1. Controversies Regarding Cancer Surveillance in IBD Stephen B. Hanauer, MD Professor of Medicine & Clinical Pharmacology Chief, Section of Gastroenterology & Nutrition University Of Chicago

2. Susceptibility to colorectal cancer (CRC) 1 American Society of Clinical Oncology 1999; 2 Choi 1994; 3 Gyde 1982 1 1 1 1 1 2, 3

3. Cumulative risk of developing CRC in UC 0 5 10 15 20 25 051015202530 Time from diagnosis (years) Lower CL Cumulative risk of CRC 1 Upper CL Copenhagen 1962–1997 2 1 Eaden 2001; 2 Winther 2001 Cumulative probability (%) CRC slide kit, Munkholm et al 2002

4. Sporadic Colon Cancer vs. Colitis- associated Colon Cancer Sporadic Arises from protruding adenomatous polyp Only 3-5% experience multiple synchronous colon cancers Mean age-60’s Left sided predominance Colitis Arises from flat dysplasia or a DALM Approximately 12% experience multiple synchronous colon cancers Mean age-30 to 40’s More uniformly throughout the colon

5. Colorectal Cancer (CRC) and Ulcerative Colitis Cumulative Risk of CRC –2% at 10 years of disease –8% at 20 years of disease –18% at 30 years of disease Overall prevalence of CRC in UC –All UC patients - 3.7% –Pancolitis patients – 5.4%

6. Progression of IBD to cancer Normal epithelium Inflammation Polyp Dysplasia Sporadic CRC IBD Cancer Flat dysplastic tissue Indefinite  LGD  HGD

7. Progression of Dysplasia Mayo Clinic 18 pts with UC and Flat LGD followed 32mos 9/18 Progressed Cumulative incidence of progression 33% at 5 years 14 Colectomies –1 Adenoca at 74 months Ullman et al AJG 97;922:02

8. Progression of Dysplasia Mt. Sinai Hospital 46 Pts with Flat LGD followed  7 Cases CRC (5 >Stage II) 4/17 Colectomies with Advanced CA Actuarial Progression 53% at 5 years –2 Despite Surveillance Compliance Ullman et al Gastroenterol 125:1311:03

9. Risk Factors

10. Risk Factors in the Development of CRC in UC Risk FactorImportance Extent of disease++++ Duration of disease++++ Presence of PSC+++ Young age at onset++ Positive family history+ Severity of inflammation* +++

11. Severity of Inflammation & Risk of Neoplasia in UC 68 Cases matched with 136 Controls 7/88-1/02 –sex, extent, age at onset, duration of colitis, and year of index surveillance colonoscopy –Segmental colonoscopic and histological inflammation scored (0-4, normal-severe) –Significant correlation between Colonoscopic inflammation (odds ratio, 2.5; P = 0.001) Histological inflammation (odds ratio, 5.1; P < 0.001) Risk of colorectal neoplasia. Multivariate analysis, only histological inflammation score remained significant (odds ratio, 4.7; P < 0.001). Rutter et al Gastroenterol 126;141:04

12. CRC Prevention

13. 23d Preventing CRC Surveillance Surgery –Polypectomy –Colectomy Chemoprevention Sporadic Colon Cancer Colitis-associated Colon Cancer Aspirin NSAIDS Calcium/Vitamin D Folic acid Ursodeoxycholic acid 5-ASA Azathioprine

14. Conventional Surveillance Recommendations Colonoscopy –Extensive Disease - Start 8 - 10 years after disease onset –Left-sided disease - Start 15 - 20 years after disease onset –Repeat every 1-3 years Biopsies –Four every 10 cms from cecum to rectum –Additional samples of the rectosigmoid? Confirmed Dysplasia –Colectomy recommended

15. Surveillance May Decrease the Risk or Mortality of Colon Cancer Results from a US 18 year surveillance program Detection at an early stage: –Cancer found early in 80% (15/19) receiving surveillance –Cancer found early in only 41% (9/22) of those not receiving surveillance 5-year survival rate –77% for the surveillance group –36% for the non-surveillance group (p<0.03) Choi PM, et al. Gastroenterol 1993; 105: 418-24.

16. Limitations of Surveillance Dysplasia may be missed when obtaining biopsies Intra- and inter-observer variation in interpretation of dysplasia Patient Compliance High Cost to Benefit Ratio Eaden, JA and Mayberry JF. Am J Gastroenterol 2000; 95(10): 2710-19.

17. Cancer Screening In IBD WHO TO SCREEN?

18. Who With UC Should Be Screened? Extensive colitis –>10 years duration –Distal colitis? Patients with PSC –Pericholangitis?

19. Who With Crohn’s Should Be Screened? Colitis >10 years duration PSC Strictures?

20. What if You Identify Dysplasia in Crohn’s? Colectomy ? Segmental resection ? Mucosal mapping ?

21. Cancer Screening in IBD WHEN TO SCREEN?

22. Cost-effectiveness of Screening Screening intervals depend upon risk

23. Controversies Regarding Risk Definition of disease onset –Symptoms vs diagnosis Definition of disease extent –For example, isolated cecal inflammation *Definition of Disease Activity? Onset of colitis in PSC

24. Practical Applications for Surveillance Screen more often when risk is higher First decade - Ineffective Second decade - Every 2-3 years Third decade -Yearly

25. Cancer Screening In IBD HOW TO SCREEN?

26. Controversies in Screening Procedure Where to biopsy How many biopsies Definition of dysplasia Confirmation of dysplasia What to do about polyps

27. Where to Biopsy Biopsy Entire Colon Sigmoidoscopy is not enough –Sensitivity of rectosigmoid dysplasia for proximal lesions, ~42% –Less for rectal dysplasia

28. How Many Biopsies? Seattle Estimates: 64 biopsies for 95% probability of finding highest grade of dysplasia 18 biopsies for 95% probability of finding cancer or dysplasia if truly present Rubin et al. Gastro.1992;103:1611.

