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

Primary Vs. Secondary Prevention

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

FOBT

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%

Screening for CRC - FOBT Israel Average Risk Population Series A n C(%) P(%) NL Slater 85 mail, FP % Bat 86 FP % Rozen 87 volunteers % 92 volunteers % Eliakim 88 mail % Krieger 92 FP % Niv 92 FP % Total % A=approach C=compliance P=positive NL=neoplastic lesion

Survival Curve Screening of Colorectal Cancer Percentage of the Population

Sigmoidoscopy

Screening Sigmoidoscopy Reduced Rectal Cancer Mortality Direct evidence from 3 case control studies: l Selby, NEJM 1992;326: % l Newcomb, JNCI 1992;84: % l Muller, Arch Intern Med 1995;155: % 10 years protection

Screening FS in Israel (decrease in incidence , 16 to 10/100000) Neoplastic lesion Compliance (%) nyearSeries 28 (4.7%) Kiriat Uno (Bat) 45 (3.8%) Tel Aviv (Rozen) 42 (7.9%) Beer Sheva (Niv) 24 (5.7%) Dimona (Niv & Fraser) 8 (1.8%) Shouval & Nirim (Fraser & Niv) 8 (4.0%) Hagoshrim (Niv) 4 (4.0%) Chazor (Ilani, Pade & Niv) 16(13.5%) Beilinson (Niv) 175 (4.9%) Total

Screening for CRC - Comparison of FS and FOBT, Israel , Average Risk Population (FOBT 7,FS 5 papers) Method N Compliance Adenoma CRC % n % n % FOBT < Sigmo Total S/F 1/10 x 10 x 4

Colonoscopy

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)

National polyp study 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

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:

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%

Screening CRC - Distribution McCallion, Distribution of CRC in Northern Ireland: A 10% proximal shift, and 10% decrease in FS diagnostic yield ( ) FS 72% 62%

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%

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

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)

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%

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)

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

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

Simulation Model - Winawer Population of 100, 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%)

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)

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%

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)

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

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

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

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

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

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

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