Avo Artinyan, MD, MS Co-Director of Surgical Oncology Verity Medical Group Verity Medical Foundation My Background

Novel Approaches for the Treatment of Colon and Rectal Cancer: Minimally Invasive Surgery, Sphincter Preservation, and Organ Preservation

• UCSD School of Medicine – 2000

• USC/LAC – 2000-2006 – General Surgery Residency – Colorectal Research Fellowship

• City of Hope – 2006-2009 – Surgical Oncology – Robotic surgical oncology – Robotic colorectal cancer surgery Baylor College of Medicine/Michael E. DeBakey VAMC (2009) - Largest minimally-invasive/robotic colorectal cancer program in VA 2014-2015 Chief of Colon and Rectal Surgery Associate Director of Surgical Oncology Baylor College of Medicine, DeBakey Department of Surgery

Active Clinical Programs • Minimally-invasive and robotic colorectal surgery (malignant and benign), with focus on sphincter-preservation and organ preservation • Minimally-invasive gastric cancer program • General surgical oncology • Minimally invasive general surgery 2018 ▪ Co-Director of Surgical Oncology Verity Medical Group ▪ Programs in Development: ▪ Colorectal Surgery (minimally-invasive, robotic) ▪ Gastric Cancer (minimally-invasive, robotic) ▪ Pancreatic Cancer (with HPB/Transplant Program) ▪ Soft Tissue Sarcoma, Breast, Melanoma ▪ Appendiceal Neoplasms/HIPEC ▪ Other – Minimally Invasive General Surgery Today’s Agenda

• Standard Management of Colorectal Cancer – Clinical Presentation/Diagnosis – Treatment

• Novel Approaches in Colon Cancer – Minimally Invasive Surgery

• Novel Approaches in Rectal Cancer – Novel strategies for Sphincter Preservation – Strategies for Organ Preservation Colorectal Cancer Background/Epidemiology • 3rd most common cancer in the US

• 2nd leading cause of cancer death in US

• Overall 5-year survival rate – >70% combined

ACS Website Cancer Facts and Figures Basic Anatomy/Standard Terminology

COLON vs RECTUM

COLON

15cm from anal verge Surgical Anatomy Rectum

15cm • Definition Upper – ≤ 15cm from anal Rectum verge on proctoscopy 10cm

• Upper (10-15cm) Mid • Mid (5-10cm) Rectum

• Low (<5cm) 5cm Distal Rectum 4cm 2cm Surgical Anal Anatomic Anal Canal Canal Peritoneal Reflection

Upper Rectum

Mid Rectum

Distal Rectum Colorectal Cancer Management

• Primary Prevention/Screening

• Diagnosis – Clinical Presentation – Workup/Staging

• Treatment – Surgical Treatment – Adjuvant/Neoadjuvant Approaches Screening/Prevention Average Risk Patients • Screening starts at age 50 y/o – ACS recommendation at 45y/o

• Fecal blood testing every year

• Flexible sigmoidoscopy 3-5 years

• Colonoscopy every 10 years

• Double contrast BE only if other test not available

Moore, Surg Onc Clin N Amer. 19:693, 2010 Definitive Diagnostic Test

Complete Colonoscopy with Biopsy Additional Workup/Staging

• CT scan chest/abdomen/pelvis with contrast – Regional Nodal Disease – Metastatic disease

• MRI abdomen useful in specific circumstances – No advantage over CT as a primary diagnostic study

• PET CT - Selectively – Useful for suspected but not confirmed metastatic disease

Patel, et al. Ann Surg 253(4), 2011. Workup/Staging Rectal Cancer

• Rigid proctoscopy – by surgeon – Important to determine the distal extent of the lesion – Critical for surgical decision-making, e.g. sphincter preservation

• Locoregional staging studies – Determine clinical T and N stage to make treatment decisions

• Endoscopic ultrasound or MRI (rectal protocol) – ~80% accuracy – Each has certain advantages Colorectal Cancer Standard Treatment (NCCN and others)

• Colon cancer – Surgery (Colectomy) – Chemotherapy (high-risk stage II and stage III)

• Rectal cancer – Surgery (Proctectomy) – Anterior resection or APR – Preoperative chemoradiation (Stage II and III) – Postoperative chemotherapy (Stage II and III) – Other permutations • Preoperative chemotherapy without radiation (stage II and III) • Postoperative chemoradiation (fallen out of favor)

