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nature publishing group EDITORIAL 737 The Prevention of Colitis-Related Cancer by 5-Aminosalicylates: An Appealing Hypothesis that Remains Unproven Jonathan P. Terdiman, MD1 Abstract: Whether or not 5-aminosalicylates can prevent colorectal cancer among patients with colitis remains an open question. The observational studies examining this question have provided conflicting results, but none of these studies have been of sufficient quality to provide a definitive answer one way or another. include performance of surveillance colonoscopy with biopsy (6). However, colonoscopic surveillance is far from a perfect solution, both because of the intrusiveness of the procedure, and because the benefits in terms of risk reduction remain uncertain (6). Therefore, the interest in using a safe class of pharmaceuticals, such as the 5-ASAs, to reduce the risk of colitis-related cancer is understandable. Am J Gastroenterol 2011; 106:737–740; doi:10.1038/ajg.2011.56 CHEMOPREVENTION OF COLITIS-RELATED CANCER BY 5-ASAS IS BIOLOGICALLY PLAUSIBLE INTRODUCTION The idea that cancer risk among patients with colitis can be reduced by therapy with 5-aminosalicylates (5-ASAs) was first suggested by Pinczowski et al. (1) in 1994. Since that time, a large number of observational studies have been published on the topic, including one by Bernstein et al. (2) in this edition of the American Journal of Gastroenterology. The results have been conflicting, a source of frustration to practitioners. As of this writing, I believe it remains plausible, but still unproven, that 5-ASAs can reduce the risk of colitis-related colorectal cancer (CRC). Why is it that we cannot agree on the answer one way or another? WHAT WE CAN AGREE UPON Most studies (3), but not all (4), agree that patients with longstanding extensive ulcerative or Crohn’s colitis have an increased risk for CRC, with a cumulative lifetime risk in the range of 10–20%, representing a two- to fivefold increased risk compared with the risk in the general population (3). Established risk factors for developing CRC in the setting of colitis include the extent, age of onset, and duration of the disease, along with the severity of the inflammation over time (3,5). Other unequivocal risk factors include the presence of primary sclerosing cholangitis and a family history of sporadic CRC (3). Efforts to mitigate the risk There are ample pre-clinical studies reporting on the molecular mechanisms by which 5-ASAs might prevent CRC (7). These pre-clinical studies indicate that the potential beneficial effects of 5-ASAs extend beyond simply reducing colonic inflammation over time. 5-ASAs may interfere with cell-cycle progression and induce apoptosis in neoplastic cells, scavenge reactive oxygen or nitrogen metabolites to reduce the risk of DNA damage, or impact on signaling pathways crucial to neoplastic progression (7). Some of the most compelling data indicate that 5-ASAs may stop cell-cycle progression by activating replication checkpoints resulting in S-phase arrest (8). The activation of replication checkpoints can improve the fidelity of DNA replication in colorectal cells (9,10). Other recent important work on the topic suggests that 5-ASAs may stop neoplastic progression by inhibiting β-catenin signaling (11). Though these pre-clinical studies are of interest, they cannot, however, confirm that 5-ASAs reduce the risk of developing colitis-related cancer. THE PROBLEM WITH OBSERVATIONAL STUDIES All of the studies examining the association between exposure to 5-ASAs and development of CRC have been observational, either case–control or cohort studies, and herein is the root of our problem. Though randomized, controlled trials are 1 Gastroenterology Division, University of California, San Francisco, San Francisco, California, USA. Correspondence: Jonathan P. Terdiman, MD, Gastroenterology Division, University of California, San Francisco, 2330 Post Street, Suite 610, San Francisco, California 94115, USA. E-mail: [email protected] Received 12 January 2011; accepted 25 January 2011 © 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY INFLAMMATORY BOWEL DISEASE see related article on page 731 INFLAMMATORY BOWEL DISEASE 738 Terdiman imperfect, they are preferable to observational studies, even welldone ones, for assessment of a treatment effect (12,13). Observational studies are prone to introduce bias even when it appears that the treated and control groups are similar with respect to key risk factors, and the results can veer unpredictably in either direction (12). A randomized, controlled trial of 5-ASAs in the prevention of colitis-related cancer, however, has been considered impossible to undertake because of the large number of subjects and long duration of follow-up required. If we concede that we must use observational data to address this question, what would be the features of the ideal study? The study population needs to be sufficiently large and well described, and the study population must be followed for a sufficient length of time. The study subjects need to be comparable in terms of the presence or absence of other established risk factors for colitis-related cancer, comparable for exposure to other interventions that might impact on their risk for colitis-related cancer such as surveillance colonoscopy or even just visits to the doctor, and comparable for the likelihood that they would be treated with 5-ASAs. Information on the exposure to 5-ASAs needs to be sufficiently detailed in terms of dose and duration and adherence, and these data need to be