Advances in Ulcerative Colitis - Volume 3 CME

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1 1 de 12 22/01/ :46 p.m. More: Advances in Ulcerative Colitis Advances in Ulcerative Colitis - Volume 3 CME Complete author affiliations and disclosures are at the end of this activity. Release Date: December 14, 2007; Valid for credit through December 14, 2008 Target Audience This activity is intended for physicians specializing in the fields of gastroenterology and internal medicine, as well as other healthcare professionals conducting research and/or providing care for individuals with ulcerative colitis. Goal The goal of this activity is to define the latest issues challenging the physician caring for the patient with ulcerative colitis in order to enhance the care of patients with this condition and support quality clinical practice of healthcare professionals involved in their care. Learning Objectives Upon completion of this activity, participants will be able to: 1. Evaluate the latest information regarding strategies in colorectal cancer chemoprevention in ulcerative colitis 2. Review current concepts and approaches in the management of the patient with quiescent ulcerative colitis, with a view toward strategies to prevent colorectal cancer 3. Review the latest data regarding colorectal cancer in the setting of ulcerative colitis, as reflected in the recent literature Credits Available Physicians - maximum of 1.0 AMA PRA Category 1 Credit(s) for physicians All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should only claim credit commensurate with the extent of their participation in the activity. Accreditation Statements For Physicians Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity: CME@medscape.net. For technical assistance, contact CME@webmd.net. Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. Follow these steps to earn CME/CE credit*:

2 2 de 12 22/01/ :46 p.m. 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage. *The credit that you receive is based on your user profile. Supported by an independent educational grant from Shire. Legal Disclaimer The material presented here does not necessarily reflect the views of Medscape or companies that support educational programming on These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Copyright 2007 Medscape. Contents of This CME Activity 1. Ulcerative Colitis and Colorectal Cancer ChemopreventionBret A. Lashner, MD, explores the evidence for potential clinical strategies for reducing the risk of colorectal cancer/dysplasia in ulcerative colitis. Bret A. Lashner, MD (Expert Column, December 14, 2007) 2. Strategies to Prevent Colorectal Cancer in Quiescent Ulcerative ColitisFernando S. Velayos, MD, MPH, addresses issues in the management of a 40-year-old patient with long-standing ulcerative colitis, with a view toward strategies for preventing CRC. Fernando S. Velayos, MD, MPH (Case Report, December 14, 2007) 3. Colorectal Cancer and Ulcerative ColitisYvette Leung, MD, and Stephen Hanauer, MD, provide clinical commentary for select feature articles from the literature on issues related to colorectal cancer in ulcerative colitis. Yvette Leung, MD; Stephen B. Hanauer, MD, FACG (Literature Review, December 14, 2007) Expert Column - Ulcerative Colitis and Colorectal Cancer Chemoprevention Introduction Adherence to medical therapy is a major problem in ulcerative colitis, with some estimates showing that up to 60% of patients fail to take their medications as prescribed. Patients should be encouraged by their physicians to adhere to their medical regimen due to the favorable effect on their disease course. [1] What is often overlooked is the possible cancer chemopreventive effect of these medications. Hopefully, careful discussions regarding the beneficial effects of therapies such as 5-aminosalicylic acid (5-ASA/mesalamine), folic acid, and ursodeoxycholic acid, which include their potential chemopreventive effects, will ultimately lead to better adherence and improved patient outcomes. Colorectal cancer is an important problem for ulcerative colitis patients. The lifetime cumulative incidence has been estimated to be between 5.5% and 13.5%. [2] While these rates are not very different from those seen in the general population, the occurrence of cancer at a young age makes age-specific relative risks at least 3 times the baseline rate. The purported risk factors for cancer are extensive disease, long duration of disease, primary sclerosing cholangitis (PSC), family history of colorectal cancer, and possibly chronic uncontrolled inflammation. In case-control studies, cancer surveillance has been associated with a decreased risk of dying from cancer, but still rates are sufficiently elevated to make cancer an important concern. [3] Chemoprevention should be considered complementary to cancer surveillance colonoscopy. 5-ASA Agents Due to their anti-inflammatory effects, 5-ASA agents are the most commonly used medications for the treatment of ulcerative colitis. Indeed, 5-ASA therapy represents the current standard of care for mildly to moderately active ulcerative colitis. This class of drugs is also potentially useful for their chemopreventive effects, largely through mechanisms complementary to anti-inflammatory effects. 5-ASA inactivates reactive oxygen species, dampening the inflammatory cascade and inactivating potential carcinogens. By suppressing nuclear factor-kappab (NF-kB) systems, 5-ASA decreases cytokine production while increasing NF-kB-dependent apoptosis or programmed cell death of cells with abnormal DNA. Additionally, 5-ASA is also