• Metastatic Disease – Palliative treatment in general – Curative multidisciplinary therapy/surgery in individualized cases Principles of Oncologic Resection Colon Cancer • Segmental colectomy with negative margins – Proximal, distal, radial

• Appropriate lymphadenectomy – Wide mesenteric clearance with high ligation of primary draining vessel – Removal of ≥ 12 lymph nodes

• En-bloc resection of involved organs – Small bowel, abdominal wall, bladder, etc. Principles of Oncologic Resection Rectal Cancer

• Segmental proctectomy with negative margins – Anterior resection/Low Anterior Resection – Abdomino-perineal resection

• Appropriate lymphadenectomy – Upper-Mid Rectal Tumors • Partial/ TUMOR SPECIFIC mesorectal excision with 4-5cm distal margin

– Mid-Low Rectal Tumors • TOTAL MESORECTAL EXCISION (TME)

– INTACT Fascia Propria of Rectum Prognosis for Colorectal Cancer

• 5 year survival – Stage I - >93%

– Stage II - >80%

– Stage III - >70%

– Stage IV - >10% Surgical Innovations In Colon Cancer Surgical Innovations In Colon Cancer

• Primary innovation over the course of the last 20 years MINIMALLY INVASIVE COLON SURGERY • Laparoscopic colectomy

• Other more controversial innovations – Robotic colectomy – “Complete mesocolic excision” Minimally Invasive Colorectal Surgery Slow Adoption

• Laparoscopic colorectal surgery adopted slowly – More difficult, time-consuming – Longer learning curve – Historical fears about oncologic outcomes • Oncologic margins • Local recurrence • Port site recurrence

Robinson, et al., Ann Surg Oncol, 2011 Drawbacks of Open Colorectal Resections

• Large midline incisions

• Significant post-operative pain

• Prolonged length of stay – ~7 days in the US for open colorectal resections

• Complications related to open operation – Midline ventral hernias – Adhesive small bowel obstruction Laparoscopic Colectomy Evidence • Early fears regarding oncologic adequacy of technique and outcomes – Port site recurrences, appropriate nodal harvest

• 2002 – Barcelona Trial (Lacy, Spain) – colon cancer • 2004 – COST Study (Nelson, USA) – colon cancer • 2005 – COLOR Trial (European) – colon cancer • 2005 – CLASICC Trial (UK) – colon and rectal cancer

• Demonstrated: – Better short term outcomes • Decreased length of stay • Decreased use of pain medications • Decreased complication rates

– At least equivalent Disease-Free Survival (DFS) and Overall Survival

• Laparoscopy for colon cancer should be STANDARD OF CARE

Lacy et al, Lancet 2002; 359:2224-29 Nelson et al, N Engl J Med 2004;350:2050-9 Lancet Oncology 2005; Vol.6: 477-484 Not Every Minimal Operation is the Same Multiple Approaches Hand-Assisted Laparoscopy • Midline Hand Port

• Resection and anastomosis are extracorporeal

• Laparoscopic assisted open resection Multiple Approaches Laparoscopy with Extracorporeal Resection/Anastomosis • Resection and anastomosis extracorporeal

• Midline extraction site Single Incision Laparoscopy Laparoscopy with Extracorporeal Resection/Anastomosis Multiple Approaches Totally laparoscopic/robotic resection

• Intracorporeal anastomosis

• Pfannensteil or natural orifice extraction site Wound Complications Not Just Cosmetic

• Midline extraction sites – Higher rate short-term wound complications in Houston VA Series (30% vs. 13%) • Infection, disruption, dehiscence Orcutt, Tech Coloproctol, 2012

• Significantly higher risk of incisional hernia with midline extraction sites.

deSouza et al. Surg Endosc, 2011 Lee et al. Surg Endosc, 2012 CASE #1 SA

• SA – 77 year old Armenian female ➢ History of colon cancer 2013 ➢ PMH: HTN, CVA, cardiac arrhythmia

❖Laparoscopic right hemicolectomy with extracorporeal anastomosis in 2013

❖Now presents with abdominal pain CASE #1 CT Scan – Ventral Incisional Hernia (8x8cm) Surgical Treatment of Rectal Cancer

Much More Complex!!

