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• W2026879588 abstract "Background & Aims: Evidence suggests that mesalamine-based anti-inflammatory medicines may prevent colorectal cancer (CRC) in ulcerative colitis (UC). If mesalamine exerts its chemopreventive effect by its anti-inflammatory activity, then other medications that reduce colitis activity also should possess chemopreventive properties. Our aim was to determine the effect of the immunomodulators 6-mercaptopurine (6MP) and azathioprine (AZA) in preventing the development of dysplasia or CRC in UC. Methods: Patients with UC who underwent a surveillance colonoscopy in 1996–1997 were identified from a gastrointestinal pathology database. A proportional hazards analysis assessing 6MP/AZA use as a time-changing covariate was performed to evaluate the effect of 6MP/AZA on: (1) progression to any neoplasia (low-grade dysplasia, high-grade dysplasia, or CRC), and (2) progression to advanced neoplasia (high-grade dysplasia or CRC). Results: A total of 315 subjects met inclusion criteria and were followed for an average of 8 years from their first surveillance examination. There were no significant differences in rates of progression to advanced neoplasia or to any neoplasia between 6MP/AZA users and never-users by log-rank testing. The proportional hazards analysis resulted in hazard ratios of 1.06 (95% confidence interval, .59–1.93) and 1.30 (95% confidence interval, .45–3.75) when considering the effect of exposure to 6MP/AZA on progression to any or to advanced neoplasia, respectively. The results were unaffected by known potential confounders. Conclusions: In UC patients with no initial history of dysplasia, 6MP/AZA use appears to have little or no effect on the rate of neoplastic transformation in the colon. Importantly, the use of 6MP/AZA did not increase malignant transformation in UC. Background & Aims: Evidence suggests that mesalamine-based anti-inflammatory medicines may prevent colorectal cancer (CRC) in ulcerative colitis (UC). If mesalamine exerts its chemopreventive effect by its anti-inflammatory activity, then other medications that reduce colitis activity also should possess chemopreventive properties. Our aim was to determine the effect of the immunomodulators 6-mercaptopurine (6MP) and azathioprine (AZA) in preventing the development of dysplasia or CRC in UC. Methods: Patients with UC who underwent a surveillance colonoscopy in 1996–1997 were identified from a gastrointestinal pathology database. A proportional hazards analysis assessing 6MP/AZA use as a time-changing covariate was performed to evaluate the effect of 6MP/AZA on: (1) progression to any neoplasia (low-grade dysplasia, high-grade dysplasia, or CRC), and (2) progression to advanced neoplasia (high-grade dysplasia or CRC). Results: A total of 315 subjects met inclusion criteria and were followed for an average of 8 years from their first surveillance examination. There were no significant differences in rates of progression to advanced neoplasia or to any neoplasia between 6MP/AZA users and never-users by log-rank testing. The proportional hazards analysis resulted in hazard ratios of 1.06 (95% confidence interval, .59–1.93) and 1.30 (95% confidence interval, .45–3.75) when considering the effect of exposure to 6MP/AZA on progression to any or to advanced neoplasia, respectively. The results were unaffected by known potential confounders. Conclusions: In UC patients with no initial history of dysplasia, 6MP/AZA use appears to have little or no effect on the rate of neoplastic transformation in the colon. Importantly, the use of 6MP/AZA did not increase malignant transformation in UC. Patients with ulcerative colitis (UC) have an increased risk for colorectal cancer (CRC) when compared with the general population.1Eaden J.A. Abrams K.R. Mayberry J.F. The risk of colorectal cancer in ulcerative colitis a meta-analysis.Gut. 2001; 48: 526-535Crossref PubMed Scopus (2246) Google Scholar, 2Ekbom A. Helmick C. Zack M. et al.Ulcerative colitis and colorectal cancer. A population-based study.N Engl J Med. 1990; 323: 1228-1233Crossref PubMed Scopus (1541) Google Scholar, 3Itzkowitz S.H. Cancer prevention in patients with inflammatory bowel disease.Gastroenterol Clin North Am. 2002; 31: 1133-1144Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Although prophylactic colectomy is arguably the most definitive method to reduce this risk, most patients and their physicians elect to undergo a program of surveillance. This entails regular office visits and periodic colonoscopies with multiple biopsies of colonic mucosa, using the histopathologic finding of dysplasia or cancer as an indication for colectomy, and the absence of dysplasia as an indication for continued surveillance. Although there are no controlled studies showing a mortality benefit for dysplasia surveillance, some studies have suggested a survival benefit4Karlen P. Kornfeld D. Brostrom O. et al.Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study.Gut. 1998; 42: 711-714Crossref PubMed Scopus (251) Google Scholar, 5Choi P.M. Nugent F.W. Schoetz Jr, D.J. et al.Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis.Gastroenterology. 1993; 105: 418-424Abstract PubMed Google Scholar and the practice of surveillance is endorsed in several practice guidelines.6Kornbluth A. Sachar D.B. American College of Gastroenterology, Practice Parameters CommitteeUlcerative colitis practice guidelines in adults (update).Am J Gastroenterol. 2004; 99: 1371-1385Crossref PubMed Scopus (574) Google Scholar, 7Eaden J.A. Mayberry J.F. Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease.Gut. 2002; 51: V10-V12Crossref PubMed Scopus (301) Google Scholar, 8Winawer S. Fletcher R. Rex D. et al.Colorectal cancer screening and surveillance clinical guidelines and rationale—update based on new evidence.Gastroenterology. 2003; 124: 544-560Abstract Full Text PDF PubMed Scopus (1972) Google Scholar Surveillance colonoscopy has many known limitations,9Shanahan F. Quera R. CON: surveillance for ulcerative colitis-associated cancer: time to change the endoscopy and the microscopy.Am J Gastroenterol. 2004; 99: 1633-1636Crossref PubMed Scopus (9) Google Scholar, 10Eaden J. Abrams K. McKay H. et al.Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis.J Pathol. 2001; 194: 152-157Crossref PubMed Scopus (196) Google Scholar not the least important of which is the development of colorectal neoplasia despite careful observation.11Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar Because of these limitations, there is growing interest in whether chemoprevention can serve as an adjunct to dysplasia surveillance.Mesalamine-based medications are the most commonly prescribed anti-inflammatory drugs for the treatment of UC, and have been shown in some studies to prevent colorectal neoplasia in this patient population.11Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar Although the mechanism(s) by which mesalamine might exert its chemopreventive effect has yet to be established clearly, it seems reasonable that the chemopreventive activity of mesalamine compounds relates to their ability to reverse inflammation.12Itzkowitz S.H. Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease the role of inflammation.Am J Physiol. 2004; 287: G7-G17Crossref PubMed Scopus (1018) Google Scholar If this is true, we hypothesized that other anti-inflammatory medications used to treat UC also might be chemopreventive.The purine analog immunomodulators, 6-mercaptopurine (6MP) and azathioprine (AZA), are among the most commonly prescribed drugs for the treatment of UC. Although their specific mode of action continues to be investigated,13Dubinsky M.C. Azathioprine, 6-mercaptopurine in inflammatory bowel disease pharmacology, efficacy, and safety.Clin Gastroenterol Hepatol. 2004; 2: 731-743Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar they ultimately reduce colonic inflammation and are effective at maintaining remission in UC.14George J. Present D.H. Pou R. et al.The long-term outcome of ulcerative colitis treated with 6-mercaptopurine.Am J Gastroenterol. 1996; 91: 1711-1714PubMed Google Scholar, 15Hawthorne A.B. Logan R.F. Hawkey C.J. et al.Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.BMJ. 1992; 305: 20-22Crossref PubMed Scopus (419) Google Scholar, 16Rosenberg J.L. Wall A.J. Levin B. et al.A controlled trial of azathioprine in the management of chronic ulcerative colitis.Gastroenterology. 1975; 69: 96-99PubMed Google Scholar To date, only a few studies have examined the role of 6MP or AZA on the progression of neoplasia in UC. Of those that have addressed this question, no chemopreventive role for 6MP was found.17Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (462) Google Scholar, 18Fraser A.G. Orchard T.R. Robinson E.M. et al.Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.Aliment Pharmacol Ther. 2002; 16: 1225-1232Crossref PubMed Scopus (169) Google Scholar, 19Lashner B.A. Heidenreich P.A. Su G.L. et al.Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study.Gastroenterology. 1989; 97: 255-259Abstract PubMed Scopus (295) Google Scholar, 20Tung B.Y. Emond M.J. Haggitt R.C. 