3 3 de 12 22/01/ :46 p.m. known to decrease interleukin (IL)-2 production, which in turn will diminish clonal proliferation of T cells. Finally, 5-ASA activates peroxisome proliferator-activator receptor (PPAR)-gamma, which demonstrates both antiproliferative and anti-inflammatory effects. [4] Six epidemiologic studies have specifically looked at the potential of 5-ASA as a chemopreventive agent for colorectal cancer in ulcerative colitis; 4 have shown a positive effect and 2 have shown no effect. [5-10] A case-control study from Uppsala, Sweden, compared 102 ulcerative colitis patients with cancer to 196 matched controls without cancer. [5] Results showed that the use of sulfasalazine, a prodrug of 5-ASA, given for at least 3 months, was associated with a significantly diminished risk of developing cancer (odds ratio [OR] 0.38, 95% confidence interval [CI] ). Cigarette smoking and active ulcerative colitis also had independent protective effects. In a cohort study from Huddinge, Sweden, involving 143 patients with ulcerative colitis who underwent regular colonoscopies and multiple biopsies in a 20-year surveillance program, 36% developed cancer or dysplasia over the course of follow-up. [6] Among patients who received sulfasalazine for at least 6 months, there was a 34% rate of colorectal dysplasia/cancer compared with a 44% rate among patients who were taking sulfasalazine for less than 6 months (not significant). In a cohort study of colorectal cancer risk and treatment adherence conducted at Leicester General Hospital in the United Kingdom involving 175 patients with ulcerative colitis, 5.7% developed cancer within the study period. [7] Among those patients who took sulfasalazine for at least 6 months, the relative risk of developing colorectal cancer was 0.11 (95% CI ). Alternatively, a case-control study from the United Kingdom comparing 102 ulcerative colitis patients with cancer to matched controls found that sulfasalazine had no significant protective effect; however, regular therapy with other 5-ASA agents was associated with a chemopreventive effect (OR 0.19, 95% CI ). [8] In another study assessing whether 5-ASA use can prevent the development of colorectal cancer in patients with inflammatory bowel disease (IBD), Bernstein and colleagues [9] identified 25 cases of IBD with a diagnosis of colorectal cancer between the years 1997 and 2000 from the University of Manitoba Inflammatory Bowel Disease Epidemiology Database. These cases were compared to 348 matched controls (a control group of IBD patients who did not develop colorectal cancer) extracted from this same database. They found that among the cases of ulcerative colitis with colorectal cancer, 45% were 5-ASA users, whereas only 25% of controls were 5-ASA users (OR 0.48, 95% CI ), and there was no dose-response effect. Higher 5-ASA dosing did not incrementally diminish the rate of colorectal cancer development. More recently, a case-control study from the University of Chicago by Rubin and colleagues [10] compared 26 ulcerative colitis patients with cancer or dysplasia to 96 matched controls and found that use of 5-ASA 1.2 g daily was associated with a significant chemopreventive effect (OR 0.28, 95% CI ); there was a significant dose-response. A meta-analysis examining these studies and others that have principally looked at agents other than 5-ASA (such as folic acid, immunosuppressives, and corticosteroids) has revealed a significant chemopreventive effect of 5-ASA, even after adjusting for potential confounders (OR 0.51, 95% CI ) on colorectal cancer or dysplasia. [11] Therefore, even though the evidence for chemoprevention may be equivocal, because 5-ASA is also effective in maintaining disease remission, these agents should be recommended for long-term use in patients with ulcerative colitis. Folic Acid Folic acid is essential for the regeneration of the amino acid methionine, which is needed for both purine and pyrimidine biosynthesis. Folic acid deficiency is associated with DNA hypomethylation, aberrant DNA synthesis and repair, and decreased apoptosis. Furthermore, folate-sensitive fragile sites exist on genes that play an important role in carcinogenesis, particularly the p53 tumor suppressor gene. Folate deficiency may be associated with p53 mutations in ulcerative colitis patients, [12] who are especially prone to folic acid deficiency due to intestinal losses, poor intake of folic acid-containing foods such as leafy green vegetables, and competitive inhibition of absorption from sulfasalazine. [13] Any effects of folic acid deficiency have been partially ameliorated since 1998 by the fortification of flour with folic acid in the United States. A case-control study involving 99 patients with pancolitis was conducted to determine the effect of folate supplementation on the risk of dysplasia or cancer in chronic ulcerative colitis. [13] Results showed that among patients taking folic acid supplements, the risk of developing dysplasia or cancer was diminished, although not significantly (OR 0.38, 95% CI ). Another case-control study performed to better assess the association between folate supplementation and the risk of developing dysplasia or cancer included 67 ulcerative colitis patients enrolled in a cancer surveillance program. [14] In this study, red blood cell folic acid, a measure of medium-term stores, was found to be associated with a chemopreventive effect (OR for each 10-ng/mL increase in red blood cell folate: 0.82, 95% CI ). Given that these 2 case-control studies had suggested the potential protective effect of folate against neoplasia in ulcerative colitis, a historical cohort study was undertaken to better define this association. [15] This 98-patient cohort study found a