CRC and Dysplasia in IBD: Objectives of Talk. Colorectal Cancer and Dysplasia in IBD: A Case-Based Approach. Page 1

Transcription

1 Colorectal Cancer and in IBD: A Case-Based Approach Fernando Velayos MD MPH Associate Director of Translational Research University of California, San Francisco Center for Crohn s s and Colitis CRC and in IBD: Objectives of Talk 1. Describe the magnitude, cumulative risk, and risk factors for colorectal cancer in Crohn s s and ulcerative colitis Emphasis on endoscopic appearance and inflammation on the risk of CRC 2. Present 2 cases Review evidence for chemoprevention and surveillance colonoscopy Review recently published guidelines for the management of dysplasia Magnitude of the Problem 1. Approx. 1 million people with IBD (UC + Crohn s) in the USA. 2. CRC in IBD accounts for less than 1% of all CRC. But, for the patient with longstanding IBD, the fear of CRC is a concern. Cumulative Risk of CRC in Crohn sresults of meta-analysis CD: (solid black line with dark grey 95% confidence interval) UC: unstratified (black and white dot and dashed line with light grey 95% confidence interval) Cumulative risk in the general population (dashed line, no confidence interval). Site All CD Colon Ileum RR % CI Canavan C et. al.aliment Pharmacol Ther 2006: 23; 1097 Page 1

2 Cumulative Risk of CRC in UC % per year after 10 years of disease Risk Factors for CRC in Crohn s Disease Characteristic Colitis alone Prior colonic resection Prior surveillance Regular 5-ASA Smoking OR % CI Eaden et al. Gut 48:526, 2001 Siegel CA et. al Inflamm Bowel Dis 2006: 12; 491 Risk Factors for CRC in Ulcerative Colitis Duration of colitis Extent of colitis Primary sclerosing cholangitis Family history of CRC Endoscopic appearance Severity of inflammation at surveillance colonoscopy Are any of these modifiable? Endoscopic Appearance Predicts CRC Risk Case-control study- (Rutter et. al. Gastro 2004) 68 cases and 136 controls Matched for sex, age of onset, extent, duration, year of dx Multivariate analysis:» Post-inflammatory polyps: OR 2.3 ( )» Strictures: OR 4.6 ( )» Normal colonoscopy: OR 0.4 ( ) Case-control- Velayos et. al. Gastro cases and 188 controls Post-inflammatory pseudopolyps: OR 2.7 ( ) Page 2

3 Disease Severity at Surveillance Colonoscopy Predicts CRC Risk Study Rutter 2004 Ullman 2005 (ACG) Rubin 2006 (DDW) Population 68 Cases 138 Control Cohort 418 pts 56 Cases 90 Control Inflammation Measurement 0-4 scale Epithelial neutrophils (2.4 vs.. 2.1) 0-3 scale Active inflammation 6 pt inflammation scale (2.0 vs. 1.6) OR P= Rutter et al Gastr 2004; Ullman et al ACG 2005; Rubin D. et. al DDW 2006 # 12 CRC and in IBD: Goals of Talk 1. Describe the magnitude, cumulative risk, and risk factors for colorectal cancer in Crohn s s and ulcerative colitis Emphasis on endoscopic appearance and inflammation on the risk of CRC 2. Present 2 cases Review evidence for chemoprevention and surveillance colonoscopy Review recently published guidelines for the management of dysplasia Case Presentation # 1 28 year old man with a 10 year history of pancolonic ulcerative colitis Disease under relatively good control during this time 3 courses of prednisone Never hospitalized Currently : Balsalazide 750 mg tid; Azathioprine 125 mg qd Grandfather with unknown cancer; father with prostate cancer What is the evidence for Proctocolectomy Chemoprevention? Surveillance colonoscopy? Is concerned about the risk of cancer and wants to have his colon removed He asks if he there is anything he can do to reduce his risk of developing CRC and how certain are you that your recommendations will work? Page 3