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: 89-95Crossref PubMed Scopus (418) Google Scholar, 21Rutter 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 (981) Google Scholar However, there are several important limitations to these studies. First, in 3 of these studies, 6MP was not the primary variable under investigation,17Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (462) Google Scholar, 18Fraser A.G. Orchard T.R. Robinson E.M. et al.Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.Aliment Pharmacol Ther. 2002; 16: 1225-1232Crossref PubMed Scopus (169) Google Scholar, 21Rutter 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 (981) Google Scholar and in the other 2 studies, colorectal cancer was not the primary end point.19Lashner B.A. Heidenreich P.A. Su G.L. et al.Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study.Gastroenterology. 1989; 97: 255-259Abstract PubMed Scopus (295) Google Scholar, 20Tung B.Y. Emond M.J. Haggitt R.C. 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: 89-95Crossref PubMed Scopus (418) Google Scholar Second, one of the reports only studied UC patients who had primary sclerosing cholangitis,20Tung B.Y. Emond M.J. Haggitt R.C. 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: 89-95Crossref PubMed Scopus (418) Google Scholar a group considered to be at particularly high risk for developing colorectal neoplasia.11Itzkowitz S.H. Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases.Gastroenterology. 2004; 126: 1634-1648Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar Third, none of these studies accounted for dose changes over time. Finally, it is not clear whether patients studied were initially free of colorectal neoplasia.These methodologic limitations indicate that any potential chemopreventive role of 6MP/AZA remains an open question. To address this issue in a more comprehensive fashion, we performed a retrospective cohort study that takes into account the dose and duration of 6MP/AZA use to investigate whether these medications can prevent the development of dysplasia or CRC in patients with UC who were dysplasia-free at the time surveillance was initiated.Materials and MethodsCohort IdentificationAfter approval by the Mount Sinai School of Medicine institutional review board and in accordance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) guidelines, we ran a query of the Mount Sinai Hospital Gastrointestinal Pathology Registry and identified all UC patients who underwent at least 1 surveillance colonoscopy between January 1996 and December 1997. This time period was selected to allow sufficient follow-up time for patients to develop colorectal neoplasia. Records then were reviewed dating back to the time of their first surveillance examination by a gastroenterologist at our institution, whether in 1996, 1997, or earlier.All histopathologic diagnoses included in the study interval were rendered according to the criteria of the Inflammatory Bowel Disease (IBD) Morphology Study Group.22Riddell R.H. Goldman H. Ransohoff D.F. et al.Dysplasia in inflammatory bowel disease standardized classification with provisional clinical applications.Hum Pathol. 1983; 14: 931-968Abstract Full Text PDF PubMed Scopus (1589) Google Scholar Patients were included only if they had UC for at least 7 years and had a finding of no dysplasia (NoD) at their initial surveillance colonoscopy. Recommendations from a number of different sources suggest initiating dysplasia surveillance at 8 years of UC. We chose 7 years of UC as a cut-off point so that examinations performed to rule out dysplasia in the 8th year of disease would be included. Patients were excluded if they had a finding of indefinite for dysplasia, polypoid or flat dysplasia, or CRC before or during their initial colonoscopy. Patients also were excluded for prior colonic surgery of a segment of ulcerative colitis, a diagnosis of Crohn’s disease, inadequate or absent information on 6MP exposure, inaccessible medical records, or lack of endoscopic or surgical follow-up evaluation after their initial colonoscopy.Clinical InformationDating back to their first surveillance examination by a Mount Sinai gastroenterologist, a single reviewer (V.C.) abstracted demographic data for the creation of a UC Surveillance Database. All patients’ medical records were abstracted for demographic information, histologic and endoscopic findings at all colonoscopies and surgeries, and the history or presence of extraintestinal manifestations of UC. The anatomic extent of disease was classified based on histologic findings as follows: extensive colitis, histologic evidence of colitis proximal to the splenic flexure; left-sided colitis, disease proximal to the sigmoid colon but not proximal to the