Aspirin

Aspirin and other NSAIDs are all effective to some extent, though analgesics without antiprostaglandin activities, such as acetaminophen, are ineffective. As might be anticipated, activity of NSAIDs seems to be related to the dose, frequency, and duration of administration. However, there have been suggestions that aspirin, particularly in high doses, may incite rectal bleeding earlier due to its antiplatelet effects. However, Ahnen found no evidence for this in his review of the literature in 1998,36 and he concluded that there were no confounding variables such as positive fecal occult blood tests (FOBs) or healthier lifestyles in the aspirin studies.

Sjodahl40 notes that the relative risk of CRC with aspirin use is about 0.6 in large cohort studies (40% risk reduction). Attention was called to the fact that tumors in both human and experimental animal models contain increased amounts of prostaglandin E2 which is believed to have a role in the accelerated proliferation that occurs in tumor tissue and that may be attributable to the activation of COX-2

in response to mitogens and growth factors, for example, which will result in an increased production of prostaglandins. The current theory is that the mechanism for the suppressor effect of NSAIDs on carcinogenesis is COX-2 inhibition. However, reliable data on the dose of aspirin or other NSAIDs for optimal benefit for tumor suppression are lacking, and it is still premature to give general recommendations on using NSAIDs for chemoprevention of gastrointestinal cancer.

A study undertaken in Newcastle, U.K., using FAP patients with colectomies, showed an effect of short-term aspirin and sulindac treatment. The normal rectal mucosa of these patients showed a significant reduction in crypt cell proliferation following treatment (John Burn, M.D., unpublished data, 2000), although other reports have failed to demonstrate any alterations.41 Apoptosis appears to be reliably increased by NSAID treatment in the uninvolved rectal mucosa.

Two recent studies on aspirin and its role in colonic polyps have shown benefit.42'43 Sandler et al.42 performed a randomized, double-blind trial with the objective of determining the effect of aspirin on the incidence of colorectal adenomas. They randomly assigned 635 patients with a prior history of CRC to receive 325 mg of aspirin daily or placebo. Their results disclosed that one or more adenomas were found in 17 percent of patients in the aspirin group and 27 percent of patients in the placebo group (P=0.004). The mean (±SD) number of adenomas was lower in the aspirin group than the placebo group (0.30±0.87 vs. 0.49±0.99, P=0.003 by the Wilcoxon test). The adjusted relative risk of any recurrent adenoma in the aspirin group, as compared with the placebo group, was 0.65 (95 percent confidence interval, 0.46 to 0.91). The time to the detection of a first adenoma was longer in the aspirin group than in the placebo group (hazard ratio for the detection of a new polyp, 0.64; 95 percent confidence interval, 0.43 to 0.94; P=0.022).

These authors concluded that the use of aspirin may give a significant reduction in the incidence of colorectal adenomas in patients with a prior history of CRC. Given the statistically significant findings favoring aspirin over placebo, the study was stopped.

Baron et al.43 also performed a randomized, double-blind trial of aspirin as a chemoprevention agent against colorectal adenomas. They randomized 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81mg of aspirin (377 patients), or 325mg of aspirin (372 patients) daily. The findings disclosed that the incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81mg of aspirin per day, and 45 percent in the group given 325mg of aspirin per day (global p=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23).

These authors concluded that aspirin provided a moderate chemopreventive effect on adenomas in the colon.

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