Anatomic and physical constraints of pelvis History/Milestones Surgery Rectal Cancer • Rectal disease and rectal cancer

♦️ Recognized by ancient Egyptians and Greeks

♦️ Considered Incurable

Galler et al. Surg Oncol, 2011 History/Milestones Surgery Rectal Cancer Novel Approaches/Techniques

• Laparoscopic colon and rectal resections (2002-2005)

• Robotic colorectal surgery (2005-2010)

• Other novel techniques (2010 – Present) – Transanal Total Mesorectal Excision (TaTME) – Transanal Minimally Invasive Surgery (TAMIS) – Total upfront therapy (ChemoXRT and Chemoradiation) – Watch and Wait Surgical Treatment Rectal Cancer Operations • Low Anterior Resection (Sphincter-Preserving) – No evidence of sphincter/levator involvement • (~4cm-15cm) Surgical Treatment Rectal Cancer Operations

• Abdominoperineal resection/End colostomy (Non-Sphincter Preserving) – Sphincter muscle involvement – ≤30% of cases (rough guideline) Goals of Surgical Treatment for Rectal Cancer

• Early Post-Surgical/Post-Treatment Goals – Minimize morbidity and mortality – Minimize infectious complications

• Functional Goals – Preservation of GI continuity with acceptable bowel function – Preservation of sexual and urinary function – Maintenance or improvement in quality of life

• Oncologic Goals – Local control – Long-term survival/cure Current Treatment Strategy Where are We Now • Localized disease (Stage I) – Curative rectal surgery only – Local excision in well selected patients (low risk T1N0)

• Locally advanced disease (Stage II, III) – Preoperative chemoradiation (+/- upper rectal cancer) – Rectal Resection – Postoperative chemotherapy

• Metastatic disease (Stage IV) – Palliative treatment – Curative multimodality therapy with surgery in individualized cases • Liver only metastatic disease • Isolated/resectable extraabdominal disease How Are We Doing?

• Early Post-Surgical/Treatment Goals – Minimize morbidity and mortality – Minimize infectious complications

• Functional Goals – Preservation of GI continuity with acceptable bowel function – Preservation of sexual and urinary function – Maintenance and/or improvement in quality of life

• Oncologic Goals – Local control – Long-term survival/cure Early Post-Surgical/Treatment Goals

• Mostly open radical resections – High morbidity (40%) and even mortality (up to 2-5%) van der Pas, Lancet, 2013

• High incidence of infectious complications – At least 20% incidence of surgical site infections Biondo, Tech Coloproctol, 2014

– High rate of anastomotic leak • Up to 20-30% with low rectal anastomoses

– High readmission rates (up to 25%) • Significant impact on quality of life • Increase healthcare costs Damle, J Surg Res, 2015 Not Just Short-Term Outcomes

Artinyan et al. Ann Surg, 2015 How Are We Doing?

• Early Post-Surgical/Treatment Goals – Minimize morbidity and mortality – Minimize infectious complications

• Functional Goals – Preservation of GI continuity with acceptable bowel function – Preservation of sexual and urinary function – Maintenance and/or improvement in quality of life

• Oncologic Goals – Local control – Long-term survival/cure Functional Goals

• Approximately 30% of patients with rectal cancer required a permanent colostomy

Mohammed, Artinyan. Ann Surg Oncol, 2015 Other Functional Issues

• Significant incidence of urinary retention

• Sexual dysfunction both males and females – 30% incidence of erectile dysfunction in males

• Low Anterior Resection Syndrome (LARS) – Frequency, Urgency, Clustering, Leakage and Incontinence

• Most severe with preoperative chemoradiation, low rectal anastomosis Oncologic Goals

• Local recurrence rates are ~5% Bonjer, NEJM, 2015 Kapiteijn, NEJM, 2001

• Long term survival – All comers: 5yr OS 77%, DFS 81% – Pathologic Stage III (1/3 of patients): 5yr OS 60%, DFS 61%

• Significant room for improvement Laurent et al. Ann Surg, 2009 What Are the Ways Forward

• Improve early outcomes from radical rectal resection – Minimally invasive/robotic surgery

• Improve functional outcomes – Advanced techniques for sphincter preservation, nerve preservation – Minimize the need for radiation • MERCURY TRIAL and PROSPECT TRIAL – Organ preservation (minimize surgery) • Local excision • Watch and wait

