A Dose-finding Study of Aspirin for Chemoprevention Utilizing Rectal Mucosal Prostaglandin E2 Levels as a Biomarker

Epidemiological and experimental evidence indicates that aspirin can protect against colorectal cancer. Aspirin inhibits cyclooxygenase enzymes and blocks prostaglandin (PG) biosynthesis. Using rectal PGE2 levels as a mucosal biomarker, we sought to determine the optimal aspirin dose that would significantly suppress PGE2 levels for chemoprevention trials. We conducted a randomized, double-blinded study in 60 subjects with prior sporadic colorectal adenoma(s) and evaluated three aspirin doses (81, 325, and 650 mg) or placebo taken daily for 4 weeks. PGE2 levels in rectal biopsies performed at baseline and week 4 were analyzed by competitive immunoassay. Plasma salicylate levels, pill counts, and subject calendars were used to assess compliance. The 81-mg aspirin dose significantly suppressed PGE2 levels relative to placebo ( P = 0.005) and did so to an equivalent extent as did higher doses ( P > 0.4) in evaluable subjects ( n = 55) over a 4-week treatment period. Serum salicylate levels were associated with aspirin dose ( P = 0.0002). Pill counts and calendars indicated that >98% of doses were taken by all subjects. No adverse events occurred in this short-term study. The 81-mg daily aspirin dose suppressed PGE2 levels to an equivalent extent as did the 650-mg dose and supports the use of this dose for chemoprevention trials.