nonsignificant protective effect of folic acid supplementation on the risk of cancer or dysplasia (relative risk 0.72, 95% CI ), but the relative risk for folic acid supplementation on the risk of neoplasia showed a dose-response effect. Finally, in a cohort of 95 patients with long-standing ulcerative colitis who were followed in a cancer surveillance program using immunohistochemical staining for p53 mutations as a complementary test for dysplasia, p53 suppressor gene mutations were found to be associated with cancer or dysplasia (relative risk 4.53, 95% CI ); folic acid supplementation had a protective effect for p53 mutations (relative risk 0.97, 95% CI ). [12] Once again, while the evidence may be weak, because folic acid is inexpensive, safe, and recommended for prevention of atherosclerotic heart disease, it should also be recommended for long-term use in patients with IBD. Ursodeoxycholic Acid Ursodeoxycholic acid (UDCA) is often used to improve symptoms and biochemical abnormalities in patients with PSC. Indeed,

4 4 de 12 22/01/ :46 p.m. recent studies have implicated PSC as a risk factor for colorectal cancer in ulcerative colitis. [16] Theoretically, UDCA may be chemopreventive for colorectal cancer in patients with ulcerative colitis. In a cohort study involving 132 ulcerative colitis patients with PSC and 196 ulcerative colitis controls, the risk of developing colorectal cancer or dysplasia was significantly increased among PSC patients (relative risk 3.15, 95% CI ). [17] It is interesting to note that in this study, all of the excess cancer risk pertained to cancer found proximal to the splenic flexure. In theory, carcinogenic secondary bile acids, such as deoxycholic acid (which is abnormally high in patients with cholestasis), are presented to the right side of the colon in higher concentrations than the left side. Reducing the concentration of these secondary bile acids with UDCA could have chemopreventive effects. To assess the relationship between UDCA use and colonic dysplasia in patients with ulcerative colitis, Tung and colleagues [18] conducted a study involving 59 ulcerative colitis patients with PSC who were undergoing colonoscopic surveillance; 69% were on UDCA. Dysplasia was found in 32% of the UDCA users and in an exceedingly high 72% of UDCA nonusers (OR 0.14, 95% CI ). In a 52-patient, randomized, placebo-controlled clinical trial (the only randomized clinical trial done to test for cancer-chemopreventive effects of an agent in ulcerative colitis) designed to test the effect of UDCA use on liver disease progression in PSC, 10% of patients randomized to UDCA developed dysplasia and 35% of placebo-treated patients developed dysplasia (relative risk 0.26, 95% CI ). [19] Finally, in the only negative study in this setting, 120 PSC patients with ulcerative colitis, 23% of whom were treated with UDCA, were followed by Wolf and colleagues. [20] Over the course of follow-up, 28.6% of UDCA-treated patients developed cancer or dysplasia compared with 29.3% of patients who did not receive UDCA (adjusted relative risk 0.65, 95% CI ). Once again, although the evidence may be conflicting, because UDCA is recommended for the treatment of PSC, its use should also be encouraged for its possible cancer-chemopreventive effects. Conclusion On the basis of the evidence presented here, patients with ulcerative colitis should be taking a long-term 5-ASA agent for its maintenance effects as well as for its potential cancer-chemopreventive effect. Folic acid supplementation, either 1 mg daily as a sole supplement or 0.4 mg daily in a multivitamin, is also recommended to be certain that ulcerative colitis patients, who are prone to folic acid deficiency, are replete and can benefit from the potential chemopreventive effect. Likewise, ulcerative colitis patients with PSC should be taking UDCA both for the treatment of their liver disease and for possible colon cancer chemoprevention. Certainly, the cancer-chemopreventive effects associated with the use of these medications are insufficient to obviate the need for cancer surveillance colonoscopy. As underscored by the preceding discussion, the studies in cancer chemoprevention supporting these recommendations are currently weak and inconsistent -- however, the many potential benefits associated with the use of these agents should prompt physicians to strongly encourage their use in the setting of ulcerative colitis. Supported by an independent educational grant from Shire References [ CLOSE WINDOW ] References 1. Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol. 2001;96: Abstract 2. Karlen P, Lofberg R, Brostrom O, Leijonmarck CE, Hellers G, Persson PG. Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol. 1999;94: Abstract 3. Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther. 2000;14: Allgayer H. Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18: Abstract 5. Pinczowski D, Ekbom A, Baron J, et al. Risk factors for colorectal cancer in patients with ulcerative colitis. Gastroenterology. 1994; Lindberg BU, Broome U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. Dis Colon Rectum. 2001;44: Abstract 7. Moody GA, Jayanthi V, Probert CS, et al. Long-term therapy with sulfasalazine protects against colorectal cancer in ulcerative colitis. Eur J Gastroenterol Hepatol. 1996;8: Abstract 8. Eaden J, Abrams K, Ekbom A, et al. Colorectal cancer prevention in ulcerative colitis. Aliment Pharm Ther. 2000;14: Bernstein CN, Blanchard JF, Metge C, Yogendran M. Does the use of 5-aminosalicylic acid in inflammatory bowel disease prevent the development of colorectal cancer? Am J Gastroenterol. 2003;98: Rubin DT, LoSavio A, Yadron N, et al. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4: Abstract 11. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on cancer and dysplasia risk: a systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2005;100: Abstract 12. Lashner BA, Shapiro BD. Husain A, Goldblum JR. Evaluation of the usefulness of testing for p53 mutations in colorectal cancer for ulcerative colitis. Am J Gastroenterol. 1999;94: Abstract 13. Lashner BA, Heidenreich PA, Su GL, et al. Effect of folate supplementation on the incidence of dysplasia and cancer in ulcerative coiltis. Gastroenterology. 1989;97: Abstract 14. Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol. 1993;119: Abstract

