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Aspirin as adjuvant therapy for colorectal cancer: a promising new twist for an old drug.

EVEN BEFORE THE TIME OF HIPPOCRATES, WILLOW EXtracts, which contain salicylates, were used in medicine as analgesic, anti-inflammatory, and antipyretic agents. Acetylsalicylic acid was isolated in the mid-19th century, and since 1899 when it was patented, aspirin has enjoyed global popularity. The relatively recent discovery of its antiplatelet activity has also led to the widespread use of aspirin as an antistroke and cardioprotective agent, but the list of its medical applications continues to increase. More than 30 years ago, Sporn et al coined the term chemoprevention to describe and propose the use of oral drugs, chemicals, or supplements to reduce the risk of cancer. In the ensuing decades, chemoprevention research has generated high hopes and enormous increases in funding, although only a few agents have shown efficacy in clinical trials, and of those few, most are too toxic for use by average-risk individuals. In addition to its other effects, aspirin has been shown to be a potentially effective chemopreventive agent for a number of cancers, but most clearly for colorectal neoplasia. Numerous observational studies and randomized trials have demonstrated the efficacy of aspirin against the development of colorectal adenomas and cancer through its actions as an inhibitor of the cyclooxygenase 2 (COX-2) pathway, which is overexpressed in 80% to 85% of colorectal cancers. Nonetheless, aspirin is not recommended as a colorectal cancer chemopreventive agent because of its adverse effects— notably gastrointestinal irritation and bleeding. Specific COX-2 inhibitors, such as rofecoxib or celecoxib, which have less gastrointestinal toxicity than aspirin, also have failed to come into widespread use because of their unexpected cardiovascular toxicity. However, aspirin may now have yet another new role as a cancer treatment agent, at least in the adjuvant setting. In this issue of JAMA, Chan and colleagues report that, among patients with colorectal cancer participating in a large cohort study, aspirin users had a 29% lower cancer-specific mortality and a 21% lower overall mortality than nonusers. The reduction in mortality was even greater among patients who initiated aspirin use after cancer diagnosis than among those who used it before, and the benefit was limited to those with tumors that overexpressed COX-2. Although these findings are based on an observational study rather than an intervention trial, they meet many of the usual criteria for acceptance as valid and causal. In a previous observational study of stage III colon cancer patients treated in a randomized chemotherapy trial, Fuchs et al found similar survival benefits among consistent aspirin users. The finding that former aspirin users derived less benefit from subsequent aspirin use than former nonusers did is biologically plausible, considering the tumors that developed in former users were not prevented by aspirin use. Furthermore, the results were consistent across a variety of strata such as age, sex, and cancer site (colon vs rectum). Most compelling, the benefits of aspirin use were observed only among patients who had COX-2–expressing tumors, enhancing the biological plausibility of the findings. In the study by Chan et al, the survival benefits of aspirin were similar in patients who received standard adjuvant chemotherapy and those who did not, and in patients with stage I and stage II disease as well as those who had stage III disease at diagnosis. Thus, aspirin may have the potential to be useful as adjuvant therapy not just for locally advanced disease but for early stage patients as well. Further studies are needed to confirm and extend these findings, and should also investigate the use of aspirin as an agent in individuals with metastatic disease. One such study is the Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C) study, which started in 2003 and randomized patients with untreated metastatic colorectal cancer to 1 of 3 chemotherapy regimens, and in addition randomized them to either a COX-2 inhibitor (celecoxib) or placebo. The COX-2 inhibitor portion of the study was discontinued in 2005 because the cardiovascular toxicity of the agent became apparent and initial results of the trial indicated no survival benefit for the celecoxib-treated group.