 
Kansas City, KS 66160 
Phone: 913/588-7650 
FAX: 913/588-8946 
E-mail: jhamilton-reeves@kumc.edu 
 
Jeffrey M. Holzbeierlein, M.D., F.A.C.S. 
(Co-Chair, Urology) 
University of Kansas Medical Center 
3901 Rainbow Blvd. 
Kansas City, KS 66160 
Phone: 913/588-7654  
FAX: 913/588-7625  
E-mail: jholzbeierlein@kumc.edu  
 
BIOSTATISTICIANS: 
 
Joseph M. Unger, Ph.D. 
Danika Lew, M.A. 
Michael Wu, Ph.D. (Translational Medicine) 
SWOG Statistics and Data Management Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue N, M3-C102 
P.O. Box 19024 
Seattle, WA 98109 
Phone: 206/667-4623 
FAX: 206/667-4408 
E-mail: junger@fredhutch.org  
E-mail: dlew@fredhutch.org  
E-mail: mcwu@fredhutch.org  
AGENTS: 
 
IND-Exempt Agents:  
Impact Advanced Recovery® (Nestlé) 
Oral Nutrition Control (Nestlé) 
 
 
 
 
 
 
Janet Baack Kukreja, M.D., M.P.H.  
(Translational Medicine) 
University of Colorado Urology 
Phone: 816/830-5699 
E-mail: Janet.Kukreja@ucdenver.edu 
 
 
 
 
STUDY CHAMPION: 
 
James R. Mark, M.D. 
(GU Medical Oncologist) 
Sidney Kimmel Cancer Center 
Thomas Jefferson University 
1025 Walnut St, Suite 1102 
Philadelphia, PA 19107 
Ph: 215/955-1706 
Fax: 215/923-1884 
Email: james.mark@jefferson.edu  
 
 
 
 
 

 
 
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PARTICIPANTS 
 
U.S.-Only Participants: 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 
See Section 13.2b.3 for site approval requirements 
 
 
 
 

 
 
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TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................................................. 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
PROTOCOL CONTACT INFORMATION ..................................................................................................... 5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.1 
Primary Objective ............................................................................................................................. 8 
1.2 
Secondary Objectives ...................................................................................................................... 8 
1.3 
Tertiary Objectives ........................................................................................................................... 8 
1.4 
Translational Medicine Objectives ................................................................................................... 8 
2.0 
BACKGROUND ............................................................................................................................... 9 
3.0 
PRODUCT INFORMATION ........................................................................................................... 16 
3.1 
Impact Advanced Recovery® / Oral Nutrition Control ................................................................... 16 
4.0 
STAGING CRITERIA ..................................................................................................................... 19 
4.1 
Staging Criteria (AJCC Eighth Edition, 2010) ............................................................................. 19 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 20 
5.1 
Disease Related Criteria ................................................................................................................ 20 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 20 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 21 
5.4 
Specimen Submission Criteria ....................................................................................................... 21 
5.5 
Regulatory Criteria ......................................................................................................................... 21 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 22 
7.0 
TREATMENT PLAN ...................................................................................................................... 22 
7.1 
Pre-Treatment ................................................................................................................................ 22 
7.2 
Treatment: Preoperatively .............................................................................................................. 24 
7.3 
Radical Cystectomy Surgery .......................................................................................................... 24 
7.4 
Treatment: Postoperatively ............................................................................................................ 25 
7.5 
Patient Compliance Document ...................................................................................................... 26 
7.6 
Follow-up Visit (Day 2 after Surgery) ............................................................................................. 26 
7.7 
Follow-up Visit (Day 30 after Surgery, ± 7 days) ........................................................................... 27 
7.8 
Follow-up Visit (90 Days after Surgery, ± 7 days) ......................................................................... 28 
7.9 
Criteria for Removal from Protocol Treatment ............................................................................... 28 
7.10 
Discontinuation of Treatment ......................................................................................................... 28 
7.11 
Follow-Up Period ............................................................................................................................ 28 
7.12 
Unblinding ...................................................................................................................................... 28 
7.13 
COVID-19 Guidance ...................................................................................................................... 28 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 29 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 29 
8.2 
Dose Modifications ......................................................................................................................... 29 
8.3 
Dose Modification Contacts ........................................................................................................... 29 
8.4 
Adverse Event Reporting ............................................................................................................... 29 
9.0 
STUDY CALENDAR ...................................................................................................................... 30 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 32 
10.1 
Measurement of Complications ..................................................................................................... 32 
10.2 
Secondary Endpoints ..................................................................................................................... 32 
10.3 
Disease-Free Survival .................................................................................................................... 33 
10.4 
Overall Survival .............................................................................................................................. 33 
10.5 
Performance Status ....................................................................................................................... 33 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 34 
11.1 
Primary Analysis ............................................................................................................................ 34 
11.2 
Secondary Analysis ........................................................................................................................ 34 
11.3 
Data and Safety Monitoring Committee ......................................................................................... 35 

 
 
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12.0 
DISCIPLINE REVIEW .................................................................................................................... 35 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 35 
13.1 
Registration Timing ........................................................................................................................ 35 
13.2 
Investigator/Site Registration ......................................................................................................... 35 
13.3 
OPEN Registration Requirements ................................................................................................. 39 
13.4 
Registration Procedures................................................................................................................. 40 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 41 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 41 
14.1 
Data Submission Requirement ...................................................................................................... 41 
14.2 
Master Forms ................................................................................................................................. 41 
14.3 
Data Submission Procedures ........................................................................................................ 41 
14.4 
Data Submission Overview and Timepoints .................................................................................. 43 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 45 
15.1 
Blood for Translational Medicine and Banking (REQUIRED) ........................................................ 45 
15.2 
Specimens for the TM Stool Microbiome (REQUIRED IF PATIENT CONSENTS) ....................... 48 
15.3 
Questionnaires: Instructions for administration .............................................................................. 50 
15.4 
Phone Interview: 24 Hour Diet Recalls .......................................................................................... 51 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 52 
16.1 
Adverse Event Reporting Requirements ........................................................................................ 52 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 56 
18.0 
APPENDIX ..................................................................................................................................... 65 
18.1 
Product Compositions .................................................................................................................... 66 
18.2 
Tertiary Objectives ......................................................................................................................... 67 
18.3 
Body Composition Assessment by Dual-Energy X-ray Absorptiometry ........................................ 72 
18.4 
S1600 Patient Intake Calendar ...................................................................................................... 73 
18.5 
PG-SGA ......................................................................................................................................... 85 
18.6 
24-hour Dietary Recall ................................................................................................................... 87 
18.7 
S1600 Site Requirements Form .................................................................................................. 94 
18.8 
Guidelines for Emergency Unblinding of Coded Intervention ........................................................ 95 
18.9 
Translational Medicine Study Stool Microbiome ............................................................................ 97 
18.10 
SWOG Biospecimen Processing Instructions .............................................................................. 105 
 

 
 
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PROTOCOL CONTACT INFORMATION 
 
 
Patient Advocate 
Amy Geschwender, Ph.D. 
E-mail: ageschwender@gmail.com  
 
Eligibility, RAVE, Data Submission: 
 
SWOG Statistics and Data Management Center  
E-mail: cancercontrolquestion@crab.org   
or Phone: 206/652-2267 
 
Regulatory, Protocol, Informed Consent: 
 
SWOG Operations Office 
E-mail: protocols@swog.org or Phone: 210/614-8808 
 
 
Medical Queries (treatment or toxicity related 
questions): 
 
Email: jhamilton-reeves@kumc.edu or call:  
Jill Hamilton-Reeves, Ph.D., R.D., C.S.O. or Phone: 
913/588-7650 
Patient-Generated 
Subjective 
Global 
Assessment (PG-SGA) 
Prior 
to 
registration 
or 
using 
telemedicine: 
edgelab@kumc.edu 
Study visit procedures, phone interviews, and 
PG-SGA 
Study Team Email: S1600@swog.org 
 
Specimen 
Tracking 
System 
(STS) 
Amendments, Errors, Connectivity Issues and 
Technical issues with the SWOG CRA 
Workbench: 
 
technicalquestion@crab.org 
 
Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-
IAM) 
 
To review CTEP-IAM account (new requests, reset 
passwords): 
 
 https://ctepcore.nci.nih.gov/iam/index.jsp 
Access to iMedidata Rave  
See Protocol Section 14.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or  
Email: ctsucontact@westat.com 
Questions related to: 
Oncology 
Patient 
Enrollment 
Network 
(OPEN) 
See Protocol Section 13.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or  
Email: ctsucontact@westat.com 
Patient Transfers: 
patienttransfer@crab.org 
Serious Adverse Event Reporting questions:  
See Protocol Section 16.1  
Email: adr@swog.org  

 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the 
Regulatory 
Submission 
Portal. 
 
Sign in at www.ctsu.org, and 
select 
the 
Regulatory 
Submission. 
 
Institutions with patients waiting 
that are unable to use the Portal 
should 
alert 
the 
CTSU 
Regulatory Office immediately at 
1-866-651-2878 
to 
receive 
further instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
 
Refer to the patient enrollment 
section 
of 
the 
protocol 
for 
instructions on using the Oncology 
Patient 
Enrollment 
Network 
(OPEN). OPEN can be accessed 
at 
https://www.ctsu.org/OPEN_SYS
TEM/ 
 or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Refer to the data 
submission 
section 
of 
the 
protocol for further instructions.  
: 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy 
the 
CTSU 
on 
data 
submissions. 
 
Other 
Tools 
and 
Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG CRA 
Workbench. 
via 
the 
SWOG 
website (www.swog.org)  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-
IAM username and password.  
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center (SDMC) by phone or email: 
206/652-2267 
cancercontrolquestion@crab.org   
 
For treatment or toxicity related questions contact the Study Chairs by phone or email: Jill Hamilton-
Reeves, Ph.D., R.D., C.S.O, phone: 913/588-7650 or email jhamilton-reeves@kumc.edu; or Jeffrey M. 
Holzbeierlein, M.D., phone 913/588-7654 or email jholzbeierlein@kumc.edu  
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org  
 
 
 

 
 
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SCHEMA 
 
Patients Diagnosed with Bladder Cancer Planning To Receive Radical Cystectomy 
 
 
 
 
Randomize 
 
 
 
 
Blinded Nutrition Therapy 
 
 
Blinded Nutrition Therapy 
(Specialized Immune-Modulating Nutrition Drink)      vs                            (Oral Nutrition Control Drink) 
 
 
 
Prior to beginning Nutrition Therapy: Specimen submission, DXA scan, laboratory values, patient-
completed questionnaires, diet recall phone interview 
 
 
 
 
Nutrition Therapy 
 (Days -5, -4, -3, -2, -1) 
 
 
 
 
 
Radical Cystectomy Surgery (Day 0) 
 
 
 
 
 
Nutritional Therapy  
(Days 1, 2, 3, 4, 5) 
 
 
 
Day 2: Specimen submission, laboratory values 
 
 
 
30-Day Assessment of Surgical Complications 
Specimen submission, DXA scan, laboratory values, patient-completed questionnaires, diet recall phone 
interview 
 
 
 
90-Day Assessment of Surgical Complications 

 
 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To compare the impact of consuming perioperative specialized immune-
modulating drinks (SIM, Impact Advanced Recovery®, Nestlé) to oral nutrition 
supplement control drinks (ONS, Oral Nutrition Control, Nestlé) on post-operative 
complications (any vs. none) within 30 days after scheduled radical cystectomy 
(RC). 
 
1.2 
Secondary Objectives 
 
a. 
To assess whether SIM use compared to ONS reduces late-phase post-operative 
complications within 90 days after scheduled RC. 
 
b. 
To assess whether SIM use compared to ONS reduces infections. 
 
c. 
To assess whether SIM use compared to ONS reduces skeletal muscle wasting.  
 
d. 
To assess whether SIM use compared to ONS reduces high grade post-operative 
complications. 
 
e. 
To assess whether SIM use compared to ONS reduces readmission rates.  
 
f. 
To assess whether SIM use compared to ONS improves quality of life.  
 
g. 
To assess whether SIM use compared to ONS improves disease-free survival after 
surgery and overall survival. 
 
1.3 
Tertiary Objectives 
 
a. 
To assess the impact of SIM use on the expansion of myeloid-derived suppressor 
cells.  
 
b. 
To assess the impact of SIM use on pro-inflammatory cytokines and neutrophil: 
lymphocyte ratios. 
 
c. 
To assess the impact of SIM use on post-operative arginine deficiency and amino 
acid metabolism. 
 
d. 
To explore the association of dietary intake variables (nutrition status, calories, 
protein, and immune-enhancing factors) and study outcomes. 
 
1.4 
Translational Medicine Objectives 
 
a. 
To describe the microbiome of the gut in patients undergoing radical cystectomy 
and urinary diversion prior to initiation of immunonutrition or a nutrition control. 
 
b. 
To define the microbiome change in patients undergoing radical cystectomy and 
urinary diversion after they have received blinded immunonutrition or control 
nutritional supplement.  
 
c. 
To correlate cancer treatments, postoperative complications (specifically 
infections) and nutritional status with microbiome composition. 

 
 
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2.0 
BACKGROUND 
 
Bladder cancer (BCa) is common. The standard treatment for advanced BCa involves radical 
cystectomy (RC), which is plagued by very high rates of complications and mortality. (1,2) RC 
impairs gut function and metabolism in part due to reconstruction which routes urine through 
intestinal segments. As a result, infection, rapid skeletal muscle wasting, and other complications 
are common. (3,4,5,6) New surgical care pathways preserve gut function after RC and have 
opened a new potential avenue for intervention: perioperative nutrition. (7,8) Preliminary studies 
are promising; however, there is a critical need to identify the most effective forms of perioperative 
nutritional support, and to determine their impact on RC surgical outcomes. Without this care, RC 
will continue to save lives, but at a high cost in terms of downstream adverse surgical complications. 
 
Our long-term goal is to unlock the potential of nutrition interventions to improve outcomes, survival, 
and quality of life in cancer patients. The objective of this project is to determine the impact of a 
specialized form of nutritional support on surgical outcomes and to better understand the 
mechanisms by which it acts. 
 
Poor nutritional status is associated with higher complication rates after RC. (9,10,11) Specialized 
Immunonutrition (SIM) is fortified with nutrients (L-arginine, omega-3 fatty acids, dietary 
nucleotides, and vitamin A) that have immediate effects on immune and inflammatory responses, 
muscle sparing, and wound healing after surgery. In a randomized pilot trial of 29 patients, we 
found that giving SIM before and after RC reduced post-operative complications by 33% and most 
notably, reduced infections by 39% compared to 
an identical Oral Nutrition Support (ONS) lacking 
the immuno-modulators. (12) After RC, the SIM 
intervention significantly restrained the expansion 
of myeloid derived suppressor cells (MDSC), 
dampened 
the 
post-surgical 
inflammatory 
response with a reduced magnitude of IL-6 
elevation, and reduced muscle wasting by 10% 
compared to ONS. (13,14) Using perioperative 
SIM may benefit patients undergoing RC in a way 
that standard nutrition supplementation cannot. 
While the results of our pilot study are 
encouraging in that they show SIM improves 
immune response, a larger clinical trial is needed 
to 
definitively 
confirm 
whether 
SIM 
can 
significantly reduce post-operative complications. 
(15) A reduced post-operative complication rate 
is the key surgical outcome that would influence 
adoption of a new intervention aimed at improving 
the safety of RC.  
 
 
 
 
 
 
Bladder cancer is prevalent and treatable, but morbidity, recurrence, and mortality are high. BCa is 
the fourth leading cancer in men, the sixth most common cancer in the United States, and has the 
highest lifetime treatment cost of all cancers. (16,17,18) Furthermore, up to 30% of all newly 
diagnosed patients present with muscle-invasive BCa. (19) The American Society of Clinical 
Oncology recently endorsed treatment guidelines for muscle-invasive BCa to include neoadjuvant 
Figure 1: MDSCs after RC, Eur Urology, 69(3), 2016 

 
 
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chemotherapy followed by radical cystectomy (RC). (20,21) Unfortunately, RC is associated with 
high rates of post-operative complications (66%), infections (25%), and cancer recurrence (34%). 
(22,23,24) Ninety-day mortality rates are 7%. (25) 
 
Immune suppressive factors lead to complications. It is plausible that many complications 
associated with RC are initiated by an exaggerated adaptive immune suppression and 
inflammatory response, especially infections and muscle wasting. Major surgeries disrupt T helper 
(Th)1-Th2 balance to a Th2 predominant response which impairs cell mediated immunity, leaving 
patients more susceptible to infection. (26) Myeloid-derived suppressor cells (MDSC) are immune 
cells that expand rapidly after physical injury but quickly differentiate into granulocytes, 
macrophages, or dendritic cells. MDSC accumulation suppresses T-cells, and lowers the 
resistance to infection. MDSCs express and release arginase-1, depleting plasma arginine 
concentrations. (27) Arginine deficiency imposed by surgery impairs T-cell function, contributes to 
protein degradation from muscle, impairs wound healing, and negatively affects blood flow and 
tissue oxygenation needed for healing. The pilot data show that SIM counteracts the Th1-Th2 shift 
(P=0.027), restrains the expansion of immune suppressive cells [MDSCs; between groups over 
time P=0.005 and significantly lower in SIM 2 d after RC (P<0.001); Figure 1], and lowers the 
neutrophil:lymphocyte ratio (P=0.039) compared to ONS. (28,29)  
 
Rapid weight loss and muscle wasting 
following RC are commonly observed. 
(30,31) Interleukin (IL)-6 is released in 
response to surgery, and the magnitude of 
IL-6 elevation is associated with post-
operative 
complications 
and 
muscle 
wasting. (32,33,34) Therefore, a strategy 
to prevent an exaggerated post-surgical IL-
6 response may be an effective way to 
reduce 
common 
complications. 
We 
reported 
lower 
post-operative 
IL-6 
(P=0.020; Figure 2) and a trend of less 
profound 
appendicular 
muscle 
loss 
(P=0.078; Figure 3) in RC patients 
consuming SIM compared to ONS. (35) 
 
Figure 2: IL-6 after RC, Journal of Urology (in review) 

 
 
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Improving nutritional status before and after RC is a promising approach to reducing post-operative 
complications. Many cystectomy patients have poor nutritional status at completion of neoadjuvant 
chemotherapy, which is then compounded by the catabolic effects of RC. (36,37) Using the 
Nutritional Risk Screening (NRS-2002) tool, between 21-55% of patients were found to be at risk 
of malnutrition before cystectomy. (38,39,40,41) However, using a more robust, validated, 
malnutrition screening and assessment tool, the Patient-Generated Subjective Global Assessment 
(PG-SGA), we found that 27.6% of patients were moderately or severely malnourished before 
surgery. (42) Given the short lag time between diagnosis and surgery and the likely feeding issues 
from neoadjuvant chemotherapy, 
reversing malnutrition prior to 
surgery 
is 
not 
realistic. 
Impracticality is compounded by 
the disproportionate burden of 
this disease in smokers and the 
frail elderly. However, there are 
promising data showing that 
short term supplementation with 
L-arginine, omega-3 fatty acids, 
dietary nucleotides, and vitamin 
A before and after surgery has 
profound and measurable acute 
effects 
on 
immune 
and 
inflammatory response, muscle 
preservation, 
and 
blood 
flow/tissue 
oxygenation. 
Effective nutrition interventions 
are a critical unmet need given 
that evidence showing that 
complications and death after 
RC may be attributable to poor nutritional status. (43,44,45,46)  
 
The goal of perioperative use of SIM is not merely to serve as the substrate for nutritional 
improvement but to influence the intensity and perhaps the duration of the systemic inflammatory 
response underlying the protein catabolism of cancer, major surgery, and infection.  Thus, if the 
catabolic effect of surgery is diminished by SIM, then there will be short and long-term benefit for 
net anabolism. A nitrogen balance test would not be valid in this setting; therefore, we focus on 
body composition because lean tissue loss has severe pathologic consequences.  We aim to 
prevent muscle degradation from amino acid deficiencies and elevated pro-inflammatory cytokines 
induced by surgery. The dual-energy X-ray Absorptiometry time points were chosen based on 
longitudinal body composition data from RC patients in our pilot and from Mathur et al. (47) This 
study reported a 7% loss in total body protein, two weeks following RC. Six months later, only 63% 
of the lost muscle was regained. (48) In our pilot, appendicular skeletal muscle Index (muscle in 
the arms and legs) was better preserved in the SIM group with a 7% loss compared to a 17% loss 
in the ONS group, two weeks following RC (P=0.078; Figure 3). (49) However, we found many 
patients felt too ill to return for a scan two weeks after surgery, but most patients felt well enough 
to return at 30 days for a scan. The appendicular skeletal muscle was very similar at two weeks 
and 30 days post-surgery. The FAACT trial outcome index and anorexia subscales were used in 
our pilot and the SIM showed better quality of life scores than the ONS group but the differences 
were not statistically significant (P=0.15 for both), but the pilot was underpowered for this outcome. 
Also, the anorexia and cachexia subscale asks about issues common after RC such as: taste 
alterations, appetite, early satiety, and pain while eating. These data are crucial for optimizing 
nutrition interventions to help patients. 
 
Figure 3: Loss of uscle in the arms & legs after RC, Journal of Urology (in 
review). 

 
 
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Feeding the gut before and after RC surgery is a new opportunity. Few nutrition intervention studies 
in the cystectomy population have been published. Before enhanced recovery after surgery (ERAS) 
pathways were widely adopted, only parenteral nutrition (TPN) studies or pre-surgery oral 
supplements had been used for nutritional support. (50,51,52) A recent study in RC showed that 
following a regular healthy diet decreased the length of stay compared to TPN post-operative 
feeding. (53) Similar to other surgical nutrition support literature, TPN in RC has led to higher 
infection rates when compared to consuming a regular diet (32% vs 11%; p = 0.001). (54) These 
data are not surprising since the guidelines from the Society of Critical Care Medicine/American 
Society of Parenteral and Enteral Nutrition (SCCM/ASPEN) suggest that enteric feeding is best to 
maintain gut integrity and modulate the immune response. (55)  
 
Specialized immunonutrition (SIM) before and after surgery has strong potential for reducing post-
operative complications. The SCCM/ASPEN Critical Care guidelines recommend that surgical 
patients consume perioperative immune modulating formulas that include arginine and nutrient 
combinations along with arginine, regardless of baseline nutrition status. (56) The quality of 
evidence for this recommendation was determined to be moderate to low revealing that we do not 
have the most robust scientific evidence. Although the notion of SIM to improve surgical outcomes 
has been studied since 1992, there is a surprising gap in the understanding of how SIM works. (57) 
Moreover, the literature is riddled with underpowered studies. Other issues that weaken the 
evidence are studies that lack a calorie and protein matched control, use non-uniform dosing, and 
use self-report rather than nutrient biomarkers as objective measures of compliance. 
(58,59,60,61,62,63,64) Additionally, meta-analyses of SIM draw mixed or conflicting conclusions, 
adding to the confusion. (65,66,67) In addition, in over two decades, this very simple formula has 
only undergone one minor reformulation (the sugar content was lowered). Thus, a large, well- 
designed, adequately powered, clinical trial in this area is needed to help RC patients, drive 
knowledge discovery, and generate hypotheses for ways to improve nutrition strategies for even 
better surgical outcomes.  Although randomized controlled trials (RCTs) with iso-caloric and iso-
nitrogenous controls have provided clues as to how SIM might improve surgical outcomes or offer 
no benefits, key knowledge gaps remain. (68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84) 
 
Our scientific premise is that SIM has high potential as an effective, low-risk, and ground-breaking 
strategy to improve surgical outcomes and quality of life for patients with bladder cancer who 
undergo RC. Published data show that this is a promising strategy, but these studies lack scientific 
rigor which has manifested and enabled ambiguity and thus no change in the standard of care. Our 
study is designed to provide conclusive evidence about the efficacy of this approach. A negative 
study would be highly informative and go far towards putting this concept to rest; a positive study 
would change practice. However, even a negative study has the potential to provide important 
information about disease mechanisms and biology. The carefully selected mechanistic work will 
be conducted in experienced laboratories that are either CLIA-certified or have published data for 
their endpoints demonstrating their capabilities. The key correlative aims were chosen to drive 
discovery.  
 
• 
Cystectomy has been overlooked and understudied. To change practice, it is important to 
study the effect of the intervention in the surgical context in which it is used, especially 
given the uniqueness of, and high rate of morbidity in, RC. To date, there are only two 
published studies in this area. In a small (n=60), case-controlled, pilot study in the RC 
population, Bertrand and colleagues reported that SIM taken before surgery resulted in a 
reduction of 30 day  post-operative complications (40% vs. 77% in the historical control) (P 
= 0.008) and infection rates (23% vs. 60% in the historical control) (P = 0.008). (85) 
However, this study is limited by the use of historical controls. Our group has previously 
published the only blinded RCT of immunonutrition in RC. (86)  
 
• 
How does immunonutrition work? Studies of how the SIM works and correlative 
mechanisms are limited, usually with very small subsets of patients within larger studies. 
(87,88,89) Our preliminary data on a possible mechanism is promising. The studies 

 
 
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proposed will provide insight into mechanisms and will inform what can be done to optimize 
nutrition interventions. For knowledge discovery, it is critical to know how the nutrition 
intervention is changing both biology and clinical outcome.  
 
• 
Only two large trials in the United States. Large double-blind randomized controlled trials 
of SIM are very limited in the US with only two published studies across all malignancies, 
both published in the 1990s: a post-operative feeding only trial in upper GI (n = 85; 2 arms) 
and peri-and postoperative in head/neck (n = 136; 4 arms). (90) Undoubtedly, our 
knowledge base has grown since these studies were conducted with further insight about 
immunology and better surgical practice. Since the 1990’s most of the work in this field has 
taken place outside of the US. Importantly, there are other unmeasured differences 
between the healthcare system in the US and other countries where this work has been 
conducted. The surgical approach, the market in cystectomy care, and the peri-operative 
pathways and inpatient stays are drastically different. For example, a recent well-designed 
large (n = 264) multi-center trial conducted in Spain found that colorectal patients 
administered perioperative immunonutrition had fewer 30-day complications than the 
control group (23% vs. 35%, P=0.035). (91) These data are encouraging and would 
suggest that our results will be positive, but the same gaps remain: correlative translational 
science, data from RC which is a more morbid surgery than colorectal surgery, and data 
from US practices.  
 