• Improve oncologic outcomes – Novel multimodality therapies MINIMALLY INVASIVE SURGERY FOR RECTAL CANCER Minimally Invasive Colorectal Surgery Slow Adoption

• Laparoscopic/robotic rectal cancer surgery adopted even more slowly

• Result – Most rectal minimally invasive procedures are done by a small number of surgeons in the US

Robinson, et al., Ann Surg Oncol, 2011 Laparoscopic Rectal Resection (LAR and APR)

• Multiple metanalysis and at least 2 randomized trials (COLOR II, COREAN trial) – Improved short-term outcomes – Similar to better oncologic outcomes

• Other trials (ACOSOG and ALACART) – No benefit with laparoscopic surgery

Bonjer et al, NEJM, 2015 Kang et al, Lancet Oncol, 2010 Disadvantages of Laparoscopic Rectal Surgery

• Laparoscopy is not ideally suited for rectal surgery

• Technically difficult

• High conversion rates even in experienced hands

• Concerns with radial margins (CLASICC, COLOR II) – 10-12% radial margin positivity The Solution: Robotic Surgery Advantages of the Robot (Surgeon)

• Improved vision – 3D vision (depth perception) – Increased magnification – Camera controlled by the surgeon

• Improved instrumentation – 7 degrees of freedom (=human hand) – No counterintuitive movements – Scalable motion, Tremor elimination – 3rd arm

• Ergonomic operating position – Decreased surgeon stress/fatigue Advantages of the Robot (Patient)

• Lower conversion rates compared to laparoscopy – <10% in most series – 1/~120 cases in my single surgeon series

• Excellent Short-term outcomes – Low Mortality  0 – 2.3% – Low Anastomotic leak rates  1.8% – 12.1% – Low blood loss  150-283ml

• Oncologic Outcomes – Circumferential margin positivity • <1% in most studies Pigazzi, Surg Endosc, 2005 – LR rates – 1.5%-3.1% Hellan, Ann Surg Oncol, 2007 Baik, Ann Surg Oncol, 2009 Pigazzi, Ann Surg Oncol, 2010 • Potential better functional outcomes Kwak, DCR, 2011 – Better preservation of hypogastric nerves – Potentially higher sphincter preservation rates Disadvantages of the Robot

• Operative times longer than open – But equivalent or better than laparoscopic resection

• Expensive – But not prohibitive and getting cheaper

• No downside for the patient • ROBOTIC VIDEO PLACEHOLDER FUTURE SYSTEMS

Single Port ▪ Natural orifice / trans-umbilical ▪ da Vinci-like capability ▪ Large range of motion (multi- quadrant capability)

Flexible Systems Other Surgical Approaches

• Transanal Total Mesorectal Excision (Laparoscopic TaTME) – Unclear benefit – Favored by surgeons who do no use the robot

• Single Incision Laparoscopic Surgery (SILS) – No benefit over laparoscopy – Difficult for the rectum – Hernias a problem Sphincter-Preservation

• Sphincter-preservation rates have improved over time recently – Better understanding of appropriate distal margins – Better instrumentation and advanced techniques CASE #2 RD • 64 y/o Armenian male – Bright red rectal bleeding – Colonoscopy/proctoscopy • Anterior rectal adenocarcinoma • 5.5cm from anal verge • 1.5cm off the sphincter muscle

– MRI – T3N0 (stage 2 disease) – Neoadjuvant chemoradiation 1.5cm

– Robotic LAR • 1.5cm gross margin, negative microscopic margins • 0/16 nodes ypT3N0 • ROBOTIC VIDEO PLACEHOLDER Robotic Sphincter Preservation Transabdominal Intersphincteric Resection Problems with Aggressive Sphincter Preservation • Sphincter preservation difficult for distal rectal cancers

• Poor functional outcomes – Particularly with respect to GI function (LARS) – Life-limiting and life-altering

• Potential solution: Organ preservation – Local excision – Watch and wait  No surgery at all in complete responders Local Excision of Rectal Cancer Rationale

• Full thickness removal of disease in the lumen – Does not address lymph nodes

• Oncologic success directly proportional to ability to identify patients without nodal disease

• Benefits – Avoids the morbidity of radical surgery – Minimal functional deficits Local Excision Techniques

• ~ <4cm – Traditional transanal excision

• We along with other groups described procedure with SILS port – SILS TEM (2009-2010) – TransAnal Minimally Invasive Surgery (TAMIS) Oncologic Indications – Local Excision

