Evaluating Intermittent Dosing of Aspirin for Colorectal Cancer Chemoprevention.

Aspirin reduces colorectal cancer risk but has a potential for adverse effects. Recent preclinical data suggest that intermittent dosing of aspirin may minimize adverse effects while maintaining efficacy. We conducted a three-arm double-blind randomized placebo-controlled phase II trial. The primary objective of the study was to test for the equivalency of two aspirin schedules, i.e., the effects of daily aspirin 325 mg/day continuously (cont-ASA) for 12 weeks or intermittently and 3 weeks on/3 weeks off on biomarkers related to colorectal carcinogenesis in rectal mucosa. A placebo group enabled the estimation of spontaneous biomarker variation. Eighty-one participants were randomized, of whom forty-five were evaluable. For the primary endpoint of decrease in the Ki-67:BCL2-associated X ratio, we could not establish equivalence for the two treatment regimens and also found no significant difference between them. For the secondary endpoint, cont-ASA treatment was significantly more effective in reducing the Ki-67:terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling ratio. Among exploratory endpoints, we found more reduction in epithelial COX-2 expression in the cont-ASA arm compared with the intermittent aspirin dosing arm. We did not observe significant differences in other secondary and exploratory endpoints. Intermittent aspirin dosing in 3-week cycles does not produce the same biologic effect as continuous dosing. Future studies should examine whether a 1-week on/1-week off schedule can maximize the efficacy and minimize the side effects. Prevention Relevance: In this three-arm double-blind randomized placebo-controlled phase II trial, we could not establish equivalence for daily aspirin 325 mg versus intermittent aspirin (3 weeks on/3 weeks off) on Ki-67:BCL2-associated X ratio. However, compared with intermittent aspirin administration, continuing aspirin was significantly more effective in reducing the Ki-67:terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling ratio and COX-2 in rectal mucosa.