splenic flexure; and proctosigmoiditis, disease confined to the sigmoid colon and rectum. Pathology reports were reviewed for all surveillance colonoscopies from the time of initial surveillance at Mount Sinai until the end point (see later) was reached. The degree of dysplasia, if any, was recorded, as was the number of biopsy specimens reviewed. Endoscopy notes were reviewed, as were any surgical reports, and both were correlated with the corresponding pathology report. Exposure to medications (mesalamine-based agents, purine analogs, cyclosporine, corticosteroids, folate, and any experimental medications used to treat active UC or to maintain its remission) was recorded as positive if a patient had at least 3 months of consistent use of the medication beginning with the time of his or her first surveillance examination. A second reviewer (S.M.) revisited the medical records to abstract detailed information pertaining to 6MP/AZA use from the time of initial NoD to the time of end point. Patients were considered to have used 6MP/AZA if they had at least 3 months of consistent use of the medication. In addition, to permit analysis of data using the time-changing covariate method (see later), dates of initiation of medication use, dose and/or formulation changes, and cessation of use were recorded. On entry into a Microsoft Access database (Microsoft, Inc, Redmond, WA), dosages were converted into 6MP equivalents for analysis by multiplying azathioprine and Imuran (Prometheus Laboratories, San Diego, CA) doses by .5, and keeping 6MP and Purinethol (GlaxoSmithKline, Inc, Research Triangle Park, NC) doses unchanged.Definitions and End PointsPatients entered the study at the time of their first surveillance colonoscopy of record at Mount Sinai at which NoD was found. We defined the date of this initial examination as time 0 for each patient. The development of low-grade dysplasia (LGD), high-grade dysplasia (HGD), or CRC was defined collectively as any neoplasia. HGD or CRC was defined as advanced neoplasia. All patients were followed-up from time 0 until they reached one of the following end points: (1) advanced neoplasia, (2) colectomy for reasons other than HGD or CRC, or (3) their last or most recent colonoscopy on record. A finding of LGD was included for measuring any neoplasia as an outcome, but patients were not censored for a finding of LGD unless they also had 1 of the 3 end points just listed. Follow-up time was the duration of time between time 0 and the end point. All diagnoses were rendered by expert staff members of Mount Sinai’s Division of Gastrointestinal Pathology and confirmed in intradepartmental conference by its director, a gastrointestinal pathologist with 2 decades of experience in the evaluation of IBD-associated dysplasia (N.H.).Data AnalysisMeans and SDs were calculated for all continuous variables and proportions were calculated for all binary variables. Crude proportions are shown for descriptive purposes.The 2 outcomes of interest in this study were progression to any neoplasia and progression to advanced neoplasia. Life-table analysis was used to describe the progression and to test for the influence of covariates known at entry, such as duration of disease, extent of disease, primary sclerosing cholangitis, and age at onset of disease.The influence of the primary variable of interest, purine analog use, was not always constant during follow-up evaluation. To account for this variable’s changing status during follow-up evaluation and to allow for assessment of its cumulative effect, it was analyzed as a time-changing covariate in a proportional hazards model (Cox regression), with values updated as follow-up evaluation proceeded (Figure 1). The time-changing approach additionally was applied to test the influence of a known predictor of outcome: histologic status (NoD compared with LGD or indefinite for dysplasia). With the exception of the handling of purine analog exposure as a time-changing covariate, there are no differences between this type of proportional-hazards modeling and any other similar model that examines the influence of independent variables on a time-dependent outcome. The influence of purine analog use and histologic findings were considered separately and jointly. In separate analyses, purine analog use was characterized first by comparing those who ever used these medications with nonusers. Because some patients were on 6MP or AZA for a short period during their surveillance, usage also was assessed as a binary variable at the threshold of 25 mg/day of 6MP equivalents, thereby combining those with minimal exposure and those who never took