Why it’s time for updated U.S. colorectal cancer prevention guidelines in inflammatory bowel disease

Abstract

Patients with chronic ulcerative colitis and Crohn’s colitis are at an increased risk of subsequent dysplasia and adenocarcinoma of the colorectum. Recognition of this risk has led to systematic efforts to identify at-risk patients and incorporate prevention approaches. The primary approach is outlined in a number of different guidelines, all of which recommend periodic colonoscopic surveillance to identify neoplasia and make decisions about surgery.1Cairns S.R. Scholefield J.H. Steele R.J. et al.Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).Gut. 2010; 59: 666-689Crossref PubMed Scopus (840) Google Scholar, 2Bernstein C.N. Weinstein W.M. Levine D.S. et al.Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.Am J Gastroenterol. 1995; 90: 2106-2114PubMed Google Scholar, 3Farraye F.A. Odze R.D. Eaden J. et al.AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.Gastroenterology. 2010; 138: 738-745Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 4Levin B. Lieberman D.A. McFarland B. et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology. 2008; 134: 1570-1595Abstract Full Text Full Text PDF PubMed Scopus (1673) Google Scholar This approach to secondary prevention of cancer in inflammatory bowel disease (IBD) is based on mostly older data and limited by our incomplete knowledge about the natural history of neoplasia in chronic colitis or even how to distinguish one type of dysplasia from another. The term dysplasia-associated lesion or mass is out of date and is being replaced by more descriptive terminology such as endoscopically discreet polypoid lesion or endoscopically invisible lesion. Newer high-definition colonoscopes and dye spray chromoendoscopy offer better visualization of the epithelium and challenges us to understand whether dysplasia found by such approaches has the same value or prognosis of the dysplasia diagnosed with our previous technology. In addition, given that we can now see so much better during our colonoscopies (even with white light alone), it is recognized that random biopsies are of low yield and likely unnecessary.5van den Broek F.J. Stokkers P.C. Reitsma J.B. et al.Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences.Am J Gastroenterol. 2014; 109: 715-722Crossref PubMed Scopus (86) Google Scholar Finally, as we have come to appreciate the important risk factor of histologic inflammation and its contribution to neoplastic risk, we also have realized that many older studies may be invalid because they did not adjust for this significant confounder. As such, how we treat patients and when we recommend surgery in the presence of some types of dysplasia is being actively redefined in favor of “smarter” and “more efficient” approaches involving risk stratification and ongoing follow-up rather than immediate colectomy. Given all this uncertainty and advancing technology, the current IBD surveillance guidelines have many limitations. They were out of date almost as soon as they were published, and they are often ignored or not followed by our colleagues.2Bernstein C.N. Weinstein W.M. Levine D.S. et al.Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.Am J Gastroenterol. 1995; 90: 2106-2114PubMed Google Scholar This is because of the confusion about the meaning of dysplasia, an absence of hard data regarding benefit, but also the observations by experienced clinicians in practice who believe that the guidelines do not reflect the “real world,” that obtaining the recommended number of random biopsy samples is time-consuming and inefficient, and because patients who are in stable remission often have limited follow-up, so prevention is forgotten or delayed. Compounding this challenging issue further is the fact that there is a divergence of recommendations in international guidelines. This divergence is attributed to the difference in interpretation of available evidence, but also reflects general differences in our nations’ health care strategies and resource use. In the United States (the country with the most expensive health care system in the world), the strategy used by the American Gastroenterological Association (AGA) in 20093Farraye F.A. Odze R.D. Eaden J. et al.AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.Gastroenterology. 2010; 138: 738-745Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar and similar strategies recommended by other U.S. societies4Levin B. Lieberman D.A. McFarland B. et al.Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.Gastroenterology. 2008; 134: 1570-1595Abstract Full Text Full Text PDF PubMed Scopus (1673) Google Scholar, 6Itzkowitz S.H. Present D.H. Crohn's et al.Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis. 2005; 11: 314-321Crossref PubMed Scopus (498) Google Scholar divide at-risk patients into annual or biannual colonoscopies. The British Society of Gastroenterology (BSG) guidelines published in 2010 include a recommended approach of pancolonic dye spray chromoendoscopy with targeted biopsies and furthermore incorporate the degree of inflammation at the time of the examination in the decision for subsequent recommendations for repeat examinations at 1-, 3-, or 5-year intervals.1Cairns S.R. Scholefield J.H. Steele R.J. et al.Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).Gut. 2010; 59: 666-689Crossref PubMed Scopus (840) Google Scholar There have been no prospective trials comparing one strategy with another, and it has been unknown which society’s guidelines are better in terms of clinical effectiveness, cost-effectiveness, and, importantly, compliance by clinicians and patients. The study published in this month’s issue of Gastrointestinal Endoscopy by Lutgens et al7Lutgens M. van Oijen M. Mooiweer E. et al.A risk-profiling approach for surveillance of inflammatory bowel disease-colorectal carcinoma is more cost-effective: a comparative cost-effectiveness analysis between international guidelines.Gastrointest Endosc. 2014; 80: 842-848Abstract Full Text Full Text PDF Scopus (14) Google Scholar is important because it provides a cost-effectiveness analysis comparing the AGA guideline strategy with the BSG guideline strategy, with a particular emphasis on what the authors term is the BSG “risk profiling approach.” By using a Markov model of a base case of a 40-year-old colitis patient who received a diagnosis of UC at the age 30, the authors explore different potential outcomes of stable remission, medically refractory disease, and dysplasia or colorectal cancer to test the AGA (annual or biannual) and BSG (annual, every 3 years, or every 5 years) approaches for surveillance. They use costs extrapolated from the medical literature based on 3 previous (and relatively old) studies of third-party payer reimbursement rates in a U.S. health care model.8Nguyen G.C. Frick K.D. Dassopoulos T. Medical decision analysis for the management of unifocal, flat, low-grade dysplasia in ulcerative colitis.Gastrointest Endosc. 2009; 69: 1299-1310Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 9Holubar S.D. Long K.H. Loftus Jr., E.V. et al.Long-term direct costs before and after proctocolectomy for ulcerative colitis: a population-based study in Olmsted County, Minnesota.Dis Colon Rectum. 2009; 52: 1815-1823Crossref PubMed Scopus (21) Google Scholar, 10Loftus Jr., E.V. Friedman H.S. Delgado D.J. et al.Colectomy subtypes, follow-up surgical procedures, postsurgical complications, and medical charges among ulcerative colitis patients with private health insurance in the United States.Inflamm Bowel Dis. 2009; 15: 566-575Crossref PubMed Scopus (22) Google Scholar As with most models of this kind, there are many assumptions and extrapolations necessary to determine which health state the fictional patient is in and what additional outcomes he or she may have, and subtle changes in one assumption or another may have resulted in different results related to clinical effectiveness, quality-adjusted life-years (QALYs), and direct costs. Nonetheless, the exercise is an important one, and it is of interest that both guidelines were equally effective as measured by QALYs, but not surprising that fewer colonoscopies (as occur in the BSG guidelines) dominate the strategy from a cost-effectiveness and “willingness-to-pay” point of view. It would seem prudent, therefore, for us to adopt a similar strategy of fewer colonoscopies in lower risk patients, provided that we can adequately and confidently identify such patients. However, we should be clear on the distinction between these guidelines and the conclusions of this analysis. The thrust of the Lutgens et al article discusses that a risk-profiling approach to cancer surveillance in IBD occurs with the BSG guidelines but not with the AGA guidelines, but it is important to remember that both sets of guidelines incorporate risk profiling, by distinguishing patients based on duration of disease, extent of disease, and the presence or absence of primary sclerosing cholangitis. The significant distinction between these guidelines is that the BSG guidelines incorporate additional risk stratification by extrapolating what we know about inflammation as a risk and the improved sensitivity of dye spray chromoendoscopy, and are willing to spread out colonoscopies in specific patient groups to every 3 or every 5 years. There are some additional practical and clinical challenges not addressed in the Lutgens et al analysis. These include the absence of calculations related to direct and indirect costs associated with chromoendoscopy (supplies as well as endoscopy time saved or added), the absence of costs related to pathology interpretation of specimens (which may favor the approach that focuses on targeted biopsies over random ones), and, as they mention, the additional challenges related to patients’ willingness to undergo colonoscopy or to agree to surgery when dysplasia is identified, which we have learned is different from what the gastroenterologist or surgeon may recommend.11Siegel C.A. Schwartz L.M. Woloshin S. et al.When should ulcerative colitis patients undergo colectomy for dysplasia? Mismatch between patient preferences and physician recommendations.Inflamm Bowel Dis. 2010; 16: 1658-1662Crossref PubMed Scopus (38) Google Scholar