1. An Evidence Based Approach to Colorectal Cancer Screening J. C. Ryan, M.D. Associate Professor of Medicine UCSF and SF VAMC 9/22/2014

2. Colorectal Cancer Lifetime incidence of 6% Common cause of cancer death, 2nd in men, 3rd in women Well defined precursor lesion (adenoma) with long lag time until the development of cancer Reasonable target for screening

3. USPSTF CRC Screening Recommendations Colonoscopy q10 yr Flex Sig q5 yr Fecal Testing q1 yr Flex Sig q5 yr and FOBT q1 yr ACBE/CT colography q5 yr

4. Colonoscopy of Asymptomatic Patients 37.7% have colorectal neoplasia: 27% TA <10 mm 5% TA >10 mm 3% Villous adenoma 1.7% High grade dysplasia/CIS 1.0% Invasive cancer

5. Screening Sigmoidoscopy Will detect 70% of patients with colonic neoplasia Distal adenomas on sig prompt colonoscopy 30% of patients (with only right sided neoplasia) will be missed Will reduce cancer from 6% to 2% in the population

6. Colon Cancer Risk Reduction Colonoscopy:6% to <0.5% Flex Sig:6% to 2.0% Fecal Occult blood?

7. HemoccultTesting Minnesota, 1994 NEJM: 33% improved cancer survival UK, 1997 NEJM: 15% improved cancer survival Denmark, 1997 NEJM: 18% improved cancer survival

8. Theoretical test 99.5% sensitive and specific 1000 pts from high risk (50%) population: –500 true pos, 5 false pos –Predictive value 500/505 1000 pts from low risk (0.5%) population: –5 true pos, 5 false pos –Predictive value 5/10

9. Similar test, 90% sensitive and specific 1000 pts from high risk population: –500 true pos, 100 false pos –Predictive value 500/600 = 83% 1000 low risk patients: –5 true pos, 100 false pos –Predictive value 5/105 = 4%

10. Performance characteristics of FOBT? Noncolonoscopically controlled trial in patients with advanced neoplasia: –Up to 79.4% sensitive with select tests (NEJM. 334:155.1996) Noncolonoscopically controlled trial in largely symptomatic cancer pts: –66% sensitivity (Ann Int Med.112:328.1990)

11. FOBT 66-79% Sensitive? Trials did not focus on asymptomatic patients? (not average risk) Not colonoscopically controlled (Only FOBT+ patients were colonoscoped) “Those with great enthusiasm have no controls and those with great controls have no enthusiasm”

12. Colonoscopically Controlled Trials of Hemoccult II –Imperiale, et al, NEJM. 351:2704. 2004 -Lieberman. NEJM. 345:555. 2002 ImperialeN = 2507Std HC-IILiebermanN = 2885Rehyd HC-II Patient groupFOBT+FOBT-% PositiveFOBT+FOBT-% Positive Total patients14423615.8%23926468.6% No neoplasia8217024.6%9815595.9% Adenoma <10 mm152715.2%688177.7% Advanced adenoma4336010.7%6125823.4% Cancer42712.9%12 50%

13. Fecal blood testing (Hemoccult II) Essentially random test that is positive leads to colonoscopy 6% of the time Over 10 yr, [1- (0.94) 10 ] = (1 - 0.53) = 47% of patients eventually will be FOBT+ and receive colonoscopy 2.5% of SFVA patients aged 50-75 every year get a symptom generated colonoscopy (25% over 10 yrs) Total colonoscopies over 10 yr period is approx 71% in FOBT screening programs

14. Screening Resources per 10,000 Patients/10 yr CF Program (20% refuse screening): –8,000 (80%) total naïve colonoscopies (screening and symptom generated) Annual FOBT 6% positive rate: –76,896 x 3 = 230,688 FOBT tests –4,620 colonoscopies for +FOBT over 10 yr –2500 symptom generated colonoscopies (screened nonetheless) over 10 yr –7120 (71%) total naïve colonoscopies

15. Is Hemoccult II useful in conjunction with Flex sig? Flex Sig alone: –70.3% of pts with neoplasia detected Flex Sig plus one time FOBT: –75.8% of pts with neoplasia detected –5.0% more colonoscopies needed to detect the additional 5.5% of patients (Lieberman, NEJM 2002)

