1. Screening and chemoprevention of CRC Yaron Niv, M.D. Rabin Medical Center Tel-Aviv University

2. Primary Vs. Secondary Prevention

3. Colorectal Cancer Screening Guide-lines For those at average risk (choosing from the following): l Annual FOBT l A sigmoidoscopy every 5 years l A combination of FOBT and sigmoidoscopy l A colonoscopy every 10 years or once in a life-time For those at increased risk: a colonoscopy

4. FOBT

5. Published FOBT Prospective, Randomized, Controlled Studies Series Minnesota Funen Nottingham Gothenburg Biennial Annual Biennial Biennial 2 screens Period 13 y 13 y 10 y 8 y 8y Colono 28% 38% 4% 4% 7% Mortality reduction 21% 33% 18% 15% 12%

6. Screening for CRC - FOBT Israel 1985-1998 Average Risk Population Series A n C(%) P(%) NL Slater 85 mail, FP 3233 17-42 4.6 9 0.28% Bat 86 FP 1339 46 2.3 4 0.30% Rozen 87 volunteers 1176 100 3.6 10 4.19% 92 volunteers 2868 100 4.0 69 2.41% Eliakim 88 mail 20251 35 2.0 50 0.25% Krieger 92 FP 1057 100 1.9 0 0.00% Niv 92 FP 2590 71 4.0 34 1.32% Total 32514 46 2.9 176 0.54% A=approach C=compliance P=positive NL=neoplastic lesion

7. Survival Curve Screening of Colorectal Cancer Percentage of the Population

8. Sigmoidoscopy

9. Screening Sigmoidoscopy Reduced Rectal Cancer Mortality Direct evidence from 3 case control studies: l Selby, NEJM 1992;326:653 - 59% l Newcomb, JNCI 1992;84:1572 - 80% l Muller, Arch Intern Med 1995;155:1741 - 60% 10 years protection

10. Screening FS in Israel (decrease in incidence 1982-1998, 16 to 10/100000) Neoplastic lesion Compliance (%) nyearSeries 28 (4.7%)48 6001986Kiriat Uno (Bat) 45 (3.8%)10011761987Tel Aviv (Rozen) 42 (7.9%)14 5291992Beer Sheva (Niv) 24 (5.7%)95 4201996Dimona (Niv & Fraser) 8 (1.8%)51 4461996Shouval & Nirim (Fraser & Niv) 8 (4.0%)50 2001998Hagoshrim (Niv) 4 (4.0%)10 1001999Chazor (Ilani, Pade & Niv) 16(13.5%)10 1182000Beilinson (Niv) 175 (4.9%)473589 Total

11. Screening for CRC - Comparison of FS and FOBT, Israel 1982-1998, Average Risk Population (FOBT 7,FS 5 papers) Method N Compliance Adenoma CRC % n % n % FOBT 32514 <46 141 0.44 40 0.12 Sigmo 3171 47 132 4.16 15 0.47 Total 35685 273 0.77 55 0.15 --------------------------------------------------------------- S/F 1/10 x 10 x 4

12. Colonoscopy

13. Screening Colonoscopy in the Average Risk Population l Visualization of the entire colon, biopsy and removal of all polyps l Proximal distribution of colonic neoplasm l Positive FOBT or sigmoidoscopy lead to total colonoscopy l FOBT alone may prevent fewer cancer deaths than colonoscopy l Effectiveness: 80% compliance by FOBT = 50% to colonoscopy l Once in a lifetime colonoscopy may be preferred (cost < $750)

14. National polyp study 1978-1993 l A cohort of >1400 patients who had undergone colonoscopy and removal of adenomas was followed by colonoscopy for a mean of 5.9 years. l 70%-90% reduction was found in the incidence of colorectal cancers relative to what was expected based on 3 different historical control groups. Winawer, N Engl J Med 1993;329:1977

15. Preventive Effect of Colonoscopy 5-year incidence of adenomas after negative colonoscopy in asymptomatic average- risk persons 154 repeated colonoscopies (median 66m), 41 (27%) patients with adenoma, only one > 1 cm, no cancer! Rex, Gastroenterology 1996; 111:1178-81

16. Screening Colonoscopy in the Average Risk Population l Visualization of the entire colon, removal of all polyps l Rising proximal distribution of colonic neoplasm l Positive FOBT or sigmoidoscopy lead to total colonoscopy l FOBT alone may prevent fewer cancer deaths than colonoscopy l Effectiveness: 80% compliance by FOBT = 50% to colonoscopy l Once in a lifetime colonoscopy may be preferred (cost < $750) 50% 70%

17. Screening CRC - Distribution McCallion, Distribution of CRC in Northern Ireland: A 10% proximal shift, and 10% decrease in FS diagnostic yield (1976-1994). 76-78 90-94 FS 72% 62%

18. A distal significant polyp may predict a proximal lesion Advanced Proximal Neoplasm (APN) (size, histology, no.) Source distal APN l NEJM 92, GE 94 TA<1cm 0.8% TA>1cm 11.8% l NEJM 97 TA<1cm 16.0% TA>1cm 29.0% l Ann Int Med 98 TA<1cm 5.4% TA>1cm 7.9% l JAMA 99 Tubular 4.8% Villous 11.7%