5 5 de 12 22/01/ :46 p.m. 15. Lashner BA, Provencher KS, Seidner DL, et al. The effect of folic acid on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology. 1997;112: Abstract 16. Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002;56: Abstract 17. Shetty K, Rybicki L, Brzezinski A, Carey WD, Lashner BA. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol. 1999;94: Abstract 18. Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med. 2001;134: Abstract 19. Pardi DS, Loftus EV, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124: Abstract 20. Wolf JM, Rybicki LA, Lashner BA. The impact of ursodeoxycholic acid on cancer, dysplasia, and mortality in ulcerative colitis patients with primary sclerosing cholangitis. Aliment Pharmacol Ther. 2005;22: Abstract Case Report - Strategies to Prevent Colorectal Cancer in Quiescent Ulcerative Colitis History of Present Illness A 40-year-old man who recently moved to your city presents to your office to establish care. You interview the patient and he reveals he was diagnosed with pancolonic ulcerative colitis nearly 20 years ago. At initial presentation, his colitis was quite active. He had multiple hospitalizations for flares and was prescribed several courses of steroids during the first few years after diagnosis. Fortunately, his disease has become less active in the past several years. He now experiences 1-2 mild flares per year, typically when he stops taking 5-aminosalicylic acid (5-ASA [mesalamine]), his primary therapy for ulcerative colitis. When he experiences a flare, he has increased urgency, loosening of bowels, increased frequency, and small amounts of blood in the stool. If he resumes his 5-ASA/mesalamine therapy, these symptoms often subside within a week. At this office visit, he tells you that he feels quite well and that his ulcerative colitis is under good control. He leads an active life and enjoys running and biking. He travels significantly for his work as a software engineer and is not concerned about taking long trips. At baseline, he reports 2 formed bowel movements per day, without blood or urgency. He does not awaken at night to have a bowel movement. He denies associated arthritis, eye redness, discomfort, or rashes. For the past several years, his primary therapy has consisted of 4.8 g of 5-ASA daily. You note that for the past few years, he has undergone a surveillance colonoscopy every 1-2 years, with no evidence of dysplasia. Additional History You review his medical records and note that on prior surveillance colonoscopies, he has had scattered pseudopolyps throughout the colon. When sampled, these pseudopolyps have not shown evidence of dysplasia. Endoscopically, his disease has been described as mild and quiescent on surveillance endoscopies, with variable amounts of mild erythema. Random biopsies taken throughout the colon have typically revealed chronic inflammatory cells, consistent with quiescent disease. Further review of his record reveals that he has a family history of colorectal polyps; his father was diagnosed at age 62. There is no family history of inflammatory bowel disease or colorectal cancer. He describes himself as a lifetime nonsmoker. Evaluation The patient is a robust-appearing and well-groomed individual. His physical examination is quite unremarkable. His abdominal exam is without associated tenderness to palpation, guarding, or rebound. Laboratory tests are similarly unremarkable. He has a normal complete blood count, and C-reactive protein, amylase, and creatinine levels. At this initial visit, you counsel the patient regarding his disease, the importance of maintenance 5-ASA therapy to reduce flares, and strategies for colorectal cancer prevention. He tells you that he feels quite well and was surprised that his prior doctor believed that he had an increased risk of developing colorectal cancer. The patient wants to know if you think he has an elevated risk of developing colorectal cancer. If so, he wants to know what his risk factors are. How do you answer? A. His risk is elevated and estimated to be 40% after 20 years of disease. Ulcerative colitis is the third highest risk condition for developing colorectal cancer, but risk factors are not well defined. B. His risk is elevated, but much lower than 40%. He has had minimal inflammation on colonoscopy for the past several years, which reduces his risk significantly. C. His risk is elevated, but his personal risk cannot be estimated. He has several risk factors, including extent of disease, duration of disease, family history of colorectal polyps, and presence of pseudopolyps. D. His risk is not elevated. Even though he has ulcerative colitis, he has minimal inflammation, his prior colonoscopies have not shown dysplasia, and he is taking chronic 5-ASA therapy, all factors associated with a lower risk of colorectal cancer. Risk of Colorectal Cancer in Ulcerative Colitis