29. How Many Biopsies? Chicago Data: –Biopsies at 10 cm intervals throughout colon –Additional biopsies of nodular or polypoid mucosa –Findings at colonoscopy preceding colectomy

30. What To Do About Polyps Age of patient Location of polyp Type of polyp Surrounding mucosa

31. Polyps Under Age 40 Sessile Pedunculated In Colitis Proximal Colectomy Survey Around Lesion Dysplasia No Dysplasia Colectomy Follow (?) Survey Around Lesion Dysplasia No Dysplasia ColectomyFollow (?)

32. Polyps Over Age 50 Small Sessile Pedunculated In Colitis Proximal PolypectomySurvey Around Polyp Dysplasia No Dysplasia Colectomy Survey Around Polyp Dysplasia Colectomy Polypectomy No Dysplasia Follow (?) Polypectomy

33. Confirmation of Dysplasia Interobserver Agreement 45-77% In practice only 43% of doctors request second pathologic opinions* *Bernstein et al. Am J Gastro. 1995;90:2106.

34. Chemoprevention

35. Chemoprevention of CRC – drug therapy Salicylates – aspirin 1,2 NSAIDs - Sulindac etc 4 Drug therapy5-ASA – mesalamine 3 CRC Adenomas CRC Adenomas Cell proliferation Apoptosis CRC Adenomas 1 Thun 1991; 2 Kune 1988; 3 Allgayer 2002; 4 Giardiello 1993; 5 Reddy 2000 5 5 5

36. Evidence for 5-ASA chemoprevention Case-control studies 1-3 In-vitro studies Animal studies Epidemiological studies Expert opinions 1 Eaden 2000; 2 Pinczowski 1994; 3 Moody 1996

37. 5-ASA Mechanism of Action in CRC Prevention Precise mechanism unknown Proposed mechanisms –Increased apoptosis –Decreased cell proliferation –Inhibition of production of oxidative radicals, prostaglandins, and leukotrienes –Improvement in DNA repair Bus PJ, et al. Aliment Pharmacol Ther 1999;13:1397-1402.

38. Risk reduction in the prevention of adenomas, dysplasia and cancer in general and in IBD Prevention/ reduction of 5-ASANSAID ASA (%) Folic acid (%) Ursodiol (%) Calcium (%) Oestrogen (%) EGF + NSAID (%) General population Adenomas/ dysplasia Ongoing 1 12–56 2 15–29 3 -44 4 26 5 87 6 (Mouse) Cancer-60 7 75 8 -29–35 9 96 6 (Mouse) IBD Adenomas/ dysplasia --55–68 10 85 11 --- Cancer81 12 16 13 28 10 ---- 1 Salofalk German National Trial; 2 Giovannucci 1994; 3 Giovannucci 1993; 4 Bonithon-Kopp 2000; 5 Calle 1995; 6 Torrance 2000; 7 Thun 1991; 8 Giovannucci 1998; 9 Grodstein 1998; 10 Lashner 1997; 11 Tung 2001; 12 Eaden 2000 EGF; epidermal growth factor

39. Treatment 10 yrs post dx 20 yrs post dx30 yrs post d Cumulative incidence rates of CRC in UC: With 5-ASA (70%)0.4%1.5%3.4% Without 5-ASA2%8%18% Relative risk reduction 80%81% Absolute risk1.6%6.5%14.6% NNT to avoid one case of CRC 100 / 1.6 = 62.5100 / 6.5 = 15.3100 / 14.6 = 7 Number needed to treat modified after Eaden et al. Estimated rate of CRC in the Danish cohort Risk of development of CRC in a meta-analysis of 116 studies of ulcerative colitis patients

40. Correlation Between Aminosalicylate Use and the Incidence of Colorectal Cancer PharmacotherapyDoseOdds ratio 95% CIP-value 5-ASAAll doses0.250.13-0.48 < 0.00001 Mesalazine< 1.2 g / d0.080.08-0.850.04 Mesalazine> 1.2 g / d0.090.03-0.28 < 0.00001 Sulfasalazine< 2 g / d0.560.17-1.840.34 Sulfasalazine> 2 g / day0.410.18-0.920.03 olsalazine / balsalazide0.400.04-3.580.41 Eaden et al.

41. Preventing CRC – 5ASA StudyDrug% Risk Reduction Pinczowskisulphasalazine62 EadenVarious 5-ASAs53 EadenMesalazine (  1.2 g/day) 81 RubinVarious 5-ASAs72

42. Effect of folic acid supplementation on the relative risk (RR) for CRC or dysplasia in UC 1 1 Lashner 1997 Relative risk ( CL 0.28-2.02) (CL 0.16-1.77) (CL 0.05-3.80) P = NS

43. Study design 59 IBD patients with primary sclerosing cholangitis Patients undergoing colonoscopic surveillance for dysplasia Outcome Ursodiol protects against CRC in UC (OR 0.18; 95% CL 0.05–0.61, P = 0.005) Ursodeoxycholic acid therapy and CRC chemoprevention in IBD Tung 2001

44. Conclusions Surveillance is best tool to date Apply risk to individual patient –Severity, Extent, Duration, Age at Onset, Family History, PSC Biopsy According to Mucosa at Risk –Chromoendoscopy –Additional Fecal/Biomarkers Evidence Favors 5-ASA Maintenance Urso in PSC Folic Acid?