S1316 - MBO Professional Slide Set, Version 01 S1316 – The Malignant Bowel Obstruction Study A Prospective Comparative Effectiveness Trial for Malignant Bowel Obstruction SWOG Study Chairs: Robert S. Krouse, M.D., SAVAHCS/University of Arizona, Surgical Oncology Brian Badgwell, M.D., MD Anderson Cancer Center Alliance Investigator: Amy Abernethy, M.D., Duke University Medical Center Nurse Chair: Virginia Sun, R.N., Ph.D., City of Hope Other Key Staff on S1316 are: Biostatisticians: Garnet Anderson, Ph.D., and Katie Arnold, M.S., SWOG Statistical Center, Fred Hutchinson Cancer Research Center Arizona Diet, Behavior and Quality of Life Assessment Lab Cynthia A. Thomson, Ph.D., R.D. Canyon Ranch Center for Prevention & Health Promotion S1316 - MBO Professional Slide Set, Version 01

S1316 - MBO Professional Slide Set, Version 01 S1316 JACS Paper on MBO Aggressive non-surgical palliative care options can help avoid an operation There are many clinical scenarios when an operation is unlikely to benefit MBO patients Can we test which treatment strategy (surgery vs. “aggressive” palliative management) is optimal in MBO? S1316 - MBO Professional Slide Set, Version 01

S1316 - MBO Professional Slide Set, Version 01 S1316- MBO Study Aims To assess the quality of life outcome of the number of days alive and outside of the hospital within the first 91 days (13 weeks) after registration, for patients with malignant bowel obstruction who receive surgical intervention as compared to non-surgical intervention. Research Questions: Are there differences in HRQOL outcomes for patients with MBO who receive surgical intervention as compared to non-surgical intervention? Are there clinical factors that predict better HRQOL outcomes for patients with MBO who receive surgical or non-surgical intervention? S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Primary Endpoint “Good days” = days out of the hospital and alive in the first 91 days (13 weeks) after registration Secondary Endpoints Days with NG tube Days eating (Diet recalls) HRQOL (MDASI-GI, EQ-5D-5L) Morbidity/Mortality Survival The endpoints chosen were based on the extensive literature and clinical experience with MBO patients. The primary endpoint is “Days out of the hospital and alive”. There is ample evidence that the primary goal for patients with end stage disease is to be at home/out of the hospital. While it is imperative to collect other quality of life data, this is the optimal objective outcome for this population. Over 90% of hospice care is at home; therefore, days out of the hospital means days out of the acute care setting. While this is typically at home, it can also be at an inpatient hospice facility. S1316 - MBO Professional Slide Set, Version 01

S1316 Study Timeline Study accrues Training Study closes to accrual 2014 2015 2016 2017 2018 2019 2020 Work on secondary analyses Study accrues Complete data clean-up Analyze data for primary endpoint Prepare abstract Write and publish primary paper Prepare for study activation Obtain IRB approvals Study closes to accrual Study data complete and submitted Training S1316 - MBO Professional Slide Set, Version 01

S1316 - MBO Professional Slide Set, Version 01 S1316 - MBO Study Schema Meets all eligibility requirements (N=180) Consents to randomization (N=50) Consents to non-randomized treatment (N=130) Surgery (50%) (Arm 1) Non-surgical management (50%) (Arm 2) Surgery (Arm 3) Non-surgical management (Arm 4) Arms 1 and 3: Surgery Patients on surgical management will undergo abdominal surgery as defined by the treating physician. Surgery is defined as an operative procedure. Information regarding patient treatment will be collected. While randomization to Arm 1 will determine a patient’s initial care, the treating physician will take changes in their clinical course or other circumstances into account in determining the ongoing care plan. Arms 2 and 4: Non-surgical Management Patients on non-surgical management will be offered non-surgical management as determined by the treating physician. Information regarding patient treatment will be collected. While the research team believes there is sufficient equipoise to randomize to such a trial, it is likely infeasible to accrue the entire population to a RCT at this time. Therefore, this study proposes to accrue a large number (n=180) and randomize a subset of these (n=50) accruing at selected institutions demonstrating substantial interest in and commitment to this question. This combined approach builds on the strengths of each design to give more reliable results. While the RCT component of this hybrid design could be considered a pilot trial, by embedding this trial in a larger non-randomized component, we believe we will have stronger inference than could be achieved by either alone. All patients will be followed for 53 weeks. S1316 - MBO Professional Slide Set, Version 01

S1316 Patient Timeline Follow-up Complete Data for primary endpoint reported Hospitalization with MBO Day 0 Registration Week 53 Week 13 Report all hospitalizations Site calls patient weekly for assessments Patient has dietary recall every 4 weeks Site calls patient every 4 weeks for assessments Patient has dietary recall every 4 weeks S1316 - MBO Professional Slide Set, Version 01