SIM nutrients (L-arginine, omega-3 fatty acids, and dietary nucleotides) have immediate biological 
effects that set the stage for improved surgical outcomes later. Most of the SIM studies mentioned 
above use a short-term feeding strategy before and after surgery. A short intervention works 
because the nutrients act on acute mechanisms that occur perioperatively. Arginine supply is vital 
to the immune response as T-cells need it for healthy immune function (for lymphocyte proliferation 
and T-cell receptor integrity).  (92) Surgery depletes the arginine supply. A group of immune cells, 
MDSCs, expand due to the predominant Th2 response following surgery. MDSCs contain 
Arginase-1 which rapidly depletes arginine by metabolizing it to ornithine and urea. In turn, the 
arginine necessary for the proliferation of lymphocytes and the formation of nitric oxide for tissue 
oxygenation is insufficient, resulting in an increased risk of infection and poor wound healing. 
Mechanistic work by Fletcher et al. showed that L-arginine deprivation induces MDSC expansion; 
we discovered that the reverse is also true, supplementing L-arginine as part of SIM suppresses 
MDSC expansion. (93,94) Emerging data suggest cancer-induced cachexia (muscle wasting) may 
also be partly driven by the expansion of MDSCs. Arginine deficiency triggered by surgery impairs 
protein synthesis and healing because arginine is a conditionally indispensable amino acid in states 
of tissue injury and repair. Therefore, inadequate arginine even in the absence of a dramatic 
change in MDSC counts will lead to muscle degradation.  
 
Omega-3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), 
modulate immune cell function and inflammation through a variety of pathways. (95) Resolvins and 
protectins, derived from EPA and DHA, speed up the resolution of inflammation and improve 
healing after surgery. (96) Clinical data also show that EPA and DHA improve wound healing. (97) 
EPA also inhibits muscle degradation relevant to the muscle-wasting process. (98)  Vitamin A, as 
all-trans retinoic acid, promotes the maturation of MDSCs. Mature myeloid cells lose the capacity 
to suppress T cell function. (99) Under conditions of surgical stress, dietary nucleotides become 
essential—they stimulate lymphocyte differentiation and contribute to T cell homeostasis to the 
Th1-dominated response. (100) 
 
The S1600 trial prepares for and corrects the nutrient (arginine) deficiency known to be triggered 
by surgery in a very brief (10 day) intervention. 
 
 

 
 
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Arginine deprivation has detrimental effects on patient outcomes after surgery.  Data from Bobak 
et al. (101) demonstrate that arginine deprivation using ADI-PEG induces endoplasmic reticulum 
stress in human solid tumor cell lines. Arginine deprivation increases tumor resistance to immune 
editing by the immune suppressive effects of MDSC expansion and reduced T cell proliferation. 
Arginine deficiency may also lead to wound breakdown, muscle wasting, thrombosis, and infection 
susceptibility. In summary, our objective is to support the patients’ overall acute nutritional needs 
for a healthy surgical recovery without imposing any long-term harm. 
 
Arginine deprivation using the ADI-PEG drug is being tested as a therapy against various cancers. 
(102,103) The JCO Phase I trial by Beddowes et. al. (104) shows that in a biomarker-selected 
subset of patients with ASS1-deficient cancers, ADI-PEG, which is a drug that converts arginine to 
citrulline and ammonia, shows activity worthy of further study in the medical oncology 
setting.  These authors make no suggestion that arginine supplementation in patients with 
established cancer prior to surgery could carry any clinical risk.  Likewise, no preclinical data exist 
to suggest that arginine supplementation prior to surgery unfavorably influences cancer recurrence 
or new cancer development. Since ASS1 is decreased or lost in 40% of bladder cancers (105) and 
can be reversed with ADI-PEG, then arginine supplementation would not impose any long-term 
risk. (106)  ASS1 loss has been identified in bladder cancer, and in studies of cell lines ASS1 
deficient cells were sensitive to ADI-PEG. (107)  
 
The pre-clinical ADI-PEG data have several limitations. The data available do not account for the 
clinical context of arginine demand and requirements to support the immune system in the surgical 
setting. The pre-clinical data do not take into account the necessity of adequate arginine to prevent 
wound breakdown, muscle wasting, thrombosis, and infection susceptibility in surgical patients. 
Lastly, the preclinical data also do not take into account the immune contribution to staving off 
tumors. In summary, the hypotheses from ADI-PEG studies have not yet been tested in models 
translatable to the acute surgical oncology context. 
 
In contrast, published clinical data show improved tumor-free and overall survival in patients with 
head and neck cancer taking extra arginine or Impact Advanced Recovery supplementation around 
the time of cancer treatment. Buijs reported an increase in tumor-free survival in patients 
consuming perioperative arginine for their head and neck surgery. (108,109,110) Similarly, 
Senesse (Phase II trial) reported a decrease in tumor recurrences in patients receiving arginine 
replacement therapy (Impact Advanced Recovery) during chemotherapy for head and neck cancer. 
(111,112) These patients have been followed for more than 12 years. Of note, the majority of these 
cancers demonstrate high arginase/MDSC infiltration. Our pilot data show arginine 
supplementation leads to MDSC restraint and T cell support, which may protect against the spread 
of cancer.  
 
The totality of evidence does not support tumorigenic effects of supplemental arginine. 
 
Standard ONS is high in protein and micronutrient content, but lacks the immunomodulating 
ingredients. Some data suggest ONS intake will provide benefit to surgical patients and a significant 
difference will not be detected between complication rates and postoperative muscle mass when 
compared to SIM. (113) Therefore, it is critical to use standard ONS as a control and test it against 
SIM in a blinded study design. ONS and SIM will be packaged identically and flavored the same. 
Although both drinks will be vanilla flavor, a taste test will not be provided before the randomization 
because participants with great taste sensitivity may detect a slight variation in flavor from the fish 
oil in the SIM. Regarding the taste and acceptability of the drinks, our pilot study found no striking 
differences in the adherence to the drinks. 100% consumed the SIM intervention drink and 93% 
consumed ONS the control drink.  
 
 

 
 
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The 30 day time point is preferable as the primary endpoint, given our data on the biologic 
mechanisms of the intervention showing that SIM counteracts the Th1-Th2 shift, restrains the 
expansion of immune suppressive cells, blunts the magnitude of IL-6 elevation, and lowers the 
neutrophil:lymphocyte ratio within days of the operation. These data suggest that the biology shifts 
quickly, but there are insufficient data to know how long the latency lasts from these biological 
effects to a clinically meaningful impact on overall complications. The majority of published 
immunonutrition trials with post-operative complications as the primary outcome do not list the 
timeframe in which the outcomes are collected. In addition, most trials did not use the Clavien-
Dindo scheme for standardized complication reporting. Therefore, we think it is important to retain 
both time points, including the 30 and 90 day complication rates as measured outcomes, in case 
there is latency between surgery and a clinically significant effect of SIM on complication rates.  
 
To develop the strongest study design to answer our research questions, we examined the 
evidence and design of larger and more contemporary immunonutrition trials. The strongest 
immunonutrition trial published to date is the SONVI study. (114)  This recent, well-designed, large 
multi-center trial (n=264) conducted in Spain was designed and powered to examine the overall 
post-operative 30 day complication rate. The study found that colorectal patients administered 
perioperative immunonutrition had fewer 30-day complications than the control group. (115) 
However, we could not use complication rates from a colorectal population for our power calculation 
estimates; therefore, we used the 30 day complication rates from a cystectomy population for our 
power calculations. (116) We assumed a relative reduction of 35% (on the somewhat conservative 
end of the estimate of 37% indicated in the Bertrand paper), from 65% down to 42% (a 23% 
absolute reduction). (117) 
 
In summary, nutrients in SIM work synergistically and immediately to improve immune response, 
dampen inflammatory response, preserve muscle, and enhance wound healing in surgical patients.  
 
Inclusion of Women and Minorities and Planned Enrollment Report 
 
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.  
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
2 
6 
0 
0 
8 
Native Hawaiian or Other 
Pacific Islander 
0 
1 
0 
0 
1 
Black 
or 
African 
American 
4 
8 
0 
0 
12 
White 
39 
126 
3 
10 
178 
More Than One Race 
0 
0 
0 
0 
0 
Total 
45 
142 
3 
10 
200 
 
 
 

 
 
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3.0 
PRODUCT INFORMATION 
 
3.1 
Impact Advanced Recovery® / Oral Nutrition Control 
 
a. 
DESCRIPTION 
 
Test product:  Impact Advanced Recovery® (Nestlé) is a complete nutritional 
source or may be served as a supplemental source of balanced nutrition. The 
supplement is specifically designed to support the body’s immune system by 
addition of omega-3 fatty acids, arginine, and dietary nucleotides.  
 
Control product:  An Oral Nutrition Control (Nestlé) will be used in isocaloric 
amounts in the control group.  Nestlé is specifically manufacturing the control oral 
supplement for this study. 
  
The products used in this study are considered medical foods by the U.S. Food 
and Drug administration with documented safety in multiple clinical trials.  
 
The term medical food, as defined in Section 5(b) of the Orphan Drug Act (21 
U.S.C. 360ee (b) (3)) is "a food which is formulated to be consumed or 
administered enterally under the supervision of a physician and which is intended 
for the specific dietary management of a disease or condition for which distinctive 
nutritional requirements, based on recognized scientific principles, are established 
by medical evaluation." 
 
Medical foods are not drugs and, therefore, are not subject to any regulatory 
requirements that specifically apply to drugs. IND regulations do not apply to the 
product due to the product being regulated as a food. 
 
 Nestlé (and Nestlé Health Science) has a strict process that assures minimal 
variability, excellent standardization, quality control, and stability. Both intervention 
and control products undergo the same testing before and after manufacturing. 
Product manufacturing, composition, release, and stability are carefully monitored 
as per the FDA compliance program (7321.002) and are subject to FDA review for 
manufacture and distribution of medical foods and infant formula. Prior to release, 
each batch is inspected and verified to be in compliance with FDA’s CFR Title 21, 
Part 110, Part 113, and Part 101.   
 
The tables below compare the two products in terms of energy and macronutrient 
content as well as immune-modulating ingredients.  An additional table 
demonstrating the similarity of the products is located in Appendix 18.1. 

 
 
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Table 1:  Energy and macronutrient content Impact Advanced Recovery ®/Oral 
Nutrition Control 
 
 
Test 
& 
Control 
Product 
 
 
FDA 
Category & 
Indication 
One serving 
Three servings 
(daily amount) 
 
Fluid 
Energy 
Total 
protein 
FatB 
Carbo-
hydratesC 
Fluid 
Energy 
 
Test (Nestlé): 
ORAL 
IMPACT 
Advanced 
Recovery  
 
 
Formula 
food  
 
178 ml 
 
200 
kcal 
 
 
18 gA 
 
8 g 
 
15 g 
 
534 ml 
 
600 kcal 
 
Control 
(Nestlé): 
 
 
 
Formula 
food  
 
178 ml 
 
185 
kcal 
 
14 g 
 
8 g 
 
15 g 
 
534 ml 
 
555 kcal 
A  Protein content starts out the same in the intervention and control. In order to 
fortify l-arginine in the intervention, there is a 4 g protein difference per 6 fl. oz. 
serving between products.  
B  Both products contain 1.3 g MCT per 178 mL serving. 
C Both products contain approximately 13 g sugar per 178 mL serving. 
 
Table 2: Differences in immune-modulating ingredients  
 
 
Test 
& 
Control 
Product 
 
 
FDA 
Category & 
Indication 
One serving 
Three servings (daily amount) 
 
Supplemental 
L-Arginine 
g/d 
EPA + 
DHA 
g/d 
Dietary 
Nucleotides 
g/d 
Supplemental 
L-arginine g/d 
EPA+DHA
g/d 
Dietary 
Nucleotides
g/d 
 
Test 
(Nestlé): 
ORAL 
IMPACT 
Advanced 
Recovery  
 
Formula 
food  
 
4.2 
 
1.1 
 
 
0.43 
 
12.6 
 
3.3 
 
1.29 
 
Control 
(Nestlé): 
 
Formula 
food  
 
0 
 
0 
 
0 
 
0 
 
0 
 
0 
 
Both products contain 2.8 g glutamine per 178 mL serving inherent to the casein 
protein source. Both products contain 575 mcg of beta-carotene and 290 mcg of 
retinol per 178 mL serving. Both products contain 5 mg of zinc per 178 mL serving. 
 
b. 
DOSING AND ADMINISTRATION 
 

 
 
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Both products will be provided in liquid format for oral intake.  See Section 7.0 for 
additional details. 
 
c. 
HOW SUPPLIED 
 
Study products are supplied free of charge by Nestle for distribution by McKesson 
Specialty Pharmacy. 
 
Patient-specific supplies will be sent to the registering investigator at the time of 
registration/randomization.   
 
Upon randomization to the study, the SWOG Statistics and Data Management 
Center will provide McKesson Specialty Pharmacy with randomization information 
via secure data transmission. 
 
Upon receipt of patient registration and randomization, McKesson will place a call 
to the study site confirming the order was received and provide the estimated day 
and time of arrival for the study drink.  McKesson will prepare shipment of patient 
specific study product.  Each shipment will include sufficient study product for the 
two 5-day treatment periods.  It will be packaged in one box with all 30 drink bottles.  
Each shipment also includes a patient label with the following information: 
• 
Study Number 
• 
Lot identification 
• 
Expiration date 
• 
Storage conditions 
• 
Detailed dosing instructions 
• 
Patient ID number, initials, and date dispensed 
 
In addition, each individual drink bottle will be labeled with the SWOG patient ID 
number and patient initials. 
 
Packaging will be labeled “Complete Nutrition Product. For Clinical Trial Use Only. 
This product has been specifically provided for use in a clinical trial. It is to be used 
only under the supervision of the study physician. If you have any questions 
regarding the use of this product, please contact your study personnel.” 
 
Orders will be generated by McKesson Specialty Pharmacy using the 
randomization information provided by the SWOG Statistics and Data 
Management Center, on the next business day following patient registration.  
Orders will be processed and shipped Monday through Friday for next business 
day delivery.  All shipments will be sent via FedEx for Priority Overnight delivery.  
McKesson Specialty Pharmacy will be closed the following holidays: New Year’s 
Eve, New Year’s Day, Memorial Day, Independence Day, Labor Day, 
Thanksgiving, Thanksgiving Friday, Christmas Eve, and Christmas Day. 
 
Packages are tracked until confirmed delivered and delivery exceptions are 
managed with the highest level of urgency to ensure therapy start date adherence. 
Packing slips with the shipment tracking number will be faxed to the designated 
site coordinator for all shipments. 
 
d. 
STORAGE AND STABILITY 
 
At each clinical trial site, the study products will be maintained in a dry environment, 
at temperatures between 5 ºC (41 ºF) and 25 ºC (77 ºF). Investigators and site staff 

 
 
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are reminded to check and record temperatures and ensure that thermometers (as 
applicable) are working correctly as required for proper storage of study product.  
 
Store unopened.  Once opened, unused portion should be tightly covered, kept 
refrigerated, and used within 24 hours. NOTE:  For this study, one bottle should 
be consumed between meals and any bottle not wholly consumed per protocol 
requirements should be discarded and a new bottle opened for the next expected 
time point.  The patient should record the amount consumed from the bottle on the 
Patient Intake Calendar (see Section 18.4).     
 
e. 
PRODUCT ACCOUNTABILITY 
 
Each trial site will inventory and acknowledge receipt of all shipments of study 
products. All study products must be stored in accordance with the manufacturer's 
instructions. 
 
Product transfer:  MAY NOT be transferred from one patient to another patient or 
from one protocol to another protocol. All other transfers (e.g., a patient moves 
from one participating institution to another participating institution) must be 
approved in advance by emailing protocols@swog.org. 
 
Product Returns: All unused product must be destroyed on-site in accordance with 
institutional policy.  Opened bottles with remaining products should be documented 
in the patient-specific accountability record (i.e., logged in as "# of bottles 
returned") and destroyed on-site in accordance with institutional policy. 
 
Product accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing, and 
destruction of all study drinks received from the distributor using the NCI Oral Drug 
Accountability 
Record 
Form, 
available 
on 
the 
NCI 
home 
page 
(http://ctep.cancer.gov). A separate record should be maintained for each patient 
on this protocol. 
 
 
4.0 
STAGING CRITERIA 
 
4.1 
Staging Criteria (AJCC Eighth Edition, 2010) 
 
Patients will be staged according to standard of care methods. All patients will undergo 
cystoscopy with transurethral resection of the tumor, adequate for staging as muscle 
invasive. 
 
Consistent with World Health Organization/International Society of Urologic Pathology 
(WHO/ISUP) – tumors will be classified as either low or high-grade. Tumor will also be 
classified for TIS (CIS): Carcinoma in situ (non-invasive flat carcinoma) in addition to the 
primary tumor stage since TIS (CIS) is an independent predictor of recurrence. 
 
Primary Tumor (T) 
TIS (CIS)  
 
Carcinoma in situ (non-invasive flat carcinoma) 
Ta 
 
Non-invasive papillary carcinoma 
T1 
 
Tumor invades the submucosa or lamina propria 
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 

 
 
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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 nodes 
 
Distant metastasis (M) 
 
M0 
No distant metastasis  
 
 
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 in OPEN. Section 5 may be printed and used by the site, but is not to be uploaded in RAVE 
(unless specially stated). For each criterion requiring test results and dates, please record this information 
on the Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential eligibility issues 
should be addressed to the SWOG SDMC in Seattle at 206/652-2267 or cancercontrolquestion@crab.org 
prior to registration. NCI policy does not allow for waiver of any eligibility criterion 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
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 any of the days mentioned in 
Section 5 falls on a weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have a tissue diagnosis of primary urothelial cell carcinoma of the 
bladder by TURBT or partial cystectomy. Patients may not have any evidence of 
unresectable disease or metastatic disease as assessed by exam under 
anesthesia or imaging (CT, MRI, PET). 
 
b. 
There must be plans for the cystectomy to be performed within 28 days after 
registration.  
 
c. 
Surgery must be planned to be performed under pre-approved, study-specific 
surgical guidelines (see Section 7.3).   
 
5.2 
Prior/Concurrent Therapy Criteria 
 

 
 
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a. 
Patients must have completed any neoadjuvant chemotherapy or immunotherapy 
(intravesical or systemic) ≥ 14 days prior to registration and any toxicities resolved 
to at least Grade 2.  
 
b. 
Patients may have a history of radiation therapy. Radiation therapy must have 
been completed ≥ 180 days prior to registration. 
 
c. 
Patients may have a history of prior partial cystectomy. Prior partial cystectomy 
must have been completed at least 180 days prior to registration. 
 
d. 
Patients with planned adjuvant chemotherapy within 90 days after radical 
cystectomy are not eligible. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must be ≥18 years of age.  
 
b. 
Patients must be able to swallow liquid and have no refractory nausea, vomiting, 
malabsorption, or significant small bowel resection that would preclude adequate 
absorption. Patients on tube feeding are not eligible. 
 
c. 
Patients must have their baseline nutrition status assessed using the Scored 
Patient-Generated Subjective Global Assessment (PG-SGA) by a clinician or 
licensed healthcare practitioner (trained physician, nurse, or dietitian) within 14 
days prior to registration and must not have a global category rating of Stage C 
(severely malnourished). 
 
d. 
Patients must not have galactosemia. 
 
e. 
Patients must not have known active viral infections such as human 
immunodeficiency virus (HIV) or hepatitis, as these chronic viral infections may 
cause cachexia and immunodeficiency and thus alter the biology regarding the 
study endpoints. 
 
f. 
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 two years. 
Prostate cancer found at cystectomy would not be considered a prior malignancy.  
 
g. 
Patients must not be pregnant or nursing as the conditions preclude candidacy for 
radical cystectomy.  
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must consent and be willing to have specimens collected and submitted 
as described in Section 15.1. 
 
b. 
Patients must be offered the opportunity to participate in additional specimen 
banking as outlined in Section 15.2.  
 
5.5 
Regulatory Criteria 
 

 
 
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a. 
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give informed consent in 
accordance with institutional and federal guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.3 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. 
 
c. 
Patients must consent and provide their telephone contact information for four 24-
hour dietary recall phone interviews to be conducted by staff at the Exercise, Diet, 
Genitourinary, & Endocrinology Laboratory (EDGE) Research Laboratory (see 
Sections 7.1c, 7.7e, and 15.3). 
 
d. 
Patients must be able to understand and speak English and/or Spanish because 
the dietary recall phone interviews will only be conducted in English or Spanish. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Randomization will be balanced on the following stratification factors using a maximal allocation 
procedure: 
 
1. 
Planned diversion type (neobladder vs. other); and 
 
2. 
Prior neoadjuvant therapy (any vs. none); and 
 
3. 
Baseline nutrition status (well-nourished [Stage A] vs. moderate malnutrition [Stage B], as 
assessed by the PG-SGA [see Section 7.1a]). 
 
 
7.0 
TREATMENT PLAN 
 
For nutrition dose modification questions, please contact Jill Hamilton-Reeves, Ph.D., R.D., C.S.O., 
phone: 913/588-7650 or email jhamilton-reeves@kumc.edu. For surgical-related questions, please 
contact Jeffrey M. Holzbeierlein, M.D., phone 913/588-7654 or email jholzbeierlein@kumc.edu.  
For dosing principles or questions, please consult the SWOG Policy #38 "Dosing Principles for 
Patients on Clinical Trials" at http://swog.org. 
 
7.1 
Pre-Treatment 
 
a. 
Initial assessment of nutrition status 
 
Prior to registration/randomization, the Scored Patient-Generated Subjective 
Global Assessment (PG-SGA) must be completed to identify and categorize 
patients at risk for malnutrition.  If the patient scores as severely malnourished, do 
not enroll the patient. 
 
Patient-generated component (PG):  The patient will complete items one through 
four on the first page of the questionnaire (weight, food intake, symptoms, 
activities, and function). If the patient has a severe visual deficit or cannot read, 
the clinician may interview the patient.  
 
Do not allow patients to see the second page of the questionnaire as this 
might influence their response. 

 
 
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Clinician component (SGA and scoring):  The clinician (trained physician, nurse, 
or dietitian) completes the remainder of the form. The clinician completes the 
worksheets to score weight loss, the disease/stages, metabolic demand, and 
physical exam and totals the PG-SGA score.  The physical components evaluate 
subcutaneous fat, muscle, and fluid states (edema or ascites). (Scores will be 
reported on the S1600 Nutrition Status form.) An optional training video for 
consistency in grading mild, moderate, and severe is available on the S1600 
protocol abstract page on the SWOG and CTSU websites. The estimated time to 
complete the scoring and the form is 1-5 minutes.  The site will complete the S1600 
Nutrition Status form to report PG-SGA scores and upload the PG-SGA form to 
Rave® per Section 14.4. 
 
A PG-SGA form is located on the abstract page of the CTSU website.  A sample 
PG-SGA with scoring tips is also located in Section 18.5. 
 
At any time before or during the study, treatment teams are encouraged to help 
patients obtain nutritional education or counseling from a registered dietitian or 
registered nurse as deemed necessary. 
 
For questions about the PG-SGA, please contact S1600question@swog.org . 
 
b. 
Baseline study visit – do not schedule for a Friday  
 
Note: Baseline is after registration and before beginning preoperative nutrition 
drinks 
 
After registration/randomization, the patient will have a baseline study visit 
consisting of the following.  This visit is anticipated to take 40-45 minutes. 
 
• 
Laboratory tests:  complete blood count (CBC) with differential, and (if clinically 
indicated) albumin and prealbumin 
• 
Blood draw for submission (see Section 15.1).  NOTE: The blood for 
submission and for laboratory tests must be from the same blood draw. 
• 
DXA scan (see Section 18.3) 
• 
S1600 Functional Assessment of Anorexia Cachexia (FAACT) Questionnaire 
and the S1600 Wong-Baker FACES® Pain Rating Scale (FACES).  See 
Section 15.3 for instructions for administration of patient questionnaires. 
 
In addition, study staff will do the following: 
 
• 
Dispense the patient-specific blinded study product (15 drink bottles) to the 
patient for him/her to take home.   
• 
Instruct the patient on the administration of the study drink per Section 7.2a.  
• 
Provide the patient with a copy of the “Patient Intake Calendar – Before 
Surgery” located in Section 18.4. 
• 
Instruct the patient to discontinue any supplements containing fish oil until after 
completion of study. 
• 
Provide the patient with a copy of the “Food Amounts Booklet” and “Patient 
Instructions for Food Amounts Booklet” and explain that the patient may refer 
to it during the phone interviews described in Section 15.4. 
• 
If the patient is unable to pick up the study product from the clinic, study staff 
are responsible for shipping 15 drink bottles to the patient in time to begin 
consumption five days before the surgery date.   

 
 
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• 
If patient consented to participating in specimen banking, provide the patient 
with 2 kits for stool sample collection to cover  timepoints per Section 15.2.: 
o 
After registration, but before beginning nutritional drink 
o 
After nutrition/before surgery (at least 4 days of drinks completed 
 
• 
Call the patient at home six days before the surgery date to remind the patient 
to begin taking the study drinks the following morning. If patient consented, to 
participating in specimen banking remind the patient to collect the stool sample 
and record collection date on the Intake Calendar. 
 
For 
questions 
about 
study 
visit 
procedures, 
please 
contact 
S1600question@swog.org . 
 
c. 
Phone Interview – Before Surgery 
 
Patients will be called two separate times by nutrition staff from the EDGE 
Research Laboratory at least 6 days before surgery prior to start of preoperative 
nutrition therapy for completion of a 15-minute phone interview regarding diet.  
Nutrition staff will collect diet data for a weekday on one call and a weekend day 
on the other call (see Section 15.4 and Section 18.6). 
 