6 6 de 12 22/01/ :46 p.m. It is true that the cumulative probability of developing colorectal cancer is significantly higher in chronic ulcerative colitis than in the general population. [1] Data from a comprehensive meta-analysis suggest that this probability is 2% after 10 years of disease, 8% after 20 years of disease, and 18% at 30 years after a diagnosis of chronic ulcerative colitis. [2] By comparison, the lifetime cumulative probability of developing colorectal cancer for the general population in the United States is approximately 5%. Described in terms of relative risk, chronic ulcerative colitis increases the relative risk of colorectal cancer 5.7-fold compared with the general population. [3] Severity of histologic inflammation at surveillance colonoscopy appears to be an important biological risk factor for the development of colorectal cancer in chronic ulcerative colitis. [4] Clinically, duration and anatomic extent of colonic inflammation are the most important risk factors for colorectal cancer. [3] Other established risk factors include primary sclerosing cholangitis (PSC) [5] and a family history of colorectal cancer. [6] Results from a meta-analysis suggest that PSC in chronic ulcerative colitis increases the relative risk of colorectal cancer 4.8-fold compared with chronic ulcerative colitis alone. [5] Family history of colorectal cancer increases the risk of colorectal cancer 2.5-fold compared with chronic ulcerative colitis alone. A family history of colorectal cancer at age < 50 years increases the relative risk even further, at 9.2-fold. [6] Pseudopolyps have recently been described as a risk factor. [4,7] The reasons for this association are not yet fully known. Perhaps pseudopolyps are a historical marker of more severe inflammation. Alternatively, pseudopolyps may obscure the sensitivity of surveillance colonoscopy. You remind the patient that ulcerative colitis confers an elevated risk for colorectal cancer. Although his personal risk cannot be estimated, the risk of colorectal cancer is estimated to be 18% after 20 years of disease. You inform him he has several risk factors for colorectal cancer, including pancolonic disease, duration of ulcerative colitis, family history of colorectal polyps, and presence of pseudopolyps. The patient is concerned when he hears this information regarding his risk of developing colorectal cancer. He asks if there is anything he can do to reduce this risk, and what the data are to back up your recommendations. How do you respond? A. There are no modifiable risk factors in ulcerative colitis, and therefore there is nothing he can do to reduce his risk. B. He can reduce his risk by undergoing regular surveillance colonoscopy. Case control and case series support a protective effect. C. He can reduce his risk by adhering to 5-ASA therapy. Case control data support a protective effect. D. Both B and C are appropriate strategies. Factors Protective Against the Development of Colorectal Cancer in Ulcerative Colitis It is interesting that some populations of chronic ulcerative colitis patients do not have an increased risk for colorectal cancer compared with the background population. [8] This suggests that the risk of colorectal cancer may be modifiable in ulcerative colitis. Several important protective factors against colorectal cancer have been defined that may account for this reduced risk. [7-9] The ultimate protective factor against the development of colorectal cancer in chronic ulcerative colitis is to remove the organ at risk when the risk starts to increase -- ie, proctocolectomy for all patients, beginning 8-10 years after the onset of disease. Clearly, this strategy is not desirable to most patients. As a result, this aggressive surgical intervention has been replaced by an aggressive strategy of surveillance colonoscopy every 1-2 years beginning at 8-10 years after the onset of disease, with proctocolectomy reserved for those patients with histologic evidence of dysplasia on mucosal biopsies. [10] The evidence that surveillance colonoscopy reduces the risk of colorectal cancer and mortality in chronic ulcerative colitis derives from several case-control studies and case series. [10-12] Case-control studies have reported that a prior history of surveillance colonoscopy reduces the odds of developing colorectal cancer by 60%-80%. [9,11] Case series have demonstrated that 5-year survival rates are higher for chronic ulcerative colitis patients with colorectal cancer detected within a surveillance program than for those who present with symptomatic cancers detected outside of a surveillance program. [12] In contrast to these favorable studies, other studies have highlighted the failures of surveillance colonoscopy in this setting. A pooled analysis of prospective studies has shown that there is a high rate of coexisting cancer even when dysplasia is the worst histologic lesion detected at surveillance in ulcerative colitis. [13] There are also many instances of colorectal cancer developing even between closely spaced surveillance examinations. [14] On balance, results from a recently published 30-year surveillance program from St. Mark's Hospital in London likely reflect the clinical efficacy of surveillance colonoscopy in a population with excellent (94.3%) compliance. [14] This study demonstrated a reduction in the incidence of colorectal cancer over time. Furthermore, it concluded that unlike the aggressive strategy of surgery after 10 years of disease, a strategy of surveillance colonoscopy allowed the vast majority of asymptomatic patients with extensive ulcerative colitis to retain their colon. This strategy was effective but not perfect, as some patients still developed colorectal cancer despite undergoing surveillance colonoscopy.

