CRC Risk Factors. U.S. Adherence Rates Cancer Screening. Genetic Model of Colorectal Cancer. Epidemiology and Clinical Consequences of CRC

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1 10:45 11:45 am Guide to Colorectal Cancer Screening SPEAKER Howard Manten M.D. Presenter Disclosure Information The following relationships exist related to this presentation: Howard Manten MD: No financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Epidemiology and Clinical Consequences of CRC Third most common cancer in U.S 147,000 new cases/yr Second leading cause of cancer death 56,000 deaths Average patient CRC death Loses 13 years of life A person at age 50 has about a 5% lifetime risk 2.5% CRC related death U.S. Adherence Rates Cancer Screening Adherence Rates Breast Cancer 69% * Cervical Cancer 86% * Prostate Cancer 75%** Colorectal Cancer 45% * * Seeff. Cancer 2002;95: ** Sirovich. JAMA 2003;289: Intrinsic Age Personal history of colorectal polyps or cancer Inflammatory bowel disease Race/ethnicity CRC family history Inherited syndromes FAP HNPCC American Cancer Society CRC Risk Factors Extrinsic Diet Red meat, processed meat Cooking methods Physical inactivity Obesity Smoking Alcohol Type II diabetes Genetic Model of Colorectal Cancer DNA Alteration Normal Epithelium APC Adenoma K ras BAT 26 (sporadic) p53 Late Adenoma 2-5 yrs Early Cancer Optimum phase for early detection Adapted from Fearon ER, Vogelstein B. Cell 1990;61: Typically 10+yrs Late Cancer

2 HNPCC LYNCH SYNDROME Modified Amsterdam Criteria 3 relatives with HNPCC related cancer (CRC, uterine, small bowel, renal pelvis or ureter) 2 generations affected 1 person diagnosed at age < 50 y 1 person is a first degree relative of the other two Vasen et al. Gastroenterology 1999;116:1453. ACG CRC Guidelines Overweight/Obese Patients Increased relative risks for CRC/adenomas Special efforts are warranted -ensure screening take place Other High Risk Patients Risk Screening GYN cancer 3.5 Colonoscopy q 5 (age < 50y) Breast cancer 1.1 Same as average risk Weinberg. Ann Int Med 1999;131:189. Schoen. Am J Gastroenterol 1994;89:835. ACG CRC Screening 2009 Family History Single first degree relative with Colorectal cancer or Advanced adenoma (> 1cm, HGD,villous) Diagnosed at age 60 years Recommended screening: Same as average risk Colonoscopy q10 years beginning at 50 Rex et al. ACG CRC Screening 2009 Family History Invasive CRC Screening Tests Single first degree relative Colorectal cancer or advanced adenoma < 60 yrs Or two first degree relatives Colorectal cancer or advanced adenomas Recommended screening: Colonoscopy every 5 years beginning at age 40 or 10 years <age at diagnosis of youngest affected Flexible sigmoidoscopy Colonoscopy ACBE CT Colography (CTC)

3 Adenomatous Polyps and Cancer Flexible sigmoidoscopy : 5 years Colonoscopy : 10 yrs Double contrast barium enema : 5 yrs CT colonography (CTC) : 5 yrs ACS/MSTF CRC 2008 Guideline Assumptions Non-invasive Tests Less likely to prevent cancer Repeated at regular intervals to be effective If abnormal - need invasive test (colonoscopy) If patients are not willing to Have repeated testing or Have colonoscopy if the test is abnormal Programs will not be effective Tests That Primarily Detect Cancer Annual guaiac based fecal occult blood test With high test sensitivity for cancer (Hemoccult Sensa) Annual fecal immunochemical test (FIT) Stool DNA test (sdna) Interval uncertain ACS/MSTF Guidelines 2008 Fecal Occult Blood Tests Acceptable option if: Annual screening with high sensitivity test (Hemoccult Sensa) Any (+) followed up with colonoscopy Following digital rectal/pelvic exam Not recommended and should not be done Fecal Immunochemical Tests More specific for human blood Guaiac based tests Detection of peroxidase in human blood React to dietary peroxidase FIT is not subject to false negative results FITs also are more specific for LGI bleeding Globin degraded by UGI digestive enzymes FIT vs gfobt FIT: better performance overall FIT: 10 12% gains in adherence FIT: 2x # patients detected with advanced neoplasia Commercially available FITs may vary in performance