Standard indications • Tis disease • Low-risk T1 disease – Well-mod diff, no LVI, low Kikuchi classification – Recurrence rates of low risk T1 disease after local excision are 5% or less

Evolving indications • T2N0 – preoperative chemoradiation + local excision – LR rates equivalent to radical resection in Italian randomized trial – Subject of ACOSOG Z6041 trial – 5% LR with ChemoXRT and Local Excision

Lezoche, et al.Surg Endosc, 2008 Lezoche Surg Endosc, 2011, 1222 Lezoche et al, Br J Surg, 2012 Blair and Ellenhorn, Am Surg, 2008 Anatomic Constraints TAMIS

• Posterior lesions – 5cm-15cm

• Anterior, anterolateral and lateral lesions – 5cm-10cm

• More proximal lesions approached with planned peritoneal entry `

Artinyan (Ch. 27) Surgery for Cancers of the Gastrointestinal Tract. Springer, 2015 CASE #3 TK • 70 y/o Armenian female – First screening colonoscopy – 1.5cm broad base polyp in the rectum – 7cm from anal verge on proctoscopy

– Pathology • Well-differentiated adenocarcinoma • No high risk features

– Staging – low risk T1N0 3-4cm • Would ordinary be offered rectal resection

– Transanal Minimally Invasive Surgery

Local excision of an upper rectal lesion (14- 18cm)

Hussein, Artinyan. Ann Surg Oncol. 2014 Watch and Wait More Aggressive Organ Preservation • Rationale – After conventional chemoradiation • 15-25% of patients have pathologic complete response (stage II-III) patients

– With extended chemoradiation/chemotherapy • 30-50% CR rates

– What would happen if you did nothing further?? Watch and Wait (Habr Gama, Ann Surg 2004)

– 265 patients - locally advanced mid-distal rectal cancers (0-7cm) – Underwent preop 5FU based chemoradiation – 27% had cCR – Watched them – no other therapy – Median 5 year follow up • Local recurrence rate 2.8% • Systemic recurrence was very low • 5yr overall survival of 100%, DFS 92% Paradigm Shift

SHOULD WE BE OPERATING ON THESE PATIENTS AT ALL???

NOT YET CLEAR Problems

• Other groups could not replicate results

• Habr Gama (IROBP 2014) – 183 patients – 31% local recurrence rate (both early and late) • 21% of these not salvageable – Overall non salvageable local recurrence rate of (7%)

Habr-Gama, IJROBP, 2014 Novel Multimodality/Preoperative Treatments

• Focus to increase complete response rates in low rectal cancers

• Total upfront therapy – ChemoXRT  Chemotherapy  Surgery – XRT  Chemotherapy  Surgery (RAPIDO) – Chemotherapy  ChemoXRT  Surgery (NRG GI002)

• Other permutations – Hypofractionated neoadjuvant chemoradiotherapy – Hyperfractionated neoadjuvant chemoradiotherapy – Chemotherapy  Selective ChemoXRT  Surgery (PROSPECT)

• Immune Checkpoint Inhibitors? – May have a role at some point How Do We Make Sense of All of This?? Treatment of Rectal Cancer is Diverging

• Diverging at the Peritoneal Reflection

• Upper rectal cancers behave like colon cancers – Lower recurrence rates – Lower complication rates from surgery – UP FRONT SURGERY – OMISSION OF XRT (MERCURY, PROSPECT)

• Mid and lower rectal cancers – Much higher recurrence rates – Higher rate of surgical complications – MINIMIZATION OR OMISSION OF SURGERY (ORGAN PRESERVATION) – TOTAL NEOADJUVANT THERAPY (TNT, NRG I002) “KITCHEN-SINK PREOPERATIVE THERAPY” Opportunity – Verity/NANT

If you have always done it that way, it is probably wrong. Charles Kettering

Novel neoadjuvant therapies/immunotherapies Exciting Times in the Treatment of Colon and Rectal Cancer Greater Emphasis on Quality of Life My Contact Information

818-606-2200 (Cell, call or text) [email protected]

Glendale Office 818-839-2480 1505 Wilson Terrace, Ste 150 Glendale, CA

Downtown LA Office 213-484-5543 201 S. Alvarado St., Ste 407 Los Angeles, CA

Hollywood Office (Coming Soon)