Controversies Regarding Cancer Surveillance in IBD

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 1 1 1 1 2, 3 1American Society of Clinical Oncology 1999; 2Choi 1994; 3Gyde 1982

3. 25 20 15 Lower CL Cumulative risk of CRC1 10 Upper CL Copenhagen 1962–19972 5 0 0 5 10 15 20 25 30 Time from diagnosis (years) Cumulative risk of developing CRC in UC Cumulative probability (%) CRC slide kit, Munkholm et al 2002 1Eaden 2001; 2Winther 2001

4. 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 Sporadic Colon Cancer vs. Colitis-associated Colon Cancer

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 IBD Flat dysplastic tissue Inflammation IndefiniteLGDHGD Cancer Normal epithelium Polyp Dysplasia Sporadic CRC

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

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. Preventing CRC • Surveillance • Surgery • Polypectomy • Colectomy • Chemoprevention 23d

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 Pedunculated Sessile Proximal Survey Around Lesion In Colitis Survey Around Lesion Dysplasia Colectomy No Dysplasia No Dysplasia Dysplasia Follow (?) Colectomy Colectomy Follow (?)

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

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 5 CRC Adenomas Salicylates – aspirin1,2 5 CRC Adenomas Cell proliferation Apoptosis Drug therapy 5-ASA – mesalamine3 NSAIDs - Sulindac etc4 5 CRC Adenomas 1Thun 1991; 2Kune 1988; 3Allgayer 2002; 4Giardiello 1993; 5Reddy 2000

36. Evidence for 5-ASA chemoprevention • Case-control studies1-3 • In-vitrostudies • Animal studies • Epidemiological studies • Expert opinions 1Eaden 2000; 2Pinczowski 1994; 3Moody 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 EGF; epidermal growth factor 1Salofalk German National Trial; 2Giovannucci 1994; 3Giovannucci 1993; 4Bonithon-Kopp 2000; 5Calle 1995; 6Torrance 2000; 7Thun 1991; 8Giovannucci 1998; 9Grodstein 1998; 10Lashner 1997; 11Tung 2001;12 Eaden 2000

39. Treatment 10 yrs post dx 20 yrs post dx 30 yrs post d Cumulative incidence rates of CRC in UC:   With 5-ASA (70%) 0.4% 1.5% 3.4% Without 5-ASA 2% 8% 18% Relative risk reduction 80% 81% 81% Absolute risk 1.6% 6.5% 14.6% NNT to avoid one case of CRC 100 / 1.6 = 62.5 100 / 6.5 = 15.3 100 / 14.6 = 7 Risk of development of CRC in a meta-analysis of 116 studies of ulcerative colitis patients Number needed to treat modified after Eaden et al. Estimated rate of CRC in the Danish cohort

40. Pharmacotherapy Dose Odds ratio 95% CI P-value 5-ASA All doses 0.25 0.13-0.48 < 0.00001 Mesalazine < 1.2 g / d 0.08 0.08-0.85 0.04 Mesalazine > 1.2 g / d 0.09 0.03-0.28 < 0.00001 Sulfasalazine < 2 g / d 0.56 0.17-1.84 0.34 Sulfasalazine > 2 g / day 0.41 0.18-0.92 0.03 olsalazine/ balsalazide 0.40 0.04-3.58 0.41 Correlation Between Aminosalicylate Use and the Incidence of Colorectal Cancer Eaden et al.

41. Preventing CRC – 5ASA

42. Effect of folic acid supplementation on the relative risk (RR) for CRC or dysplasia in UC1 (CL 0.28-2.02) (CL 0.16-1.77) (CL 0.05-3.80) Relative risk P = NS 1Lashner 1997

43. Ursodeoxycholic acid therapy and CRC chemoprevention in IBD • 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) 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?