19. Factors associated with an increased risk of APN Levin, JAMA 1999;281:1611 Lieberman, N Engl J Med 2000;343:162 Imperiale, N Engl J Med 2000;343:169 l Age > 65 years l Villous histology in distal adenoma l Distal adenoma > 1cm l Multiple distal adenomas l Positive family history of CRC

20. Screening Colonoscopy in the Average Risk Population l Visualization of the entire colon, removal of all polyps l Proximal distribution of colonic neoplasm l Positive FOBT or sigmoidoscopy lead to total colonoscopy l FOBT alone may prevent fewer cancer deaths than colonoscopy l Effectiveness: 80% compliance by FOBT = 50% to colonoscopy l Once in a lifetime colonoscopy may be preferred (cost < $750)

21. Published FOBT Prospective, Randomized, Controlled Studies Series Minnesota Funen Nottingham Gothenburg Biennial Annual Biennial Biennial 2 screens Period 13 y 13 y 10 y 8 y 8y Colono 28% 38% 4% 4% 7% Mortality reduction 21% 33% 18% 15% 12%

22. Screening Colonoscopy in the Average Risk Population l Visualization of the entire colon, removal of all polyps l Proximal distribution of colonic neoplasms l Positive FOBT or sigmoidoscopy lead to total colonoscopy l FOBT alone may prevent fewer cancer deaths than colonoscopy l Effectiveness: 80% compliance by FOBT = 50% to colonoscopy l Once in a lifetime colonoscopy may be preferred (cost < $750)

23. Positivity Rates of FOBT (%) St John, DDW, 1998; Rozen, Dig Dis Sci 1997.

24. FOBT - The Importance of Proper Evaluation Niv Y, JCG 1990;12:393 Kibbutz A Kibbutz B P l Population 700 750 l > 40 y 223 173 l FOBT + 33(25%) 8( 6%) <0.01 l Adenomas>1cm 2( 6%) 2(25%) <0.05

25. Simulation Model - Winawer Population of 100,000 - 4988 CRC cases, 2391 deaths expected Cases Deaths Complication reduction reduction deaths Annual FOBT 2378(48%) 1330(56%) 52 Colonoscopy every 10 y 3570(72%) 1763(74%) 73 433 21

26. Screening Colonoscopy in the Average Risk Population l Visualization of the entire colon, removal of all polyps l Proximal distribution of colonic neoplasms l Positive FOBT or sigmoidoscopy lead to total colonoscopy l FOBT alone may prevent fewer cancer deaths than colonoscopy l Compliance has a direct effect on detection rate l Once in a lifetime colonoscopy may be preferred (cost < $750)

27. Compliance is the single most important determinant of effectiveness Lieberman, Gastroenterology 1995;109:1781. For the same decrease in mortality: FOBT 80% = = FOBT + FlEX. SIG. 60% = = COLONOSCOPY 50%

28. Screening Colonoscopy in the Average Risk Population l Visualization of the entire colon, removal of all polyps l Proximal distribution of colonic neoplasms l Positive FOBT or sigmoidoscopy lead to total colonoscopy l FOBT alone may prevent fewer cancer deaths than colonoscopy l Compliance has a direct effect on detection rate l Once in a lifetime colonoscopy may be preferred (cost < $750)

29. Cost-effectiveness Model for Colon Cancer Screening – Markov model – Amnon Sonnenberg (Sheba 2002) ($ per year of life saved) FOBT every year, Sigmo every 5 years, Colono once in a lifetime

30. Inappropriate CRC screening Fisher, AJGE 2005;100:2526 (North Carolina) l 500 consecutive primary care patients for whom FOBT had been ordered l 35% - inappropriate (at least one reason) l 18% - severe co morbid illness 13% - GI bleeding 7% - history of CRC or IBD 5% - had undergone colonoscopy within prior 5 years 3% - younger than 50 yr

31. Primary prevention l תזונה דלת שומן ועשירה בפירות, ירקות וסיבים l משקל תקין l המנעות מעישון ואלכוהול l תוספת סידן 1500 מג ' ליום l עדויות בלתי ישירות : אספירין, NSAIDs, סלניום, חומצה פולית, ויטמין D

32. Proliferation, Differentiation, Apoptosis l High fat diet – soluble fatty acids, bile acids – colonic epithelium cell damage – proliferation l Calcium precipitate fatty and bile acids l Calcium decreases cell proliferation and induces differentiation

33. Chemoprevention – prevention studies l Intermediate biomarkers – 1. Early – change in proliferation – number of crypt-proliferating cells and an upward shift of the proliferative zone 2. Late - recurrence of adenomatous polyps after polypectomy

34. Effect of a diet high in diary foods upon proliferation (early marker) Holt, JAMA 1998;280:1074 l 70 post polypectomy patients l Group A – diet containing 1200mg Ca/day, Group B – baseline diet Rectal biopsy – 0,6,12 months – [ 3 H]thymidine incorporation into DNA, differentiation markers l Significant lower proliferation, higher differentiation

35. Effect of calcium supplements on recurrence of adenomas (late marker) Baron, Ann NY Acad Sci 1999;889:138 l 930 post-polypectomy patients l Group A – 1200mg Ca/day, Group B – placebo l Colonoscopy – 1y, 2y l 19% decrease in recurrent adenoma, 24% decrease in the average number