S1316 - MBO Study Accrual Goal Study will accrue 180 eligible patients Study expects to accrue over 3 years Two study components Randomization component (n=50) Non-randomized component (n=130) While the research team believes there is sufficient equipoise to randomize to such a trial, it is likely infeasible to accrue the entire population to a RCT at this time. Therefore, this study proposes to accrue a large number (n=180) and randomize a subset of these (n=50) accruing at selected institutions demonstrating substantial interest in and commitment to this question. This combined approach builds on the strengths of each design to give more reliable results. While the RCT component of this hybrid design could be considered a pilot trial, by embedding this trial in a larger non-randomized component, we believe we will have stronger inference than could be achieved by either alone. S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Eligibility Criteria MBO due to intra-abdominal cancer Admission to hospital Surgical candidate (would tolerate an operation and indication for surgery) Performance status (Zubrod Performance Status of 0 - 2 one week prior to admission) Able to complete questionnaires in English Required studies: H & P, CT or MRI for disease assessment, and serum albumin will be collected after admission but prior to treatment. Optional studies: CBC and electrolyte panel will be collected after admission but prior to treatment. S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Ineligibility Criteria (cont’d) MBO not due to intra-abdominal cancer Patient actively dying Patient requires an emergency surgical procedure, e.g., acute abdomen Patient refuses to allow study staff to contact him/her for study follow-up S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Timeline for Initial Patient Care Up to 3 working days Up to 2 working days |----------------------------|---------------------------| Surgical Consult or admission to Surgical Service Register to S1316 Begin Treatment Time from initial surgical consult to start of treatment should not be more than a week. Treatment may begin on the same day as the surgical consult as long as the order of events is preserved (surgical consult first, then registration, then treatment). Treatment must begin after registration. Patients for whom treatment is initiated prior to registration are ineligible. S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Initial Data Submission Baseline data Onstudy, MDASI-GI, EQ-5D-5L MBO treatment and complications data for initial hospitalization Pathology report to confirm primary cancer Radiology reports to confirm MBO S1316 - MBO Professional Slide Set, Version 01

S1316 - MBO Professional Slide Set, Version 01 S1316 – MBO Study Follow-Up Weekly phone assessments and data collection by study site staff for first 13 weeks and every 4 weeks thereafter up to one year Dietary recall phone calls every 4 weeks up to one year MBO treatment and complications data for all hospitalizations in first 13 weeks All patient-completed study forms will be administered via telephone or in person, if patient is in the hospital and allows an in-person visit. Follow-up assessments of patients are based from the date of registration. The time window for each phone assessment is +/- 2 days to allow for scheduling. If a follow-up call or visit is missed, the information that was missed will be included during the next completed call or visit. Every effort should be made to collect the follow-up data in identical fashion across all study arms (surgical vs. non-surgical management, randomized vs. non-randomized). S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Dietary Recall Self-reported diet measurement methods Relies on patient or caregiver to report foods consumed in prior 24-hour period Collected by Arizona Diet, Behavior, Quality of Life Assessment Lab through phone contact S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Criteria for Removal from Protocol Follow-up Completion of 53 weeks on study Medical condition that the treating investigator believes precludes continued participation Patient refusal for any reason, including discontinuation of weekly phone calls All reasons for discontinuation of follow-up will be documented but hospitalization data and vital status will still be reported. If a patient no longer wants to complete the study phone calls, if appropriate, the site should ask if the follow-up calls can be made solely to the patient’s designated representative before removing a patient from follow-up. S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Analysis Plan Study includes two components: randomized (n=50) and non-randomized (n=130) Inference will be based on assigned treatment Randomized component will use randomized treatment (intent to treat) Non-randomized component will use initially chosen treatment (pseudo-intent to treat) S1316 - MBO Professional Slide Set, Version 01

Analysis Plan (cont’d) Initial analysis will use pooled data from both components Use multivariate linear regression model Include parameters for potential confounders Include parameter for study component (randomized vs. non-randomized) S1316 - MBO Professional Slide Set, Version 01

Analysis Plan (cont’d) Assess bias in treatment group (surgical vs. non-surgical) between components (randomized vs. non-randomized) No evidence of residual bias after controlling for potential confounders? Use pooled data for primary analysis Evidence of residual bias? Report on both components Use randomized data only for primary analysis If the approach of Prentice et al., proves unwieldy because the number of covariates required to adjust for imbalance in the non-randomized component is too large for the sample size available, we will pursue the use of propensity scores. A strategy similar to that used for the primary endpoint will be employed for secondary endpoints. S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Recruitment Materials & Resources Professional Slide Set Patient Brochure Resources: S1316 webpage - http://swog.org/Visitors/S1316/Index.asp S1316 Working Group: S1316@swog.org Conference calls S1316 - MBO Professional Slide Set, Version 01

S1316 – MBO Study Participating Study Sites University of Arizona Setsuko K. Chambers, MD (Gyn Onc) Valentine Nfonsam, MD (Colorectal Surg) Duke University Amy P. Abernethy, MD (Med Onc/HPM) Paul J. Mosca, MD, PhD (Surg Onc) Angeles Secord, MD (Gyn Onc) MD Anderson Cancer Center Brian D. Badgwell, MD, MS (Surg Onc) Richard Royal, MD (Surg Onc) Robert Coleman, MD (Gyn Onc) Larissa Meyer, MD (Gyn Onc) George Chang, MD (Surg Onc) Karen Lu, MD (Gyn Onc) City of Hope Cancer Center Betty Ferrell, PhD, MA (Nursing Research) Ernest Han, MD (Gyn Onc) Gagandeep Singh, MD (Surg Onc) Yuman Fong, MD (Surg Onc) University of Michigan Phillip E. Rodgers, MD (HPM) Samantha Hendren, MD (Colorectal Surg ) Kevin Reynolds, MD (Gyn Onc) Memorial Sloan-Kettering Cancer Center Dennis Chi, MD (Gyn Onc) Nadeem Abu-Rustum, MD (Gyn Onc) Ginger Gardner, MD (Gyn Onc) Larissa K. F. Temple, MD (Colorectal Surg) S1316 - MBO Professional Slide Set, Version 01

S1316 - MBO Professional Slide Set, Version 01 Thank You S1316 - MBO Professional Slide Set, Version 01