these medications. Finally, the possibility of a dose effect over time was assessed by considering the cumulative average dose of purine analogs as a continuous variable. Histologic findings were considered as negative or positive, and analyzed for association with progression to advanced neoplasia. A patient was classified as having a positive histologic history at the time of the first diagnosis of indefinite dysplasia or flat LGD. All analyses were performed using SAS software (SAS, Cary, NC) on a personal computer.ResultsOf the 543 patients identified who underwent surveillance colonoscopy in the calendar year 1996–1997, 315 patients ultimately met our inclusion criteria. Of these, 96 (30.5%) were exposed to 6MP or AZA (Table 1). The 6MP/AZA-exposed and -unexposed groups were very similar with respect to sex, age, duration and extent of disease, and the presence of primary sclerosing cholangitis. With respect to follow-up evaluation, the 6MP/AZA-exposed and -unexposed groups had comparable surveillance patterns, with approximately 8 years of follow-up evaluation, an average of 6 colonoscopies with examinations performed every 21 months, and a similar number of biopsy specimens per examination available for review. Of those patients who had taken 6MP or AZA, the average duration of use was 7.4 years and the average dose while on the medication was 60.6 ± 19.5 mg/day of 6MP equivalents.Table 1Cohort and Surveillance CharacteristicsTotal6MP/AZA+6MP/AZA−a6MP/AZA status by end of follow-up period.Patient characteristics N (%)31596 (30.5)219 (69.5) Male, N (%)169 (54)53 (55)116 (53) UC duration, ybMean (SD).18.2 ± 8.915.7 ± 7.019.4 ± 9.5 Age at diagnosis, ybMean (SD).28.6 ± 12.328.6 ± 13.328.5 ± 12.0 Extensive colitis, N (%)251 (80)77 (79)174 (80) Primary sclerosing cholangitis, N (%)4 (1)0 (0)4 (2)Surveillance patterns Total number of examinations18936541239 Examinations per patientbMean (SD).6.0 ± 2.86.2 ± 2.85.9 ± 2.8 Examination interval, mobMean (SD).21.7 ± 9.520.3 ± 7.422.3 ± 10.2 Biopsy specimens per examinationbMean (SD).13.9 ± 4.113.4 ± 3.714.1 ± 4.26MP use Average duration, ybMean (SD).—7.4 ± 3.4— Average dose, mgbMean (SD).—60.6 ± 19.5— Mesalamine, n (%)248 (79)83 (86)165 (75) Glucocorticoids, n (%)183 (58)81 (84)102 (47) Cyclosporine, n (%)13 (4)11 (11)2 (1) Folate, n (%)101 (32)36 (38)65 (30)a 6MP/AZA status by end of follow-up period.b Mean (SD). Open table in a new tab When analyzed as simple proportions of progression to the given end points, before accounting for dose and duration of medication use, the 2 groups had similar outcomes (Table 2). Approximately 16% of those exposed to 6MP/AZA and 18% of those not exposed progressed to any neoplasia; 5% of each group ultimately developed advanced neoplasia. There was a somewhat higher rate of colectomy for reasons other than HGD or CRC in the 6MP/AZA-exposed group (11.5% vs 5.5%, P = .06).Table 2Crude End Point RatesTotal6MP/AZA+6MP/AZA−N31596219Time to end point, y7.9 + 3.48.1 + 3.57.9 + 3.3Any neoplasia, N (%)54 (17)15 (16)39 (18)Advanced neoplasia, N (%)16 (5)5 (5)11 (5)Colectomy, no HGD/CRC, N (%)23 (7.3)11 (11.5)12 (5.5) Open table in a new tab By univariate analysis, none of the variables tested reached a P value of .15 or less threshold for inclusion into the multivariable model. The variables tested were extent of disease, age at diagnosis, primary sclerosing cholangitis, male sex, and history of use of the following: mesalamine, cyclosporine, corticosteroids, or folate during the patient’s disease history.Subsequent analysis by the proportional hazards model assessed 6MP/AZA use in 3 ways. First, we tracked patients, switching them from nonuser to user status at the time of their first exposure to 6MP. We found neither a beneficial nor harmful effect for progression to any neoplasia (hazard ratio, 1.06; 95% confidence interval [CI], .59–1.93) or to advanced neoplasia (hazard ratio, 1.30; 95% CI, .45–3.75) (Table 3).Table 3Proportional Hazards Analysis6MP/AZA exposureControl for model fIND/fLGDAny exposure≥25 mg/dayAverage daily doseAny neoplasia, HR (CI)1.06 (.59–1.93)1.00 (.54–1.87)1.21 (.70–1.02)—Advanced neoplasia, HR (CI)1.3 (.45–3.75)1.49 (.52–4.32)1.95 (.82–4.60)3.5 (1.24–9.84)fIND/fLGD, flat indefinite for dysplasia or flat low-grade dysplasia; HR (CI), hazard ratio and 95% confidence interval. Open table in a new tab Knowing that some patients were only on 6MP/AZA for part of their surveillance, we calculated an average use of 6MP/AZA use over time for each patient and assessed the impact of exposure at a threshold of 25 mg/day mean exposure (using the time-changing covariate model) as a cut-off between users and