For 
questions 
about 
the 
phone 
interviews, 
please 
contact 
S1600question@swog.org 
 
7.2 
Treatment: Preoperatively  
 
Agent 
Dose 
Route 
Schedule 
 
Blinded Nutrition 
3  daily 
oral 
5 days before Radical 
Drink 
(178 mL per bottle) 
Cystectomy surgery; 
 
 
 
 
 
between meals          
 
 
a. 
Patients drink 3 blinded bottles daily (178 mL per bottle) of blinded nutrition drink 
between meals for 5 days before surgery. Patient should consume 178 ml 3 times 
a day for 5 days up until the night before surgery as a supplement to their regular 
diet. The drink should be served chilled. Study oral supplements are offered in 
addition to regular meal intake and are not intended as meal replacements. 
 
b. 
Patients complete the S1600 Intake Calendar to record adherence to the 
preoperative nutrition therapy and return the calendar to the study staff on the day 
of surgery (see Section 7.5). 
 
7.3 
Radical Cystectomy Surgery  
 
Because blood samples are required to be collected and shipped on Day 2 following 
surgery (see Section 15.1), surgery should take place on a Monday, Tuesday, or 
Wednesday. 
 
a. 
Antibiotics 
 
The recommended antibiotic protocol is 24 hours of cefoxitin.  If the patient has 
penicillin allergy, gentamicin/clindamycin is an allowable substitution. If another 
regimen is followed, broad spectrum and enteric coverage should be considered 
and documented. 

 
 
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b. 
Considerations 
 
Radical Cystectomy must occur within 1 day after the last ingestion of the drink.  
Study sites must adhere to the following guidelines adapted from the Enhanced 
Recovery After Surgery (ERAS) principles to preserve gut function so the patients 
can continue to take nutrition supplements after surgery.  
 
1. 
No bowel preparation 
 
2. 
No nasogastric tubes 
 
3. 
Prescribe opioid-free pain control or minimize narcotics.  
 
4. 
Feed study nutrition drinks to patients within 24 hours after surgery. 
 
5. 
In addition, it is recommended that patients receive alvimopan to avoid 
opioid-induced constipation. 
 
c. 
Postoperative hydration 
 
It is recommended that patients receive an intravenous solution of 5% glucose and 
electrolytes to prevent dehydration until recovery of oral food intake. 
 
7.4 
Treatment: Postoperatively  
 
Agent 
Dose 
Route 
Schedule 
 
 
 
Blinded Nutrition 
3 bottles daily 
oral  
For 5 days after Radical 
Drink 
(178 mL per bottle) 
Cystectomy surgery; 
 
 
between meals          
 
 
a. 
After surgery, patients consume 3 blinded bottles daily (178 mL per bottle) of 
nutrition drink between meals as a supplement to their regular diet for 5 days after 
surgery, to be administered by the nurse or dietitian. The study staff will deliver the 
patient’s 15 bottles of blinded nutrition drink to the surgical unit (for accessibility to 
the patient prior to their 24 hours post-surgery time point), along with study staff 
contact information, a copy of the S1600 protocol (for the surgical unit’s reference), 
and a copy of the S1600 Patient Intake Calendar – After Surgery. Study staff 
should label each bottle with the patient’s hospital ID (in addition to the study 
labeling already included per Section 3.0) to ensure the bottles are administered 
to the correct patient.  Study staff will instruct the patient’s nurse or dietitian to keep 
the bottles refrigerated until dispensed so that the drinks are served cold. The 
patient should return their S1600 Patient Intake Calendar – Before Surgery on the 
day of surgery, so study staff should coordinate with the surgical unit to collect this 
form. 
 
b. 
Patients should resume intake within 24 hours after surgery.  If resumption of diet 
is delayed, patients will resume the study drink once they can tolerate it (within 24-
72 hours after surgery per protocol recommendation). Every effort should be made 
to have the patient begin post-operative consumption of the study nutrition drinks 
within at most 72 hours after surgery, though the patient should still consume the 
drinks even if resumption of diet is delayed more than 72 hours after surgery.  
Patient will consume the drinks for five days, regardless of what day diet is 

 
 
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resumed.  Nurse or dietitian in the unit will initiate post-operative feeding once the 
physician order with approval to start the study drink is charted in the participant’s 
medical record. 
 
c. 
Postoperative Oral Nutrition Therapy Considerations: 
 
1. Start with lower volumes and increase as tolerated to give 178 ml 3 times a 
day. 
 
2. Educate patient to take the drink very slowly in increments over the course of 
2-4 hours or longer. Study drink must be kept chilled. 
 
3. Encourage patient to walk around the unit before taking a second small dose. 
 
4. If patient feels too bloated, nauseous, or exhibits excessive burping, or 
hiccupping, then it is permissible to stop and wait for several hours before 
trying another feeding. 
 
5. Patient can receive other food (e.g., regular diet) if allowed by the surgeon, but 
minimize sugary drinks or foods (sodas, juices, gelatin). 
 
d. 
The study staff are responsible for getting the remainder of patient-specific study 
product (15 drink bottles) to the post-op unit for the nurse or dietitian there to 
dispense to the patient starting the day following surgery as described in Section 
7.3a.  If the patient is discharged from the hospital before consuming all 5-day 
supply of study product, the remaining  should be sent home with instructions to 
continue until all are consumed. 
 
e. 
If patient consented to participating in specimen banking, provide the patient with 
the kit for stool sample collection for first bowel movement after hospital discharge 
per Section 15.2. 
 
7.5 
Patient Compliance Document  
 
Study staff will provide the patients with the S1600 Patient Intake Calendar (Section 18.4) 
for his/her completion. (NOTE:  There are two calendars:  one for Before Surgery and one 
for After Surgery.)  The patient will complete this intake calendar, recording daily 
consumption in servings (complete, half or no intake) during pre-op and post-op and return 
the Before Surgery calendar on the day of surgery and the After-Surgery calendar at the 
30-day follow-up visit.  Study staff will review and ascertain patient adherence at the end 
of preoperative treatment and postoperative treatment. The study staff will report drink 
adherence on the S1600 Treatment Form (Preoperative and Postoperative). The S1600 
Patient Intake Calendar will be used as a source of evaluation of patient compliance and 
is expected to serve as a self-reminder and motivational tool for patients to comply with the 
recommended intake of nutritional support for this study. (NOTE: Compliance will be based 
on day counts of the study products consumed and confirmed at the end of the study with 
retrospective plasma fatty acid analysis. See Section 18.2) The completed patient intake 
calendar should be kept in the patient’s clinic chart.  Note that the calendar is provided only 
as a tool for tracking patient compliance.  Do not submit patient calendars to the SWOG 
Data Operations Office. 
 
7.6 
Follow-up Visit (Day 2 after Surgery) 
 

 
 
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a. 
Patients will have a blood draw for laboratory tests and sample submission for 
translational studies (see Section 15.1). This will take place on Day 2 after surgery, 
regardless of what day diet is resumed. 
• 
Laboratory tests:  complete blood count (CBC) with differential, and (if 
clinically indicated) albumin and prealbumin 
• 
Blood draw for submission (see Section 15.1).  NOTE:  The blood for 
submission and for laboratory tests must be from the same blood draw. 
 
The patient will be administered the S1600 Wong-Baker FACES® Pain Rating 
Scale (FACES).  See Section 15.3 for instructions for administration of patient 
questionnaires. 
 
7.7 
Follow-up Visit (Day 30 after Surgery, ± 7 days) 
 
a. 
Call the patient prior to 30-day follow-up to remind them to bring their stool samples 
to the visit. If patient does not bring the samples, the site will send a mailer home 
with instructions to the patient to ship their stool samples to the SWOG 
Biospecimen Bank (ambient).  Sites will be instructed to add a comment in the 
SWOG Specimen Tracking System. 
 
b. 
The patient will be assessed by the surgeon for surgical complications per Clavien-
Dindo grading (see Section 10.1a) on the S1600 30-Day Post-Op Assessment 
Form and the form must be signed by the surgeon. 
 
c. 
Patients will have a DXA Scan and a blood draw for laboratory tests and sample 
submission for translational studies (see Section 15.1 and Section 18.3). 
 
• 
Laboratory tests:  complete blood count (CBC) with differential, and (if 
clinically indicated) albumin and prealbumin. 
 
• 
Blood draw for submission (see Section 15.1).  NOTE:  The blood for 
submission and for laboratory tests must be from the same blood draw. 
 
d. 
Patients will complete the following questionnaires: 
 
• 
S1600 
Functional 
Assessment 
of 
Anorexia 
Cachexia 
(FAACT) 
Questionnaire 
 
• 
Scored Patient-Generated Subjective Global Assessment (PG- SGA).  
NOTE:  Clinician will also complete a portion of this form.  Refer to Section 
7.1a for patient and clinician instructions. 
 
• 
S1600 Wong-Baker FACES® Pain Rating Scale (FACES).  
 
e. 
The study staff must complete the S1600 Cover Sheet for Patient-Completed 
Questionnaires as well as complete and submit required forms per Section 14.4. 
 
f. 
Patients will be called by staff at the EDGE Research Laboratory for completion of 
two 15-minute 24-hour dietary recall phone interviews (for one weekday and one 
weekend day) (see Section 15.4). 
 
g. 
The study staff should collect the completed S1600 Patient Intake Calendar – After 
Surgery from the patient. 
 

 
 
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7.8 
Follow-up Visit (90 Days after Surgery, ± 7 days) 
 
The patient will be assessed by the surgeon for late-phase surgical complications per 
Clavien-Dindo grading (see Section 10.1a) on the 90-Day Post-Op Assessment Form and 
the form must be signed by the surgeon. 
 
7.9 
Criteria for Removal from Protocol Treatment 
 
a. 
Patient has completed protocol treatment and the S1600 90-day Post-Op 
Assessment Form has been submitted. 
 
b. 
Patient does not consume ≥ 80% (12 of 15 bottles) of pre-surgical 
supplementation. 
 
c. 
Patient does not undergo planned radical cystectomy surgery. 
 
d. 
Patient requires tube feeding any time prior to completion of 10 days of study drink. 
 
e. 
Patients may withdraw from the protocol treatment at any time for any reason.  
 
7.10 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented on the S1600 Off Protocol 
Notice. 
 
NOTE: Patient follow-up must be completed and forms must be submitted for all patients 
regardless if the Off Protocol Notice is submitted prior to completion of Section 7.9a. 
 
7.11 
Follow-Up Period 
 
All patients will be followed for 3 years after radical cystectomy surgery or until death, 
whichever occurs first.  See Section 9.0 and Section 14.4j for follow-up and forms 
submission guidelines. See COVID-19 Guidance in Section 7.13. 
 
7.12 
Unblinding 
 
Patients may be unblinded to their treatment assignment on request at the end of the study, 
after study results have been published.  Institutions will be notified when patient unblinding 
information is available for the study.  For emergency unblinding criteria and procedures, 
see Section 18.8. 
 
7.13 
COVID-19 Guidance 
 
Patient-Reported Outcome Questionnaires via Telemedicine (Phone or Virtual Visit), 
please see Section 15.3.  
 
Follow-up Visits via Telemedicine (Phone or Virtual Visit):  
• 
Follow-up visits at timepoints indicated in Section 9.0, Footnote (H) of the Study 
Calendar may be conducted via telemedicine (Phone or Virtual Visit) to provide 
continuity of care and patient follow-up provided that the Responsible Investigator 
determines that the phone/virtual visit is adequate to achieve the central purpose 
of the visit and assure the safety of the patient. 
• 
Study visits may also be delayed or missed if in the judgment of the Responsible 
Investigator the benefit of delay/omission of a visit outweighs the risks of exposure 

 
 
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of the patient to the virus by coming in for an in-person visit and an alternative 
method (phone or virtual visit) is not possible.  
• 
The above alterations would need to be thoroughly documented in the medical 
record by the Responsible Investigator with the reason for the deviation and brief 
justification for why the deviation was considered to be minor (e.g., routine follow-
up on patient no longer on active therapy). 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 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 5.0. 
 
8.2 
Dose Modifications  
 
a. 
Before surgery, no dose modifications will be allowed.  
 
b. 
Mild gastrointestinal upset, loose stools and nausea after supplementation may 
occur. After surgery, if the patient feels bloated, nauseated, or is burping 
excessively, then he or she will be allowed to wait to resume a few hours before 
trying the drinks again. If resumption of diet is delayed (within 72 hours of surgery), 
patients will resume the supplement once they can tolerate it and resumption is 
cleared by the treating physician. 
 
8.3 
Dose Modification Contacts 
 
a. 
For treatment or dose modification questions, please contact the Study Chairs by 
phone or email: Jill Hamilton-Reeves, Ph.D., R.D., C.S.O, phone: 913/588-7650 or 
email jhamilton-reeves@kumc.edu; or Jeffrey M. Holzbeierlein, M.D., phone 
913/588-7654 or email jholzbeierlein@kumc.edu. 
 
8.4 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.1 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

 
 
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9.0 
STUDY CALENDAR  
 
Click here for Footnotes 
REQUIRED STUDIES 
Pre-
Study  
Baseline  A 
D 
-5 
D 
-4 
D 
-3 
D 
-2 
D 
-1 
Day 0 
SURGERY  K 
D 
1 
D 
2 
D 
3 
D 
4 
D 
5 
D 30 J 
D 90J 
F/U H 
PHYSICAL 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
  
 
Medical History & Comorbidities 
X 
X 
 
 
 
 
 
  
  
 
 
 
 
X 
X 
 
Zubrod Performance Status 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Body Weight & Height 
X 
X 
 
 
 
 
 
  
  
 
 
 
 
X 
  
 
Assess Surgical Complications B 
  
  
 
 
 
 
 
  
  
 
 
 
 
X 
X 
 
Recurrence Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Review Intake Calendar C 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
SPECIMENS 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
  
 
Blood per Section 15.1 
  
X 
 
 
 
 
 
  
  
X 
 
 
 
X 
 
 
Stool per Section 15.2 (Optional) 
 
X 
X 
 
X 
 
 
 
 
LABORATORY 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
Prealbumin, if clinically indicated 
  
X 
 
 
 
 
 
  
  
X 
 
 
 
X 
 
 
Albumin, if clinically indicated 
  
X 
 
 
 
 
 
  
  
X 
 
 
 
X 
 
 
CBC with Differential, Platelets 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA Body Composition   
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
SURGERY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radical Cystectomy 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PATIENT COMPLETED 
QUESTIONNAIRES 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
  
 
S1600 FAACT E 
  
X 
 
 
 
 
 
  
  
 
 
 
 
 X 
  
 
S1600 PG-SGA G 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
S1600 Pain Scale FACES E 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
S1600 Patient Intake Calendar 
  
 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
 
  
 
Phone Interview  F 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blinded Nutritional Drink 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 

 
 
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NOTE: Forms are found on the protocol abstract page of the CTSU website (www.ctsu.org). Form submission guidelines are found in Section 14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as 
outlined in https://www.swog.org/clinical-trials/protocol-workbench.   
 
Footnotes: 
 
A  Baseline is after registration and before beginning preoperative nutrition drinks. 
B  Includes Clavien-Dindo (I-V) grading (see Table 1 in Section 10.1a) 
C  Site personnel to review patient reported compliance for preoperative period at the time of surgery, and post-operative period on Day 30 ± 7  
days (see Section 7.5). 
E See Section 15.3 for further details. 
F The site must complete the S1600 Telephone Contact Form and FAX it to the EDGE Laboratory at 913/574-0515 within 24 hours after registration. 
Please phone the EDGE lab at 913/945-7519 to ensure the FAX was received.  Nutrition staff from the EDGE Research Laboratory will contact 
patients directly by phone to conduct diet recall interviews (see Section 15.4). 
G The Scored Patient-Generated Subjective Global Assessment (PG-SGA) will be completed by the patient and the clinician (see Section 7.1a). 
H  Includes recurrence and vital status at Months 3, 6, 9, 12, 18, 24 and 36 months after radical cystectomy surgery or until death.  See Section 14.4j. 
See COVID-19 Guidance in Section 7.13. 
J Day 30 visit to take place within 7 days before or after Day 30 (after surgery date).  Day 90 visit to take place within 7 days before or after Day 90 
(after surgery date). 
K Because blood samples are required to be collected and shipped on Day 2 following surgery (see Section 15.1), surgery should take 
place on a Monday, Tuesday, or Wednesday.  
 
 

 
 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
 
 
10.1 
Measurement of Complications 
 
a. 
Primary Endpoint: Post-operative Complications A post-operative complication is 
defined as a binary indicator variable indicating whether the patient experienced 
any complication (any/none; Clavien-Dindo grades I-V; Table 1). (118) 
 
Table 1. Clavien-Dindo Scheme 
Clavien-Dindo Grades 
Definition 
Grade I 
 
Any deviation from the normal postoperative course 
without the need for pharmacological treatment or surgical, 
endoscopic 
or 
radiological 
interventions. 
Allowed 
therapeutic regimens are drugs as antiemetic, antipyretics, 
analgesics diuretics, electrolytes, and physiotherapy. 
Grade II 
 
Requiring pharmacological treatment with drugs other than 
such allowed for grade I complications. Blood transfusions 
and total parenteral nutrition are also included. 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
Grade IIIa 
Intervention not under general anesthesia 
Grade IIIb 
Intervention under general anesthesia 
Grade IV 
 
Life-threatening complications (including central nervous 
system complications) requiring intermediate care or 
intensive care unit management 
Grade IVa 
Single-organ dysfunction (including dialysis) 
Grade IVb 
Multi-organ dysfunction 
Grade V 
Death of a patient 
Suffix “d” 
 
 
If the patient suffers from a complication at the time of 
discharge, the suffix “d” (for “disability”) is added to the 
respective grade of complication. This label indicated the 
need for a follow up to fully evaluate the complication. 
 
 
10.2 
Secondary Endpoints 
 
a. 
In addition to grading, complications will be defined using surgery-specific 
categories (ileus, deep vein thrombosis, pneumonia, wound infection, urinary tract 
infection, return to operation room, pulmonary embolus, myocardial infarction, 
cerebral vascular accident, dehiscence, sepsis, respiratory failure, bowel leak, 
urine leak, small bowel obstruction, death, or other). Post-operative ileus will be 
defined as a delay in feeding of greater than or equal to five days post-operatively.   
 
b. 
Postoperative Infections. Infectious complications are defined by the use of non-
prophylactic antibiotics to treat infection. In addition, infections will be categorized 
by intra-abdominal infection or surgical site infection. 
 

 
 
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c. 
Anthropometrics & Body composition. Changes in fat mass and non-bone lean 
tissue (muscle mass) will be assessed by dual-energy X-ray Absorptiometry (GE 
Lunar DXA, Software version 13.5 or newer version, Madison, WI, or Hologic, 
Software version APEX 5.5.3.1 or newer version) at baseline and 30 days. The fat-
free mass index (FFMI) and the appendicular skeletal muscle will be examined 
over time. Body weight (in a hospital gown without shoes) will be measured using 
a digital scale accurate to ± 0.1 kg. Height will be determined using a wall-mounted 
stadiometer (± 0.1 cm). See Appendix 18.3 for further information. 
 
d. 
Quality of Life. Functional Assessment of Anorexia/Cachexia Therapy (FAACT) 
will be completed by the patient at baseline and 30 days post-operation. (119) The 
FAACT trial outcome index and anorexia subscales were used in our pilot and the 
SIM showed better scores than the ONS group but the differences were not 
statistically significant (P=0.15 for both), but the pilot was underpowered for this 
outcome. Also, the anorexia and cachexia subscale asks about issues common 
after RC such as: taste alterations, appetite, early satiety, and pain while eating. 
These data are crucial for optimizing nutrition interventions to help patients. 
 
e. 
Readmission Rates. Readmission will be defined as admission to any hospital after 
discharge home until 90 days after surgery. The reason for readmission will be 
recorded.  
 
10.3 
Disease-Free Survival 
 
From date of surgery 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 
 
From date of randomization to date of death due to any cause.  Patients last known to be 
alive are censored at their last contact date. 
 
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.   
 

 
 
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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Analysis 
 
The primary objective is to compare, by arm, the proportion of patients who experience any 
complication (Clavien-Dindo grades I–V) by day 30 after surgery. Prior evidence suggests 
that approximately 65% of patients will experience complications by Day 30. 
(120,121,122,123) The design stipulates that a 35% relative reduction in the complication 
rate due to the intervention would be clinically meaningful, representing a reduction in the 
complication rate from 65% down to 42% (a 23% absolute reduction). The design also 
anticipates a 5% non-adherence rate (which reduces the nominal effect size). Based on a 
two-arm binomial design with continuity correction, a one-sided alpha = 0.05 test and 80% 
power, a total of 146 eligible, randomized patients will be needed. In addition, in this 
population, it is anticipated that 20% of patients will drop out after surgery by Day 30, and 
a small portion of patients (3%) will drop out prior to surgery. Incorporation of this dropout 
rate inflates the required sample size by a factor of 146/0.77 = 190 eligible patients. Finally, 
assuming a 5% ineligibility rate, a total of 200 registered patients will be required. The high-
grade complication rate (Clavien Dindo scheme III-V) will also be examined. If the control 
arm high grade complication rate is 20%, 200 patients will give ≥ 80% power to detect an 
absolute reduction of 15% (down to 5%). 
 
The primary analysis will be based on a multivariable logistic regression under intent-to-
treat among all randomized patients, irrespective of their eligibility status, adjusting for the 
specified stratification factors: a. Diversion type (neobladder vs. ileal conduit); b. Prior 
neoadjuvant chemotherapy (any vs. none); and c. Nutrition status (well-nourished vs. 
moderate malnutrition). A Fisher’s exact test will also be conducted to establish whether 
the results are sensitive to model assumptions.  A single interim analysis for efficacy will 
be conducted when 50% of patients achieve their endpoint at the alpha=0.005 level.  
Accordingly, the final analysis will be conducted at the alpha=0.045 level. A separate 
analysis among all eligible randomized patients will also be conducted. 
 
To minimize missed assessments, SWOG utilizes an electronic system to remind 
institutions in real-time that patients are due for follow-up assessment. Nonetheless 
missing data will occur. To bracket the final result, Lachin’s worst rank analysis will be used 
by imputing the missing data in the following manner: 1) all missing observations will be 
assigned the worst rank; 2) all missing observations will be assigned the best rank; 3) all 
missing observations in the experimental arm will be assigned the worst rank, and all 
missing observations in the control arm will be assigned the best rank; and 4) all missing 
observations in the experimental arm will be assigned the best rank, and all missing 
observation in the control arm will be assigned the worst rank. Finally, using delta 
adjustment, we will examine how biased the imputation will need to be to substantively 
influence statistical significance (i.e. turn from statistically significant to not statistically 
significant) at any given alpha level. (124) In particular, the “truth” will be bracketed by 
analysis 3 and 4, above. Interpretation will be influenced by the amount of missing data 
and the magnitude of potential differences between the observed and best/worst-case 
findings, suggesting uncertainty in the primary result due to missing data. 
 
11.2 
Secondary Analysis  
 
A set of secondary objectives will also be examined. Additional factors that are potentially 
prognostic for complication rates will be examined as covariates in separate logistic 
regression analyses, to assess the sensitivity of the primary logistic regression model 

 
 
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results to additional covariate adjustment; factors include BMI (< 30 vs. ≥ 30), age (< 65 
vs. ≥ 65 years), gender (male vs. female), diabetes mellitus, pathologic staging, pro-
inflammatory cytokines known to affect appetite, background diet, current use of 
supplements, and any autoimmune disease. Also, in addition to the primary endpoint 
assessment of any complication at Day 30, we will assess the complication rate at day 90, 
as well as a composite endpoint with three levels (complications by Day 30, complication 
after Day 30 but by Day 90, and no complications by Day 90). In addition, we will examine 
the impact of SIM use on the Day 30 and Day 90 rates of infection (as determined by 
antibiotic use outside of prophylaxis), skeletal muscle mass, high-grade post-operative 
complications (Clavien Dindo Grades III–V), and readmission rates. To consider whether 
dropout may be non-random (i.e., informative), which could influence the results, a 
sensitivity analysis will be conducted that counts dropouts as events. Although death rates 
are anticipated to be low, 2-year overall survival by arm will be explored using Kaplan Meier 
curves, as will disease-free survival. The relationship between compliance and outcomes 
will be explored. A set of tertiary objectives will also be examined as indicated in Appendix 
18.2. 
 
11.3 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
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 6 months from the SWOG Statistical Center, and will meet at the Group's bi-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 
 
Discipline Review is not required for this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Study sites must meet requirements and have approval for study participation before 
registering patients to the study(See Section 13.2b.3 and Section 18.7). 
 
Patients must be registered prior to initiation of treatment (at least 10 days and no more 
than 28 days prior to planned surgery).   
 
13.2 
Investigator/Site Registration 
 
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 to CTEP. 
 
a. 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 

 
 
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and to renew their registration annually. To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account at https://ctepcore.nci.nih.gov/iam. In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, Rave, 
or acting as a primary site contact) must complete their annual registration using 
CTEP’s 
web-based 
Registration 
and 
Credential 
Repository 
(RCR) 
at 
https://ctepcore.nci.nih.gov/rcr.     
 
RCR utilizes five-person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, 
Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-
sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and Cancer Trials Support Unit (CTSU) websites and 
applications. In addition, IVRs and NPIVRs must list all clinical practice sites and 
Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks 
in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance).  
 
