Reports

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14th United European Gastroenterology Week

Berlin, Germany / October 21-25, 2006

Dr. Michael Kamm, Chairman of Medicine, St. Mark’s Hospital, London, UK, addressed the audience, “I am very impressed by the extent of the protection afforded by 5-ASA [5-aminosalicylic acid] which reduced the risk of colorectal cancer [CRC] by as much as 80%. Not only did the regular use of 5-ASA result in a substantial decrease in cancer risk, those patients who were most compliant achieved the greatest reduction. That is good circumstantial and cross-sectional evidence.”

He noted that patients with long-lasting ulcerative colitis (UC) in a Swedish trial developed CRC at six times the expected rate of matched control groups in the general population, and the more extensive the disease, the greater the risk. Authors of that study proposed that UC patients less than 15 years of age with pancolitis who do not have their colon removed, might carry a lifetime cancer risk as high as 40%. A significant 72% risk reduction was observed in that trial when UC patients were given 5-ASA for at least three months.

Mutational Prevention

Pharmacologic agents might exert chemoprotective effects against CRC by a number of biochemical and cellular mechanisms, Dr. Kamm remarked, but 5-ASA has a range of additional properties which may be important in helping to avoid the need for surgery, including anti-oxidant and free radical-scavenging properties, anti-proliferative and pro-apoptotic effects, as well as altering the chemical milieu in the gut. Supporting the proposal that genetic and immune factors are involved in the evolution of IBD, he stated it is also noteworthy that the latest in vitro evidence indicates 5-ASA might actually interfere with specific processes in the molecular pathways involving mutations related to cancer development.

According to Dr. Christoph Gasche, Associate Professor of Medicine, Medical University of Vienna, Austria, CRC develops through different mutational pathways than most solid tumours. The chronic inflammation of IBD leads to DNA mutations through the impairment of DNA repair mechanisms, including mismatch and base excision repair and cell-cycle checkpoints as well as oxidative stress. Cell cycle checkpoints monitor the mutational pathways of cell replication and chromosome alignment to ensure the integrity of the cellular DNA during cell division.

Dr. Gasche described two events recently identified by workers at his institution with collaborators in San Diego and North Carolina showing that 5-ASA first activates a cell cycle checkpoint during the synthesis phase (S-phase) of the cell cycle when replication of a potentially cancerous cell is most likely to occur. He explained that this slows cell turnover, which improves the fidelity of DNA so fewer code errors arise (in this case by 20%) during replication, thereby reducing the frequency of aberrant mutations. Fewer deviant mutations add up to a slowing of the cancer development process.

“By adding 5-ASA to cells and calculating changes in the numbers of mutations, we found that, depending on the clone, the mutation rate dropped by 18% and 25%,” Dr. Gasche reported. “That was not the case for a known chemopreventive drug such as ASA despite its structural similarities. So there is good reason to suggest that the molecular effects of 5-ASA act atop its anti-inflammatory and oxygen-radical-scavenging activities. It goes beyond the singular anti-inflammatory mechanisms of other agents to engage with cell replication cycle checkpoints, slow cell-cycle progression during S-phase and improve the fidelity of DNA replication.” He concluded, “For people with colitis and a risk of IBD, taking mesalazine on a regular basis could prevent cancer in the long term.”

Preventing Inflammation-driven Carcinogenesis

Other new findings in basic science have led to current proposals that 5-ASA may also participate in the control of tumour suppressor genes. Dr. Ajay Goel, Division of Gastroenterology, Baylor University Medical Center, Dallas, US, noted that although not previously studied in the context of 5-ASA, methylation-induced silencing of tumour suppressor genes is another key genetic mechanism known to be associated with CRC in IBD. His study tested the hypothesis that 5-ASA could prevent inflammation-driven carcinogenesis through promoter demethylation, permitting the re-expression of methylation-silenced tumour suppressor genes.

Dr. Goel reported a novel mechanism for the action of 5-ASA in which inhibition of key DNA methyltransferases is associated with demethylation of transcriptionally-silenced genes implicated in CRC. Aberrant methylation of gene promoters is an epigenetic modification that is important in the development of IBD-associated CRC and happens early in the multistep progression of these neoplasms; consequently, screening patients for epigenetic signatures of gene methylation and timely institution of 5-ASA therapy may help improve the control of IBD-associated CRC.

Accumulating Evidence and Consensus

Dr. Axel Dignass, Markus-Krankenhaus, Frankfurt/Main, Germany, commented that clinicians will have to continue to rely on retrospective case-control and cohort studies to judge the risk of CRC in IBD, because it will probably never be possible to conduct prospective, randomized, controlled trials since patients would have to be followed for more than 20 years. To date, there are several retrospective trials showing significant risk reductions in CRC with 5-ASA and two non-significant ones.

However, he noted that a meta-analysis from the Mayo Clinic reported last year that even with the negative trials included in the analysis, 5-ASA had a significant overall protective effect on the combined cancer and dysplasia reduction adjusted odds ratio. Looking carefully at the data, he reported that there appears to be no equivalent benefit with respect to CRC from other agents used for IBD, either immunomodulators or new biologic treatments.

Dr. Dignass mentioned that because of accumulating evidence, soon-to-be-published new European guidelines compiled by an expert consensus panel this year will include a statement that chemoprevention with 5-ASA may reduce CRC in UC and should be considered for all UC patients.

Achieving Best Outcome in Clinical Practice

Dr. Simon Travis, Clinical Director, Gastroenterology and Endoscopy, John Radcliffe Hospital, Oxford, UK, remarked that compliance and adherence to 5-ASA is what matters in successful chemoprevention of CRC in clinical practice. He noted that his opinion is supported by a study of 99 patients in UC remission (Am J Med 2003;114:39-43) in which all who relapsed in less than six months had taken <80% of their prescribed medication; 68% of those who relapsed by 12 months had taken <80% of their dose vs. 26% of those who took at least 80%.

“The important message you can tell your patients in the clinic is that if you stop taking your tablets, you have a more than five times greater risk of relapsing,” Dr. Travis stressed. “Patients who took <80% of their prescribed 5-ASA had a relapse odds ratio of 5.5 (95% Cl, 2.3-13.2).”

Studies show that compliance is inversely proportional to increasingly complicated drug regimens and that long treatment periods to achieve and maintain benefit are often difficult for patients to endure, Dr. Travis stated. They want simple therapy; otherwise, it is not unlikely that >40% of them will stop taking their tablets within two weeks. A trial of single vs. divided doses of 5-ASA showed a clear trend of greater (90%) consumption with single doses within six months as opposed to 76% given divided doses. Simple dosing options are becoming available, including sachets, and a variety of approaches to once-daily therapy are currently being explored, he observed.

University of Chicago researchers also discovered that noncompliant patients were more likely to be male, unmarried, fully employed and suffering left-side UC. Age, occupation, family history of IBD, and duration of remission were not associated with noncompliance.

Thus, the keys to improved chemoprevention compliance with 5-ASA are empathy with the patient and a simple and safe dosing regimen.