7 7 de 12 22/01/ :46 p.m. 5-ASA, a structural derivative of acetylsalicylic acid (aspirin), is a cornerstone and first-line therapy for mild-to-moderate chronic ulcerative colitis. Inflammation is a known risk factor for colorectal cancer, and 5-ASA shares several important anti-inflammatory and anticancer properties with aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). [15,16] Multiple studies suggest that 5-ASA therapy is an additional protective factor against the development of colorectal cancer in patients with ulcerative colitis. A recent meta-analysis of 9 observational studies involving a total of 1932 patients reported a protective association between 5-ASA use and colorectal cancer (odds ratio [OR] 0.51; 95% confidence interval [CI]: ), which equates to a 49% reduction in the risk of colorectal cancer or colorectal cancer/dysplasia with regular 5-ASA use. [17] In fact, it appeared that the studies that defined 5-ASA use by some marker of consistency and intensity of use (as opposed to simple duration) were the ones that consistently showed a protective effect of 5-ASA. [17] In a community-based cohort study of 175 patients with ulcerative colitis, compliance with sulfasalazine (prodrug of 5-ASA) resulted in a significant reduction in the risk of colorectal cancer. One hundred and sixty-eight charts were reviewed. The crude proportion of patients who developed colorectal cancer was 3% (5 of 152) in the compliant group and 31% (5 of 16) in the noncompliant group (P <.001). [18] In a case-control study of 102 patients with ulcerative colitis and colorectal cancer matched to controls, regular 5-ASA use reduced the odds of developing colorectal cancer by 53% (OR 0.47; 95% CI: ). [19] Finally, in a nested case-control study involving 18,969 patients with inflammatory bowel disease in the UK General Practice Research Database, regular 5-ASA users (defined as at least 6 prescriptions in the previous 12 months) had a significantly reduced risk for colorectal cancer compared with irregular 5-ASA users (adjusted OR 0.60; 95% CI: ). [20] It is important to note that much of the evidence for chemoprevention with 5-ASA is based on small observational studies and biological plausibility. Therefore, it should be emphasized that this strategy, although promising, remains unproven. As a result, surveillance strategies should not be altered due to the consumption of putative chemopreventive agents. [10] After speaking with your patient, he understands that regular surveillance colonoscopy and regular 5-ASA use (ie, adhering to his prescribed therapy) have been identified as potential protective factors against the development of colorectal cancer in ulcerative colitis. The patient explains that while he obviously does not want to develop colorectal cancer, he would like to undergo less frequent surveillance colonoscopy and take less 5-ASA for his ulcerative colitis. He does not want to go against his physician's recommendations, so he would like you to give him permission to do this. How do you respond to this request? A. Reduce the frequency of surveillance colonoscopy to every 5 years but do not change the dose of 5-ASA. B. Reduce the frequency of surveillance colonoscopy to every 4 years and the dose of 5-ASA to 2.4 g per day. C. Continue surveillance colonoscopy every 1-2 years, but reduce the dose of 5-ASA to at least 1.2 g per day. D. Make no changes; do not "rock the boat." Continued Management At present, tailored guidelines that determine when the next surveillance colonoscopy should be performed on the basis of clinical and endoscopic data do not exist. Therefore, at this time, most gastroenterology societies recommend that patients with at least 10 years of pancolonic ulcerative colitis undergo a surveillance colonoscopy every 1-3 years (depending on the society). [10] A recently published consensus guideline recommends that the initiation of surveillance colonoscopy and the interval for subsequent exams not be altered due to the consumption of 5-ASA or other putative chemopreventive agents. [10] Despite this, the hope is that at some point in the future, patients can be further stratified into high- and low-risk groups, eliminating the current aggressive surveillance regimen for those patients in the low-risk group. To this end, Rutter and colleagues [21] examined colonoscopic markers of cancer risk among 68 cases (with ulcerative colitis and colorectal neoplasia) and 136 controls (ulcerative colitis alone) and noted all endoscopic findings (post-inflammatory polyps; scarring; strictures; backwash ileitis; a shortened, tubular, or featureless colon; severe inflammation; and normal-looking surveillance colonoscopies). They found that a macroscopically normal-looking colonoscopy reduced the risk for colorectal neoplasia by more than 60% (OR 0.38; ), with the 5-year risk no different from that of matched general population controls. Although it is too early to advocate changing guidelines, the goal would be to tailor guidelines on the basis of endoscopic and clinical risk factors. With regard to changing 5-ASA therapy, this patient is asking what the minimum dose of 5-ASA is that he can consume and still derive a chemopreventive effect. Maintenance therapy can be quite variable, but typically ranges from g of 5-ASA per day. Two studies have suggested that a chemoprotective benefit is still derived with a 5-ASA dose of 1.2 g per day. [19,22] However, it is important to not look only at the dose of 5-ASA, but rather to consider the dose that maintains the patient in clinical remission, which may be higher for different patients. Long-standing inflammation is one of the most important risk factors for the development of colorectal cancer in ulcerative colitis. The main goal of maintenance 5-ASA therapy is to maintain clinical remission; a secondary effect may be the reduction of colorectal cancer risk. Case Follow-up and Conclusion