assessed in a standardized, valid, and reliable manner. Similarly, the outcome of interest, CRC and/or dysplasia, needs be assessed in a standardized and reliable manner. PREVIOUS STUDIES OF 5-ASA USE THE RISK OF COLITIS-RELATED CANCER Unfortunately, none of the observational studies published or presented on this topic completely satisfy the high-quality standard outlined above. Let’s briefly review a number of key studies, both positive and negative to understand their strengths and weaknesses. The seminal case–control study by Pinczowski et al. (1) found that ≥3 months of 5-ASA therapy was protective against the development of colitis-related cancer (relative risk, 0.38; 95% confidence interval (CI), 0.2–0.69). The study had the virtue of being first to make this observation, and it was the only one to find a protective effect specifically for sulfasalazine. The study was large, population based, and the length of follow-up was appropriate, though imprecisely specified. The study however is limited by a lack of data on the dose and duration of treatment with 5-ASAs. In fact, the investigators could only categorize subjects as having used more or less than 3 months of therapy over time. The study also used very imprecise surrogates to establish disease activity over time, and importantly, the data for the study were all collected by a single investigator by chart review, who was not blinded to the outcome of interest. Eaden et al. (14) undertook a case–control study using very similar methods to that employed by Pinczowski. Eaden et al. found that regular 5-ASA use reduced cancer risk by 75%. The Eaden study provided more detailed information about drug exposure, and more detailed information about other healthrelated behaviors that might reduce CRC risk than was reported by Pinczowski. Eaden et al. established that not all 5-ASAs may The American Journal of GASTROENTEROLOGY be protective, with a protective effect only seen with the use of mesalamine and not sulfasalazine, and Eaden et al. found that visiting a doctor regularly also reduces risk. To some, the latter finding suggests that regular use of 5-ASAs might simply be a marker of healthy behavior, which might result in a lower cancer risk, rather than a true chemopreventive agent. The Eaden study did not ascertain cases and controls from the same population, and it still employed unblinded chart review to collect the data. The case–control study by van Staa et al. (15) was the first on the topic to use a well-validated, population-based data set, the United Kingdom’s General Practice Research Database. Use of the General Practice Research Database would be expected to provide higher-quality data than usually available through chart review, and the General Practice Research Database includes computerized data regarding drug prescriptions. The study, however, was limited to users of 5-ASAs, and therefore only compared regular users as compared with irregular users, and no drug data were available beyond the prior 24 months. The study did have data on exposure to important health-related behaviors, such as seeing the doctor or having a colonoscopy, but not regarding the extent or severity of the colitis. A protective effect for regular 5-ASA therapy in the year preceding CRC was found (odds ratio (OR), 0.60; 95% CI, 0.38–0.96). The studies by Pinczowski et al. (1), Eaden et al. (14), and van Staa et al. (15) all found a protective effect for 5-ASA use with respect to the development of colitis-related cancer. However, a growing number of studies, including the one by Bernstein et al. (2), in this edition of AJG, have produced less certain (5,16), or frankly negative results (2,17,18). Let’s review several of these studies in more detail. Rutter et al. (5) published a case–control study using data from the St. Mark’s Hospital dysplasia surveillance database. The study is notable because both the cases and controls are drawn from a well-characterized group of patients all undergoing surveillance colonoscopy. The study also does a very admirable job of assessing the severity of colonic inflammation over time. Unfortunately, data regarding drug exposure are not very detailed. Rutter et al. found that use of 5-ASAs for > 10 years was not protective for colorectal neoplasia (cancer or dysplasia) (OR, 2.38; 95% CI, 0.67–8.54). However, when sulfasalazine users were excluded from the analysis, a protective effect for mesalamine use was suggested, but could not be confirmed (OR, 0.65; 95% CI, 0.26–1.62). Unfortunately, the reported risk associated with 5-ASA use was not adjusted in a multivariate analysis that included other key variables, such as the histological inflammation score. My colleagues and I performed the largest case–control study to date regarding the impact of 5-ASA therapy on colitis-related cancer risk, and the results were unequivocally negative (18). Using two large insurance administrative claims databases, we compared 364 cancer cases with 1172 controls. The study had the virtues of being large, population-based, and having access to computerized drug prescription data. The study suffers, however, from a lack of long-term drug data, with the analysis limited to drug use in the 12 months before the CRC diagnosis, and from a complete lack of detail regarding the extent and severity of the colitis over time. | VOLUME 106 APRIL 2011 www.amjgastro.com Use of 5-ASA therapy of any dose or duration during the 12 months before the CRC diagnosis was not associated with a reduced risk of CRC (OR, 0.97; 95% CI, 0.77–1.23), nor was there a protective effect when the analysis was