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please 
contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
 

 
 
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b. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:  
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the 
National Clinical Trials Network (NCTN) and NCI Community Oncology 
Research Program (NCORP) Research Bases after March 1, 2019, all 
U.S.-based sites must be members of the NCI Central Institutional Review 
Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB 
review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the 
CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) 
approval to the CTSU Regulatory Office following country-specific 
regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific 
Worksheet for Local Context (SSW) to the CIRB using IRBManager to 
indicate their intent to open the study locally. In order for the SSW approval 
to be processed, the Signatory Institution must inform the CTSU which 
CIRB-approved institutions aligned with the Signatory Institution are 
participating in the study. The NCI CIRB’s approval of the SSW is 
automatically communicated to the CTSU Regulatory Office, but sites are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can 
be set at the network or protocol level. Questions about establishing site 
preferences can be addressed to the CTSU Regulatory Office by emailing 
the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 

 
 
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2. 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page 
located on the CTSU members’ website. Permission to view and download 
this protocol and its supporting documents is restricted and is based on 
person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a 
PO on the protocol.  
• 
Log on to the CTSU members’ website (https://www.ctsu.org) 
using your CTEP-IAM username and password; 
• 
Click on Protocols in the upper left of your screen 
• 
Enter the protocol number in the search field at the top of the 
protocol tree, or 
• 
Click on the By Lead Organization folder to expand, then select 
SWOG, and protocol number S1600 
• 
Click on Documents, select Site Registration, and download and 
complete the forms provided. (Note: For sites under the CIRB 
initiative, IRB data will load automatically to the CTSU as 
described above.) 
 
3. 
Requirements For S1600 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
• 
Site must meet all five criteria listed on the S1600 Site 
Requirements Form (see Appendix 18.7).  This form must be 
completed and submitted to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website as a protocol 
specific requirement prior to registering any patients. 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via 
the Regulatory Submission Portal on the CTSU website.  
 
Regulatory Submission Portal:  www.ctsu.org (members’ area) → 
Regulatory Tab → Regulatory Submission 
 
Institutions with patients waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately 
at 1-866-651-2878 in order to receive further instruction and support. 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site’s registration status on the members’ side of the 
CTSU website.   
 
• 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
• 
Click on the Regulatory tab at the top of your screen 

 
 
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• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status shown only reflects institutional compliance with site 
registration requirements as outlined above. It does not reflect compliance 
with protocol requirements for individuals participating on the protocol or 
the enrolling investigator’s status with the NCI or their affiliated networks. 
 
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. 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold 
a minimum of an AP registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
Patient has met all eligibility criteria within the protocol stated timeframes and the 
affirmation of eligibility on the Registration Worksheet has been signed by the 
registering investigator or another investigator designate. 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). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
 
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: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 

 
 
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d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
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 
 
n. 
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.  Access OPEN at 
https://open.ctsuorg, from the OPEN link on the CTSU members’ website. Further 
instructional information is in the OPEN section of the CTSU website at 
https://www.ctsuorg, https://open.ctsu.org, or from the OPEN Patient Registration 
link on the SWOG CRA Workbench. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 

 
 
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b. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
c. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsuorg or at https://open.ctsuorg. For 
any additional questions contact the CTSU Help Desk at 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. 
 
 
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 specific page on the CTSU website 
(www.ctsu.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 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Medidata Rave is a clinical data management 
system being used for data collection for this trial/study. Access to the trial in Rave 
is controlled through the CTEP-IAM system and role assignments. To access Rave 
via iMedidata: 
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account; and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the enrolling 
site: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or 
Rave 
Investigator. 
Refer 
to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
o 
To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must 
hold a minimum of an AP registration type; 
o 
To hold Rave Investigator role, the individual must be registered 
as an NPIVR or IVR; and 

 
 
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o 
To hold Rave Read Only role, site staff must hold an Associates 
(A) registration type. 
 
If the study has a Delegation of Tasks Log (DTL), individuals requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 
a study invitation e-mail from iMedidata. To accept the invitation, site staff 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. Site staff 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 can be accessed by clicking 
on the link in the upper right pane of the iMedidata screen. If an eLearning is 
required and has not yet been taken, the link to the eLearning will appear under 
the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will 
be granted, and a Rave EDC link will display under the study name.  
 
Site staff 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 in the 
Data Management > Rave section at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).  
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
d. 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. The DQP is located on the CTSU members’ 
website under Data Management. The Rave Home section displays a table 
providing summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are available to 
access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. The DQP is accessible by site staff that 
are rostered to a site and have access to the CTSU website. Staff that have Rave 
study access can access the Rave study data using a direct link on the DQP. To 
learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. Note: Some 
Rave protocols may not have delinquent form details or reports specified on the 

 
 
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DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be 
available on the DQP. Site staff should contact the LPO Data Manager for their 
protocol regarding questions about Rave Calendar functionality. 
 
14.4 
Data Submission Overview and Timepoints  
 
Please reference the ORP Manual on the CRA Workbench (www.swog.org) for detailed 
General Forms and Guidelines, as well as some disease-specific and study-specific forms. 
There are also many other chapters available in the manual to be used for regular reference 
of SWOG processes and procedures. 
 
a. 
WITHIN 24 HOURS AFTER REGISTRATION: 
 
FAX the S1600 Telephone Contact Form directly to the EDGE Research 
Laboratory at 913/574-0515 per form instructions.  Phone the EDGE lab at 
913/945-7519 to ensure the FAX was received. 
  
b. 
WITHIN 7 DAYS AFTER REGISTRATION:    
  
Submit the following: 
 
S1600 Onstudy Form 
 
S1600 Nutrition Status Form 
 
S1600 Wong-Baker Pain Scale 
 
Scored Patient-Generated Subjective Global Assessment (PG-SGA)* 
 
Pathology report from TURBT* 
 
*NOTE: Include all TURBT reports within the last two years including the report 
with the primary diagnosis. Upload reports via the Source Documentation: 
Baseline form in Rave®. 
 
c. 
PRIOR TO BEGINNING PREOPERATIVE TREATMENT, AT DAY 2 AFTER 
CYSTECTOMY, AND AT DAY 30 ± 7 DAYS AFTER CYSTECTOMY: 
 
Collect, process, and submit specimens as outlined in Section 15. 
 
d. 
WITHIN 14 DAYS AFTER PREOPERATIVE TREATMENT:  
 
Submit the following: 
 
S1600 Treatment Form 
 
S1600 Adverse Event Form 
 
S1600 Laboratory Values Form 
 
S1600 FAACT form  
 
S1600 Cover Sheet for Patient-Completed Questionnaires 
 

 
 
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S1600 Body Composition Form 
 
Scan Report from DXA* 
 
Laboratory report including CBC with differential* 
 
*NOTE: Upload the DXA scan report via the Source Documentation: Baseline form 
in Rave®. Upload lab results via the Source Documentation: Lab folder in Rave. 
 
e. 
WITHIN 14 DAYS AFTER CYSTECTOMY: 
 
Submit the following: 
 
S1600 Cystectomy Form 
 
Operative report from cystectomy* 
 
Pathology report from cystectomy* 
 
*NOTE: Upload reports via the Source Documentation: Follow Up form in Rave®. 
 
f. 
IF PATIENT DOES NOT UNDERGO CYSTECTOMY, WITHIN 14 DAYS AFTER 
PLANNED CYSTECTOMY DATE:  
 
Submit the S1600 Off Protocol Notice. 
 
g. 
WITHIN 14 DAYS AFTER POSTOPERATIVE TREATMENT:  
 
Submit the following: 
 
S1600 Adverse Event Form 
 
S1600 Wong-Baker Pain Scale 
 
S1600 Laboratory Values Form 
 
Laboratory report including CBC with differential* 
 
*NOTE: Upload lab reports via the Source Documentation: Lab form in Rave®. 
 
h. 
WITHIN 14 DAYS AFTER 30-DAY POSTOPERATIVE ASSESSMENT: 
 
Submit the following: 
 
S1600 30-Day Post-Op Assessment Form** 
 
S1600 Treatment Form 
 
S1600 Adverse Event Form 
 
S1600 Laboratory Values Form 
 
S1600 Nutrition Status Form 
 
Scored Patient-Generated Subjective Global Assessment (PG-SGA)* 

 
 
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S1600 FAACT form 
 
S1600 Cover Sheet for Patient-Completed Questionnaires 
 
S1600 Body Composition Form 
 
S1600 Wong-Baker Pain Scale 
 
Scan Report from DXA* 
 
Laboratory report including CBC with differential* 
 
*NOTE: Upload the PG-SGA and DXA scan reports via the Source Documentation: 
Follow Up form in Rave®.  Upload lab reports via the Source Documentation: Lab 
form in Rave®. 
 
**NOTE: This form must be both submitted electronically, and the completed 
version signed (paper or electronically) by the surgeon uploaded via the Source 
Documentation: Follow Up form in Rave®. 
 
i. 
WITHIN 14 DAYS AFTER 90-DAY POSTOPERATIVE ASSESSMENT:  
 
Submit the following: 
 
S1600 90-Day Post-Op Assessment Form** 
 
S1600 Off Protocol Notice 
 
**NOTE: This form must be both submitted electronically and the completed 
version signed (paper or electronically) by the surgeon uploaded via the Source 
Documentation: Follow Up form in Rave®. 
 
j. 
AT 3 MONTHS, 6 MONTHS, 9 MONTHS, 12 MONTHS, 18 MONTHS, 24 
MONTHS, AND 36 MONTHS AFTER CYSTECTOMY OR UNTIL DEATH: 
 
Submit the SWOG Follow Up Form. 
 
k. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Blood for Translational Medicine and Banking (REQUIRED) 
 
Blood specimens for translational medicine are required to be submitted as described 
below.    
 
Please call the EDGE lab at 913/945-7519 when a patient blood draw has been scheduled 
so they may anticipate sample receipt. 
 
If the patient consents to future testing, any leftover blood will remain at the EDGE 
Repository for future analysis.  

 
 
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a. 
Collection 
 
Collect blood in purple top EDTA tubes, but process separately, as two different 
sets: 
• 
Set A: collect 12 mL of blood in purple EDTA tubes.  
• 
Set B: collect 12 mL of blood in purple EDTA tubes for a total of 24 mL.  
 
NOTE: Different sized tubes may be used to collect the required amount of blood. 
Avoid using < 3mL collection tubes.   
 
The blood will be collected at the following three time points: 
 
1. 
After registration prior to starting preoperative nutrition therapy (Baseline 
Study Visit) – MUST BE COLLECTED ON MONDAY, TUESDAY, 
WEDNESDAY, OR THURSDAY ONLY 
 
2. 
Day 2 after surgery – May be collected any non-holiday weekday, Monday 
through Friday 
 
3. 
Day 30 (±7 days) after surgery – MUST BE COLLECTED ON MONDAY, 
TUESDAY, WEDNESDAY, OR THURSDAY ONLY 
 
NOTE: EDGE Lab cannot receive samples on holidays. 
 
NOTE: The blood for submission must come from the same draw as blood for 
laboratory tests (see Sections 7.1b, 7.6, and 7.7b). 
 
b. 
Labeling and Processing 
 
All submitted specimens must be labeled with the: 
 
• 
SWOG patient number 
• 
Patient initials 
• 
Collection date and time (date the specimen was collected from the 
patient) 
• 
Date and time plasma was frozen 
 
c. 
Processing of Set A purple top tubes. Remove 1 mL whole blood and aliquot into 
1 Eppendorf tube, 1.5 mL tube size and freeze at -80◦C until shipping. After 
removing 1 mL whole blood from one of the tubes, centrifuge that tube along with 
the rest of the Set A purple tops tubes at 180 rcf (relative centrifugal force) for 10 
minutes at room temperature.  
 
Remove supernatant from Set A purple top tubes (plasma, top layer), aliquot 250 
mcl plasma into each of 11 Eppendorf tubes, 1.5 mL tube size, and 500 mcl plasma 
into 1 screw cap tube, 2 mL tube size, and freeze at -80°C until shipping.   Tubes 
must be labeled with patient ID using a label that will remain in place at -80°C. 
 
d. 
Shipment of Set B purple top tubes (12mL) 
 
Set B purple top tubes must be shipped overnight the same day it is 
collected.  Ship at ambient temperature.   
 

 
 
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Please pack tubes carefully.  Cardboard express mail envelopes alone are NOT 
adequate – please additionally pack the tubes in Styrofoam or with extra 
padding.  If freezing or very warm conditions are anticipated, insulated containers 
and packing materials are recommended.  Samples must be shipped and received 
at room temperature. 
 
Please call the EDGE lab at 913/945-7519 a few days before shipping the Set B 
purple tubes so they can watch for its arrival. 
 
If shipping Monday, Tuesday, Wednesday, or Thursday, ship to the following 
address: 
 
Lab #229:   
EDGE Research Laboratory 
University of Kansas Medical Center 
University Receiving Dock 
ATTN:  Misty Bechtel 
2106 Olathe Blvd. 
Kansas City, KS 66160 
 
Note that Friday shipments are only permitted for Day 2 Set B purple top 
tubes.  If shipping on a Friday, ship to the following address: 
 
Lab #234: 
FedEx Office Print and Ship 
ATTN:  KU Med, Misty Bechtel or EDGE Lab Team 
5437 Johnson Drive 
Mission, KS 66205 
 
e. 
Shipment of plasma aliquots and whole blood aliquot (Set A) 
 
Plasma and whole blood aliquots may be batch shipped as long as they are 
submitted within 3 months after collection.  Ship on dry ice overnight Monday 
through Thursday (NO FRIDAY SHIPMENTS) to the following address: 
 
Lab #229:   
EDGE Research Laboratory 
University of Kansas Medical Center 
ATTN:  Misty Bechtel 
2106 Olathe Blvd. 
Kansas City, KS 66160 
 
f. 
Additional instructions 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site (http://swog.org) and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at https://spectrack.crab.org (select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and 
demo) are available after signing in to SpecTrack.  
 

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S1600 
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3. 
First bowel movement on return to home (+/- 2 days). 
 
b. 
Omnigene-GUT Kit Stool Ordering 
 
Immediately after identifying a patient for the trial, sites must contact SWOG 
Biospecimen Bank to order Omnigene-GUT kits via the following URL: 
https://kits.bpc-apps.nchri.org. Orders placed by noon Eastern should be received 
within 3-4 business days. 
 
c. 
Omnigene-GUT Kit Stool Labeling  
 
Sites will be instructed to label tubes with:  
• 
SWOG patient number  
• 
Patient initials 
• 
Specimen type 
• 
Collection date  
 
NOTE: The collection date will be filled by the patient on the tube and the Intake 
Calendar. Sites must verify the date has been added on the tube prior to shipping. 
 
d. 
Specimen Collection and Submission Instructions 
 
Collection kits will be sent home with the patients at 2 different times to reduce 
patient error.  
 
(1) 2 kits will be provided after registration for the collection of: 
• 
After registration, but before beginning nutritional drink 
• 
After nutrition/before surgery (at least 4 days of drinks completed) 
 
(2) 1 kit will be provided after surgery when site staff provides nutritional drinks 
 
Due to the sensitive nature of the collections, patients will collect the specimens at 
home.  Patients must be instructed to bring their specimen back to the site on a 
subsequent visit.  
 
Site phone calls 
• 
Call the patient at home six days before the surgery date to remind patients 
to collect their stool sample. 
• 
Call patient prior to 30-day follow-up to bring their samples to appointment. 
 
Note for the 30-Day Follow-up visit: If the patient did not bring their stool specimen, 
the site must supply the patient with a mailer, shipping label, and instructions to 
ship specimen ambient to the SWOG Biospecimen Bank. Shipping labels created 
using the Kit Management website are valid for 1 week from date created.  The 
site must make a note in STS that the patient will be mailing in their specimen.  
 
The specimens must be shipped to the SWOG Biospecimen Bank within 1-3 
days of receiving them from the patient. Specimens remain stable in all weather 
conditions and are shipped ambient. Collection and shipment instructions are 
provided with the Omnigene-GUT kit. 
 
 

 
 
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Lab #201: 
SWOG Biospecimen Bank 
 
 
Solid Tissue, Myeloma & Lymphoma Division 
 
 
Phone: 614/722-2865  
E-mail: bpcbank@nationwidechildrens.org 
 
e. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the online 
system via the CRA Workbench. To access the CRA Workbench, go to the SWOG 
Web site (http://swog.org) and logon to the Members Area. After you have logged 
on using your SWOG roster ID number and password, click on the CRA 
Workbench link to access the home page for CRA Workbench website. Non- 
SWOG users may log into SpecTrack using their CTSU UserID and password on 
the SpecTrack login page located at  
https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  
SpecTrack start-up instructions (both written and demo) are available after signing 
in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen Tracking 
system must be printed  and placed in the pocket of the specimen bag if it has one, 
or in a separate resealable bag.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page 
(https://spectrack.crab.org/Instructions); or contact the Data Operations Center at 
206/652-2267 to be routed to the Data Coordinator for further assistance. 
 
15.3 
Questionnaires: Instructions for administration 
 
Patient-Reported Outcome Questionnaires via Telemedicine (Phone or Virtual Visit):  
 
In response to the COVID-19 pandemic, PROs may be conducted via telehealth when the 
following conditions are met:  
• 
For all patient reported outcome questionnaire timepoints, participating sites may 
follow-up with patients via telemedicine (phone or virtual visit) to conduct the 
questionnaires and patient follow-up provided that the Responsible Investigator 
determines that the phone/virtual visit is adequate to achieve the central purpose 
of the visit and assure the safety of the patient.  
• 
Patient must be provided with a copy of the questionnaire via mail or email. 
• 
The staff at EDGE are available to assist with the patient’s telemedicine site to 
perform the Patient-Generated Subjective Global Assessment (PG-SGA) prior to 
registration. 
If 
sites 
would 
like 
assistance, 
please 
contact 
EDGE 
edgelab@kumc.edu with any questions.  
 
 

 
 
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a. 
Administration of questionnaires 
 
1. 
The first time the patient completes the questionnaires: Please read to the 
patient the instructions attached to each patient questionnaire. Explain the 
specific administration times for this protocol. Patients should be directed 
to report all symptoms and limitations whether or not they are related to 
the cancer or its treatment. 
 
2. 
It is permissible to assist patients with completing the questionnaires being 
careful not to influence the patient's response. Note on the S1600 Cover 
Sheet for Patient-Completed Questionnaires what assistance was 
required and indicate reason (e.g., elderly, too sick, etc.). Discourage 
family members from: 1) being present while the patient completes the 
questionnaire and/or 2) influencing patient responses to the questions. 
 
3. 
It is very important to review the questionnaires after the patient has 
completed them to be sure all of the questions have been answered and 
that only one answer is marked. If the patient has marked more than one 
answer per question, ask the patient which answer reflects how she is 
feeling. If the patient has skipped a question, tell the patient that a question 
was not answered and ask if she would like to answer the question. Always 
give the patient the option to refuse. Indicate on the form by the question 
that the patient did not want to answer this question. 
 
4. 
If a patient refuses or cannot complete the questionnaire for some reason, 
this must be documented on the S1600 Cover Sheet for Patient 
Completed Questionnaires and submitted. 
 
5. 
If the patient completed on-treatment questionnaires and the patient 
immediately has disease recurrence:  
• 
If the patient did not receive any treatment between completing 
the questionnaires and learning of the recurrence, then the 
questionnaires can be used as recurrence questionnaires.  
• 
If the patient received any treatment, then separate recurrence 
questionnaires must be completed (even if only one day later) 
 
b. 
Additional quality control procedures: 
 
When a patient is registered on S1600, a calendar should be made with dates of 
upcoming patient-completed questionnaires noted. A copy of this calendar can be 
given to the patient with the notation that the questionnaires should be completed. 
You may wish to photocopy the Study Calendar, Section 9.0, and include the 
patient's name and specific dates. A copy of this should be kept in the patient file.   
 
If a patient refuses or cannot complete the patient questionnaires at one time 
point, he or she should be asked to do so at the next scheduled assessment 
time. Submit the S1600 Cover Sheet for Patient-Completed Questionnaires 
documenting the reason why the questionnaires were not done. 
 
15.4 
Phone Interview: 24 Hour Diet Recalls 
 
Within 24 hours after patient registration, study staff must FAX the S1600 Telephone 
Contact Form to the Exercise, Diet, Genitourinary, & Endocrinology (EDGE) Research 
Laboratory at 913/574-0515. Phone the EDGE lab at 913/945-7519 to ensure the FAX was 

 
 
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received.  After registration prior to beginning the study nutrition therapy and again around 
30 days after surgery, nutrition staff from the EDGE Research Laboratory will interview the 
patient over the phone to obtain two 24-hour dietary recalls (one weekday and closest 
weekend day) at each time point. The interview is conducted over the phone so that 
nutrition staff may be able to clarify ambiguities with the patient and ensure data collection 
completeness. Each phone interview will take approximately 15 minutes. 24-hour food 
recalls will be analyzed with Nutrition Data System for Research (NDSR). Energy, 
macronutrients, fish oil, and amino acid intake will be summarized and reported to control 
for the background diet.   
 
Note: If the patient is having their visit locally at EDGE, the phone interview can be 
conducted during the patient’s visit. 
 
 
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. 82, No. 12, January 19, 2017) 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. 82, No. 12, January 19, 2017) 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 

 
 
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patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported to SWOG 
Operations Office using 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 
 
c. 
When to report an event in an expedited manner 
 
When the adverse event requires expedited reporting, submit the report within 10 
calendar days of learning of the event as specified in Table 16.1. 
 
In the rare event when Internet connectivity is disrupted notification is made to 
SWOG by telephone at 210-614-8808 or by email adr@swog.org .  An electronic 
report MUST be submitted immediately upon re-establishment of internet 
connection. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required.  
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures.  
 
e. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.1. The commercial 
agent(s) used are Impact Advanced Recovery and Oral Nutrition Control Drink. If 
there is any question about the reportability of an adverse event or if Internet 
connectivity is disrupted please telephone or email the SAE Program Manager at 
the Operations Office, 210/614-8808 or adr@swog.org  before preparing the 
report. 
 
NOTE: For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is entered 
into RAVE, the Rules Engine will confirm whether or not the adverse event 
requires expedited reporting.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website.  Sites are encouraged to 
confirm the Expedited Reporting Evaluation Recommendation with the 
reporting criteria outlined in Table 16.1. 
 
 

 
 
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Table 16.1. Expedited reporting requirements for adverse events 
experienced by patients on Blinded Nutritional Drink within 30 days of the 
last administration of the commercial agent(s), Impact Advanced Recovery 
and Oral Nutrition Control Drink.   
 
 
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 via CTEP-AERS 
within 10 calendar days of learning of the eventb. 
 
a This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent(s), regardless of attribution. Any death that occurs more 
than 30 days after the last dose of treatment with a commercial agent(s) and 
is attributed (possibly, probably, or definitely) to the agent(s) 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 within 5 
calendar days by fax to 210-614-0006. 
 
 
f. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy: Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss: Pregnancy loss is defined in CTCAE as “Death in utero.” 
Pregnancy loss should be reported expeditiously as Grade 4 “Pregnancy 
loss” under the Pregnancy, puerperium and perinatal conditions 
SOC.   
 
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death.   
 
 

 
 
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3. 
Death Neonatal: “Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth.”    A neonatal death should 
be reported expeditiously as Grade 4 “Death neonatal” under the 
General disorders and administration SOC. 
 
Neonatal death should NOT be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 210-614-0006.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at: 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm    
 
 

 
 
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17.0 
BIBLIOGRAPHY
 
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Oncol, 33: 54, 2016. 
 
34  
Miura T, Mitsunaga S, Ikeda M, et al. Characterization of patients with advanced pancreatic cancer 
and high serum interleukin-6 levels. Pancreas, 44: 756, 2015. 
 
35  
Perioperative Immunonutrition Modulates Inflammatory Response after Radical Cystectomy: 
Results of a Pilot Randomized Controlled Clinical Trial.  Hamilton-Reeves JM, Stanley A, Bechtel 
MD, Yankee TM, Chalise P, Hand LK, Lee EK, Smelser W, Mirza M, Wyre H, Hull H, Carlson SE, 
Holzbeierlein 
JM. 
 
J 
Urol. 
2018 
Mar 
5. 
pii: 
S0022-5347(18)42469-X. 
doi: 
10.1016/j.juro.2018.03.001. [Epub ahead of print] 
 
36  
Mathur S, Plank LD, Hill AG, et al. Changes in body composition, muscle function and energy 
expenditure after radical cystectomy. BJU Int, 101: 973, 2008. 
 
37  
McDonald ML, Liss MA, Nseyo UU, et al. Weight Loss Following Radical Cystectomy for Bladder 
Cancer: Characterization and Effect on Survival. Clin Genitourin Cancer, 2016. 
 
38  
Karl A, Staehler M, Bauer R, et al. Malnutrition and clinical outcome in urological patients. Eur J 
Med Res, 16: 469, 2011. 
 
39  
Rettig TC, Verwijmeren L, Dijkstra I M, et al. Postoperative Interleukin-6 Level and Early Detection 
of Complications After Elective Major Abdominal Surgery. Ann Surg, 263: 1207, 2016. 
 
40  
Cerantola Y, Valerio M, Hubner M, et al. Are patients at nutritional risk more prone to complications 
after major urological surgery? J Urol, 190: 2126, 2013. 
 
41  
Roth B, Birkhauser FD, Zehnder P, et al. Parenteral nutrition does not improve postoperative 
recovery from radical cystectomy: results of a prospective randomised trial. Eur Urol, 63: 475, 2013. 
 
42  
Smelsor W, Bechtel MD, Holzbeierlein JM, et al. Malnutrition status and an intervention for 
malnutrition in patients undergoing radical cystectomy. In: South Central Section of the AUA. 
Colorado Springs, CO, 2016. 
 
43  
McDonald ML, Liss MA, Nseyo UU, et al. Weight Loss Following Radical Cystectomy for Bladder 
Cancer: Characterization and Effect on Survival. Clin Genitourin Cancer, 2016. 
 
44  
Munbauhal G, Drouin SJ, Mozer P, et al. Malnourishment in bladder cancer and the role of 
immunonutrition at the time of cystectomy: an overview for urologists. BJU Int, 114: 177, 2014. 
 
45  
Karl A, Staehler M, Bauer R, et al. Malnutrition and clinical outcome in urological patients. Eur J 
Med Res, 16: 469, 2011. 
 