4 ACS/MSTF Guidelines 2008 Fecal Immunohistochemical Test ACG Guidelines 2009 Fecal Testing Annual screening with FITs Detect a majority of prevalent CRC Acceptable option for colorectal screening Average risk adults aged 50+ Positive test should lead to colonoscopy Preferred cancer detection test is annual FIT Superior performance characteristics Gains in adherence Doubling in the detection of advanced lesions Little loss of positive predictive value Stool Based Testing FOBT or FIT Fecal occult blood tests (gfobt) Fecal immunochemical tests (FIT) Blood in the stool is a non-specific finding May originate from CRC or larger polyps Single test limitations for detection bleeding Pseudoperoxidase Heme or hemoglobin Human globin > 1-2 cm Fecal DNA Testing Adenoma and carcinoma cells Contain altered DNA, are continuously shed DNA is stable in stool Differentiated/isolated from bacterial DNA No single gene mutation is present Shed by every adenoma or cancer Multi target DNA stool assay Required to achieve high sensitivity CRC Molecular Pathways Fecal DNA Markers K-ras APC P53 BAT-26 (marker of microsatellite instability) Marker of DNA Integrity Analysis (DIA) ACS/MSTF Guidelines 2008 Fecal DNA Testing Acceptable option for CRC screening Interval uncertain Manufacturer recommending a 5 yrs

5 ACG 2009 Guidelines Fecal DNA FIT as preferred cancer detection test More extensive data High cost of fecal DNA ACS/MSTF Guidelines 2008 Flexible Sigmoidoscopy Acceptable option provided: Beyond 40 cm Adenomas in the distal colon are used as Indication for the need for colonoscopy Appropriate interval uncertain Every 5 years in most clinical settings Concerns quality and completeness FSIG q 5 + FIT yearly Colonoscopy Related Risk Reduction of CRC Canadian study (administrative database) Risk reduction for 14 yrs for distal CRC Risk reduction for only 7 yrs for proximal CRC Canadian study (administrative database) Population based case-controlled study Risk reduction left sided CRC (OR 0.33) No risk reduction right sided CRC (OR 0.99) Improving Colonoscopy Quality Exam Improve performance success (cecum) Improve neoplasm detection Improve neoplasm response (intervention) Improve adequacy of prep (patient) Clin Gastroenterol Hepatol 2008;6: Ann Intern Med 2009;150:1-8. Conventional Colonoscopy Quality Time Rockford study Time > 6 mins Time > 8 min Adenoma detection rate(adr) 25 to 52% Mayo study Median polyp yield at 6.7 min Correlation with longer times (p<0.001) ACG Guidelines 2009 Colonoscopy Screening Preferred Colorectal Cancer Prevention Test Colonoscopy Every 10 Years Second examination at five years? Might not substantially impact incidence CRC NEJM 2006;355: Gastrointest Endosc Clin Gastroenterol Hepatol 2008;6:

6 ACG Guidelines 2009 Colonoscopists Guidance Measure individual adenoma detection rates of 1 adenoma at least 25% of time in men and 15% women Measure withdrawal times Average at least six minutes in normal exams Some colons effectively examined < 6 minutes ACG CRC Guidelines Polypectomy Technique Many perforations are related to polypectomy Small polyps are numerous Contribute substantially to the overall risk Majority small polyps will not harm patients ACG CRC Guidelines Polypectomy Technique Effective removal small polyps Cold snare polypectomy or biopsy Not associated with bleeding or perforation Insufficient data available from RCT Not mandate particular polypectomy techniques Carefully consider the polypectomy techniques In particular those utilized for small polyps Surveillance Colonoscopy after polypectomy or colorectal cancer resection No polyps or hyperplastic polyp 1 2 small polyps(<10mm) 3 10 polyps 10 or more polyps 1 or more polyps (> 10mm) Adenoma (HD) Colorectal Cancer 10 years 5 10 years 3 years 3 years or less 3 years 3 years 1 3 years Adequacy of Colonoscopy Up to 25% of patients undergoing colonoscopy have poor bowel preparation Lowers the detection of small polyps (<9mm) Increased risk of procedural complications Decreased completion rates Increases the time the endoscopist takes to try to suction and clean the colon COLONOSCOPY BOWEL PREP SCALES Inadequate prep inability to detect a 5mm polyps Will need a repeat colonoscopy Less than 10 years NOW Van Dongen 2011

