Optimizing Risks and Benefits of Selective Cox2 Inhibitors for Colorectal Cancer Prevention

At the time of this writing, final data reporting the efficacy of selective Cox-2 inhibitors for colorectal cancer prevention have not yet been published. Fortunately, these studies were all near completion at the time that drug-associated increased cardiovascular risk was identified. As a result, these studies will produce valid efficacy data for the primary prevention endpoint, which involves colonoscopic detection of adenomas after 3 years of planned study drug use. Based upon their demonstrated efficacy in patients with FAP, we can assume that selective Cox-2 inhibitors will be at least as effective or more so than nonselective NSAIDs for colorectal adenoma prevention.

In the short term, the continued use of the selective Cox-2 inhibitors for cancer chemopre-vention will depend upon the balance of risks and benefits revealed in these studies. Balancing risks and benefits is a complicated process, and one that must be approached with caution. It is important to remember that the currently available studies were designed to assess prevention of colorectal adenomas, not to determine the cardiovascular effects of selective Cox-2 inhibitors. In considering the anticipated data, it stands to reason that individuals with the highest risk of colorectal neoplasia and the lowest risk of cardiovascular disease will benefit most from selective Cox-2 inhibitors. There are, however, multiple factors involved in risk stratification, and at this time we will be forced to draw conclusions based upon incomplete data.

Some of the variables involved in determining risk and benefit are evident before drug treatment begins. In colorectal tumorigenesis, we know that small tubular adenomas rarely if ever progress to invasive cancer. In addition, it is uncommon for a patient with a single small tubular adenoma to develop recurrent colorectal adenomas. Data from large colonoscopy trials show that patients with multiple adenomas, single adenomas 1 cm or more in diameter, or adenomas with villous or tubulovillous histology are most likely to develop recurrent disease. In evaluating the efficacy of a chemopreventive agent, therefore, it is important to select a study cohort with these characteristics and to evaluate the ability of the drug to inhibit these more advanced lesions. Within the large adenoma prevention trials, it may also be possible to cautiously examine the relationship between pre-existing cardiovascular risk factors, such as diabetes or a history of myocardial infarction, and the risk of cardiovascular complications while using selective Cox-2 inhibitors.

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