8 8 de 12 22/01/ :46 p.m. The risk of developing colorectal cancer in chronic ulcerative colitis is significantly elevated -- however, low rates of colorectal cancer observed in several populations suggest that this risk may be modifiable. At the present time, the main strategy for cancer prevention in ulcerative colitis is regular surveillance colonoscopy, in accordance with published guidelines. There are emerging data linking severity of inflammation at surveillance colonoscopy with increased colorectal cancer risk as well as additional data suggesting that regular 5-ASA therapy may reduce the risk of colorectal cancer. Even so, maintenance chronic ulcerative colitis therapy should be prescribed with the primary goal of maintaining clinical remission. A secondary benefit of this practice, in conjunction with regular surveillance colonoscopy, may be the prevention of colorectal cancer. In this case, the patient agreed to continue his current regimen of surveillance colonoscopy every 1-2 years and reduce his 5-ASA to 2.4 g per day. Supported by an independent educational grant from Shire References [ CLOSE WINDOW ] References 1. Clevers H. Colon cancer--understanding how NSAIDs work. N Engl J Med. 2006;354: Abstract 2. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48: Abstract 3. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990;323: Abstract 4. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126: Abstract 5. Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002;56: Abstract 6. Askling J, Dickman PW, Karlen P, et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology. 2001;120: Abstract 7. Velayos FS, Loftus EV Jr, Jess T, et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology. 2006;130: Abstract 8. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Gastroenterology. 2006;130: Abstract 9. Karlen P, Kornfeld D, Brostrom O, Lofberg R, Persson PG, Ekbom A. Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study. Gut. 1998;42: Abstract 10. Itzkowitz SH, Present DH. Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis. 2005;11: Abstract 11. Choi PM, Nugent FW, Schoetz DJ Jr, Silverman ML, Haggitt RC. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology. 1993;105: Abstract 12. Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology. 1994;107: Abstract 13. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet. 1994;343: Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology. 2006;130: Abstract 15. Allgayer H. Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18(Suppl 2): Abstract 16. Rubin DT, Cruz-Correa MR, Gasche C, et al. Colorectal cancer prevention in inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review and update. Inflamm Bowel Dis Oct 11; [Epub ahead of print]. 17. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol. 2005;100: Abstract 18. Moody GA, Jayanthi V, Probert CS, Mac Kay H, Mayberry JF. Long-term therapy with sulphasalazine protects against colorectal cancer in ulcerative colitis: a retrospective study of colorectal cancer risk and compliance with treatment in Leicestershire. Eur J Gastroenterol Hepatol. 1996;8: Abstract 19. Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther. 2000;14: van Staa TP, Card T, Logan RF, Leufkens HG. 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut. 2005;54: Abstract 21. Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut. 2004;53: Abstract 22. Rubin DT, LoSavio A, Yadron N, Huo D, Hanauer SB. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4: Abstract Literature Review - Colorectal Cancer and Ulcerative Colitis Introduction The risk of colorectal cancer in ulcerative colitis is well established and is related to the extent and duration of colitis, the presence of primary sclerosing cholangitis, and active inflammation. This has led to the recommendation to initiate screening colonoscopies beginning 8 to 10 years after the onset of ulcerative colitis symptoms followed by surveillance examinations every 1 to 2 years. [1] Although the optimal surveillance strategy has not been identified, the recommendation to obtain 4-quadrant biopsies every 10

9 9 de 12 22/01/ :46 p.m. cm in the colon will detect approximately 90% of dysplasia or cancer, [2] even though only a minority of the surface area of the colon is sampled. The use of combined chromoscopy and endomicroscopy for the identification of potential neoplastic lesions may offer the ability to increase diagnostic yield. In ulcerative colitis, the optimal management of flat low-grade dysplasia (LGD) also remains controversial. [3,4] Unlike the finding of high-grade dysplasia (HGD), there is no uniform recommendation for colectomy with LGD, as studies differ with regard to the concurrent and future risks for HGD and colorectal cancer once LGD is identified. A recent meta-analysis of studies published over the last 2 decades offers a pooled estimate of the incidence and relative risk of developing colorectal cancer and other advanced lesions. Identifying both potential risk factors and protective factors for the development of colorectal cancer in ulcerative colitis may help to guide treatment and recommendations for surveillance strategies. Increasing evidence points to disease activity as being a key risk factor in the development of colorectal neoplasia in ulcerative colitis. What is the Value of Combined Chromoscopy and Endomicroscopy for the Diagnosis of Intraepithelial Neoplasias in Ulcerative Colitis? Kiesslich R, Goetz M, Lammersdorf K, et al. Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology. 2007;132: Summary: This study combined chromoscopy with confocal laser endomicroscopy to detect and analyze intraepithelial neoplasias in ulcerative colitis during ongoing endoscopy. A total of 161 patients with ulcerative colitis were randomized to undergo conventional colonoscopy or chromoscopy-guided endomicroscopy. The primary study endpoint was the number of detected intraepithelial neoplasias. In the conventional colonoscopy group, 4 biopsy specimens were taken every 10 cm. In the chromoscopy/endomicroscopy group, chromoscopy with methylene blue was used to identify potential neoplastic lesions. Endomicroscopy was then performed on circumscribed lesions in the colon that were graded for the presence of in vivo intraepithelial neoplasia according to predefined crypt and vessel architecture changes. Endomicroscopy was performed every cm, and biopsies were taken in the presence of mucosal irregularities as well as in normal mucosa from each segment of the colon (to determine the histologic extent and severity of ulcerative colitis). Targeted biopsies were also taken from circumscribed lesions in both groups. A total of 134 circumscribed lesions were identified after chromoscopy with methylene blue. A total of 5580 confocal images from these circumscribed lesions were analyzed during ongoing endoscopy, and the results were compared with 311 targeted biopsy specimens (ie, with histologic results). Compared to conventional colonoscopy with random biopsy specimens, 4.75-fold more neoplasia could be detected using chromoscopy-guided endomicroscopy, with 19 intraepithelial neoplastic lesions found vs 4 (P =.005), despite the fact that 50% fewer biopsies were taken (P =.008). Significantly, more flat intraepithelial neoplasias were found in the chromoscopy-guided endomicroscopy group compared with the conventional colonoscopy group: 16 vs 2 (P =.002). Confocal endomicroscopic images also demonstrated high accuracy for predicting the presence of intraepithelial neoplasia compared to histologic results, with a sensitivity of 94.7%, specificity of 98.3%, and overall accuracy of 97.8%. The negative predictive value for mucosa with a normal endomicroscopic appearance not containing intraepithelial neoplasia was 99.1%. Comment: The goal of cancer surveillance in patients with ulcerative colitis is to detect neoplasia at an early stage. The unmet goal at this time is to find an optimal technique that will maximize the diagnostic yield given that any surveillance strategy only samples a small minority of the surface area of the mucosa. Chromoendoscopy is helpful in identifying mucosal lesions. Confocal endomicroscopy has the additional advantage of viewing subsurface cellular structures in vivo. [5] Confocal laser endoscopy integrates a laser microscope into the distal tip of a conventional endoscope and allows imaging of both cellular and subcellular structures during ongoing endoscopy, and thus, immediate recognition of intraepithelial neoplasia that correlates well with the gold standard of histologic exam. Furthermore, chromoscopy with endomicroscopy requires fewer biopsies than conventional colonoscopy. Future studies should help determine the reproducibility and feasibility of confocal laser endoscopy as application of the technology expands beyond research centers. Abstract What is the Risk of Cancer or Any Advanced Lesion Once LGD is Diagnosed? Thomas, T, Abrams KA, Robinson RJ, Mayberry JF. Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther. 2007;25: Summary: The objective of this meta-analysis was to determine the incidence and relative risk of advanced lesions (ie, HGD or cancer) in ulcerative colitis patients with flat LGD or LGD with dysplasia-associated lesion or mass (DALM) identified during surveillance colonoscopies. A total of 20 studies were included in the analysis, with more than 2677 ulcerative colitis patients. The average age of patients with LGD was 42 years, and the average duration of colitis at the time of diagnosis of LGD was 17 years. In the 20 surveillance studies, 508 patients were identified with flat LGD or DALM. Subsequent to the diagnosis of LGD, an average of 4.3 colonoscopies was performed per patient from 8 studies, in a total of 288 patients. Seventy-three advanced lesions were found during subsequent surveillance: 47 HGDs, 18 colorectal cancers, and 8 DALMs. Of the 47 patients with HGD found preoperatively, 13 had cancer found in the surgical specimen. In total, 31 colorectal cancers were detected, of which 55% were stage Duke's A or B. In 98 patients, colectomy was performed within 6 months of initial diagnosis of LGD or for nonprogressive LGD; among these 98, 25 cases of colorectal cancer and 11 cases of concurrent HGD were identified. Thus, in total, 37% (36/98) of patients with LGD found on surveillance had a coexisting advanced lesion. The incidence of cancer was 14/1000 patient-years duration (pyd) and the incidence of any advanced lesion was 30 of 1000 pyd. The detection of LGD on