a group composed of rare users and nonusers. When analyzed at this threshold in the proportional-hazards model, we again found no appreciable protection or harm for 6MP/AZA use. Finally, we analyzed the mean 6MP/AZA dose as a continuous variable to allow for the possibility of a cumulative dose effect. Again, there was no appreciable difference, with a calculated hazard ratio for progression to advanced neoplasia of 1.95 (95% CI, .82–4.60) for each 25 mg/day increase in 6MP/AZA use (Table 3).As a positive control for the time-changing covariate method of statistical modeling, we analyzed the effect of finding flat early grade dysplasia (indefinite for dysplasia or LGD) at surveillance on subsequent progression to advanced neoplasia. The model correctly identified these higher-risk patients as being more likely to progress to more advanced stages of neoplasia (Table 3). When controlling for a finding of early grade dysplasia in multivariate analysis, the estimate of the effect of 6MP was not altered meaningfully.DiscussionThe purine analog immunodulators are effective and of acceptable safety in the induction and maintenance of remission in UC.14George J. Present D.H. Pou R. et al.The long-term outcome of ulcerative colitis treated with 6-mercaptopurine.Am J Gastroenterol. 1996; 91: 1711-1714PubMed Google Scholar, 15Hawthorne A.B. Logan R.F. Hawkey C.J. et al.Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.BMJ. 1992; 305: 20-22Crossref PubMed Scopus (419) Google Scholar, 16Rosenberg J.L. Wall A.J. Levin B. et al.A controlled trial of azathioprine in the management of chronic ulcerative colitis.Gastroenterology. 1975; 69: 96-99PubMed Google Scholar As such, these agents successfully reduce inflammation in the colon. Unlike mesalamine, the question of whether these medications might act as chemopreventive agents has never been explored rigorously. A handful of studies have reported negative findings with respect to a possible role for 6MP/AZA in CRC chemoprevention in IBD. However, for the most part, 6MP/AZA use was not the primary variable studied, or CRC was not the primary end point analyzed.Connell et al17Connell W.R. Kamm M.A. Dickson M. et al.Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease.Lancet. 1994; 343: 1249-1252Abstract PubMed Scopus (462) Google Scholar studied 755 patients with IBD who had taken 2 mg/kg/day of AZA between 1962 and 1991. Exposure ranged from 2 days to 15 years. CRC rate was one of several end points measured. Paradoxically, in an overall analysis of the data, they found significantly more observed cases of cancer than expected. However, when they analyzed only patients with UC in a nested case-control study, the observed-expected ratio was not statistically significant. Fraser et al18Fraser A.G. Orchard T.R. Robinson E.M. et al.Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.Aliment Pharmacol Ther. 2002; 16: 1225-1232Crossref PubMed Scopus (169) Google Scholar examined the records of 2204 patients with IBD, 626 of whom had a history of AZA use. Duration was reported in ranges from 0 to more than 60 months, but the dose of medication was not noted. AZA did not show any effect on the rates of all cancers measured, including CRC and HGD. This held true even when UC patients were analyzed separately. In a study designed to determine the effect of folate deficiency on the risk for dysplasia or CRC in 98 patients with UC, Lashner et al19Lashner B.A. Heidenreich P.A. Su G.L. et al.Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study.Gastroenterology. 1989; 97: 255-259Abstract PubMed Scopus (295) Google Scholar reported that the use of AZA for at least 6 months had no effect (relative risk, 1.12; 95% CI, .26–4.17). Again, dose and duration of use were not assessed. In a study of UC patients who also had primary sclerosing cholangitis, Tung et al20Tung B.Y. Emond M.J. Haggitt R.C. 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: 89-95Crossref PubMed Scopus (418) Google Scholar showed that ursodiol use prevented the development of colorectal dysplasia and cancer. As a secondary variable, they looked at the effect of other medications, such as AZA, although neither the dose nor the duration of AZA use was described. When comparing patients who developed dysplasia with those who did not, the use of AZA had no significant protection or harm in this higher-risk group of UC patients, with a calculated odd" @default.
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• W2026879588 title "Chemoprevention of Colorectal Neoplasia in Ulcerative Colitis: The Effect of 6-Mercaptopurine" @default.
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