18. All Studies

19. Studies with: Colonoscopic controls Asymptomatic screening age patients

20. Varying the FIT Cutoff Alters Cancer Specificity StudyLevi (2007) N 1204Park (2010) N 770DeWijk (2012) N 1256 Cutoff% PosAdv AdCancer% PosAdv AdCancer% PosAdv AdCancer 5017%NR72%14.2%44.1%12/13 (92.3%)10%35.4%7/8 (88%) 7512.5%NR67%12.3%37.3%12/13 (92.3%)6.6%31%6/8 (75%) 10011.6%NR61%11.3%33.9%12/13 (92.3%)5.6%29.2%6/8 (75%) 1259.8%NR53%10%28.8%11/13 (84.6%) 1509.4%NR53%7.9%27.1%11/13 (84.6%)

21. Only: Colonoscopic controls Asymptomatic screening age patients FIT positive <10%

22. Hi Quality FIT Studies StudyN% PositiveSens AASens CRC Levi (2007)10009.4%NR53% Morikawa (2005)21,8055.6%27.1%65.8% Chiu (2013)18,2967.3%28%78.6% Brenner (2013)22355.0%23.4%60.0% Brenner (2013)22355.0%20.4%53.3% Brenner (2013)22355.0%25.7%73.3%

23. Colonoscopy Nearly 100% sensitive for the detection of cancer, 91% for polyps National Colon Polyp Study predicts that colonoscopy will diminish colon cancer risk from 6% to <0.5% and will prevent death from colon cancer

24. Cost per year of life saved Flex Sig every 5 yr$23K Flex Sig plus annual FOBT$80K FOBT annually$80-220K Colonoscopy every 10 years$5.6K Dialysis$55K Mammography$80-140K? Pap Smears$70-120K Air bags$450K

25. SF-VAMC GI Unit 44,000 screening age pts 1994: Commitment to CF strategy 1996: Only 57 screening colonoscopies 1998: Direct screening and scheduling by GI nurses 1999: Telephone scheduling by GI nurses 1999: Elimination of routine clinic visits for path FU 1997-2003: Marked increase in exams for even minimal chronic symptoms (de facto screening) 2002-2005: Steady state reached at 76-79% with CRC screening from reminder data

26. CRC at the SF-VAMC 1995-2000: 486 (81 cases/year) 2001:52 cases 2002: 26 cases 2003:16 cases 2004:11 cases 2005:13 cases Total118 cases

27. SF VAMC CRC 2001-2005 118 cases, 108 of whom were from our minority (21%) unscreened population 10 cases occurred in our previously screened (79%) surveillance population –7 had villous elements in index polyps –3 had delayed colonoscopic surveillance

28. Conclusions Endoscopic screening methods (Colon and Flex Sig) are acceptable methods for CRC prevention Fecal testing is beneficial in that it prompts a screening colonoscopy Fecal testing does not reduce colonoscopy demands and Hemoccult-II misses >87% of colon cancers in screening patients Practitioners who use Fecal testing as primary screening have been successfully sued for missed cancers The majority of positive fecal tests do not have advanced neoplasia (false positive)

29. Special Consult Considerations Request for colonoscopy in patient with FOBT+ despite negative screening colon 2 yr ago. No anemia or symptom.

30. If the majority of positive FOBT+ are false positive, nearly all positive FOBT in those with up to date colonoscopy are false positive Recommendation: “Please discontinue Fecal testing” Special Consult Considerations

31. Request for colonoscopy in patient with negative screening colon 2 yr ago because his spouse was dx’ed with CRC and he is “worried” about cancer. No anemia or symptoms.

32. Special Consult Considerations Request for colonoscopy in patient with negative screening colon 2 yr ago because his spouse was dx’ed with CRC and he is “worried” about cancer. No anemia or symptoms. Recommendation: Please tell this patient not to worry anymore. A complication from an unindicated colonoscopy is very difficult to defend!

33. Special Consult Considerations Request for colonoscopy due to new onset constipation or a solitary episode of hematochezia. Patient with screening colon 2 yr ago showing no neoplasia. No anemia or other symptoms.

34. Special Consult Considerations Request for colonoscopy due to new onset constipation or a solitary episode of hematochezia. Patient with screening colon 2 yr ago showing no neoplasia. No anemia or other symptoms. Most CRC sx manifest in the distal colon. Recommend examine distal colon with Flex Sig

35. Special Consult Considerations Request for colonoscopy due to new onset recurrent hematochezia over 2 months. Patient with screening colon 2 yr ago showing no neoplasia. Hct 36 no other symptoms. Recommendation: Repeat colonoscopy to look for missed lesions

36. Acknowledgements Ann Hayes, R.N. and Ken McQuaid, M.D. The nurses of the San Francisco VA GIDC