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15th United European Gastroenterology Week

Paris, France / October 27-31, 2007

The lifetime risk of colorectal cancer in patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC), is several times higher than in the general population, increasing gradually with duration of disease. After 30 years, it is estimated that 18% of patients with UC will develop colorectal cancer. The association between 5-aminosalicylate (5-ASA) treatment and protection from colorectal cancer has been observed in multiple retrospective studies, and a meta-analysis has now placed the risk reduction at 49% (OR 0.51, 95% CI: 0.38-0.69) (Velayos et al. Am J Gastroenterol 2005;100:1345-55). The meta-analysis contained data from nine studies (three cohort and six case-controlled trials) with almost 2000 participants. Based on these and other data, guidelines from the European Crohn’s and Colitis Organization (ECCO) have been altered accordingly.

“It is now written down in the ECCO guidelines that 5-ASA compounds may reduce the incidence of colorectal cancer in UC patients and should be considered for all patients with this disease,” reported Dr. Philippe Marteau, Lariboisière Hospital, Paris, France. Citing guidelines that are in press, Dr. Marteau stated that the data supporting the ECCO recommendations are compelling, but the challenge for physicians is making sure that patients are compliant with maintenance 5-ASA, particularly those who are in remission and are no longer motivated by their symptoms to take their medicine.

PODIUM Results

There are several formulations of 5-ASA available, but newer agents, such as mesalazine, have largely replaced sulfasalazine, which is less well-tolerated. Once-daily dosages now appear to be an option over twice-daily dosages, based on similar or greater efficacy. This was emphasized by results of the recently completed PODIUM (Pentasa Once Daily in Ulcerative Colitis for Maintenance of Remission) trial presented at the UEGW. Although this study was developed as a non-inferiority study, the once-daily, higher-dose regimen was found to be significantly more effective. It is the first study to show a statistical advantage for a once-daily regimen of 5-ASA over a twice-daily regimen in maintenance of remission.

“Once-daily studies conducted with other mesalazine drugs have focused on acute disease where compliance isn’t so much of a problem. None of them suggested superior efficacy compared to multiple doses. It is therefore particularly interesting that this trial of the mesalazine sachets focuses on maintenance and has shown superior efficacy for the once-daily, single-sachet regime,” reported Dr. Axel U. Dignass, Markus Hospital, Frankfurt, Germany.

In this study, 362 UC patients at participating centres in eight European countries were randomized to receive the once-daily 2 g sachet of mesalazine or twice-daily 1 g sachet. About two-thirds of the patients had a history of left-sided UC with the remaining diagnosed with pancolitis, but all patients were required to be in remission at entry. The study hypothesis was that rates of relapse, defined as a score >2 on the Ulcerative Colitis – Disease Activity Index (UC-DAI) or a score of 2 with an adjustment of therapy, would be similar in the two groups.

At the end of 12 months, 73.8% of once-daily patients were in clinical and endoscopic remission compared with 63.6% in the twice-daily group (P=0.024). Although it has long been speculated that once-daily therapy could improve outcome, this is the first study to demonstrate it. According to Dr. Dignass, the slightly greater compliance in the once-daily group did not reach statistical significance, which is not surprising in the confines of a well-controlled study in which patients are being specifically questioned about compliance. Although he indicated that the non-significant improvement in compliance might have contributed to the efficacy advantage, he suggested that there might be other benefits of taking a large dose once daily.

“There may be a number of other influencing factors that have yet to be proven, such as differences in sustained bioavailability of active drug substance between the pH-independent, sustained-release profile of mesalazine compared to more pH-dependent formulations,” Dr. Dignass told delegates.

Simplified Maintenance Therapy for Chemoprevention

While these are promising results for maintaining remission, they are also encouraging for chemoprevention, because simplified dosing is considered critical to keeping UC patients on 5-ASA regimens indefinitely. According to Dr. Michael Kamm, St. Mark’s Hospital, London, UK, “Once-a-day therapy is the story, actually. I do believe that this is the way forward.” He made this statement in the context of both relapse and cancer prevention, noting that both are important indications for treatment with this agent.

The same point was made by Dr. Pierre Michetti, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, and Dr. Pia Munkholm, Herlev Hospital, University of Copenhagen, Denmark. Each agreed that all UC patients should receive maintenance 5-ASA therapies. They also confirmed that placing UC patients on long-term 5-ASA therapy would be facilitated by the development of once-daily formulations.

“At this point, I even reintroduce mesalazine in patients who are no longer being maintained on 5-ASA because of the evidence of chemoprevention,” Dr. Michetti commented. In a presentation that focused on current techniques for early detection of dysplasia to prevent cancer, Dr. Michetti emphasized that there are limitations to all methods of surveillance. Although he acknowledged that new tools, particularly chromoendoscopy, could improve dysplasia detection rates, the best approach would be strategies to prevent these early lesions and their potential to transition to colorectal cancer.

The chemoprotection from 5-ASA was initially attributed to inhibition of the cyclo-oxygenase-2 (COX-2) enzyme, which has been considered a target for prevention or treatment of several cancers, but Dr. Munkholm reported that 5-ASA would likely offer additional mechanisms of benefit. While suppressing pro-neoplastic pathways mediated by COX-2, including cell proliferation, 5-ASA increases apoptosis and inhibits effects mediated by tumour necrosis factor alpha, which also includes cell proliferation. More recent studies also suggest that 5-ASA may turn off genetic signals for cancer induction.

“It was first hypothesized that the ability of mesalamine to prevent cancer was related to control of inflammation, but other drugs with anti-inflammatory properties, such as thiopurine, do not seem to protect nearly as well,” concurred Dr. Marteau. “What is now very interesting is looking at the specific anti-inflammatory mechanisms of 5-ASA drugs. For one, these drugs are dependent on peroxysome proliferator-activated receptor gamma ligands, which act as anti-proliferative agents in the human colon and induce apoptosis in colon cell lines. Additionally, 5-ASA slows down DNA replication and cell cycle progression, activates the replication checkpoint, and improves replication fidelity in colorectal cells.”

According to Dr. Marteau, randomized placebo-controlled trials to confirm chemoprevention from 5-ASA are unlikely due to the difficulty of collecting sufficient long-term data and the ethical issues of denying 5-ASA, a standard first-line therapy, to UC patients. However, he indicated that the consistency of benefit in retrospective data has provided sufficient support for 5-ASA chemoprevention as acknowledged in the revised ECCO guidelines.

Summary

The ability of 5-ASA to reduce the risk of colorectal cancer in UC patients by almost half is derived from retrospective data, but the consistency of protection has been observed across multiple studies. This has led experts to suggest that all UC patients should be maintained on one of these agents even if remission is being maintained by another agent. The ability to maintain patients on long-term 5-ASA is being facilitated by the development of once-daily agents which, in the recent PODIUM study comparing a once-daily 2 g sachet to a twice-daily regimen of two 1 g sachets, were found more effective for preventing relapse.