4 What is the evidence for chemopreventive agents reducing the risk of CRC in CUC Chemoprevention Use of a medication or other substance to reduce or prevent the development of cancer UDCA appears to reduce the risk of neopalsia in UC/PSC Author (Year) OR/RR 95 % CI P value Most evidence based on small observational studies and biological plausibility Strategy is promising, but unproven Tung 2001 Pardi Surveillance strategies should not be altered based on consumption of putative chemopreventive agents -CCFA Consensus Conference on Colorectal Cancer Screening and Surveillance. Inflamm Bowel Dis 2005: 11(3): 314 Trend toward reduction in neoplasia risk with folic acid supplementation in UC Author (Year) Lashner 1989 Lashner 1997 Rutter 2004 Velayos 2006 Definition mg/day 0.4 or 1.0 mg/day Any use Any use (MVI) OR/RR % CI ( ) ( ) ( ) ( ) ( ) P value NS NS NS NS NS Pooled analysis suggests reduction in colorectal cancer/dysplasia risk with 5-ASA in UC Cohort Cancer Moody (1996) 10 - Lashner (1997) 4 25 Lindberg (2001) 7 43 Case-Control Pinczowski (1994) Eaden (2001) Rubin (2003) Van Staa (2003) Bernstein (2003) Rutter (2004) Pooled odds ratios OR:0.51 ( ) Odds ratio -Velayos et al Am J Gastro July Lower Risk Higher Risk Cancer/ Cancer/ Page 4

5 Relationship between medication use and CRC among 188 cases and controls with CUC Variables 5ASA use > 1 year Corticosteroid use >1 year Immunomodulator use Aspirin NSAIDs OR % CI What is the evidence for Proctocolectomy Chemoprevention? Surveillance colonoscopy? -Velayos et al Gastroenterol 2006; 130:1941. Proper Surveillance-Who and When CCFA Consensus Conference (Itzkowitz-IBD J 2006) Screening» 8 years after the onset of IBD» Regardless of disease extent» PSC: beginning at diagnosis of CUC Surveillance» Every 1-2 years British Society of Gastroenterology (Eaden J Gut 2002) Screening» 8 years after the onset of IBD Surveillance-based on disease extent, duration, PSC» Pancolitis-begin immediately» Left-sided: begin after years of disease» Frequency: every 3 years 2 nd decade, every 2 years 3 rd decade, every year fourth decade What is the evidence for surveillance colonoscopy reducing the risk of CRC in CUC Pro Case-control studies and case series Odds of CRC reduced by 60-80% 5-year survival higher when CRC detected within surveillance program than outside of one Con High rate of coexisting cancer even when dysplasia is the highest lesion detected at colonoscopy CRC can develop between closely spaced surveillance exams Physicians and patients do not adhere to guidelines» 88% physicians take less 15 biopsies per exam» Data from 3 continents show dysplasia managed in an inconsistent manner Page 5

6 Colonoscopic surveillance allows most patients to retain colon but is not wholly effective in cancer prevention Reduction in incidence cancer over time Continuation of Case- Management of Patient returns sometime later having undergone surveillance in his home town 16 of 30 interval cancers (CRC after neg colonoscopy or >=C at surveillance) 4pts disseminated cancer 9 with >=Duke C»(median 1.5 yrs after colonoscopy; 4/13 within 12 months) 3 failed to fup with appts Rutter et. al Gastro :1030 Surveillance Results Case Presentation # 2 Endoscopic findings Colonoscopy 1999 Pathology findings Normal What is the macroscopic classification of his dysplasia Loc C: AC TC DC S R Colonoscopy 2006 Normal 2 pseudopolyps Scattered pseudopolyps Scarred mucosa; pseudo Scarred mucosa; pseudo Scarred mucosa, no polyps Path No colitis No colitis No colitis Chronic colitis Chronic colitis Adenomatous changes and chronic colitis What should you do with these findings? Colectomy Watchful waiting/repeated surveillance colonoscopy» Low grade dysplasia has low risk of developing into CRC Loc DC S R Sigmoidoscopy 2006 Scarred mucosa; pseudo Scarred mucosa; pseudo Scarred mucosa, no polyps Path Chronic colitis Chronic colitis Chronic colitis, low-grade dysplasia/ adenomatous change Page 6