46  
Gregg JR, Cookson MS, Phillips S, et al. Effect of preoperative nutritional deficiency on mortality 
after radical cystectomy for bladder cancer. J Urol, 185: 90, 2011. 
 
47  
Mathur S, Plank LD, Hill AG, et al. Changes in body composition, muscle function and energy 
expenditure after radical cystectomy. BJU Int, 101: 973, 2008. 
 
 

 
 
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48  
Mathur S, Plank LD, Hill AG, et al. Changes in body composition, muscle function and energy 
expenditure after radical cystectomy. BJU Int, 101: 973, 2008. 
 
49  
Perioperative Immunonutrition Modulates Inflammatory Response after Radical Cystectomy: 
Results of a Pilot Randomized Controlled Clinical Trial.  Hamilton-Reeves JM, Stanley A, Bechtel 
MD, Yankee TM, Chalise P, Hand LK, Lee EK, Smelser W, Mirza M, Wyre H, Hull H, Carlson SE, 
Holzbeierlein 
JM. 
 
J 
Urol. 
2018 
Mar 
5. 
pii: 
S0022-5347(18)42469-X. 
doi: 
10.1016/j.juro.2018.03.001. [Epub ahead of print] 
 
50  
Bertrand J, Siegler N, Murez T, et al. Impact of preoperative immunonutrition on morbidity following 
cystectomy for bladder cancer: a case-control pilot study. World J Urol, 32: 233, 2014. 
 
51  
Munbauhal G, Drouin SJ, Mozer P, et al. Malnourishment in bladder cancer and the role of 
immunonutrition at the time of cystectomy: an overview for urologists. BJU Int, 114: 177, 2014. 
 
52  
Roth B, Birkhauser FD, Zehnder P, et al. Parenteral nutrition does not improve postoperative 
recovery from radical cystectomy: results of a prospective randomised trial. Eur Urol, 63: 475, 2013. 
 
53  
Declercq P, De Win G, Van der AaF. et al. Reduced length of stay in radical cystectomy patients 
with oral versus parenteral post-operative nutrition protocol. Int J Clin Pharm, 37: 379, 2015. 
 
54  
Roth B, Birkhauser FD, Zehnder P, et al. Parenteral nutrition does not improve postoperative 
recovery from radical cystectomy: results of a prospective randomised trial. Eur Urol, 63: 475, 2013. 
 
55  
McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of 
Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) 
and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral 
Nutr, 40: 159, 2016. 
 
56  
McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of 
Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) 
and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral 
Nutr, 40: 159, 2016. 
 
57  
Daly JM, Lieberman MD, Goldfine J, et al. Enteral nutrition with supplemental arginine, RNA, and 
omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome. 
Surgery, 112: 56, 1992. 
 
58  
Bertrand J, Siegler N, Murez T, et al. Impact of preoperative immunonutrition on morbidity following 
cystectomy for bladder cancer: a case-control pilot study. World J Urol, 32: 233, 2014. 
 
59  
Gianotti L, Braga M, Vignali A, et al. Effect of route of delivery and formulation of postoperative 
nutritional support in patients undergoing major operations for malignant neoplasms. Arch Surg, 
132: 1222, 1997. 
 
60  
Braga M, Gianotti L, Vignali A, et al. Preoperative oral arginine and n-3 fatty acid supplementation 
improves the immunometabolic host response and outcome after colorectal resection for cancer. 
Surgery, 132: 805, 2002. 
 
61  
Braga M, Gianotti L, Nespoli L, et al. Nutritional approach in malnourished surgical patients: a 
prospective randomized study. Arch Surg, 137: 174, 2002. 
 
 

 
 
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62  
Aida T, Furukawa K, Suzuki D, et al. Preoperative immunonutrition decreases postoperative 
complications by modulating prostaglandin E2 production and T-cell differentiation in patients 
undergoing pancreatoduodenectomy. Surgery, 155: 124, 2014. 
 
63  
Fujitani K, Tsujinaka T, Fujita J, et al. Prospective randomized trial of preoperative enteral 
immunonutrition followed by elective total gastrectomy for gastric cancer. Br J Surg, 99: 621, 2012. 
 
64  
Giger-Pabst U, Lange J, Maurer C, et al. Short-term preoperative supplementation of an 
immunoenriched diet does not improve clinical outcome in well-nourished patients undergoing 
abdominal cancer surgery. Nutrition, 29: 724, 2013. 
 
65  
Drover JW, Dhaliwal R, Weitzel L, et al. Perioperative use of arginine-supplemented diets: a 
systematic review of the evidence. J Am Coll Surg, 212: 385, 2011. 
 
66  
Marimuthu K, Varadhan KK, Ljungqvist O, et al. A meta-analysis of the effect of combinations of 
immune modulating nutrients on outcome in patients undergoing major open gastrointestinal 
surgery. Ann Surg, 255: 1060, 2012. 
 
67  
Hegazi RA, Hustead DS, Evans DC. Preoperative standard oral nutrition supplements vs 
immunonutrition: results of a systematic review and meta-analysis. J Am Coll Surg, 219: 1078, 
2014. 
 
68  
Hamilton-Reeves J M, Bechtel MD, Hand LK, et al. Effects of Immunonutrition for Cystectomy on 
Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. Eur Urol, 69: 
389, 2016. 
 
69  
Daly JM, Lieberman MD, Goldfine J, et al. Enteral nutrition with supplemental arginine, RNA, and 
omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome. 
Surgery, 112: 56, 1992. 
 
70  
Gianotti L, Braga M, Vignali A. et al. Effect of route of delivery and formulation of postoperative 
nutritional support in patients undergoing major operations for malignant neoplasms. Arch Surg, 
132: 1222, 1997. 
 
71  
Braga M, Gianotti L, Vignali A, et al. Preoperative oral arginine and n-3 fatty acid supplementation 
improves the immunometabolic host response and outcome after colorectal resection for cancer. 
Surgery, 132: 805, 2002. 
 
72  
Aida T, Furukawa K, Suzuki D. et al. Preoperative immunonutrition decreases postoperative 
complications by modulating prostaglandin E2 production and T-cell differentiation in patients 
undergoing pancreatoduodenectomy. Surgery, 155: 124, 2014. 
 
73  
Giger-Pabst U, Lange J, Maurer C. et al. Short-term preoperative supplementation of an 
immunoenriched diet does not improve clinical outcome in well-nourished patients undergoing 
abdominal cancer surgery. Nutrition, 29: 724, 2013. 
 
74  
Moya P, Soriano-Irigaray L, Ramirez JM. et al. Perioperative Standard Oral Nutrition Supplements 
Versus Immunonutrition in Patients Undergoing Colorectal Resection in an Enhanced Recovery 
(ERAS) Protocol: A Multicenter Randomized Clinical Trial (SONVI Study). Medicine (Baltimore), 
95: e3704, 2016. 
 
75  
Braga M, Gianotti L, Radaelli G. et al. Perioperative immunonutrition in patients undergoing cancer 
surgery: results of a randomized double-blind phase 3 trial. Arch Surg, 134: 428, 1999. 
 

 
 
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76  
Marano L, Porfidia R, Pezzella M. et al. Clinical and immunological impact of early postoperative 
enteral immunonutrition after total gastrectomy in gastric cancer patients: a prospective 
randomized study. Ann Surg Oncol, 20: 3912, 2013. 
 
77  
Okamoto Y, Okano K, Izuishi K. et al. Attenuation of the systemic inflammatory response and 
infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids 
supplemented immunonutrition. World J Surg, 33: 1815, 2009. 
 
78 
Takeuchi H, Ikeuchi S, Kawaguchi Y. et al.: Clinical significance of perioperative immunonutrition 
for patients with esophageal cancer. World J Surg, 31: 2160, 2007. 
 
79  
Senkal M, Zumtobel V, Bauer KH. et al. Outcome and cost-effectiveness of perioperative enteral 
immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective 
randomized study. Arch Surg, 134: 1309, 1999. 
 
80  
Farreras N, Artigas V, Cardona D. et al. Effect of early postoperative enteral immunonutrition on 
wound healing in patients undergoing surgery for gastric cancer. Clin Nutr, 24: 55, 2005. 
 
81 
Daly JM, Weintraub FN, Shou J. et al. Enteral nutrition during multimodality therapy in upper 
gastrointestinal cancer patients. Ann Surg, 221: 327, 1995. 
 
82 
Falewee MN, Schilf A, Boufflers E, et al. Reduced infections with perioperative immunonutrition in 
head and neck cancer: exploratory results of a multicenter, prospective, randomized, double-blind 
study. Clin Nutr, 33: 776, 2014. 
 
83 
Snyderman CH, Kachman K, Molseed L. et al.: Reduced postoperative infections with an immune-
enhancing nutritional supplement. Laryngoscope, 109: 915, 1999. 
 
84  
Hubner M, Cerantola Y, Grass F, et al. Preoperative immunonutrition in patients at nutritional risk: 
results of a double-blinded randomized clinical trial. Eur J Clin Nutr, 66: 850, 2012. 
 
85  
Bertrand J, Siegler N, Murez T, et al. Impact of preoperative immunonutrition on morbidity following 
cystectomy for bladder cancer: a case-control pilot study. World J Urol, 32: 233, 2014. 
 
86  
Hamilton-Reeves J M, Bechtel MD, Hand LK, et al. Effects of Immunonutrition for Cystectomy on 
Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. Eur Urol, 69: 
389, 2016. 
 
87  
Gianotti L, Braga M, Vignali A, et al. Effect of route of delivery and formulation of postoperative 
nutritional support in patients undergoing major operations for malignant neoplasms. Arch Surg, 
132: 1222, 1997. 
 
88  
Braga M, Gianotti L, Vignali A, et al. Preoperative oral arginine and n-3 fatty acid supplementation 
improves the immunometabolic host response and outcome after colorectal resection for cancer. 
Surgery, 132: 805, 2002. 
 
89  
Braga M, Gianotti L, Radaelli G, et al. Perioperative immunonutrition in patients undergoing cancer 
surgery: results of a randomized double-blind phase 3 trial. Arch Surg, 134: 428, 1999. 
 
90  
Snyderman CH, Kachman K, Molseed L. et al. Reduced postoperative infections with an immune-
enhancing nutritional supplement. Laryngoscope, 109: 915, 1999. 
 
 

 
 
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91  
Moya P, Soriano-Irigaray L, Ramirez JM, et al. Perioperative Standard Oral Nutrition Supplements 
Versus Immunonutrition in Patients Undergoing Colorectal Resection in an Enhanced Recovery 
(ERAS) Protocol: A Multicenter Randomized Clinical Trial (SONVI Study). Medicine (Baltimore), 
95: e3704, 2016. 
 
92  
Taheri F, Ochoa JB, Faghiri Z. et al. L-Arginine regulates the expression of the T-cell receptor zeta 
chain (CD3zeta) in Jurkat cells. Clin Cancer Res, 7: 958s, 2001. 
 
93  
Cuenca AG, Cuenca AL, Winfield RD, et al. Novel role for tumor-induced expansion of myeloid-
derived cells in cancer cachexia. J Immunol, 192: 6111, 2014. 
 
94  
Hamilton-Reeves JM, Bechtel M.D, Hand LK. et al.:Effects of Immunonutrition for Cystectomy on 
Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. Eur Urol, 
69:389, 2016. 
 
95  
Chapkin RS, Kim W, Lupton JR, et al. Dietary docosahexaenoic and eicosapentaenoic acid: 
emerging mediators of inflammation. Prostaglandins Leukot Essent Fatty Acids, 81: 187, 2009. 
 
96  
Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid mediators. Annu Rev 
Pathol, 3: 279, 2008. 
 
97  
McDaniel JC, Belury M, Ahijevych K, et al.: Omega-3 fatty acids effect on wound healing. Wound 
Repair Regen, 16: 337, 2008. 
 
98  
Murphy RA, Yeung E, Mazurak VC, et al. Influence of eicosapentaenoic acid supplementation on 
lean body mass in cancer cachexia. Br J Cancer, 105: 1469, 2011. 
 
99  
Zhu X, Herrera G, Ochoa JB. Immunosupression and infection after major surgery: a nutritional 
deficiency. Crit Care Clin, 26: 491, 2010. 
 
100  
Mirza, N., Fishman, M., Fricke, I. et al.: All-trans-retinoic acid improves differentiation of myeloid 
cells and immune response in cancer patients. Cancer Res, 66: 9299, 2006 
 
101  
Bobak Y, Kurlishchuk Y, Vynnytska-Myronovska B, Grydzuk O, Shuvayeva G, Redowicz MJ, Kunz-
Schughart LA and Stasyk O. Arginine deprivation induces endoplasmic reticulum stress in human 
solid cancer cells. Int J Biochem Cell Biol. 70:29-38, 2016. 
 
102  
Bobak Y, Kurlishchuk Y, Vynnytska-Myronovska B, Grydzuk O, Shuvayeva G, Redowicz MJ, Kunz-
Schughart LA and Stasyk O. Arginine deprivation induces endoplasmic reticulum stress in human 
solid cancer cells. Int J Biochem Cell Biol. 70:29-38, 2016. 
 
103  
Allen MD, Luong P, Hudson C, Leyton J, Delage B, Ghazaly E, Cutts R, Yuan M, Syed N, Lo Nigro 
C, Lattanzio L, Chmielewska-Kassassir M, Tomlinson I, Roylance R, Whitaker HC, Warren AY, 
Neal D, Frezza C, Beltran L, Jones LJ, Chelala C, Wu BW, Bomalaski JS, Jackson RC, Lu YJ, 
Crook T, Lemoine NR, Mather S, Foster J, Sosabowski J, Avril N, Li CF and Szlosarek PW. 
Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as 
monitored longitudinally by PET imaging. Cancer Res. 2014;74:896-907. 
 
104  
Beddowes E, Spicer J, Chan PY, Khadeir R, Corbacho JG, Repana D, Steele JP, Schmid P, 
Szyszko T, Cook G, Diaz M, Feng X, Johnston A, Thomson J, Sheaff M, Wu BW, Bomalaski J, 
Pacey S and Szlosarek PW. Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, 
Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic 
Cancers. J Clin Oncol. 35:1778-1785, 2017. 
 

 
 
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105  
Allen MD, Luong P, Hudson C, Leyton J, Delage B, Ghazaly E, Cutts R, Yuan M, Syed N, Lo Nigro 
C, Lattanzio L, Chmielewska-Kassassir M, Tomlinson I, Roylance R, Whitaker HC, Warren AY, 
Neal D, Frezza C, Beltran L, Jones LJ, Chelala C, Wu BW, Bomalaski JS, Jackson RC, Lu YJ, 
Crook T, Lemoine NR, Mather S, Foster J, Sosabowski J, Avril N, Li CF and Szlosarek PW. 
Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as 
monitored longitudinally by PET imaging. Cancer Res. 2014;74:896-907. 
 
106  
Bobak Y, Kurlishchuk Y, Vynnytska-Myronovska B, Grydzuk O, Shuvayeva G, Redowicz MJ, Kunz-
Schughart LA and Stasyk O. Arginine deprivation induces endoplasmic reticulum stress in human 
solid cancer cells. Int J Biochem Cell Biol. 70:29-38, 2016. 
 
107  
Sahu D, Gupta S, Hau AM, et al. Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer 
Regulates Survival through General Control Nonderepressible 2 Kinase-Mediated Eukaryotic 
Initiation Factor 2alpha Activity and Is Targetable by Pegylated Arginine Deiminase. The American 
journal of pathology. 2016. 
 
108  
Buijs N, van Bokhorst-de van der Schueren MA, Langius JA, Leemans CR, Kuik DJ, Vermeulen 
MA and van Leeuwen PA. Perioperative arginine-supplemented nutrition in malnourished patients 
with head and neck cancer improves long-term survival. Am J Clin Nutr. 92:1151-6, 2010. 
 
109  
Assenat E, Latournerie M, Thézenas S, Gaillet S, Janiszewski C, Flori N, Dupuy AM, Azria D, 
Crapez E, Garrel R and Senesse P. A prospective phase II study evaluating the efficacy of oral 
immune modulating formulae on acute oral mucositis during radiochemotherapy in head and neck 
neoplasms. European e-Journal of Clinical Nutrition and Metabolism. 6:e171-e177. 
 
110  
Senesse P, Graff-Cailleaud P, Sire C, Gallocher O, Lavau-Denes S, Garcia-Ramirez M, Alfonsi M, 
Cupisool D, Kaminsky M, Fiore S, Flori N, de Forges H, Garrel R, Janiszewski C, Thezenas S and 
Boisselier P. Double blind multicenter phase III GORTEC trial evaluating the efficacy of oral 
immune modulating formulae therapy during adjuvant radiochemotherapy in head and neck 
squamous cell carcinoma. Paper presented at: ASPEN Clinical Nutrition Week 2016; Austin, TX 
USA. 
 
111  
Assenat E, Latournerie M, Thézenas S, Gaillet S, Janiszewski C, Flori N, Dupuy AM, Azria D, 
Crapez E, Garrel R and Senesse P. A prospective phase II study evaluating the efficacy of oral 
immune modulating formulae on acute oral mucositis during radiochemotherapy in head and neck 
neoplasms. European e-Journal of Clinical Nutrition and Metabolism. 6:e171-e177. 
 
112  
Senesse P, Graff-Cailleaud P, Sire C, Gallocher O, Lavau-Denes S, Garcia-Ramirez M, Alfonsi M, 
Cupisool D, Kaminsky M, Fiore S, Flori N, de Forges H, Garrel R, Janiszewski C, Thezenas S and 
Boisselier P. Double blind multicenter phase III GORTEC trial evaluating the efficacy of oral 
immune modulating formulae therapy during adjuvant radiochemotherapy in head and neck 
squamous cell carcinoma. Paper presented at: ASPEN Clinical Nutrition Week 2016; Austin, TX 
USA. 
 
113  
Hess JR, Greenberg NA. The role of nucleotides in the immune and gastrointestinal systems: 
potential clinical applications. Nutr Clin Pract, 27: 281, 2012. 
 
114  
Hegazi RA, Hustead DS, Evans DC. Preoperative standard oral nutrition supplements vs 
immunonutrition: results of a systematic review and meta-analysis. J Am Coll Surg, 219: 1078, 
2014.  
 
 

 
 
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115  
Moya P, Soriano-Irigaray L, Ramirez JM, et al. Perioperative Standard Oral Nutrition Supplements 
Versus Immunonutrition in Patients Undergoing Colorectal Resection in an Enhanced Recovery 
(ERAS) Protocol: A Multicenter Randomized Clinical Trial (SONVI Study). Medicine (Baltimore), 
95: e3704, 2016. 
 
116  
Moya P, Soriano-Irigaray L, Ramirez JM, et al. Perioperative Standard Oral Nutrition Supplements 
Versus Immunonutrition in Patients Undergoing Colorectal Resection in an Enhanced Recovery 
(ERAS) Protocol: A Multicenter Randomized Clinical Trial (SONVI Study). Medicine (Baltimore), 
95: e3704, 2016. 
 
117  
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics 31:103-115, 1975. 
 
118  
Bertrand J, Siegler N, Murez T, et al. Impact of preoperative immunonutrition on morbidity following 
cystectomy for bladder cancer: a case-control pilot study. World J Urol, 32: 233, 2014. 
 
119  
Clavien, P. A., Barkun, J., de Oliveira, M. L. et al.: The Clavien-Dindo classification of surgical 
complications: five-year experience. Ann Surg, 250: 187, 2009. 
 
120  
Ribaudo, J. M., Cella, D., Hahn, E. A. et al.: Re-validation and shortening of the Functional 
Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Qual Life Res, 9: 1137, 2000. 
 
121  
Shabsigh A, Korets R, Vora KC. et al. Defining early morbidity of radical cystectomy for patients 
with bladder cancer using a standardized reporting methodology. Eur Urol, 55: 164, 2009. 
 
122  
Daneshmand S, Ahmadi H, Schuckman AK, et al. Enhanced recovery protocol after radical 
cystectomy for bladder cancer. J Urol, 192: 50, 2014. 
 
123  
Bertrand J, Siegler N, Murez T, et al.  Impact of preoperative immunonutrition on morbidity following 
cystectomy for bladder cancer: a case-control plot study.  World J Urol, 32:233,2014. 
 
124  
Lachin JM, CCT, 1999. 
 
 

 
 
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18.0 
Appendix 
 
18.1 
Product Compositions 
 
 
18.2 
Tertiary Objectives 
 
18.3 
Body Composition Assessment by Dual-Energy X-ray Absorptiometry 
 
18.4 
S1600 Patient Intake Calendar 
 
18.5 
PG-SGA 
 
18.6 
24-hour Dietary Recall 
 
18.7 
S1600 Site Requirements Form 
 
18.8 
Guidelines for Emergency Unblinding of Coded Intervention 
 
18.9 
Translational Medicine Study Stool Microbiome 
 
18.10 
SWOG Biospecimen Processing Instructions 
 
 
 

 
 
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18.1 
Product Compositions  
 
Impact Advanced Recovery †† 
Oral Nutrition Control 
Serving Size 
 
6.0 fl oz 
6.0 fl oz 
Calories 
kcal 
200 
185 
Total Fat* 
g 
8 
8 
Sodium 
mg 
200 
200 
Potassium 
mg 
450 
450 
Total Carbohydrate 
g 
15 
15 
Total Sugars 
g 
~13 
~13 
Protein 
g 
18 
14 
Vitamin A** 
IU 
1126 
1126 
Vitamin C 
mg 
20 
20 
Calcium 
mg 
270 
270 
Iron 
mg 
4 
4 
Vitamin D 
IU 
152 
152 
Vitamin E 
IU 
14 
14 
Vitamin K 
mcg 
22 
22 
Thiamin 
mg 
0.4 
0.4 
Riboflavin 
mg 
0.6 
0.6 
Niacin 
mg 
5.3 
5.3 
Vitamin B6 
mg 
0.5 
0.5 
Folic Acid 
mcg 
65 
65 
Vitamin B12 
mcg 
0.8 
0.8 
Biotin 
mcg 
10 
10 
Pantothenic Acid 
mg 
2.7 
2.7 
Phosphorus 
mg 
240 
240 
Iodine 
mcg 
50 
50 
Magnesium 
mg 
75 
75 
Zinc 
mg 
5 
5 
Selenium 
mcg 
16 
16 
Copper 
mg 
0.3 
0.3 
Manganese 
mg 
0.7 
0.7 
Chromium 
mcg 
12 
12 
Molybdenum 
mcg 
15 
15 
Chloride 
mg 
400 
400 
Choline 
mg 
90 
90 
* Contains 1.3g MCT per 178 mL 
**Includes 50% Vitamin A activity from Beta-Carotene 
†† Includes 4.2 g of the amino acid L-arginine per 237 mL 
 
 
 

 
 
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18.2 
Tertiary Objectives 
 
• 
Frequencies of Myeloid-derived suppressor cells (MDSCs). Our team discovered that 
SIM restrains MDSC expansion. (1) Expansion of myeloid derived suppressor cells 
(MDSC) suppresses T-cells, and lowers the resistance to infection. Peripheral blood 
mononucleocytes (PBMCs) will be collected at baseline, post-operative Day 2 and 
post-operative Day 30 based on the findings of our pilot study. (2) Samples will be 
analyzed by flow cytometry as they are received at the University of Kansas. MDSC 
subpopulations are defined according to published methods of grouping granulocytic 
((Lin- CD11b+ CD33+ CD14- CD15+), monocytic (Lin- CD11b+ CD33+ CD14+ CD15-
), and immature (Lin- CD11b+ CD33+ CD14- CD15-). (3) Dr. Augusto Ochoa will run 
final analyses on all immune data.  
 
• 
Neutrophil-to-lymphocyte ratio (NLR). NLR has been suggested as a biomarker for 
predicting clinical course in surgical populations. (4) In our pilot study, NLR was 
significantly lower in the SIM group compared to the ONS group 3 hours after incision 
(P = 0.04). (5) The complete blood count (CBC) with differential is taken as part of 
routine care. The ratio of the absolute neutrophil to lymphocyte count is obtained from 
this test. The lymphocyte count is also used to calculate the absolute number of 
MDSCs.  
  
• 
Inflammation biomarkers related to complications and muscle wasting. Elevated IL-6 
is associated with post-operative complications and muscle loss. Also, a depressed 
Th1 and dominant Th2 response after surgery is associated with infectious 
complications. In our pilot study, the change in plasma IL-6 levels from surgery to 
POD2 was significantly lower in the SIM group compared to the ONS group (P = 0.022), 
and the average IL-6 concentration in the plasma was significantly lower in SIM group 
compared to the ONS group on POD 2 (P=0.020), suggesting earlier resolution of 
inflammation in the SIM group. (6) SIM intake has reduced plasma IL-6 compared to 
control groups in other clinical trials. (7,8,9,10,11) Our pilot study also showed that 
Th1-Th2 balance was shifted towards Th1 three hours after incision, which may mean 
that participants were better able to ward off an infection. We measure Th1-Th2 
balance by evaluating the ratios of IFNγ:IL-4 and TNFα:IL-13. SIM intake has improved 
Th1-Th2 balance after colorectal surgery, which further supports our prediction. (12) 
Cytokines will be analyzed in our lab by MILLIPLEX MAP Human Th17 Panel, 
Magnetic, 8-plex with IL-6, IL-4, IFN gamma, IL-13, TNF alpha, IL-1b, IL-31, IL-5, and 
IL-17A run on all three blood draws (baseline, post-operative day 2, post-operative day 
30) for each patient.  
  
