Sulphasalazine use as a preventive factor for colorectal cancer in ulcerative colitis patients—a review

There is an increased risk of colorectal cancer among patients with ulcerative colitis (1,–8). This increased risk is obvious for morbidity as well as mortality from colorectal cancer, thus ruling out surveillance bias as an explanation. Duration of disease, extent at diagnosis, and age at diagnosis are the only recognized risk factors for a malignant transformation (1). However, it is interesting to note that studies of patients in the 1950s and 1960s show a stronger association between ulcerative colitis and colorectal cancer (5,–8) compared with studies presented later (1,3,9). Although poor methodology in some of these studies may be the underlying reason for this difference, it is not unlikely that the differences in cancer risk in the 1950s compared with the 1990s truly reflect differences in risk. Moreover, keeping in mind that ulcerative colitis is a “modern” disease, figures from both the United States and Scandinavia show clearly an increasing incidence from the Second World War up to the 1980s (8,10,11). This means that there has been an increasing prevalence, and we are presently facing an increasing number of patients with ulcerative colitis with a long duration, i.e., >20-30 years. It is therefore of interest to note that an expected increase of colorectal cancer in ulcerative colitis cases of long duration has failed to materialize so far, at least in Sweden. This is mirrored by a continuous decrease in the incidence of colon cancer in Sweden among persons under the age of 50 years since the beginning of 1960 (12). The absence of an increase could, of course, be due to a different natural course of the disease. It is evident from several recent studies that an excessive number of ulcerative proctitis patients (10) is responsible for a substantial part of the increase in incidence, but this difference still cannot explain the absence of an increase in trend of colorectal cancer in ulcerative colitis patients. Another feasible explanation is that this is due to better surveillance of this patient group, i.e., regular examinations with colonoscopy to detect precancerous changes such as dysplasia. However, in a recent cross-sectional study performed on a sample of patients with extensive ulcerative colitis in central Sweden, we found that only 20% of patients with long-standing ulcerative colitis, i.e., a duration >10 years, were enrolled in colonoscopic surveillance programs. It is therefore not unlikely that the use of a more aggressive pharmacological therapy at least partly could explain the decrease in the occurrence of colorectal cancer in this patient group. Since the introduction of sulphasalazine >50 years ago, >10 million patient-years have been generated by patients undergoing both short-term and long-term sulphasalazine therapy. The majority have been ulcerative colitis patients for whom sulphasalazine, until recently, was the first alternative in most centers worldwide. In Sweden, it has been estimated that approximately two-thirds of all patients diagnosed with ulcerative colitis after 1965 have had sulphasalazine therapy lasting at least 3 months (13). The aim of this review is to present what has been published to date concerning the risk of colorectal cancer in patients with ulcerative colitis after sulphasalazine use. The notion that the use of sulphasalazine protects against malignant transformation in the colorectal tract is not new. Already in the 1980s, researchers from Israel (11) noted the low incidence of colorectal cancer among ulcerative colitis patients in a population-based cohort. The authors attributed this finding to the frequent use of maintenance therapy with sulphasalazine or 5-aminosalicylic acid. Furthermore, a similar finding has been presented in what is probably the best-documented population-based cohort of patients with ulcerative colitis worldwide, in which longitudinal data have been assembled repeatedly in Copenhagen (9). The Copenhagen group has, so far, failed to find any difference in the incidence of colorectal cancer in their patient group compared with the general population. Although the very high colectomy rate can partly explain this finding, patients were also consistently maintained on long-term sulphasalazine therapy, giving further credence to the hypothesis that sulphasalazine may reduce the incidence of colorectal cancer. It is also obvious from another recent study that patients with ulcerative colitis in Denmark, as a whole, do not differ from other populations, i.e., there exists a substantially increased risk of colorectal cancer in ulcerative colitis patients in Denmark (14). Finally, in an evaluation of the effect of colonoscopic surveillance on cancer mortality in patients with ulcerative colitis in Leeds, in the United Kingdom (15), the authors made a similar observation: “A review of the notes of patients with colorectal cancer suggested that virtually none of them were taking disease suppressive drugs such as sulphasalazine, regularly or at all.” The authors therefore postulated that unsuppressed inflammation, although causing few or no symptoms, places these patients at an increased risk of developing colonic cancer. Further indirect inference can be drawn from the controversy regarding colonoscopy surveillance programs for patients with ulcerative colitis to decrease the mortality from this malignancy. In two recent studies from the United Kingdom, it is of interest to note that of the 57 patients who dropped out of the surveillance program at St. Marks Hospital (16), 5 died of colorectal cancer and in Leeds (15), 41 defaulted, of which 1 died of colorectal cancer. These numbers imply that those dropping out of surveillance programs are at a greater risk of dying of colorectal cancer than are those who remain within the program. This could mean that a comparison between those within a program with colonoscopy and those outside could be confounded by reasons for staying or dropping out. Disease activity and/or exposure to