7 ACG Guidelines 2009 Pre- Colonoscopy Prep Best established is the principle of splitting At least half preparation day of colonoscopy If all given day before Probability poor preparation increases Particularly in the cecum and ascending colon Allow clear liquids until 2 hours prior to exam From anesthesia guidelines Anesthesiology 1999;90: BOSTON BOWEL PREP SCALE Colon prep determined in 3 sites Right,Tranaverse and Left colon ZERO unprepped colon ONE portion of segment not seen well TWO minor prep issues THREE entire mucosa seen Valuedated Scale BOSTON BOWEL PREP SCALE Good Prep (Definition) Total score greater than 6 All segments greater than 2 Repeat colonoscopy needed in 10 years Validated Split Dose Superior to full dose PEG with respect to Colon Cleansing Patient compliance Patient s willingness to repeat the same bowel preparation Nausea Kilgore et al 2011 Liquid coming from the bowel before colonoscopy should look like. Alternatives to Colonoscopy CT Colonography, Virtual Colonoscopy Similar to standard colonoscopy in its ability to detect CRC and precancerous polyps in people 65 years and older (D. Johnson et al, J. Radiology, Feb. 24, 2012)

8 Patient Number CTC Screening Trials N>500 Average/High Risk (4) Polyp > 1CM All Polyps Cancer All Polyps Sens % Mean Spec % Mean Sens % Mean Sens % Mean Spec % Mean Range Range Range Range Range NA NA Reporting Risks for CTC ACR guidelines suggest No reporting for <6mm Option of watching 6 9 mm Cost of surveillance repeat in 1 3 yrs Radiology 2005;236:3-9. CTC Screening: ACRIN Trial American College Radiology Imaging Network 15 US sites (academic and private practice) 2600 asymptomatic patients (2531 participated) Scheduled for colonoscopy Stool tagging 24 hrs before 16 grams barium 3 doses Colonoscopy blinded to CTC 99% same day CTC Screening: ACRIN Trial >5mm >6mm >7mm >8mm >9mm >1cm SENS 65% 78% 84% 87% 90% 90% SPEC 89% 88% 87% 87% 86% 86% PPV 45% 40% 35% 31% 25% 23% NPV 95% 98% 99% 99% 99% 99% N Engl J Med 2008;359: N Engl J Med 2008;359: ACS/MSTF Guidelines CTC for Average Risk CRC Screening Acceptable option to begin at 50 yrs Polyps >6mm refer for colonoscopy Interval uncertain but suggest q 5 yrs Colonoscopy Surveillance after Polypectomy or Colorectal resection(ctc) Hyperplastic polyps repeat 10 years No reporting for <6mm Option of watching 6 9 mm Cost of surveillance repeat in 1 3 yrs Specificity issues again Radiology 2005;236:3-9.

9 Small polyps = Small worry? Effect of Waiting Markov model analysis Small (6 9 mm) polyp were simulated to either: (1) Undergo immediate COLO for polypectomy (2) Wait 3 years for a repeat CTC (WAIT) Hur et al. Clin Gastroenterol Hepatol 2007;5(2): Extracolonic Findings of CTC Meta analysis of 17 CTC studies found: 40% of patients had extra colonic findings 14% underwent further investigation Additive costs but also a potential additive risks e.g. radiation, biopsy, preparation Br J Radiol 2005;78(925): CTC= Virtual Colonoscopy No prep No risk Future Screening Tools Pillcam Colon US approved only for incomplete colonoscopy FUTURE ENDOSCOPIC Modifications Third eye Scope Modifications Caps and tip slides Chromoendoscopy. Fluorescents(Auto and Dye) How often does the average person need to be screened for colon cancer? Colonoscopy Every 10 years Sigmoidoscopy Every 5 years Double Contrast Barium Enema Every 5 years Virtual colonoscopy Every 5 years Stool tests (FOBT, ifobt, FIT) Every year.

10 CRC Screening Guidelines Conclusions Menu of options Cancer detection vs prevention Risks/benefits of new technology New risk profiles for patients (ACG) Claims of increased adherence new tests -must be proven or otherwise