• 
Arginine deficiency & Plasma Amino Acid Metabolism. The systemic inflammatory 
response affects carbohydrate (glucose), lipid, and amino acid metabolism which all 
contribute to the adverse nutritional impact of cancer, surgical response, and infection. 
However, it is amino acid metabolism that is the final pathway responsible for lean 
tissue maintenance, loss, and repletion. Analyses of amino acid profiles are a critical 
piece to foster a better understanding of whether amino acid deficiencies persist even 
after SIM supplementation. These data are key to optimizing new nutrition 
interventions to help patients. Amino acid profiles provide insight regarding the 
dysregulated amino acid metabolism thought to play a role in how SIM supports the 
immune system, improves wound healing, prevents muscle degradation, and 
increases blood flow and tissue oxygenation. The theory surrounding the efficacy of 
SIM involves preventing arginine deficiency after surgery. (13) Our preliminary data 
revealed that prior to surgery, RC patients were arginine deficient. Sufficient levels of 
plasma arginine are based on the reference range, 80-100 μmol/L. (14) However, SIM 
supplementation prevented further depletion of arginine at post-operative day 2, 
whereas arginine plummeted in the ONS group after surgery. Furthermore, our data 

 
 
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showed that the SIM group had significantly higher plasma ornithine concentrations 
compared to the ONS group at the time of surgery (P = 0.001) and ornithine 
concentrations were significantly different between the two groups over time (P = 0.04). 
Ornithine is the product of arginine metabolism by arginase, and these data suggest 
that the increase in ornithine reflects a greater availability of proline and polyamines, 
which contribute to better wound healing through collagen formation. Several ratios are 
available to help interpret the amino acid flux around trauma. A full panel of amino 
acids will be measured in the plasma using the Ultraperformance liquid 
chromatography (UPLC) with ultraviolet detection at the Institute for Metabolomic 
Disease, Baylor Research Institute. (15) 
  
• 
Nutrition Status. We will screen and assess for malnutrition using the Patient-
generated subjective global assessment (PG-SGA), version 2014, a validated tool for 
the oncology population which captures nutrition impact symptoms. (16) The PG-SGA 
will be completed by the patient and study team staff. A training video is available on 
the S1600 study abstract page on the SWOG web site. The PG-SGA will be obtained 
at baseline to identify and categorize patients at risk for nutrition deficiency and will be 
repeated at the 30 day visit to monitor subjective short-term changes in nutritional 
status. The Scored PG-SGA includes patient-generated historical components (Weight 
History, Food Intake, & Nutrition Impact Symptoms) and a professional assessment 
(Diagnosis, Age, Metabolic stress, and Physical Exam). The malnutrition assessment 
will be used to categorize whether patients are: 1) well nourished, 2) moderately 
malnourished, or 3) severely malnourished. Change in grades of malnutrition at 
baseline and 30 days will also be evaluated. Nutrition status will be considered as a 
potential covariate as we analyze the data.  
  
• 
Background Dietary Intake. On baseline and day 30, two 24-h dietary recalls (one 
weekday and closest weekend day) will be analyzed with Nutrition Data System for 
Research (NDSR). If the patient consents, his or her contact information will be 
obtained at registration. A study dietitian, staffed by Dr. Hamilton-Reeves, will interview 
the patient by phone at scheduled times. Dietary intake data gathered by interview is 
governed by a multiple-pass interview approach. (17) Five distinct passes provide 
multiple opportunities for the participant to recall food intake. The first pass involves 
obtaining from the participant a listing of all foods and beverages consumed in the 
previous 24 h. This listing is reviewed with the participant for completeness and 
correctness (second pass). The interviewer then collects detailed information about 
each reported food and beverage, including the amount consumed and method of 
preparation (third pass). In the fourth pass, the interviewer then probes for commonly 
forgotten foods. Finally, the detailed information is reviewed for completeness and 
correctness (fifth pass). Energy, macronutrients, fish oil, arginine, EPA, DHA, vitamin 
A, and dietary supplement intake will be summarized and reported to control for the 
background diet. Background diet will be summarized and reported to control for the 
background diet.   
 
• 
Measures of Treatment Compliance Biomarkers. Plasma fatty acid profiles are 
biomarkers of intake compliance enhancing the rigor of our study. The high 
concentrations of EPA and DHA in the formula will be reflected in the plasma 
phospholipid fatty acid composition as demonstrated by Senkal et al. Plasma fatty acid 
profiles reflect fat intake over the previous days to weeks and triacylglycerides reflect 
fat intake over the previous hours to days making these ideal compliance markers for 
our intervention. Plasma fatty acid profiles will be analyzed by gas chromatography 
and reported as weight percent of total fatty acids. The fatty acid profiles from the day 
2 post-surgery blood will be measured by collaborator Dr. Susan Carlson.  
 

 
 
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• 
Neutrophil Extracellular Traps (NETs). NETs are meshes of DNA with associated 
neutrophil enzymes, including proteases such as Neutrophil Elastase and 
myeloperoxidase. NETs are detected in plasma from humans and mice with lung 
inflammation using a sandwich enzyme-linked immunosorbent assay (ELISA). The 
amount of NETs is determined by a sandwich ELISA using antibodies against the DNA 
scaffold and the NET-associated protease neutrophil elastase. ABTS is used as a 
substrate for the HRP (HorseRadish Peroxidase) conjugated Anti-DNA antibody and 
given an absorbance reading value (at 405 nm) used to compare the samples. 50 
microliters of plasma are needed to perform this assay (150 microliter would be the 
best to be on the safe side and to perform duplicates). In this assay, developed by the 
Egeblad lab, healthy donors have no detectable NETs while transfusion related acute 
lung injury (TRALI) patients have values of ≈200-times that of healthy donors. The 
NETs will be measured at baseline, post-operative Day 2 and post-operative Day 30 
by collaborator Dr. Mikala Egeblad. 
 
Tertiary objectives include comparing the impact of consuming SIM compared to ONS for 
restraining MDSCs, decreasing inflammation, and modulating nutrient metabolism. To limit 
the influence of outliers and aid interpretation across a panel of markers, the marker level 
results will be log normal–standardized and split at the median level, creating an indicator 
variable (high vs. low levels of each marker). Assuming complete information, the accrual 
goal of n = 200 total patients will provide adequate power (>80%) to detect a >20% change 
in the proportion of patients with high or low marker levels due to SIM, based on a two-arm 
normal design, one-sided alpha = 0.05 testing, and assuming the average rate of high or 
low marker levels across arms of 50%.  
 
In addition, we will examine whether these biomarkers influence the association between 
intervention and the clinical outcomes. As a more exploratory analysis, we will use a two-
sided nominal P-value = 0.10 to identify potentially significant interactions. (18) Under a 
binomial interaction design, equal sample sizes in each cell, a one-sided alpha = 0.10, and 
a 65% event probability for the ONS arm, n = 200 patients will give adequate power (≥ 
80%) to detect a 3.8-fold increased odds of complications on the ONS arm in stratum 1 
(i.e., high-expression group) if there is no effect in stratum 2 (i.e., low-expression group). 
In the case of a significant interaction indicating differential complication rates by arm 
between marker categories, further specific analyses will be performed to identify the actual 
differences. It is recognized that these results will not be definitive due to the limited power 
and multiple testing problem, although hypotheses will be based on biologic rationale. 
Promising observations will need to be validated in future data sets due to the exploratory 
nature of this component of the study. 
 
We will also explore whether dietary intake variables, derived from data obtained from the 
dietary intake telephone interview, influence the association between intervention and 
outcome. The specific variables of interest include calorie intake, protein intake, nutrition 
status, and immune-enhancing nutrients. 
 
Analyses will be based on multivariable logistic regression, adjusting for appropriate 
covariates, including stratification factors. Descriptive statistics will be used to express 
means and standard deviations of different marker levels by time point. We will examine 
marker levels at both 2 days post-operation and 30 days post-operation. To examine 
measures over time (baseline, day 2, and day 30), linear mixed models will be used. 
 
 

 
 
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References 
 
1  
Hamilton-Reeves JM, Bechtel MD, Hand LK, Schleper A, Yankee TM, Chalise P, Lee EK, 
Mirza M, Wyre H, Griffin J and Holzbeierlein JM. Effects of Immunonutrition for Cystectomy 
on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. 
Eur Urol. 69:389-92, 2016. 
 
2  
Hamilton-Reeves JM, Bechtel MD, Hand LK, Schleper A, Yankee TM, Chalise P, Lee EK, 
Mirza M, Wyre H, Griffin J and Holzbeierlein JM. Effects of Immunonutrition for Cystectomy 
on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. 
Eur Urol. 69:389-92, 2016. 
 
3  
Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA. Myeloid 
cells obtained from the blood but not from the tumor can suppress T-cell proliferation in 
patients with melanoma. Clin Cancer Res. 18:5212–5223, 2012. 
 
4  
Vaughan-Shaw PG, Rees JRE and King AT. Neutrophil lymphocyte ratio in outcome 
prediction after emergency abdominal surgery in the elderly. International Journal of 
Surgery. 157-162, 2012. 
 
5  
Hamilton-Reeves JM, Bechtel MD, Hand LK, Schleper A, Yankee TM, Chalise P, Lee EK, 
Mirza M, Wyre H, Griffin J and Holzbeierlein JM. Effects of Immunonutrition for Cystectomy 
on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. 
Eur Urol. 69:389-92, 2016. 
 
6  
Hamilton-Reeves JM, Stanley A, Bechtel MD, Yankee TM, Chalise P, Hand LK, Lee EK, 
Smelser W, Mirza M, Wyre H, Hull H, Carlson SE, Holzbeierlein JM. J Urol. 2018 Mar 5. 
pii: S0022-5347(18)42469-X. doi: 10.1016/j.juro.2018.03.001. [Epub ahead of print] 
Perioperative Immunonutrition Modulates Inflammatory Response after Radical 
Cystectomy: Results of a Pilot Randomized Controlled Clinical Trial. 
 
7  
Braga M, Gianotti L, Radaelli G, Vignali A, Mari G, Gentilini O and Di Carlo V. Perioperative 
immunonutrition in patients undergoing cancer surgery: results of a randomized double-
blind phase 3 trial. Arch Surg. 134:428-33, 1999. 
 
8  
Braga M, Gianotti L, Vignali A and Carlo VD. Preoperative oral arginine and n-3 fatty acid 
supplementation improves the immunometabolic host response and outcome after 
colorectal resection for cancer. Surgery. 132:805-14, 2002. 
 
9  
Hubner M, Cerantola Y, Grass F, Bertrand PC, Schafer M and Demartines N. Preoperative 
immunonutrition in patients at nutritional risk: results of a double-blinded randomized 
clinical trial. Eur J Clin Nutr. 66:850-5, 2012. 
 
10  
Uno H, Furukawa K, Suzuki D, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H and Miyazaki 
M. Immunonutrition suppresses acute inflammatory responses through modulation of 
resolvin E1 in patients undergoing major hepatobiliary resection. Surgery. 60:228-364, 
2016. 
 
11  
Mikagi K, Kawahara R, Kinoshita H and Aoyagi S. Effect of preoperative immunonutrition 
in patients undergoing hepatectomy; a randomized controlled trial. Kurume Med J. 58:1-8, 
2011. 
 
 

 
 
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12  
Matsuda A, Furukawa K, Takasaki H, et al. Preoperative oral immune-enhancing nutritional 
supplementation corrects TH1/TH2 imbalance in patients undergoing elective surgery for 
colorectal cancer. Dis Colon Rectum, 49: 507, 2006. 
 
13  
Popovic PJ, Zeh HJ, 3rd and Ochoa JB. Arginine and immunity. The Journal of nutrition. 
137:1681s-1686s, 2007. 
 
14  
Ross AC, Cabellero B, Cousins RJ, Tucker, KL, Ziegler, T. R. Modern Nutrition in Health 
and Disease. 2014. 
 
15  
Peake RW, Law T, Hoover PN, Gaewsky L, Shkreta A and Kellogg MD. Improved 
separation and analysis of plasma amino acids by modification of the MassTrak AAA 
Solution Ultraperformance(R) liquid chromatography method. Clin Chim Acta. 423:75-82, 
2013. 
 
16  
Ottery FD. Definition of standardized nutritional assessment and interventional pathways 
in oncology. Nutrition. 12:S15-9, 1996. 
 
17  
Johnson RK, Driscoll P and Goran MI. Comparison of multiple-pass 24-hour recall 
estimates of energy intake with total energy expenditure determined by the doubly labeled 
water method in young children. J Am Diet Assoc. 96:1140-4, 1996. 
 
18  
Green S, Liu PY and O'Sullivan J. Factorial design considerations. J Clin Oncol. 20:3424-
30, 2002. 
 
 

 
 
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18.3 
Body Composition Assessment by Dual-Energy X-ray Absorptiometry 
 
1. 
Use the DXA scanner manufacturer’s recommendations for QA (phantom) block 
scanning.  At minimum, the QA (phantom) block should be used for calibration 
every day or 3 times per week if the DXA scanner is idle. 
2. 
Refer to the participant’s body positioning and imaging guidelines recommended 
by your DXA scanner’s manufacturer. In general, the participant’s body should be 
positioned with hands at the side (not touching the legs) with feet positioned as if 
standing. 
3. 
Ensure your DXA machine gets yearly service and calibration by an authorized 
technician. There should be a record of this on site. 
4. 
The participant pre-scanning procedures are: 
a. 
no radio contrast dye within 72 hours  
b. 
have the participant change into a gown 
c. 
participant should be free of all metal 
d. 
A height and weight are needed prior to performing the scan. 
e. 
If a participant is wider than the scan area, the patient can be positioned 
for a half body (mirror image) scan. Refer to the guidelines recommended 
by your DXA scanner’s manufacturer for half body positioning. 
 
 
 

 
 
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18.4 
S1600 Patient Intake Calendar 
 
a. 
ENGLISH Version 
 
S1600 Patient Intake Calendar 
Before Surgery 
 
(Please bring this form with you at time of surgery and give to the study coordinator) 
 
SWOG Patient ID 
 
 
 
 
Patient Initials (L, F, M)   
 
 
 
 
Study Physician Name 
 
 
 
 
 
 
 
If applicable, Stool Collection Dates 
 
1. Stool Collection Date:___________________________ 
 
2. Stool Collection Date:___________________________ 
 
If you have questions, contact:  
 
 
 
 
 Telephone   
 
 
 
 
 
 
 
 
Keeping record of how much of the Nutrition Drink you consume is an important part of the study. 
Please use this calendar to help you. As a guideline, remember the following: 
 
• 
Check the box next to the drink when you consume it 
• 
Answer all BOLDED questions 
o 
Check “Yes” or “No” to answer if you finished all of the drink or not   
o 
Choose the answer for how much you estimate is left  
 
Other important reminders: 
• 
Drinks can be stored in the refrigerator or at room temperature, but the taste is better when 
consumed cold.  Remember to gently shake the drink before consuming. 
• 
Discontinue any supplements containing fish oil until after the completion of the study. 
 
 

 
 
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BEFORE SURGERY: 
DAY 1: 
 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
DAY 2: 
 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
DAY 3: 
 
 
Date: 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 

 
 
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DAY 4: 
 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
DAY 5: 
 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
 
Date of surgery: 
__________________      
 
Bring this completed form with you to your surgery and give to the study coordinator. 
We will be thinking of you, especially during your surgery! 
 
 
 
 
 

 
 
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S1600 Patient Intake Calendar 
After Surgery 
 
(Please bring this form with you to your 30-day visit and give to the study coordinator) 
 
SWOG Patient ID 
 
 
 
 
Patient Initials (L, F, M)   
 
 
 
 
Study Physician Name  
 
 
 
 
 
 
 
 
 
If you have questions, contact:   
 
 
 
 Telephone   
 
 
 
 
Keeping record of how much of the Nutrition Drink you consume is an important part of the study. Please 
use this calendar to help you. As a guideline, remember the following: 
 
• 
Check the box next to the drink when you consume it 
• 
Answer all BOLDED questions 
o 
Check “Yes” or “No” to answer if you finished all of the drink or not   
o 
Choose the answer for how much you estimate is left  
o 
If applicable, please provide stool collection date: 
 
1. Stool Collection Date:___________________________ 
 
Other important reminders: 
• 
After surgery, start drinking the Nutrition Drink the same day your doctor clears you to drink liquids.  
Please make a note of the date in the DAY 1 box below. 
• 
Drinks can be stored in the refrigerator or at room temperature, but the taste is better when 
consumed cold.  Remember to gently shake the drink before consuming. 
• 
Discontinue any supplements containing fish oil until after the completion of the study. 
 
 

 
 
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AFTER SURGERY: 
DAY 1: 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
Day 2: 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st Drink 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd Drink 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd Drink 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
DAY 3: 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
  
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 

 
 
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DAY 4: 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
DAY 5: 
 
Date: 
 
(MM/DD/YYYY) 
□ 1st DRINK 
Time consumed: 
______________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
□ 2nd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half  
□ 3rd DRINK 
Time consumed: 
_____________ 
 a.m. 
 p.m. 
 
Did you finish it? 
 Yes  
 No 
 
How much is left?  
 None 
 Less than half 
 About half 
 More than half 
Comments 
for the day 
(include 
side effects 
from 
the 
nutrition 
drinks): 
 
Your blood will be drawn for the S1600 study two days after your surgery. 
 
Your next study visit will be about 30 days after your surgery. At the 30-day visit, you will meet with the 
surgeon, have a blood draw, DXA body scan, and complete two questionnaires. 
 
Your 30-day visit is on: 
 
Date: 
 
 
 
 
 
 
Time:  
 
 
     
 
Please bring this form with you to your 30-day visit and give to the study coordinator. 
  
We appreciate your participation in this study! 
 
 

 
 
S1600 
Page 79 
Version Date 11/09/2021 
 
 
 
 
b. 
SPANISH Version 
 
S1600 Calendario de Consumo del Paciente 
Antes de la Cirúgia 
(Por favor traiga este formulario con usted en el día de la cirugía y entréguelo al coordinador del 
estudio) 
ID del Paciente SWOG________________________ Iniciales del Paciente (L, F,M)_________________ 
Nombre del Médico del Estudio ____________________________________________ 
 
Si corresponde, fechas de recolección de heces 
1. Fecha de recolección de heces:__________________________ 
 
2. Fecha de recolección de heces:__________________________ 
 
Si tiene alguna pregunta o inquietud póngase en contacto con: ______________ 
Teléfono:___________________ 
Mantener un registro de la cantidad de bebida nutricional que consume es una parte importante del estudio. 
Utilice esta hoja de seguimiento para ayudarlo(a). Como pauta, recuerdo lo siguiente: 
• 
Marque la casilla junto a la bebida cuando la consuma 
• 
Responda todas las preguntas en NEGRITA 
o 
Marque “Sí” o “No” cuando responda si bebió toda la bebida o no 
o 
Verifique la respuesta para saber cuánto de bebida quedo en la botella si usted no bebió 
todo 
Otros recordatorios importantes: 
• 
Las bebidas se pueden almacenar en el refrigerador o a temperature ambiente, pero el sabor es 
mejor cuando se consume frío. Recuerdate de agitar suavemente la bebida antes de beberla. 
• 
Suspenda cualquier suplemento nutricional que contenga aceite de pescado hasta después de la 
finalización del estudio. 
 
 

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S1600 
Page 82 
Version Date 11/09/2021 
 
 
 
 
S1600 Calendario de Consumo del Paciente 
Después de la Cirúgia 
(Por favor traiga este formulario con usted a su visita de 30 días y entrégueselo al coordinador del 
estudio) 
ID del Paciente SWOG________________________ Iniciales del Paciente (L, F,M)_________________ 
Nombre del Médico del Estudio ____________________________________________ 
Si tiene alguna pregunta o inquietud póngase en contacto con: ______________ 
Teléfono:_______________ 
Mantener un registro de la cantidad de bebida nutricional que consume es una parte importante del 
estudio. Utilice esta hoja de seguimiento para ayudarlo(a). Como pauta, recuerdo lo siguiente: 
• 
Marque la casilla junto a la bebida cuando la consuma 
• 
Responda todas las preguntas en NEGRITA 
o 
Marque “Sí” o “No” cuando responda si bebió toda la bebida o no 
o 
Verifique la respuesta para saber cuánto de bebida quedo en la botella si usted no bebió 
todo 
o 
Si corresponde, por favor proporcionar fecha de recolección de heces: 
o 
 
1. Fecha de recolección de heces:_____________________________ 
o 
 
Otros recordatorios importantes: 
• 
Después de la cirugía, comience a tomar la bebida nutricional en el mismo día que su medico le 
autorizar a tomar líquidos. Por favor tome nota de la fecha. 
• 
Las bebidas se pueden almacenar en el refrigerador o a temperature ambiente, pero el sabor es 
major cuando se consume frío. Recuerdate de agitar suavemente la bebida antes de beberla. 
• 
Suspenda cualquier suplemento que contenga aceite de pescado hasta después de la 
finalización del estudio. 
 
 

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S1600 
Page 85 
Version Date 11/09/2021 
 
 
 
 
 
18.5 
PG-SGA 
 
 

 
 
S1600 
Page 86 
Version Date 11/09/2021 
 
 
 
 
 
 
 

 
 
S1600 
Page 87 
Version Date 11/09/2021 
 
 
 
 
18.6 
24-hour Dietary Recall  
 
Purpose 
 
To obtain detailed information about all foods, beverages and dietary supplements 
consumed on a given day. 
 
Description 
 
A 24-hour dietary recall is a structured interview intended to capture detailed information 
about all foods, beverages and dietary supplements consumed by a respondent in the past 
24 hours, most commonly, from midnight to midnight the previous day.  
 
At the baseline study visit, each participant will receive a “Food Amounts Booklet”, which 
includes helpful images and measurements to assist them in estimating their dietary intake.  
These images and measurements can be readily converted to specific amounts needed 
for research purposes. 
 
Each interviewer will have received detailed training in how to conduct a 24-hour recall.  
The interviewer will explain to the participant that she/he will be asking about food types 
and amounts from the beginning of their day, from the time they wake up in the morning, 
until the end of their day, to the time they go to sleep at night.  The interviewer may suggest 
that the participant refer to the “Food Amounts Booklet”. 
 
When asking the participant what they ate yesterday, the interviewer will:   
• 
Record their consumption chronologically 
• 
Record what time they consumed the food 
• 
Record the amount of food consumed. Use descriptive props (i.e. a deck of cards 
for 3 ounces of meat) to report portion size and the interviewer copy of the Food 
Amounts Booklet 
• 
Record the preparation of each item listed making sure to note how the food was 
prepared (i.e. baked, fried, etc.), what was used to prepare the food (i.e. olive oil, 
soy oil, salt, etc.), and any other relevant information that the participant wishes to 
share. 
 
After the first “pass” of information is obtained, the interviewer will ask the respondent to fill 
in more detailed information that may have been missed.  A total of five passes will occur 
to ensure detailed and accurate information. 
 
The data obtained from the 24-hour dietary recall will be used to examine food patterns 
and nutrient intake estimates from foods and dietary supplements.   
 
The information collected during the 24-hour recall interview will be entered directly into 
the Nutrition Data System for Research (NDSR).  This software includes comprehensive 
food and supplement databases. NDSR has built-in, standard prompts for guiding the 
interviewer in obtaining from the study participant detailed information about the foods they 
ate and supplements used.  The NDSR requires specialized training and extensive practice 
in order to effectively utilize it to conduct a research interview.  Consequently, all 
interviewers will be required to complete NDSR training and certification prior to collection 
of dietary and supplement recalls from participants.  The NDSR User Manual will be used 
by interviewers as a resource.  The Manual provides documentation on program features 
as well as Data Entry Rules (DER) which assist in standardizing decisions for situations 

 
 
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when participants cannot provide information.  NDSR was developed and is supported by 
the University of Minnesota Nutrition Coordinating Center (NCC).   
 
a. Appendix A:  
English Script for 24-hour dietary recall 
 
Introduce the Recall Process 
 
“Hi (insert participant’s name), my name is (insert your name).  During this part of your visit, 
I will be performing a 24hr dietary recall where you tell me everything you had to eat and 
drink during the past 24 hours.  Everything you tell me is confidential and this will take 
about 15 minutes.  Is this OK?” 
 
“First, we’ll make a list of all the foods and beverages you had from 12 am yesterday 
morning until 12 midnight last night.  This includes all meals, snacks, drinks (including water 
and alcoholic beverages), as well as tastes or samples of foods. 
 
“Then, we’ll go back through the list and fill in the details.” 
 
“At the very end, I’ll also ask you about any vitamins, minerals or other supplements you 
took.” 
 
“Do you have any questions before we begin?” 
 
PASS 1:  Collect the Quick List 
 
The participant is encouraged to say whatever comes to mind about the previous day’s 
intake with minimal interruption.   
 
Time of meal, place of meal and meal type will be collected. 
 
No additional questions regarding details or amounts will be asked. 
Prompts: 
“After midnight, what was the first time that you had something to eat or drink?”  
“What would you consider this meal to be?” “Where did you consume this meal?” 
“What time did you consume this meal?” “What did you have at that time?” “When 
was the next time you had something to eat or drink?” 
 
PASS 2:  Review the Quick List 
 
This enables the interviewer to identify gaps in time when no food or beverages are 
reported, forgotten eating occasions and missed meals or beverages. 
Prompts: 
“Now let’s review what we have so far.” 
“Did you have anything between midnight and (insert time of first meal)?” 
Repeat the next two questions for each meal/snack: 
“At (insert meal time), you had (read all foods).  Can you think of anything else you 
had at that time?” 
“Did you have anything to eat or drink between (insert meal time) and (meal time)?” 
When appropriate ask:  ”Did you have a beverage with that meal?” 
“Finally, did you have anything to eat or drink between (insert time of last meal) 
and midnight?” 
 
 

 
 
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PASS 3:  Collect detailed information 
 
This allows the interviewer to probe for additions and obtain detail for foods and beverages, 
and amounts consumed. 
• 
Collect time, name and location of eating occasion if not provided during the 
Quick List. 
• 
Details for each food and beverage: 
o 
Brand and/or type of item 
o 
Preparation details 
o 
Cooking details 
o 
Any additions (condiments) added 
o 
How much of item was consumed (this can be asked at the end of each 
meal) 
 
Prompts: 
 
These will vary depending on the type of food or beverage consumed. 
 
PASS 4:  Ask about commonly forgotten foods 
 
This focuses on the participant’s attention on specific foods and beverages that tend to be 
most forgotten during a recall.  Ask each question and wait for a response. 
 