pharmacotherapy are variables that could act as confounders in this respect. Further credence to such a hypothesis is offered by the result from Leeds, where seven of the nine patients with ulcerative colitis and colorectal cancer were found outside the surveillance program. Patients with primary sclerosing cholangitis (PSC) complicating ulcerative colitis is another subgroup of patients who have been implicated to be at especially high risk of colorectal cancer (17). Although this might be an artefact due to an unappreciated long duration of the disease, it is of interest that a common characteristic in this patient group is a silent disease. This patient group is therefore less frequently subjected to maintenance therapy with any pharmacological compound compared with other patients with ulcerative colitis, and perhaps this is the underlying reason for the increased risk of colorectal cancer in this patient group. Pharmacotherapy with salicylic acid (aspirin) has repeatedly been shown to have a protective effect against sporadic colorectal cancer among individuals in the general population (18). This is especially prominent in other patient groups taking long-term salicylic therapy, such as patients with rheumatoid arthritis where a substantially lower incidence of colorectal cancer has been found (19). The underlying biological mechanism still remains to be explained in full, but it is not unlikely that a similar effect can be found in patients with ulcerative colitis. This hypothesis was directly addressed in a casecontrol study in Sweden (13). The authors used a population-based cohort of 3,112 cases with ulcerative colitis. One hundred twelve cases of subsequent colorectal cancer were identified in this cohort and were compared with 196 controls matched on extent and duration of disease. Moreover, at the time of diagnosis of the case, the controls had to be alive with a remaining colon and without a diagnosis of colorectal cancer. Pharmacotherapy, especially sulphasalazine, lasting at least 3 months was associated with a significant protective effect against colorectal cancer [relative risk = 0.38, 95% confidence interval (CI) 0.20-0.69]. This protective effect remained unchanged after adjusting for disease activity in a multivariate model. In the multivariate analysis, increased disease activity was associated with a nonsignificant protective effect with a point estimate of 0.8, making it very unlikely that residual confounding with regard to disease activity is the underlying reason for the protective effect of sulphasalazine therapy. In the first issue of Inflammatory Bowel Diseases ®, Lashner and Brezezinski (20), in a commentary to this study (13), question the conclusion of the authors that the use of sulphasalazine has a protective effect against malignant transformation in the colorectal tract in patients with ulcerative colitis. In this commentary, the authors instead concluded that sulphasalazine is an unlikely chemopreventive agent for colorectal cancer in this patient group (20). The authors should be commended for not uncritically accepting all the findings in the original study, and some of the concerns raised by them are valid and should be taken seriously. They hypothesize that colonoscopy surveillance, leading to cancer prevention by colectomy, might have been more frequent in the control subject. However, as already pointed out herein, one of the matching criteria was the presence of an intact colon among the controls at the time of diagnosis of the case, making this bias impossible. Although it may well be that yet unknown factors that the authors propose to be associated with disease activity protect the cell from malignant transformation, we think that such a hypothesis is highly speculative and constitutes a less likely explanation than a protective effect of sulphasalazine. The authors (20) also raise the question of the role of folic acid. Folate deficiency has been reported to be associated with an increased risk of sporadic colorectal cancer in the normal population (21). Because sulphasalazine has been reported to impair folate absorption, it has been hypothesized that sulphasalazine use could further increase the risk of colorectal cancer in patients with ulcerative colitis (22). Further credence to this hypothesis was lent by a report of a rat animal model in which sulphasalazine was initially implicated as a cocarcinogen in colon cancer because of its antifolate nature (23). However, this study was later severely criticized (24) and the authors, after refining the model, retracted their original findings and concluded that there is no cocarcinogenic effect of sulphasalazine for colon cancer in rats (25). Folate supplementation during sulphasalazine therapy is rarely used in Europe but seems to be more common in the United States. It was therefore not surprising that folate supplementation was virtually nonexistent in the Swedish study (13). This information should have been documented in the study, and it is unfortunate that this oversight by the authors has cast doubts on the validity of the results. It is also of interest to note that the most common reason in the Swedish study for nonexposure to sulphasalazine was an allergic reaction to the compound, mostly manifesting itself within the first few weeks after starting the therapy. In the only other study that has analyzed the risk of dysplasia or cancer in the colorectal tract in patients with ulcerative colitis, the only significant finding was the substantially increased risk of colorectal cancer among patients with sulpha allergy; these patients consequently were not exposed to sulphasalazine (22). The odds ratio in that study was 11.7 (CI = 1.7-83.1), a result indicating an even stronger protective effect than in the Swedish study. We conclude that sulphasalazine should be regarded as a possible chemoprotective agent for colorectal cancer in ulcerative colitis patients. However, further studies are needed using retrospective or prospective data before a general recommendation of this potential prophylaxis can be made.