InterstimTM for bowel dysfunction Project Update Randomized Crossover Trial of the Efficacy of Sacral Neuromodulation for Bowel Dysfunction following Sphincter Preserving Surgery Heather Yeo, MD, MHS Assistant Professor of Surgery and Healthcare Policy and Research 10/15/2016 I would like to thank the foundation for sponsoring my research

InterstimTM for bowel dysfunction Background Many advances in the treatment of rectal cancer Over the last twenty years the management of rectal cancers has change significantly. Improvements in neoadjuvant chemoradiation, surgical technique including TME, and the development of improved stapling devices have led to increased rates of sphincter preservation.

InterstimTM for bowel dysfunction Background National rate of sphincter preservation -- From <25% - >50%/20 years -- Up to 70% at specialized centers APR LAR VS. All of these changes have led an increased rate of sphincter preservation on a national level, from early reported rats of around 25% in the late 1980s to greater than 50% in by 2005, and even as high as 70% at specialized centers. For patients, means less permanent colostomies and more preservation of bowel continuity. Paquette et al. Dis Col Rect, 2010 Temple et al. Ann. Surg 2009

Low Anterior Resection Syndrome >50% of patients Frequency/urgency Clustering Incontinence Incomplete evacuation While Interestingly with this increased rate of sps for low rectal tumors, we as physicians have see the sequalae that as patients often have symptoms of ---- Temple, 2012, SSO Presentation Peeters et al , J Clin Oncol, 2005

InterstimTM for bowel dysfunction Options for treatment? Traditionally there hasn’t been much to offer All with poor results

Potential option for treatment InterstimTM for bowel dysfunction Potential option for treatment Recent studies show improvement in benign causes of incontinence with the use of an implantable neuromodulating device FDA Approved 1997 for urinary incontinence 2011 for fecal incontinence

Sacral Nerve Stimulation InterstimTM for bowel dysfunction Sacral Nerve Stimulation Stimulation of the sacral nerves (S3) Modulate the neural reflexes that influence the bladder, sphincter and pelvic floor Improves squeeze pressure, sensitivity, and rectal compliance

Potential Limitations of InterstimTM InterstimTM for bowel dysfunction Potential Limitations of InterstimTM Phase II trial mostly benign disease Patients not radiated Patients without rectal resection May help incontinence, but what about the other bowel symptoms associated with LARS

InterstimTM for bowel dysfunction Hypothesis The InterstimTM neuromodulating device will improve bowel function in rectal cancer patients after sphincter preserving surgery.

InterstimTM for bowel dysfunction Primary Objective To evaluate the effectiveness of InterstimTM on improving bowel function following sphincter preserving surgery using BFI Secondary Objectives: Quality of Life, Satisfaction

InterstimTM for bowel dysfunction Design Randomized Crossover Trial All patients with a successful trial receive the device Randomized to device on or off Washout Crossover device off/on Single Institution Pilot (10 patients funded by the AWSF), if successful plan to continue to multi-center study for a total of 76 pts

InterstimTM for bowel dysfunction Progress to date Long IRB Process >10 months Trial opened in late 2014 at MSKCC Slow accrual (>100 patents approached) 4 Patients Enrolled IRB Approved at NYP-WCM Legal constraints delayed second Opening at NYP in 2 weeks – 3 patients ready for trial when open

InterstimTM for bowel dysfunction Lessons Learned Early results are promising Patients are wary of device implantation and inability to have an MRI Multicenter trial will be needed We have 6 centers who are willing to collaborate if we go on to the next phase

Grant Funding Since AWSF Grant InterstimTM for bowel dysfunction Grant Funding Since AWSF Grant Empire Clinical Research Investigators Program CADC Pilot Project Funding Society for Surgery of the Alimentary Tract Career Development Award Damon Runyon Clinical Investigator Kellen Junior Faculty Fellowship Laitman Clinical Scholar Award

InterstimTM for bowel dysfunction Thank You Larissa Temple, MD Martin Weiser, MD Kelly Garrett, MD Kathleen Keenoy Karin Avila Jeff Milsom, MD Collaborators and Colleagues at MSK and Cornell Association of Women Surgeons Foundation/Ethicon, Inc.

Timing of Patient Reported Measures InterstimTM for bowel dysfunction Timing of Patient Reported Measures

Results: Symptoms at 12 Months Bowel Function after SPS Results: Symptoms at 12 Months Frequency Subscale Urgency Subscale Looking overall at our patients symptoms at 12 months we see that a large percentage of patients have symptoms. Dietary Subscale

Complications with Implantation Interstim for bowel dysfunction Complications with Implantation

Complications with Test Stimulation Interstim for bowel dysfunction Complications with Test Stimulation

Exclusion Criteria Recurrent/Metastatic Disease Interstim for bowel dysfunction Exclusion Criteria Recurrent/Metastatic Disease Immune suppressive medication Seizure disorder Prior sacral/lower spinal surgery Congenital Spinal defect/Paraplegia Rectal prolapse IBD/Crohns Pregnancy Active anal/rectal abscess Pacemaker or other electronic implanted device Immediate need for MRI Patients will be excluded if the surgeon is unable to place the temporary stimulating lead. Inability to commit to local follow up for device management.

InterstimTM for bowel dysfunction Recently this data was updated by Hull et al. Showing continued improvement at 80%@ 5 years

Bowel Function Instrument InterstimTM for bowel dysfunction Bowel Function Instrument 18 Item Instrument designed for patients who have had Sphincter Preserving Surgery Validated and used in several trials 3 Subscales Frequency Subscale Urgency Subscale Dietary Subscale Total Score=Bowel Function Index 0-100

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction SCHEMA

InterstimTM for bowel dysfunction Phase II Trial Success rate at 12-months post implant