Prompts: 
 
“That is everything from your list.  There are some foods that people might forget 
when doing a recall so to make sure this is as complete as possible, listen to the 
following and let me know if we need to add anything.” 
1. “Besides what you already reported, did you drink any water?” 
2. “Any additional coffee, tea, soft drinks, milk or juice?” 
3. “Did you have any cookies, candy, ice cream or other sweets?’ 
4. “Did you have any fruit, vegetables or cheese?” 
5. “What about any bread, rolls or tortillas?” 
6. “Did you have any chips, crackers, popcorn, pretzels, nuts or other snack 
foods?” 
7. “did you have any beer, wine, cocktails or other drinks?” 
 
PASS 5:  Review detailed information 
 
The interviewer will confirm what has been stated and document meals that are skipped or 
include nontraditional eating (i.e. meals without beverages, bread or bun removed from 
sandwich, no milk on cereal, etc.) 
 
Prompts: 
“At (time) you had (amount) of (food).  Is this correct?” 
“At the end of each meal:  Did you have anything else at that time?” 
 
The interviewer will continue to probe about between-meal snacks or missed 
meals, looking for large gaps in time when no food or beverages are reported and 
making sure that no information was inadvertently omitted. 
 
 

 
 
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NEXT STEP:  Complete the trailer questions (Is it a typical day and is it reliable data) 
 
• 
Ask the participant 
o 
“In terms of the amount of food you ate, would you say this was:  Close to 
the amount you usually eat?  A lot more than you usually eat?  A lot less 
than you usually eat?”  If more or less, have them explain why. 
Interviewer discretion: 
 
Was information:  Reliable?  Unable to recall one or more meals?  Unreliable for other 
reasons?  Explain why recall is incomplete/unusable. 
 
FINAL STEP:  Complete the dietary supplements assessment questions  
 
The interviewer can obtain supplement information for the past 24 hours. 
 
Ask the participant: 
“Now I have questions about dietary supplements you took yesterday”. 
1. “Did you take any vitamins or minerals?” (i.e. One a Day, Centrum, Vitamin C) 
2. “Did you take any amino acids?” (i.e. glutamine, arginine, lysine) 
3. “Did you take any supplements containing oils or omega-3 fatty acids?” (i.e. 
fish oil, flaxseed oil, krill oil, DHA) 
4. “Yesterday, did you take any herbal or botanical products?” (i.e. Echinacea, 
ginseng, ginkgo or St John’s Wort) 
5. “Did you take any fiber supplements?” (i.e. Metamucil, Benefiber or Fibercon) 
6. “Did you take any other dietary supplements that you haven’t told me about?” 
(i.e. garlic extract, brewer’s yeast, coenzyme Q10, glucosamine chondroitin, 
or weight loss supplements) 
7. “Did you take any over-the-counter antacids? (i.e. Tums, Rolaids, Mylanta) 
 
“Now, I’ll ask for details about each of the products that you reported.  It will be helpful to 
have the containers for as many of these products as possible.” 
 
For each supplement taken, the interviewer will ask the following questions: 
1. “Do you have the container for this product?” 
Yes 
No 
2. “Please provide the complete name of the product.” (include dosage and 
serving size) 
3. “How many times did you take this product yesterday?” 
4. “How many tablets did you take when you used the product yesterday?” 
The interviewer will then end the 24-hour dietary recall by thanking the participant for the 
time and participation. 
b. Appendix B: Spanish Guion para recordar la dieta de 24 horas 
 
Introducir el proceso de recordatorio 
 
“Hola (diga el nombre del participante), mi nombre es (diga su nombre). Durante esta parte 
de su visita, realizaré un recordatorio dietético de 24 horas en el que me contará todo lo 
que comió y bebió durante las últimas 24 horas. Todo lo que me diga es confidencial y 
tardará unos 15 minutos. ¿Está bien?” 
 

 
 
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“Primero, haremos una lista de todos los alimentos y bebidas que consumió desde las 12 
am de ayer por la mañana hasta las 12 de la noche de anoche. Esto incluye todas las 
comidas, refrigerios, bebidas (incluyendo agua y bebidas alcohólicas), así como pruebas 
o muestras de alimentos.” 
 
“Luego, repasaremos la lista y completaremos los detalles”. 
 
“Al final también le preguntaré sobre las vitaminas, minerales u otros suplementos que 
haya tomado”. 
 
“¿Tiene alguna pregunta antes de que comencemos?” 
 
PASO 1: Recopila la Lista Rápida 
 
Se anima al participante a decir lo que se le ocurra sobre la ingesta del día anterior con 
una interrupción mínima. 
 
Se recopilará la hora de la comida, el lugar de la comida y el tipo de comida. 
 
No se harán preguntas adicionales sobre detalles o cantidades. 
Indicaciones: 
“Después de la medianoche, ¿cuál fue la primera vez que comió o bebió algo?” 
“¿Cómo considerarías esta comida?” “¿Dónde consumió esta comida?” 
“¿A qué hora consumió esta comida?” “¿Qué tenía en ese momento?” “¿Cuándo 
fue la próxima vez que comió o bebió algo?” 
 
PASO 2: Revise la Lista Rápida 
 
Esto permite al entrevistador identificar brechas en el tiempo cuando no se reportan 
alimentos o bebidas, ocasiones de comidas olvidadas y comidas o bebidas omitidas. 
Indicaciones:  
“Ahora revisemos lo que tenemos hasta aquí”. 
“¿Tuvo algo entre la medianoche y (diga la hora de la primera comida)?” 
Repita las siguientes dos preguntas para cada comida / refrigerio: 
“En (diga la hora de la comida), tenia (leer todos los alimentos). ¿Puede pensar 
en algo más que tuvieras en ese momento?” 
“¿Comió o bebió algo entre (diga la hora de la comida) y (la hora de la comida)?” 
Cuando sea apropiado, pregunte: “¿Tomó una bebida con esa comida?” 
“Finalmente, ¿comió o bebió algo entre (diga la hora de la última comida) y la 
medianoche?” 

 
 
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PASO 3: Recopilar Información Detallada 
 
Esto le permite al entrevistador buscar información adicional y obtener detalles de 
alimentos y bebidas, y cantidades consumidas. 
• 
Recopile la hora, el nombre y la ubicación de la ocasión para comer si no se 
proporciona durante la lista rápida. 
• 
Detalles de cada comida y bebida: 
o 
Marca y / o tipo de artículo 
o 
Detalles de preparación 
o 
Detalles de cocción 
o 
Cualquier adición (condimentos) añadida 
o 
Cuánto del artículo se consumió (esto se puede preguntar al final de cada 
comida) 
 
Indicaciones: 
 
Estos variarán según el tipo de comida o bebida consumida. 
 
PASO 4: Pregunte acerca de los alimentos comúnmente olvidados 
 
Esto se centra en la atención del participante en alimentos y bebidas específicas que 
tienden a ser más olvidados durante un recordatorio. Haga cada pregunta y espere una 
respuesta. 
 
Indicaciones: 
 
“Eso es todo en tu lista. Hay algunos alimentos que la gente puede olvidar al hacer 
un recordatorio, así que para asegurarse de que sea lo más completo posible, 
escuche lo siguiente y avíseme si necesitamos agregar algo”. 
1. “Además de lo que ya informó, ¿bebió algo de agua?” 
2. “¿Algún café, té, refrescos, leche o jugo adicional?” 
3. “¿Comió galletas, dulces, helados u otros postres?” 
4. “¿Comió alguna fruta, verdura o queso?” 
5. “¿Qué tal pan, panecillos o tortillas?” 
6. “¿Comió papas fritas, galletas saladas, palomitas de maíz, pretzels, nueces u 
otros bocadillos?” 
7. “¿Tomó cerveza, vino, cócteles u otras bebidas?” 
 
PASO 5: Revise la información detallada 
El entrevistador confirmará lo que se ha dicho y documentará las comidas que se saltan o 
que incluyen comidas no tradicionales (es decir, comidas sin bebidas, pan extraído del 
sándwich, sin leche en el cereal, etc.) 
Indicaciones: 
“En (momento) tenia (cantidad) de (comida). ¿Es esto correcto?” 
“Al final de cada comida:¿comió algo más en ese momento?” 
 
El entrevistador continuará investigando sobre refrigerios entre comidas o 
comidas omitidas, buscando grandes brechas en el tiempo cuando no se informan 
alimentos o bebidas y asegurándose de que no se haya omitido ninguna 
información sin darse cuenta. 
SIGUIENTE PASO: Complete las preguntas del avance (¿es un día típico y son los 
datos confiables?) 

 
 
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• 
Preguntar al participante 
o 
“En términos de la cantidad de comida que comió, ¿diría que esta fue: 
cerca de la cantidad que come habitualmente? ¿Mucho más de lo que 
suele comer? ¿Mucho menos de lo que suele comer? Si es más o menos, 
pídale que le explique por qué. 
A discreción del entrevistador: 
 
¿Fue la información: confiable? ¿No puede recordar una o más comidas? ¿No es confiable 
por otras razones? Explique por qué el recordatorio está incompleto / inutilizable. 
 
PASO FINAL: Complete las preguntas de evaluación de suplementos dietéticos 
 
El entrevistador puede obtener información complementaria de las últimas 24 horas. 
 
Pregunte al participante: 
“Ahora tengo preguntas sobre los suplementos dietéticos que tomó ayer”. 
1. “¿Tomó vitaminas o minerales?” (es decir, One a Day ®, Centrum ®, Vitamina 
C) 
2. “¿Tomó algún aminoácido?” (es decir, glutamina, arginina, lisina) 
3. “¿Tomó algún suplemento que contenga aceites o ácidos grasos omega-3?” 
(es decir, aceite de pescado, aceite de linaza, aceite de krill, DHA) 
4. “Ayer, ¿tomó algún producto herbal o botánico?” (es decir, equinácea, ginseng, 
ginkgo o hierba de San Juan) 
5. “¿Tomó algún suplemento de fibra?” (es decir, Metamucil, Benefiber o 
Fibercon) 
6. “¿Tomó algún otro suplemento dietético del que no me haya hablado?” (es 
decir, extracto de ajo, levadura de cerveza, coenzima Q10, glucosamina 
condroitina o suplementos para bajar de peso) 
7. “¿Tomó antiácidos de venta libre?” (es decir, Tums, Rolaids, Mylanta) 
 
“Ahora, le pediré detalles sobre cada uno de los productos que informó. Será útil tener los 
contenedores para tantos de estos productos como sea posible”. 
 
Por cada suplemento tomado, el entrevistador hará las siguientes preguntas: 
1. “¿Tiene el contenedor para este producto?”   Sí   No  
2. “Por favor proporcione el nombre completo del producto”. (incluya la dosis y el 
tamaño de la porción) 
3. “¿Cuántas veces tomó este productor ayer?” 
4. “¿Cuántas tabletas tomó cuando usó el producto ayer?” 
El entrevistador luego finalizará el recordatorio dietético de 24 horas agradeciendo al 
participante 
por 
el 
tiempo 
y 
la 
participación. 
 
 
 
 
 

 
 
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18.7 
S1600 Site Requirements Form 
 
Prior to registering its first patient, each site must complete this form and submit it to the CTSU via the 
Regulatory Submission Portal.  (Log in to www.ctsu.org and select the Regulatory Submission sub-tab 
under the Regulatory tab.) 
 
For the site to be eligible to participate in the study, the answer to all five questions below must be 
“yes”. 
 
Name of person completing this form:  __________________________________________ 
 
CTEP-IAM Account Number:  _________________ 
 
CTEP site code(s) for all sites to which these answers apply (e.g., TX123):  ____________________ 
 
__________________________________________________________________________________ 
 
__________________________________________________________________________________ 
 
1.        Does your surgical team follow the ERAS principle of no bowel preparation for radical cystectomy 
procedures? 
 
___Yes  
___No 
 
2.        Does your surgical team routinely avoid nasogastric tube intubation for radical cystectomy 
procedures? 
 
___Yes  
___No 
 
3.        Does your surgical team allow early oral intake within 24 hours after radical cystectomy surgery? 
 
___Yes  
___No 
 
4.        Does your surgical team prescribe opioid-free pain control or minimize narcotics? 
 
___Yes  
___No 
 
5.       Does your site have access to a DXA scanner to measure body composition? 
 
___Yes  
___No 
 
 

 
 
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18.8 
Guidelines for Emergency Unblinding of Coded Intervention 
 
a. 
The following events MAY require emergency unblinding of Coded Intervention: 
 
• 
A compelling medical need as determined by a physician, e.g., occurrence of 
a severe or life-threatening reaction, inclusive of an adverse drug reaction, 
which may have been attributable to Coded Intervention, or existence of a 
condition where the knowledge of the patient's treatment assignment would 
directly influence or affect his/her immediate care; 
 
• 
ingestion of the Coded Drug by persons other than the patient or in excessive 
quantity; 
 
• 
exposure of a pregnant woman to the Coded Intervention; 
 
• 
exposure of a child to the Coded Intervention; 
 
Note:  Adverse drug reactions should be reported as required per Section 16.0 of this 
protocol. 
 
b. 
Procedure for Emergency Unblinding 
 
The procedure for unblinding the treatment assignment for a patient is as follows: 
 
• 
All unblinding must be done by the registering physician or designee. 
 
• 
Call the Washington Poison Control (WPC) collect at 206/526-2121 or at 
800/732-6985 if calling from within Washington State.  The WPC is accessible 
24 hours per day, 365 days per year for unblinding calls.  Informational calls 
should be directed to the Data Operations Center in Seattle during standard 
business hours. 
 
• 
Provide the WPC with the following information: 
 
Study number:  S1600 
SWOG patient number 
Patient name 
Coded Intervention ID number and bottle number 
Name and telephone number of the caller 
Reason unblinding is required 
 
• 
Unblinding for ingestion of the Coded Intervention by a pregnant woman will 
not require the authorization of a resource physician.  (The resource 
physicians for this study are listed at the end of this section.) 
 
• 
Unblinding for ingestion of the Coded Intervention by a child will not require 
the authorization of a resource physician. 
 
• 
Unblinding for ingestion of the drug either in excessive amounts or by a person 
other than the patient will be done ONLY when a compelling medical need 
exists and/or unblinding has been authorized by a resource physician. 
 
• 
Unblinding for a "compelling medical need" must be authorized by a physician 
designated as a resource physician for this protocol. 
 

 
 
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The treating physician (or designee) would provide the WPC with the information 
needed to determine if unblinding is required for the patient.  The WPC would 
contact the resource physician, provide the required information, and obtain the 
authorization to unblind, if necessary.  Based on the decision of the resource 
physician, the WPC would call the treating physician with either the unblinded 
treatment assignment or a treatment recommendation from the resource 
physician. 
 
If a resource physician cannot be reached by the WPC, treatment of the patient 
should proceed as if the drug ingested were an active agent. 
 
• 
Unblinding of Coded Intervention for any reason must be documented on the 
S1600 Treatment Form and the S1600 Off Treatment Notice. 
 
All unblinded participants are taken off treatment and followed per the 
requirements of the Southwest Oncology Group protocol. 
 
Any questions regarding unblinding may be directed to one of the following 
resource physicians: 
 
Norah Lynn Henry, M.D., Ph.D. (Medical Oncology) 
Daniel F. Hayes MD Breast Cancer Research Professor 
Division of Hematology/Oncology 
Disease Lead, Breast Oncology 
University of Michigan Rogel Cancer Center 
1500 E. Medical Center Dr, Rm 7322 
Ann Arbor, MI 48109 
Phone:  734/936-9868 
FAX:  734/647-9480 
E-mail:  norahh@med.umich.edu  
 
 
Jeffrey M. Holzbeierlein, M.D., F.A.C.S. (Medical Urology) 
John W Weigel Endowed Professor & Chair 
Director of Urologic Oncology 
3901 Rainbow Boulevard, MS 3016 
Kansas City KS 66160 
Phone: 913/588-7654  
FAX: 913/588-7625  
E-mail: jholzbeierlein@kumc.edu  
 
 
 
 

 
 
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18.9 
Translational Medicine Study Stool Microbiome 
 
The stool microbiome of patients in a randomized control trial of perioperative 
immunonutrition for reduction of complications following radical cystectomy and urinary 
diversion. 
 
a. 
Objectives: 
 
1. 
To describe the microbiome of the gut in patients undergoing radical 
cystectomy and urinary diversion prior to initiation of immunonutrition or a 
nutrition control. 
 
2. 
To define the microbiome change in patients undergoing radical 
cystectomy and urinary diversion after they have received blinded 
immunonutrition or control nutritional supplement.  
 
3. 
To correlate cancer treatments, postoperative complications, specifically 
infections, and nutritional status with microbiome composition 
 
b. 
Background 
 
Radical cystectomy is associated with significant complication rates; most studies 
find 60% complication rates across the world and 30% readmission rates. The 
S1600 clinical trial is examining a novel immunonutritional intervention with the 
goal of reducing these post-operative complications. 
 
Microbiomes are made up of microbiota that live in and on humans; microbiomes 
exist in the urinary tract, skin, gut/GI tract and other systems of the body. A great 
deal of research has been done with the microbiome in patients undergoing 
colorectal and pancreatic surgery. (1,2) The microbiome for both of these 
surgeries has been found to be associated with perioperative outcomes and 
complications. (3,4)  Complications and infections specifically are associated with 
microbiome in the perioperative period. (5,6) A serious complication of surgery can 
be an intestinal anastomotic leak, which is potentially driven by the microbiome. 
(7,8)  There is data in humans that the gut microbiota have a role in recovery from 
surgery involving the gastrointestinal tract, specifically anastomotic leak and 
infections. (9) Testing of probiotics has demonstrated that the complex mucosal 
immune system can be modified with probiotics in colorectal cancer and can 
improve the hosts’ immune responses. (10) In addition, modifications of the 
microbiota have been used to optimize therapeutic interventions in mice receiving 
immunotherapy. (11)  In addition, a recent meta-analysis of patients undergoing 
gastrointestinal surgery benefited from probiotics and synbiotics, and they were 
associated with lower infectious complications. (12,13,14,15) Therefore, 
microbiome profiling may enable tailored interventions specific to each patient to 
prevent postoperative complications.  The microbiome may also be modified by 
the nutrition, specifically immunonutrition, synbiotics or probiotics. (16) 
  
There is a critical gap in knowledge about which radical cystectomy patients are 
most likely to experience postoperative complications and how best to prevent 
them. Importantly, there are no consistent predictors of which patients will develop 
postoperative complications. Given the high rate of complications and the frequent 
occurrence of this operation, there is enormous room for improvement in the 
perioperative care for these patients, and identification of an intervention to reduce 
complications could have a large impact. In this proposal we will examine 

 
 
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associations between the gut microbiome and postoperative complications, in an 
attempt to identify a potentially modifiable predictor of complications. In addition, 
we will investigate the impact of the immunonutrition intervention on the gut 
microbiome in patients undergoing radical cystectomy.  
 
Preliminary studies 
 
Key publications include details on how the microbiome drives key portions of 
disease and can be modulated with novel therapies. In particular, using 16sRNA 
sequencing has been established as an association between the gut microbiome 
and immune modulated diseases in cancer patients, which has led to the 
identification of novel microbiome-targeted therapeutics. (17)   
 
An additional key publication describes the diversity of the gut microbiome and 
how the host factors of the microbiome vary between different hosts (different 
humans with varying diseases) and over time. The presence of more diverse 
intestinal microbiomes has been correlated with anti-inflammatory properties. (18) 
This provides insight that the microbiome can be modified by increasing 
diversification of the microbiome with factors such as nutrition. Importantly the 
microbial community can be targeted with clinical treatments. (19)  For example, 
one large study found a difference in C. difficile infection rates among patients with 
and without immunonutrition, indicating that there may be advantages to 
modulating the gut with immunonutrition. (20) 
 
c. 
Endpoint(s) to be used in analyses: 
 
1. 
Post Operative complications (any vs. none) 
2. 
Post Operative infections (yes/no)  
3. 
Nutritional status (malnourished vs. adequate nutrition) 
4. 
Other cancer treatments (preoperative chemotherapy vs no preoperative 
chemotherapy) 
 
d. 
Experimental approach, validated assays employed and expertise: 
 
This translational study to examine changes in the gut microbiome with 
intervention is being incorporated into the currently activated and enrolling SWOG 
S1600 trial. Patients’ stool samples will be collected with the Omnigene-GUT kit. 
This kit allows the patient to collect and preserve the samples from the comfort of 
their own home. Patients will be asked to collect a stool specimen and place a 
small sample on the kit spatula. This is then placed into the tube provided. With 
the Omnigene-GUT kit the yield of DNA is not influenced by temperature, thus it 
should be able to be shipped at any time of the year in any climate.( 21) Once the 
samples have been collected they are stable in the test tube for 60 days at room 
temperature. Collection timepoints and instructions are located in Section 15.2. 
They will begin their nutritional supplements 5 days before surgery and then 
undergo surgery per the S1600 protocol. As the S1600 protocol dictates strict 
timing of drink delivery, the first specimen can be collected anytime after S1600 
enrollment, but before initiation of their first nutritional drink (control or 
immunonutrition). After discharge from the hospital, we will have them collect the 
first bowel movement that occurs at home (+/- 2 days). Although waiting until after 
discharge means the timing of collection of the post-surgical sample will vary 
based on each patient’s duration of hospitalization, collection of the sample during 
hospitalization at each participating institution is anticipated to be logistically 

 
 
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difficult and therefore unreliable. These kits have been used in Dr. Lozupone’s lab 
previously for other studies that require shipping the specimens internationally, and 
extraction of these shipped samples has yielded the same results as fresh samples 
collected locally in the lab. (22)  SWOG Biospecimen Bank will process specimens 
per the Omnigene-GUT website. The samples will be stored in -80 degree freezer 
until end of study. Frozen samples will be shipped from SWOG Biospecimen Bank 
to the University of Colorado for analysis.  DNA will be extracted and sequenced 
using standard 16s rRNA technique, using the DNeasy PowerSoil kit from Qiagen 
using the manufacturer’s instructions, with the addition of a 65 degree incubation 
step and homogenization with bead-beating rather than vortex. (23)  The bead-
beating will facilitate release of DNA from gram positive bacteria.  
 
Bioinformatic analysis of the 16s rRNA amplicon sequences will be conducted as 
follows: The reads will be processed using QIIME v1.9.1. After filtering out reads 
containing Phred scores <30 or chimeric sequences detected by USEARCH v6.1, 
then clustered forward reads will be used for de novo operational taxonomic units 
at a 97% similarity threshold using UCLUSTref v1.2.22q and greengenes v13_8. 
After that, the operational taxonomic units are translated to taxa (for example, 
genus and species) using RDP v2.2. A phylogenetic tree of operational taxonomic 
units with FastTree v2.1.3 will be used to evaluate bacterial diversity (phylogenetic 
diversity index, sums total phylogenetic branch length observed in a subject) 
(unweighted and weighted UniFrac distances quantify unique versus shared 
phylogenetic tree branch length between two samples). Rarefaction will be used 
to accommodate differential library sizes. This bioinformatics analysis is standard 
operating procedure for Dr. Lozupone’s lab and is available freely reproduced 
using Qiita (qiita.ucsd.edu/study/description/10564). (24) The bioinformatics 
processing pipelines for microbiome data continue to evolve with best-practices 
and the state-of-the-art constantly improving.  Accordingly, alternative processing 
pipelines may be considered at the time of analysis. 
Once all the samples have been sequenced, bioinformatics analysis (described 
above) will be conducted at the University of Colorado by analysts experienced in 
the bioinformatics analysis of stool microbiome.  (25) Statistical analyses and 
correlations with endpoints (described in Section 18.9.e) will be conducted at the 
SWOG Statistics and Data Management Center. 
 
e. 
Statistical Plan:  
 
Aim 1: The objective of Aim 1 is to describe the baseline microbiota.  Alpha-
diversity metrics for each patient’s baseline samples will be calculated from 
rarefied data.  Beta-diversity metrics including UniFrac distance, Bray-Curtis 
dissimilarity, and Aitchison distance will be calculated from rarefied data and 
ordination plots will be generated.  For individual taxon level data, rank abundance 
plots will be generated and prevalence of particular bacterial taxa will be estimated.  
Clustering, based on beta-diversity, will be used to examine possible enterotypes. 
 
Aim 2: The objective of Aim 2 is to assess change in the microbiota between 
baseline, after nutrition drinks and surgery (post-operative). We will first assess the 
change using all patients (across both arms). To assess the change in alpha-
diversity, the difference in Shannon Index between predrink, pre- and post- 
operative profiles will be calculated for each individual and compared using a 
paired t-test at the nominal α=0.05 level.  Similarly, beta diversity distance matrices 
will be calculated using the pooled (baseline and post operative) samples to 
generate a 2n X 2n matrix which will be compared using PERMANOVA with patient 

 
 
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as a stratification variable; 9,999 permutations will be used to generate a p-value 
with significance called at the α=0.05 level.  
 
For individual taxon level analyses (quantified at the genus level), taxa present in 
less than 15% of samples or with average relative abundance <0.1% will be 
filtered.  Sparsity will be reduced by adding a pseudocount to raw counts or by 
application of Bayesian-multiplicative replacement. De-sparsified relative 
abundance data will be center-log-ration transformed to accommodate 
compositionality concerns and encourage normality.  Subsequently, the change 
between post- and pre-operative (transformed) data will be calculated for each 
taxon (on each patient) and the change will be compared using a paired t-test.  
Benjamini-Hochberg false discovery rate (FDR) will be controlled at the 10% level. 
 
We will repeat the analyses within each arm, separately.  Comparisons (in change) 
across arms will be conducted in Aim 3 (below). 
 
Aim 3: The objective of Aim 3 is to assess the association between microbiome 
profiles and dichotomous clinical outcomes, including preoperative chemotherapy, 
post operative complications, post-operative infections, and post-operative 
nutritional status.  Each outcome will be analyzed separately. 
 
