There are conflicting data on the efficacy of colonoscopy in reducing colorectal cancer (CRC) incidence and mortality. Several large multi-center studies found colonoscopy reduced CRC by 50-76%, though some studies found lower or no reductions. The quality of colonoscopy performance varies significantly between providers and may impact outcomes. Compliance with colonoscopy screening in the general population also remains low.

1. There are conflicting data about the efficacy of colonoscopy… M.CRESPI,D.LISI

3. CRC after negative Colonoscopy in Canada f.u. of 45,985 subj (18,606 M – 27,379 F) for 229,090 pt/year Distal CRC Proximal CRC All CRC 0.71 239 170 F 0.59 220 130 M 0.44 118 52 F 0.44 136 60 M 0.99 107 106 F 0.88 74 65 M SIR Expected Observed

4. CRC risk despite surveillance CS in the Polyp Prevention Trial (PPT) >10y follow-up, >than 3 CS after index polypectomy Leung K GIE 2010 Only 36 % reduction in CRC incidence Advanced Adenoma at baseline CS is a strong risk predictor

5. Risk of CRC after negative colonoscopy Geul K et al, 2007 About 80% subjects with CRC between 50 – 58y have already one adenoma at 50y QUALITY of OC !? Fast-growing lesions !? 0.80 0.67 Right colon Singh 2009 0.16 0.55 Left colon Overall Ransohoff 2009 0.12 – 0.33 RR

6. Retrospective population based study on Colonoscopy and death from CRC Case/control study: 10,292 cases , 51,460 controls Baxter NN 2009 Complete colonoscopy OR left CRC 0.33 OR right CRC 0.99 Any advantage of CS over FS ? Are we talking about two Colons or two Cancers ??? Only a quality problem ?

8. Risk of CRC and AA more than 10 y from a negative index colonoscopy German Colonoscopy Screening Program 2003 - 2010 Brenner H 2010 Are German endoscopists better ?!? Right Left Total 0.42 - 0.28 - 59.4 8.4 Expected - 0 CRC 25 Observed 0.82 AA Standardized Prevalence Ratio

9. Results of a large ecological study on colonoscopy coverage and CRC mortality / incidence in Ontario Rabeneck L AJG 2010 2,412,077 subj. (mean age 64y, female 53%) 14y follow-up (1993 – 2006) CRC Incidence 62,819 cases (2.6 %) Mortality 23,743 deaths (0.9 %) Result: for every 1% increase in Colonoscopy rate, 3% decrease in CRC mortality

10. Differences in protection against right/left sided CRC after a negative index CS ? Quality of CS (gastroent. Vs non-gastroent.?) Flat non polypoid lesions (more in right colon ?) Biology of proximal lesion (MSI and CIMP status ?) Why women worst ? (RR 0.99 vs 0.89 men)

12. Missed flat and depressed lesions Missed lesions on repeat colonoscopy Polypoid lesions 1.2% Flat lesions 16.7% Depressed lesions 13.6% Satosh et al. J Gastroenterol 2006

13. Pitfalls of standard colonoscopy

15. Submucosal invasion in cancerous colonic polyps Sbmucosal invasion - Submucosal invasion + 17% Flat depressed lesions Submucosal invasion - Submucosal invasion + Flat elevated lesions 0.8% Togashi et al; Annals of The Academy of Medicine of Singapore; 2003; (32 (2): 152-158

18. Cecal intubation in Europe Note: a correct index is adjusted completion rate , excluding poor preparation or diseases 81.0 5145 60 Sweden 89.0 (69 – 98) 6004 21 centers in 10 EU countries EPAGE 76.9 9223 68 UK 82.6 12706 25 Italy, Lombardia 69.6 1245 33 Portugal Rate CS Num. Centers Country

19. Quality programs Colonoscopy practice in Italy Survey in 278 Endoscopy Units Data on 12,835 Colonoscopies Cecal intubation 82.6 %; Sedation (over 90 % only in 22% of centers) Serious complications 0.5 % Perforation 0.02% Bleeding 0.2 % Cardiopulm. 0.25% Polyp detection rate 27.3 % (in screen CS 24.2%) Screening CS 13.7 % (in 2004 survey in 18 centers: 16.1 %) Yes 84.3 % No 76.2 % Minoli G. et al. for AIGO 2006 - personal comunication

20. Low public compliance to screening colonoscopy (from Jack Tippit, Saturday Evening Post)

21. Miss rate of right sided CRC by colonoscopy in Ontario in usual clinical practice (1997 – 2001) CRC patients database: 4920 subjects Missed cancers: 4% by colonoscopy performed between 6 – 36 months before CRC diagnosis. (Byrd RL 1989: missed lesions: 3% ) CRC cannot be completely eliminated even with very intensive screening Bressler B et al 2004