Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) for preventing colorectal cancer and colorectal adenoma in the general population.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 41919561 · doi:10.1002/14651858.CD015266.pub3
What was done
The authors conducted a systematic review and meta-analysis searching CENTRAL, MEDLINE, Embase, and clinical trial registries up to March 3, 2025. They included parallel-group and factorial randomized controlled trials evaluating aspirin or other NSAIDs versus placebo or no treatment for primary prevention of colorectal cancer (CRC) or colorectal adenoma (CRA) in the general population. Outcomes included CRC incidence, CRC mortality, CRA incidence, serious adverse events (SAEs), serious extracranial hemorrhage, and hemorrhagic stroke across prespecified follow-up intervals (<10 years, 10 to <15 years, and >=15 years). Study quality was assessed with Cochrane RoB 2, and evidence certainty was graded using GRADE.
What was found
The review identified 10 RCTs encompassing 124,837 participants, all evaluating aspirin (mostly 75-100 mg daily); no RCTs evaluated non-aspirin NSAIDs. For CRC incidence, aspirin resulted in little to no difference at 5 to <10 years (HR 1.00, 95% CI 0.81 to 1.24; 3 studies, 26,702 participants; moderate certainty) and 10 to <15 years (HR 0.95, 95% CI 0.77 to 1.17; 2 studies, 42,412 participants; moderate certainty), but reduced incidence at >=15 years (HR 0.78, 95% CI 0.67 to 0.91; 3 studies, 47,464 participants; very low certainty). CRC mortality showed a potential increase at 5 to <10 years (HR 1.77, 95% CI 1.02 to 3.07; 1 study, 19,114 participants; low certainty), no clear difference at 10 to <15 years (Peto OR 1.14, 95% CI 0.73 to 1.78; 1 study, 39,876 participants; low certainty), and a decrease at >=15 years (Peto OR 0.74, 95% CI 0.60 to 0.90; 5 studies, 53,909 participants; very low certainty). For safety, overall SAEs did not differ significantly (RR 1.06, 95% CI 0.84 to 1.34; 3 studies, 16,442 participants; moderate certainty), but aspirin increased serious extracranial hemorrhage (RR 1.59, 95% CI 1.30 to 1.95; 8 studies, 97,567 participants; high certainty) and hemorrhagic stroke (Peto OR 1.40, 95% CI 1.11 to 1.77; 8 studies, 105,037 participants; moderate certainty).
Why it matters
Routine aspirin in the general population provides no measurable colorectal cancer protection for at least 15 years while definitively increasing bleeding risks. Late apparent protective benefits rely on post-trial observational extensions prone to bias rather than robust trial-phase randomized evidence.
Limits
No randomized trials evaluated non-aspirin NSAIDs. All data demonstrating cancer reductions beyond 15 years came from unblinded post-trial observational follow-up susceptible to treatment crossover and confounding. Findings for adenoma incidence and early mortality had high imprecision and risk of bias, and trials were restricted to populations in North America, Europe, Australia, and Japan.
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