limited to mesalamine users. The Bernstein study (2) represents an expansion of a previously published work (19), and it has many virtues. This study is really two studies in one, a restrospective cohort study assessing CRC incidence among 8,744 subjects with inflammatory bowel disease, comparing 5-ASA users (ever, ≥1 year, ≥5 years, ≥7.5 years of cumulative use) with nonusers, and a case–control study assessing exposure to 5-ASA therapy among 101 subjects with CRC as compared with 303 controls. Data for both studies were obtained from the University of Manitoba Inflammatory Bowel Disease Epidemiology Database, which contains computerized data on prescription drug use dating back to 1995. Both studies found no protective effect for 5-ASA therapy. For example, in the cohort study, subjects who used 5-ASAs for at least 5 years (n = 1,109) the hazard ratio for developing CRC was 2.01 (95% CI, 1.04–3.9). In the case–control study, CRC cases had a similar prevalence of 5-ASA use compared with controls with respect to the number of prescriptions or median days the drug was supplied. The OR for developing CRC among those with ≥5 years of 5-ASA was 1.96 (95% CI, 0.84–4.55). The study by Bernstein has the virtues of large size and adequate length of follow-up and detailed data regarding prescription drug refills. The median number of days the drug was supplied for the entire study population was 590, with 66% of the cohort having ever taken a 5-ASA and 38% with 1 year of cumulative use and 13% with 5 years of cumulative use. The study has important limitations too. Though we are provided with detailed data on total drug exposure, the consistency of dosing over time and the actual daily dose was not reported. Is it possible that the chemopreventive effect of 5-ASAs was lost, even among those subjects with a large cumulative dose of the medication, because their use was very inconsistent over time, or because the daily dose was too small? More importantly, the investigators were unable to control for the extent and severity of disease over time. Certainly, the positive association of 5-ASA use with the occurrence of CRC may be the consequence of subjects with more inflammation over time being more likely treated with 5-ASAs. SO WHAT SHOULD WE CONCLUDE? All of the observational studies summarized above, and the others published to date, are lacking in important ways, from the methods of data collection, to the populations studied, to the length of follow-up, to the lack of data regarding critical issues such as drug exposure, or the extent and severity of the disease over time. Also, as one reads through the observational studies summarized above, you are struck by the feeling that patients treated regularly with 5-ASAs are fundamentally different than patients who are not, especially during recent years in which 5-ASA use seems to be so ubiquitous. In the end, we must conclude that none of the published studies published to date are sufficiently robust to definitively answer the question at hand, and I am afraid that further attempts to © 2011 by the American College of Gastroenterology pool the results of the published studies, as we have done previously (20) will not provide the answer either. Is it possible for any observational study to be of sufficient size and quality to sway us? The answer is yes, but it will not be easy. Given the limits of observational data in general, and the mixed results of the studies to date, we must remain skeptical that 5-ASAs prevent cancer. For an observational study to change our minds, it must have clear cut results and it must be one of very high quality, far beyond what has been published so far. The GETAID group from France has yet to publish their case–control study on the subject using data from the CESAME cohort, but the results were presented last year at DDW (21). These investigators did find a protective effect of any 5-ASA use in the year before the occurrence of CRC among the 94 colitis patients at greatest risk for colitis-related cancer (OR, 0.46; 95% CI, 0.24–0.85), and unlike previous published studies, the investigators adjusted for the propensity of the cases and controls to be treated with 5-ASAs, a more sophisticated way of adjusting for important differences in the exposed and nonexposed groups. Though we can reserve final judgment until the study is published, I think the lack of detailed data regarding drug exposure and disease severity will lead us to conclude that this study is not the last word on the topic. So what is the final word on whether or not 5-ASA therapy can reduce the risk of colitis-related cancer? As of now, I think we must conclude that the hypothesis has not been proven, though it has not been definitely disproven either. In the absence of a clear answer, I think it is wrong to advise patients that 5-ASAs are likely to be protective against cancer, or to treat patients with 5-ASA medications for this purpose. I still hold out hope that observational data of sufficient quality will be generated to provide us with a definite answer, but because of the inherent limitations of observational studies, it will not be easy to achieve this goal. CONFLICT OF INTEREST The author declares no conflict of interest. REFERENCES 1. 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Am J Gastroenterol 1995;100:1345–53. 21. Carrat F, Seksik P, Bouvier AM et al. Aminosalicylates, thiopurines and the risk of colorectal cancer in inflammatory bowel disease: a case-control study nested in the CESAME cohort. Gastroenterology 2010;138:S–47 (A 255). | VOLUME 106 APRIL 2011 www.amjgastro.com