For the primary outcome of post-operative complications, we will assess whether 
(1) baseline microbiome profiles (2) post-operative microbiome profiles and (3) 
change in microbiome profiles are associated with post-operative complications.  
 
For the baseline analyses (1) and post operative analyses (2), we will first restrict 
attention to patients randomized to the specialized immune-modulating nutrition 
drink arm.  Then we will assess the association between alpha diversity (Shannon 
index) and complications by regressing alpha diversity on indicator for 
complications and additional covariates. A 1-df test will be used to evaluate the 
association with complications at the nominal α=0.05 level.  Beta-diversity analysis 
will proceed by calculating UniFrac, Bray-Curtis, and Aitchison metrics which will 
be compared between patients with and without complications using a logistic 
version of the microbiome regression-based kernel association test (MiRKAT), a 
generalization of PERMANOVA with improved covariate adjustment, calling 
significance at the α=0.05 level.  Finally, transformed taxon abundances (as in Aim 
2) will be compared between patients with/without complications by regressing 
taxon abundance on an indicator for complications, again adjusting for additional 
covariates.  A 1-df test will again be used with FDR controlled at the 10% level.  
 
For baseline and post operative microbiome samples, we will then repeat these 
analyses restricting analyses to patients in the control arm and also pooling across 
arms (with adjustment for arm).  Finally, within the pooled analyses, we will further 
assess whether the microbiome modifies the association between treatment and 
outcomes.  For alpha diversity and individual taxon analyses, we will include two-
way interactions between Shannon index or individual taxon abundances, 
respectively, in the corresponding models and again evaluate significance using a 
1-df with FDR controlled at 10%.  For beta-diversity analysis, we will embed the 
distance matrices into kernel metrics (as in MiRKAT), but then we will use a logistic 
kernel-machine interaction test to assess whether associations between outcome 
and treatment are heterogeneous by microbiome beta-diversity profiles. 
 

 
 
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To examine whether change in microbiome profiles is related to preoperative 
chemotherapy, will conduct similar analyses as in the baseline and post-operative 
samples, except for alpha diversity and individual taxa, we will, respectively, use 
change in Shannon Index and change in taxon abundance.  For beta-diversity 
analysis, we will calculate paired analogues of the UniFrac, Bray-Curtis, and 
Aitchison distances developed by SWOG. 
 
Following analysis of the primary endpoint, we will repeat the analysis using post-
operative complication and infection status and post-operative nutritional status as 
endpoints instead. 
 
For all analyses, robust and non-parametric alternatives, as well as other data 
transformations, will be used if statistical assumptions are violated. If necessary, 
analyses will be adjusted for additional covariates, possibly including:  age, BMI, 
underlying disease (renal disease/etc), sex, baseline nutritional status, 
preoperative chemotherapy, muscle mass, etc. If necessary, we will also adjust for 
technical covariates such as storage time and time from surgery to collection (of 
the post-operative sample).  Possible batch effects will be assessed and removed 
if present per SWOG TM guidelines: the SWOG statistical center has previously 
validated the use of ComBat (on CLR transformed data) for mitigating batch effects 
in 16S data. 
 
Sample Size and Power Considerations:  
 
For Aim 1, with a sample size of 73 patients per arm (146 patients, total), we will 
be able to estimate the prevalence of particular enterotypes or particular bacterial 
taxa to within 8.1% (95% confidence interval) using all baseline samples. 
 
For Aim 2, we anticipate 80% power to detect a change in alpha-diversity from 
baseline to post-surgery of 0.23 and 0.33 standard deviations (sds) using all 
patients and patients in a particular arm, respectively.  For individual taxa, 
conservatively assuming that 90% of taxa do not have change from baseline to 
post-surgery, then at the FDR=10% level, we anticipate 80% average power to 
identify a taxon with change in abundance of 0.29 and 0.41 sds, using all patients 
and patients in an individual arm, respectively. 
 
For Aim 3, we calculate minimal detectable effect sizes assuming 42%, 65%, and 
53% complication rates in the experimental arm, control arms, and overall, 
respectively. Then for the baseline and post-operative microbiome analyses, we 
anticipate 80% power to detect a difference in alpha diversity between patients 
with/without complications of 0.67, 0.69, and 0.46 sds, in the experimental arm, 
control arm, and pooled across arms, respectively.  For individual taxon analyses, 
again assuming that 90% of taxa are not differentially abundant between, then we 
anticipate 80% average power to identify a taxon with difference in abundance 
between patients with/without complications of 0.83, 0.86, and 0.58 sds, in the 
experimental arm, control arm, and pooled across arms, respectively.  Minimal 
detectable effect sizes for analyses examining change are analogous except 
based on differences in alpha diversity and taxon abundance. 
 
 

 
 
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f. 
Data analysis performed by: 
The CU bioinformatics department (informatics and quantification) and SWOG 
statistical center (correlative analyses) 
 
g. 
Laboratory 
Catherine Lozupone, Ph.D.-  
University of Colorado 
12700 E. 19th Avenue, Room 3113  
Anschutz Medical Campus, Aurora, CO 80045 
Email: Catherine.Lozupone@ucdenver.edu  
Phone: (303) 724-7942 
 
 
 
 
 

 
 
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References 
 
1  
Bachmann R, Leonard D, Delzenne N, et al: Novel insight into the role of 
microbiota in colorectal surgery. Gut 66:738-749, 2017. 
 
2  
Schmitt FCF, Brenner T, Uhle F, et al: Gut microbiome patterns correlate with 
higher postoperative complication rates after pancreatic surgery. BMC Microbiol 
19:42, 2019. 
 
3  
Schmitt FCF, Brenner T, Uhle F, et al: Gut microbiome patterns correlate with 
higher postoperative complication rates after pancreatic surgery. BMC Microbiol 
19:42, 2019. 
 
4  
Alverdy JC, Hyman N, Gilbert J, et al: Preparing the Bowel for Surgery: Learning 
from the Past and Planning for the Future. J Am Coll Surg 225:324-332, 2017. 
 
5  
Alverdy JC, Hyoju SK, Weigerinck M, et al: The gut microbiome and the 
mechanism of surgical infection. Br J Surg 104:e14-e23, 2017. 
 
6  
Massaut E, Hendlisz B, Klastersky JA: The close interrelation between colorectal 
cancer, infection and microbiota. Curr Opin Oncol 31:362-367, 2019. 
 
7  
Gershuni VM, Friedman ES: The Microbiome-Host Interaction as a Potential Driver 
of Anastomotic Leak. Curr Gastroenterol Rep 21:4, 2019. 
 
8  
Sciuto A, Merola G, De Palma GD, et al: Predictive factors for anastomotic leakage 
after laparoscopic colorectal surgery. World J Gastroenterol 24:2247-2260, 2018. 
 
9  
Guyton K, Alverdy JC: The gut microbiota and gastrointestinal surgery. Nat Rev 
Gastroenterol Hepatol 14:43-54, 2017 
 
10  
Eslami M, Yousefi B, Kokhaei P, et al: Importance of probiotics in the prevention 
and treatment of colorectal cancer. J Cell Physiol, 2019 
 
11  
Fessler J, Matson V, Gajewski TF: Exploring the emerging role of the microbiome 
in cancer immunotherapy. J Immunother Cancer 7:108, 2019. 
 
12  
Lederer AK, Pisarski P, Kousoulas L, et al: Postoperative changes of the 
microbiome: are surgical complications related to the gut flora? A systematic 
review. BMC Surg 17:125, 2017 
 
13  
Polakowski CB, Kato M, Preti VB, et al: Impact of the preoperative use of synbiotics 
in colorectal cancer patients: A prospective, randomized, double-blind, placebo-
controlled study. Nutrition 58:40-46, 2019. 
 
14  
Skonieczna-Zydecka K, Kaczmarczyk M, Loniewski I, et al: A Systematic Review, 
Meta-Analysis, and Meta-Regression Evaluating the Efficacy and Mechanisms of 
 

 
 
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Action of Probiotics and Synbiotics in the Prevention of Surgical Site Infections and 
Surgery-Related Complications. J Clin Med 7, 2018. 
 
15  
Stavrou G, Kotzampassi K: Gut microbiome, surgical complications and probiotics. 
Ann Gastroenterol 30:45-53, 2017. 
 
16  
Kuntz TM, Gilbert JA: Introducing the Microbiome into Precision Medicine. Trends 
Pharmacol Sci 38:81-91, 2017. 
 
17  
Lozupone CA: Unraveling Interactions between the Microbiome and the Host 
Immune System To Decipher Mechanisms of Disease. mSystems 3, 2018. 
 
18  
Neff CP, Rhodes ME, Arnolds KL, et al: Diverse Intestinal Bacteria Contain 
Putative Zwitterionic Capsular Polysaccharides with Anti-inflammatory Properties. 
Cell Host Microbe 20:535-547, 2016. 
 
19  
Lozupone CA, Stombaugh JI, Gordon JI, et al: Diversity, stability and resilience of 
the human gut microbiota. Nature 489:220-30, 2012. 
 
20  
Kelley KE, Fajardo AD, Strange NM, et al: Impact of a Novel Preoperative Patient-
centered Surgical Wellness Program. Ann Surg 268:650-656, 2018 
 
21  
Song SJ, Amir A, Metcalf JL, et al: Preservation Methods Differ in Fecal 
Microbiome Stability, Affecting Suitability for Field Studies. mSystems 1, 2016. 
 
22  
Williams GM, Leary SD, Ajami NJ, et al: Gut microbiome analysis by post: 
Evaluation of the optimal method to collect stool samples from infants within a 
national cohort study. PLoS One 14:e0216557, 2019. 
 
23  
Liu C, Frank DN, Horch M, et al: Associations between acute gastrointestinal 
GvHD and the baseline gut microbiota of allogeneic hematopoietic stem cell 
transplant recipients and donors. Bone Marrow Transplant 52:1643-1650, 2017. 
 
24  
Liu C, Frank DN, Horch M, et al: Associations between acute gastrointestinal 
GvHD and the baseline gut microbiota of allogeneic hematopoietic stem cell 
transplant recipients and donors. Bone Marrow Transplant 52:1643-1650, 2017. 
 
25  
Lozupone CA: Unraveling Interactions between the Microbiome and the Host 
Immune System To Decipher Mechanisms of Disease. mSystems 3, 2018. 
 
 
 
 
 
 

 
 
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18.10 
SWOG Biospecimen Processing Instructions 
 
The SWOG Biospecimen Bank will receive stool in Omnigene-Gut kits. Upon receipt, the 
Bank will accession, barcode, homogenize and aliquot stool samples. Aliquots of stool in 
the Omnigene-Gut media will be stored in a -80°C freezer for future studies 
 
 
 
 
 

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Consent Form S1600 
Study Title for Study Participants: Testing the Effect of Nutrition on Bladder 
Cancer Surgery 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: A 
Randomized Phase III Double Blind Clinical Trial Evaluating the Effect of 
Immune-Enhancing Nutrition on Radical Cystectomy Outcomes (SIMmune) 
 
What is the usual approach to bladder cancer surgery? 
 
You are being asked to take part in this study because you have bladder cancer and will undergo 
surgery to remove all of the bladder (the organ that holds urine) as well as nearby tissues and 
organs.  In men, this includes removal of the prostate and seminal vesicles. In women, this may 
include the uterus, cervix, along with the fallopian tubes and ovaries. Nearby lymph nodes, and 
some or all of the urethra are also removed.  The study group will receive the nutritional 
supplements of interest in the study.  The control group for this study will receive a nutritional 
supplement but not the supplements of interest for the trial. 
 
People who are undergoing this surgery and are not participating in a study are usually not 
treated with nutritional supplements. 
 
What are my other choices if I do not take part in this study? 
 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above, without nutritional 
supplements 
• you may choose to take part in a different study, if one is available 
• you may choose not to undergo surgery 
• you may take a nutritious supplement which you purchase yourself over the counter 
 
Why is this study being done?  
 
You have bladder cancer and will be having surgery.  Many patients don’t get enough of 
certain types of nutrients before going in to surgery, which may cause infections and other 
problems such as muscle wasting, rapid weight loss, slow wound healing, and 
inflammation. The purpose of this study is to test whether improving nutrition before and 
after surgery can reduce the infections and other problems that sometimes occur after 
surgery. The effects of a special nutrition drink will be compared to a control.  A control is 
a liquid that looks like the study liquid but does not contain the nutrients to be studied. 
There will be about 200 people taking part in this study. 
 
 
 
 

 
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What are the study groups? 
 
This study has two study groups. One group will receive the study nutrition drink containing 
special additional nutrients, and the other group will receive the control nutrition drink that does 
not contain the special nutrients to be studied but is otherwise the same. We do not know if the 
special nutrients are helpful or harmful for your cancer. Both drinks contain milk, soy and fish 
ingredients.  Both drinks are appropriate for these diets: lactose intolerance, gluten-free, kosher, 
and halal. 
 
A computer will by chance assign you to one of the two treatment groups in the study.  This is 
called randomization.  This is done by chance because no one knows if one study group is better 
or worse than the other. Once you are put in one group, you cannot switch to the other group. 
Neither you nor your doctor can choose or will know which group you will be in.  You will have 
an equal chance of being placed in either group. 
 
 
 
 
How long will I be in this study? 
 
You will drink the study drinks for five days before your surgery and five days after.  After you 
finish the study drinks, your doctor will continue to watch you for side effects and follow your 
condition for 3 years after your surgery. 
 
What extra tests and procedures will I have if I take part in this study? 
 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there are some extra exams, tests, and procedures that you will need to have if 
you take part in this study. 
 
If the exams, tests, and procedures show that you can take part in the study, and you choose to 
take part, then you will need the following extra tests and procedures. They are not part of the 
usual approach for your type of cancer and will be provided at no cost to you.  
 
 
 
Randomize 
(The computer will 
randomly put you in a 
study group) 
Group 2 
Study Nutritional 
Drink  
 
You agree to 
take part in the 
study 
Group 1 
Control Nutritional 
Drink 

 
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During the study: 
 
• DXA Body Scan – You will have a DXA Body Scan before surgery and another scan 
30 days after surgery. The DXA Body Scan that you get in this study will expose you 
to low amounts of radiation.  Every day, people are exposed to low levels of radiation 
that come from the sun and the environment around them.  This type of radiation is 
called “background radiation. No one knows for sure whether exposure to these low 
amounts of radiation is harmful to your body. The DXA Body Scan that you get in 
this study will expose you to less radiation than you get from everyday background 
radiation. Most of the time, this amount of extra radiation is not harmful to 
you.  However, scientists believe that being exposed to too much radiation can cause 
harmful side effects.  This could include getting a new cancer.  We estimate that this 
could happen in about 1 out of every 1000 people who get a very large amount of 
extra radiation. For this test you lie down on an open “table” for approximately 8 
minutes while your body is scanned. The DXA test measures body fat, lean tissue and 
bone mineral content for the arms, legs, and trunk.  Neither you nor your health care 
plan/insurance carrier will be billed for the DXA Body Scan that will be used for this 
study.  
 
• Blood draws – You will have one blood draw before receiving the nutrition 
supplements prior to surgery, another blood draw 2 days after surgery, and another 30 
days after surgery.  At each time point, about 5 teaspoons of blood will be collected.  
This sample is required in order for you to take part in this study because the research 
on the sample is an important part of the study.  Blood samples for research will be 
drawn at the same time as the blood draws for labs.  Neither you nor your health care 
plan/insurance carrier will be billed for the collection of the blood sample that will be 
used for this study.  Your privacy is very important and the researchers will make 
every effort to protect it.  Your test results will be identified by a unique code and the 
list that links the code to your name will be kept separate from your sample and 
health information. The results will be available to the study doctor. 
 
• Questionnaires – There will be three separate occasions you will need to complete 
two to three questionnaires to collect information about how you are feeling 
physically and emotionally, and whether you are at risk for malnutrition during your 
treatment. It will take about 20 minutes to complete the questionnaires. The 
questionnaires will be given to you before the surgery, 2 days after surgery, and 30 
days after surgery. If any questions make you feel uncomfortable, you may skip those 
questions and not give an answer. Although the questionnaires are not part of regular 
cancer care, they are being conducted as part of this research study to learn more 
about how your diagnosis and treatment(s) are affecting your life.  This information 
along with that collected from other patients will help researchers in better 
understanding patients’ needs and concerns. Additionally, should you choose to stop 
taking the study drink early, you will still be given the questionnaires to complete. 
 

 
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• Calendar – You will be provided a calendar and will be asked to make note of the 
time that you drink the nutritional drinks. You will be asked to do this for the 5 days 
prior to and the 5 days after your surgery.  There is also a study calendar below that 
shows how often the extra tests will be done as well as the schedule for the intake of 
the nutritional drinks. 
 
• Phone Interview- You will be interviewed by phone to collect information about your 
eating habits four times. It will take about 15 minutes to complete each interview.  
You will be required to provide your contact information and the best times to contact 
you for the phone interviews in order for you to take part in the study.  Two 
interviews will take place at the beginning of the study (before starting the nutritional 
drinks) and two interviews will take place about 30 days after surgery. The interview 
is not part of regular cancer care, but is being done as part of this research study to 
learn more about how your diagnosis and treatment is impacting your life.  This 
information along with that from other patients will help researchers better address 
patients’ needs and concerns. If you stop the study drinks early, you will still be 
interviewed by phone. 
 
Here is a calendar of the study procedures: 
 
First study visit 
 
Blood draw for research 
Blood draws to test your blood count and liver function 
DXA body scan 
Complete questionnaires  
 
Around the time of the first 
study visit 
 
Phone interviews 
Stool sample collection before starting study drinks 
(optional) 
Every day, for five days before 
surgery 
 
Study drinks 
Stool sample collection after at least 4 days of taking study 
drinks prior to surgery (optional) 
 
Surgery 
 
Every day, for five days after 
surgery 
 
Study drinks 
Stool sample collection after return home from hospital 
(optional) 
2 days after surgery 
Blood draw for research  
Blood draws to test your blood count and liver function 
Complete questionnaire  
 
30 days after surgery 
Evaluation by surgeon for complications 
DXA body scan 
Blood draws to test your blood count and liver function 
Blood draw for research 
Complete questionnaires  
 
About 30 days after surgery 
Phone interviews 
 
About 3, 6, 9, 12, 18, 24, and 36 
months after surgery 
 
Evaluation for complications  
 

 
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Optional samples: You will be given the option to store your stool samples and/or any leftover 
blood from the blood draws during this study in a biobank. Storing samples is called 
“biobanking.” The biobank for the stool samples from this study is called SWOG Biobank and is 
supported by the NCI. The biobank for the leftover blood from this study is called the EDGE 
Research Lab biobank. This will be discussed in the section under “Optional studies” below. 
 
What possible risks can I expect from taking part in this study?  
 
• You may be asked sensitive or private questions which you normally do not discuss. 
• The study approach may not be better, and could possibly be worse, than the usual 
approach for your cancer. 
 
Let your study doctor know of any questions you have about possible side effects. You can 
ask the study doctor questions about side effects at any time. 
 
Possible Side Effects of both Study Nutritional Drinks: 
COMMON, SOME MAY BE SERIOUS 
• Diarrhea 
• Nausea  
• Vomiting 
• Loose Stools 
 
 
What possible benefits can I expect from taking part in this study? 
 
It is not possible to know at this time if the study approach is better than the usual approach so 
this study may or may not help you. This study will help researchers learn things that will help 
people in the future. 
 
Can I stop taking part in this study? 
 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, Institutional Review Board (IRB) or FDA 

 
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What are my rights in this study?  
 
Taking part in this study is your choice. No matter what decision you make, and even if 
your decision changes, there will be no penalty to you. You will not lose medical care or any 
legal rights. 
 
For questions about your rights while in this study, call the ________________________ 
(insert name of center) Institutional Review Board at __________________ (insert telephone 
number). (Note to Local Investigator: Contact information for patient representatives or other 
individuals at a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can also be listed here.) 
 
What are the costs of taking part in this study? 
 
The nutritional drinks will be supplied at no charge while you take part in this study.  It is 
possible that the nutritional drinks may not continue to be supplied while you are on the study. 
Although not likely, if this occurs, your study doctor will talk to you about your options. 
 
The cost of the DXA scans and of the research blood tests will also be covered by the study. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of 
treating your cancer while in this study, including the cost of tests, procedures, or medicines to 
manage any side effects, unless you are told that certain tests are supplied at no charge. Before 
you decide to be in the study, you should check with your health plan or insurance company to 
find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 
 
What happens if I am injured or hurt because I took part in this study? 
 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for 
injury.  Your insurance company may not be willing to pay for study-related injury.  If you have 
no insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
Who will see my medical information? 
 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 

 
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you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
• The company supporting the study, Nestle Healthcare Nutrition, and SWOG (a national 
cancer trials network) 
• The Institutional Review Board, IRB, a group of people who review the research with the 
goal of protecting the people who take part in the study 
• Researchers from the University of Kansas Medical Center and Louisiana State 
University who are involved in this study  
• The Food and Drug Administration and the National Cancer Institute  
 
Where can I get more information?  
 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service 
to get the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial 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. You can search this Web site at 
any time. 
 
Who can answer my questions about this study? 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
 
ADDITIONAL STUDIES SECTION: 
This section is about optional studies you can choose to take part in 
 
This part of the consent form is about optional studies that you can choose to take part in. You 
will not get health benefits from any of these studies. The researchers leading these optional 
studies hope the results will help other people with cancer in the future. 
 
The results will not be added to your medical records and you or your study doctor will not know 
the results. 
 

 
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You will not be billed for these optional studies. You can still take part in the main study even if 
you say ‘no’ to any or all of these studies. If you sign up for but cannot complete any of the 
studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
1. 
Future contact 
 
Occasionally, researchers working with SWOG may have another research idea that 
relates to people who were 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. 
 
 
 
 
Yes 
 
No 
 
2. 
Biobanking for possible future studies 
 
Researchers are trying to learn more about cancer, diabetes, and other health problems. 
Much of this research is done using samples from your blood. Through these studies, 
researchers hope to find new ways to prevent, detect, treat, or cure health problems. 
 
Some of these studies may be about genes. Genes carry information about features that 
are found in you and in people who are related to you. Researchers are interested in the 
way that genes affect how your body responds to treatment. 
 
WHAT IS INVOLVED? 
 
If you agree to take part, here is what will happen next: 
1) Any blood samples left over after the testing done for the main part of the study 
and some related health information may be stored in the EDGE Research Lab 
biobank, along with samples and information from other people who take part. 
The samples will be kept until they are used up. Information from your medical 
record will be updated from time to time.  
2) A stool sample will be collected at three timepoints during the study and will be 
sent to the SWOG Biobank for use in future studies. The samples will be kept 
until they are used up. Information from your medical record will be updated from 
time to time.  
3) Qualified researchers can submit a request to use the materials stored in the 
Biobanks. A science committee at the clinical trials organization, and/or the 
National Cancer Institute, will review each request. There will also be an ethics 
review to ensure that the request is necessary and proper. Researchers will not be 
given your name or any other information that could directly identify you.  

 
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4) Neither you nor your study doctor will be notified when research will be 
conducted or given reports or other information about any research that is done 
using your samples.  
5) Some of your genetic and health information may be placed in central databases 
that may be public, along with information from many other people. Information 
that could directly identify you will not be included. 
 
WHAT ARE THE POSSIBLE RISKS? 
 
1) The most common risks related to drawing blood from your arm are brief pain 
and possibly a bruise.  
2) There is a risk that someone could get access to the personal information in your 
medical records or other information researchers have stored about you. 
3) There is a risk that someone could trace the information in a central database back 
to you. Even without your name or other identifiers, your genetic information is 
unique to you. The researchers believe the chance that someone will identify you 
is very small, but the risk may change in the future as people come up with new 
ways of tracing information. 
4) In some cases, this information could be used to make it harder for you to get or 
keep a job or insurance. There are laws against the misuse of genetic information, 
but they may not give full protection. There can also be a risk in knowing genetic 
information. New health information about inherited traits that might affect you or 
your blood relatives could be found during a study. The researchers believe the 
chance these things will happen is very small, but cannot promise that they will 
not occur. 
 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? 
 
Your privacy is very important to the researchers and they will make every effort to 
protect it. Here are just a few of the steps they will take: 
1) When your sample(s) is sent to the researchers, no information identifying you 
(such as your name) will be sent. Samples will be identified by a unique code 
only.  
2) The list that links the unique code to your name will be kept separate from your 
sample and health information. Any Biobank and SWOG staff with access to the 
list must sign an agreement to keep your identity confidential. 
3) Researchers to whom SWOG sends your sample and information will not know 
who you are. They must also sign an agreement that they will not try to find out 
who you are. 
4) Information that identifies you will not be given to anyone, unless required by 
law. 
5) If research results are published, your name and other personal information will 
not be used. 
 
 

 
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WHAT ARE THE POSSIBLE BENEFITS? 
 
You will not benefit from taking part.  The researchers, using the samples from you and 
others, might make discoveries that could help people in the future. 
 
ARE THERE ANY COSTS OR PAYMENTS? 
 
There are no costs to you or your insurance. You will not be paid for taking part. If any of 
the research leads to new tests, drugs, or other commercial products, you will not share in 
any profits. 
 
WHAT IF I CHANGE MY MIND? 
 
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at 
________________________ (insert telephone number of study doctor for main trial) 
who will let the researchers know. Then, any sample that remains in the bank will no 
longer be used and related health information will no longer be collected. Samples or 
related information that have already been given to or used by researchers will not be 
returned. 
 
WHAT IF I HAVE MORE QUESTIONS? 
 
If you have questions about the use of your samples for research, contact the study 
doctor, ________________, (insert name of study doctor for main trial), at 
_____________________ (insert telephone number of study doctor for main trial). 
 
Please circle your answer to show whether or not you would like to take part. 
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
 
1. My leftover blood samples and related information may be kept in a 
Biobank for use in future health research. 
 
 YES 
 
NO 
 
2. My stool samples and related information may be collected and kept in a 
Biobank for use in future health research. 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
 

 
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My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature_____________________________________