Perhaps most importantly, as the authors state, the key analysis is not in the lower risk patients, but rather it is in the possibility of interval cancers that may occur in some patients during the longer follow-up intervals in the BSG guidelines. In this case, the more frequent colonoscopies in the AGA guidelines would dominate in effectiveness but significantly exceed the so-called “willingness-to-pay” threshold in costs. From a population-management point of view, this analysis and conclusions may be acceptable, but for the individual physician and patient, an extra colonoscopy or 2 is likely to be well worth the costs to avoid the possibility of an interval cancer and surgery. But this is a common criticism of Markov models and population-based analyses. In fact, there is evidence in the non-IBD population that U.S. gastroenterologists tend to scope more frequently than guidelines suggest already.12Shah T.U. Voils C.I. McNeil R. et al.Understanding gastroenterologist adherence to polyp surveillance guidelines.Am J Gastroenterol. 2012; 107: 1283-1287Crossref PubMed Scopus (24) Google Scholar The elephant in the room is how payers will react to an analysis such as this. More recently, we have seen more regulation regarding how the Centers for Medicare and Medicaid Services cover colorectal cancer screening at defined intervals in the non-IBD population,13Colorectal Cancer Screenings. Your Medicare Coverage. Available at http://www.medicare.gov/coverage/colorectal-cancer-screenings.html. Accessed August 26, 2014.Google Scholar which suggests that similar limitations may occur in IBD. It is therefore critical that interpretation of this analysis and any future adjustments to our guidelines account for all components of patient risk and include the additional details related to the patient who has a poor cathartic preparation or active inflammation that affects visibility and diagnosis. A future approach also might incorporate additional risk factors such as the sex of the patient (males have a higher risk of neoplasia), the use of immunomodulator therapy (appears to lower risk), and the degree of inflammation over time (which is associated with higher risks but which may change over time).14Rubin D.T. Huo D. Kinnucan J.A. et al.Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study.Clin Gastroenterol Hepatol. 2013; 11 (e1-4): 1601-1608Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 15Rutter M. Saunders B. Wilkinson K. et al.Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.Gastroenterology. 2004; 126: 451-459Abstract Full Text Full Text PDF PubMed Scopus (968) Google Scholar, 16Yang Z. Ye X. Wu Q. et al.A network meta-analysis on the efficacy of 5-aminosalicylates, immunomodulators and biologics for the prevention of postoperative recurrence in Crohn's disease.Int J Surg. 2014; 12: 516-522Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Also important is the ongoing development of noncolonoscopic biomarkers of colonic neoplasia,16Yang Z. Ye X. Wu Q. et al.A network meta-analysis on the efficacy of 5-aminosalicylates, immunomodulators and biologics for the prevention of postoperative recurrence in Crohn's disease.Int J Surg. 2014; 12: 516-522Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar which might be used between colonoscopies or to further risk-stratify patients and possibly lower costs. It is clear that IBD is much more complex than the non-IBD population, and any new guidelines will need to account for these challenges, while also remaining simple enough so that physicians and patients can understand them! There are many challenges in the development of a better approach to colorectal cancer prevention in IBD, but guidelines that incorporate new technology and emphasize an updated comprehensive risk stratification approach with directed resource allocation are clearly needed. Fortunately, a recent international consensus meeting on these issues tried to address many of the existing challenges and confusion, and that subsequent publication should contribute to revised approaches in a positive way.17SCENIC: Surveillance for colorectal endoscopic neoplasia detection and management in inflammatory bowel disease patients. Presented at the International Consensus Meeting, San Francisco, California, March 7-8, 2014.Google Scholar With updated guidelines and better risk stratification, we may not have to sacrifice detection of interval cancers because of the higher costs of colonoscopic surveillance. When we achieve this, the “willingness-to-pay” will merge with a “willingness-to-participate” and everyone (patients, providers, and payers) will be happy. The author disclosed no financial relationships relevant to this publication. A risk-profiling approach for surveillance of inflammatory bowel disease-colorectal carcinoma is more cost-effective: a comparative cost-effectiveness analysis between international guidelinesGastrointestinal EndoscopyVol. 80Issue 5PreviewColonoscopic surveillance for neoplasia is recommended for patients with inflammatory bowel disease (IBD)-related colitis. However, data on cost-effectiveness predate current international guidelines. Full-Text PDF