Review Article
5-ASA and colorectal cancer chemoprevention in inflammatory bowel disease: Can we afford to wait for ‘best evidence’?

https://doi.org/10.1016/j.dld.2005.02.012Get rights and content

Abstract

Patients with inflammatory bowel disease have a higher risk of developing colorectal cancer. The main risk factors for colorectal cancer are not suitable targets for therapeutic intervention, and primary chemoprevention is an intriguing therapeutic option. The analogies between acetyl-salycilic acid and 5-amino-salycilic acid, and the results obtained by using acetyl-salycilic acid as a chemopreventive agent in patients with sporadic colorectal cancer have prompted the study of potential chemopreventive effects of 5-amino-salycilic acid in inflammatory bowel disease. The results of both epidemiological and experimental studies have shown that long-term 5-amino-salycilic acid treatments appear to have a chemopreventive effect. The evidence for this effect is provided by retrospective and case-control studies whose results, however, do not reach the highest grades for evidence-based recommendations. Nevertheless, these results are supported by a series of experimental studies demonstrating the multiplicity of actions of 5-amino-salycilic acid. Although data regarding the chemopreventive effect of 5-amino-salycilic acid may not be rigorous enough to meet the criteria for the highest evidence-based medicine recommendations, we feel that the argument to wait until we have Grade A evidence is not necessarily rational in this case, because discontinuation of 5-amino-salycilic acid treatment to perform a randomised controlled trial would be unethical secondary to their proven efficacy for maintenance treatment.

Section snippets

Is there a role for chemoprevention of colorectal cancer in patients with inflammatory bowel disease?

Patients with inflammatory bowel disease (IBD) carry a higher risk of developing colorectal cancer (CRC) as compared to the general population [1], [2]. Clinical factors that increase the risk include disease >10 years, extensive disease, a positive family history of sporadic CRC and the concomitant presence of primary sclerosing cholangitis (PSC) [2], [3]. Some studies also identified younger age at disease onset and, in patients with UC, the presence of backwash ileitis as additional risk

Mechanism(s) of action of 5-ASA in IBD-related CRC: lessons learned from aspirin

The mechanism(s) by which aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) act in the chemoprevention of CRC in non-IBD patients have not been completely elucidated. However, data concerning the chemopreventive effect of aspirin and NSAIDs and CRC are sound and are supported by a series of independent lines of evidence. Indeed, several epidemiological studies have shown an inverse correlation between aspirin intake and the risk of CRC [20], [21], [27]. Furthermore, studies on secondary

Experimental evidence of a chemopreventive effect of 5-ASA in IBD: what we have learned from the bench

Enterocyte proliferation rate and apoptosis seem to be the main mechanisms regulating intestinal epithelial homeostasis [33], [34], [35], [36]. Progressive accumulation of specific alterations in these two regulatory activities is strictly intertwined with the colonic carcinogenesis process. As a matter of fact, apoptosis progressively decreases and proliferation increases in the sequential steps from normal mucosa to CRC [37]. Inhibition of COX activity is one of the main mechanisms by which

The clinical evidence: does the existing data constitute sufficient evidence?

In 1994, Pinczowski et al. [64] carried out a retrospective, population-based, case-control study in a Swedish cohort of more than 3000 UC patients. The aim of the study was to evaluate the possible association between CRC and various factors, including therapy with sulphasalazine (SASP). They found that treatment with SASP was independently associated with a reduction in the relative risk of developing CRC (relative risk, 0.38; 95% CI, 0.20–0.69). Moreover, this effect was not influenced by

The negative studies

Not all clinical studies reported favourable results regarding the chemopreventive effect of 5-ASA on the development of CRC in IBD patients. Negative results mainly came from studies that reported positive results with other drugs such as folate or ursodiol [74], [75], [76]. The peculiarities of the cohorts enrolled in these studies may, at least in part, account for these inconsistencies. In fact, UC patients who were studied by Lashner et al. [74] were referred for several reasons including,

5-ASA and chemoprevention in IBD: can we ask for more from the available evidence?

Evidence-based medicine (EBM) is a tool that provides the clinician with a means to make medical decisions in clinical practice using published information, versus the recommendations made by ‘experts’. These recommendations may be subject to variability due to personal beliefs and knowledge [80], [81].

The basis for the formulation of EBM comes from the compilation of personal experience as well as from other colleagues’ experience, results of experimental studies, data from observational

Conclusions

Pharmacological treatment with the 5-ASAs is a well established mainstay of IBD therapy. In clinical practice, the application of EBM is of fundamental importance in order to improve and rationalise disease management. However, data regarding SASP or 5-ASA in IBD patients may not be rigorous enough to suggest their use as CRC chemopreventive drugs according to the highest level of EBM recommendations [81]. The argument to wait until we have Grade A evidence is not necessarily rational in this

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