7 Macroscopic classification of dysplasia Suggested Surveillance Strategy High-grade Low-grade Indefinite No Flat Adenomatous polyp Flat COLECTOMY Polyp Flat or Probably positive C scopy within 6 mos. Probably negative C scopy within 1 yr DALM Adenoma-like polyp (ALM) Discrete polyp? Completely removed? No dysplasia elsewhere? C scopy in 3-6 mos: LGD confirmed? C scopy in 1-2 yrs Macroscopic classification of dysplasia illustrated in a hypothetical case of ulcerative colitis with partial colonic involvement. is shown in black, normal colon in yellow, diseased colon in red. no yes yes no Itzkowitz S. and Harpaz N. Gastroenterology 126:1634, 2004 Itzkowitz S. and Harpaz N. Gastroenterology 126:1634, 2004 What to do with findings-low grade dysplasia Low-grade What to do with findings-high grade dysplasia High-grade Flat Flat or COLECTOMY COLECTOMY C scopy in 3-6 mos: LGD confirmed? yes no Itzkowitz S. and Harpaz N. Gastroenterology 126:1634, 2004 Itzkowitz S. and Harpaz N. Gastroenterology 126:1634, 2004 Page 7

8 What to do with Findings-Indefinite dysplasia Probably positive C scopy within 6 mos. Indefinite Probably negative C scopy within 1 yr Case Presentation #2 43 year old woman with a self-reported history of IBS, but interestingly colonoscopic biopsies 12 years prior demonstrate mild chronic colitis (IBD) throughout colon Previously tried on mesalamine, mesalamine enema, steroid enema and pt reports no change in his daily BM that occasionally contain mucus Usually constipated FH: Mother with colon cancer age 45 LABS: LFTs normal Prior colonoscopies 1994: Path alone chronic colitis in cecum, transverse colon, rectum 2004: Colonoscopy: left sided colitis; Path: normal cecum, transverse; chronic active colitis in descending colon and rectosigmoid Case Presentation #2 You perform a colonoscopy because of your concern of quiescent CUC You encounter a polypoid lesion in the transverse colon in an area of quiescent colitis How would you macroscopically classify/ describe this lesion and how would you manage it endoscopically? Does your description and endoscopic management change if the lesion had the following appearance? Proper Surveillance-How Four quadrant biopsies every 10cm in flat mucosa (at least 32 biopsies) Consider biopsies every 5 cm in lower sigmoid and rectum Place biopsies in separate containers linked geographically Biopsy any suspicious or raised areas and surrounding mucosa and place in separate containers -CCFA Consensus Conference on Colorectal Cancer Screening and Surveillance. Inflamm Bowel Dis 2005: 11(3): 314 Page 8

9 Pathology returns as low grade dysplasiawhat is your recommendation now? What to do with findings-polypoid High-grade Low-grade Does your recommendation differ for the two lesions shown below? NL LGD Polyp NL LGD COLECTOMY LGD NL Flat DALM Adenomatous polyp Adenoma-like polyp (ALM) NL LGD Discrete polyp? Completely removed? No dysplasia elsewhere? no yes C scopy in 3-6 mos: LGD confirmed? yes no Itzkowitz S. and Harpaz N. Gastroenterology 126:1634, 2004 NL LGD Management of Adenomalike Polyps in UC Endoscopic resection (without surgical resection) is adequate treatment for adenomalike polyps in CUC Several small studies with f/u up to 8 years Rates of flat dysplasia and cancer are low at < 5% Rates of further adenoma ~50% Caveats No flat dysplasia Polypectomy must be complete Base of polyp should be biopsied separately and found to have no dysplasia No dysplasia elsewhere in the colon Rubin et al. Gastroenterology 1999;117:1295; Engelsgjerd et al. Gastroenterology 1999;117:1288; Odze et al. Clin Gastro Hepatol 2004;2: Summary CRC and in IBD: A Case-Based Approach Risk of CRC in IBD is significantly elevated Low rates of CRC observed in several studies suggest this risk may be modifiable-?? Better control of the disease will lead to lower rates of CRC Chemoprevention strategies appear to be promising adjuncts to surveillance, although additional data is required to optimize this t strategy clinically Surveillance colonoscopy, when properly performed appears to be effective, though not perfect Recently published consensus guidelines outline the management of dysplasia in the setting of IBD based on macroscopic appearance of dysplasia and histologic findings Page 9

10 Case#3 82 year old woman with several comorbidities including diabetes, CAD, COPD who has a 2 year diagnosis of Crohn s disease of the right colon Negative evaluation for ischemic bowel Symptoms controlled on 6MP and mesalamine On multiple colonoscopies over the past2 years: evidence of nodularity and dysplasia/ tubulovillous adenoma on random biopsies of ascending colon in a field of colitis Final Case- Would you recommend surgery? Page 10