Novel Approaches for the

Treatment of Colon and Rectal

Cancer: Minimally Invasive Surgery,

Sphincter Preservation, and Organ

Preservation

Avo Artinyan, MD, MS

Co-Director of Surgical Oncology

Verity Medical Group

Verity Medical Foundation

My Background

• 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

2014-2015Chief of Colon and Rectal SurgeryAssociate 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 CancerBackground/Epidemiology

ACS Website Cancer Facts and Figures

• 3rd most common cancer in the US

• 2nd leading cause of cancer death in US

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

Basic Anatomy/Standard Terminology

COLON vs RECTUM

15cm from anal verge

COLON

Distal Rectum

4cm Surgical Anal

Canal

2cmAnatomic Anal

Canal

5cm

10cm

15cm

Upper Rectum

MidRectum

Surgical AnatomyRectum

• Definition

– ≤ 15cm from anal verge on proctoscopy

• Upper (10-15cm)

• Mid (5-10cm)

• Low (<5cm)

Peritoneal Reflection

Mid Rectum

Upper Rectum

Distal Rectum

Colorectal Cancer Management

• Primary Prevention/Screening

• Diagnosis– Clinical Presentation

– Workup/Staging

• Treatment– Surgical Treatment

– Adjuvant/Neoadjuvant Approaches

Screening/PreventionAverage Risk Patients

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

• 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

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/StagingRectal 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 CancerStandard 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

• 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 ResectionColon Cancer

Principles of Oncologic ResectionRectal Cancer

• Segmental proctectomy with negative margins– Anterior resection/Low Anterior

Resection– Abdomino-perineal resection

• Appropriate lymphadenectomy– Upper-Mid Rectal Tumors

• Partial/ TUMOR SPECIFIC mesorectalexcision with 4-5cm distal margin

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

– INTACT Fascia Propria of Rectum

• 5 year survival

– Stage I - >93%

– Stage II - >80%

– Stage III - >70%

– Stage IV - >10%

Prognosis for Colorectal Cancer

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 SurgerySlow 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 ColectomyEvidence

• 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; 359:2224-29Nelson et al, N Engl J Med 2004;350:2050-9Lancet Oncology 2005; Vol.6: 477-484

Not Every Minimal Operation is the Same

Multiple ApproachesHand-Assisted Laparoscopy

• Midline Hand Port

• Resection and anastomosis are extracorporeal

• Laparoscopic assisted open resection

Multiple ApproachesLaparoscopy with Extracorporeal Resection/Anastomosis

• Resection and anastomosis extracorporeal

• Midline extraction site

Single Incision LaparoscopyLaparoscopy with Extracorporeal Resection/Anastomosis

Multiple ApproachesTotally laparoscopic/robotic resection

• Intracorporeal anastomosis

• Pfannensteil or natural orifice extraction site

Wound ComplicationsNot Just Cosmetic

• Midline extraction sites– Higher rate short-term

wound complications in Houston VA Series (30% vs. 13%)• Infection, disruption,

dehiscence

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

Orcutt, Tech Coloproctol, 2012

deSouza et al. Surg Endosc, 2011Lee et al. Surg Endosc, 2012

CASE #1SA

• 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 #1CT 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 TreatmentRectal Cancer Operations

• Low Anterior Resection (Sphincter-Preserving)

– No evidence of sphincter/levator involvement

• (~4cm-15cm)

Surgical TreatmentRectal 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 StrategyWhere 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, 2015Kapiteijn, 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 improvementLaurent 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 SurgerySlow 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, 2015Kang 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

– LR rates – 1.5%-3.1%

• Potential better functional outcomes– Better preservation of hypogastric nerves– Potentially higher sphincter preservation rates

Pigazzi, Surg Endosc, 2005Hellan, Ann Surg Oncol, 2007Baik, Ann Surg Oncol, 2009Pigazzi, Ann Surg Oncol, 2010Kwak, DCR, 2011

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

Flexible

Systems

▪ Natural orifice / trans-umbilical

▪ da Vinci-like capability

▪ Large range of motion (multi-quadrant capability)

Single Port

FUTURE 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 #2RD

• 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

– Robotic LAR • 1.5cm gross margin, negative

microscopic margins• 0/16 nodes ypT3N0

1.5cm

• ROBOTIC VIDEO PLACEHOLDER

Robotic Sphincter PreservationTransabdominal 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 CancerRationale

• 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, 2008Lezoche Surg Endosc, 2011, 1222Lezoche et al, Br J Surg, 2012Blair 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 #3TK

• 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• Would ordinary be offered rectal

resection

– Transanal Minimally Invasive Surgery

3-4cm

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

Hussein, Artinyan. Ann Surg Oncol. 2014

Watch and WaitMore 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

Novel neoadjuvant therapies/immunotherapies

If you have always done it that way, it

is probably wrong.

Charles Kettering

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)artinyan.avo@gmail.com

Glendale Office818-839-2480

1505 Wilson Terrace, Ste 150Glendale, CA

Downtown LA Office213-484-5543

201 S. Alvarado St., Ste 407Los Angeles, CA

Hollywood Office (Coming Soon)