July 2020's 'Paper of the Month' presents the 10-year planned follow up of the randomised control trial CAPP2 on the long-term protective effect of taking regular aspirin in patients with Lynch syndrome.

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial

Burn J, Sheth H, Elliott F, Reed L, Macrae F, Mecklin JP, Möslein G, McRonald FE, Bertario L, Evans DG, Gerdes AM, Ho JWC, Lindblom A, Morrison PJ, Rashbass J, Ramesar R, Seppälä T, Thomas HJW, Pylvänäinen K, Borthwick GM, Mathers JC, Bishop DT; on behalf of the CAPP2 Investigators.

Lancet. 2020 Jun 13;395(10240):1855-1863. doi: 10.1016/S0140-6736(20)30366-4.

What is known about the subject?

There is extensive evidence from population, case-control and polyp prevention studies as well as long-term review of historical aspirin cardiovascular prevention trials that regular intake of aspirin (acetyl salicylic acid) and other non-steroidal anti-inflammatory drugs over long periods is associated with reduced incidence of colorectal and other cancers. Two trials explored the protective effects of aspirin with cancer as a primary endpoint; the Women’s Health Study showed no effect of alternate day 81 mg aspirin up to study end at 10 years, but a subsequent reduction in colorectal cancer in the second decade. The CAPP2 Study randomised 861 carriers of hereditary cancer, Lynch syndrome, average age 42 years, to 600 mg aspirin or 30 g resistant starch, or both in a factorial design. There was no effect at the end of intervention (average 2.5 years) but there was a significant per-protocol protective effect of the aspirin at an average of 4.6 years follow-up.

What the study adds?

The mechanisms of action of aspirin of relevance to colorectal cancer prevention, including for Lynch syndrome, are unknown, thus there is no insight into the time that the intervention takes to come into full effect or the period over which a time-limited intervention will allow protection. By monitoring people with known intervention and disease status, this study examined the magnitude of the effect and provides some indications as to the magnitude of the long-term effect.

The cancer histories of all participants in CAPP2 were reviewed where possible up to the planned 10-year follow-up and a subset from three countries was followed via national registries for up to 20 years. Aspirin prescription ended in 2007 at the latest. Intention-to-treat Cox proportional hazards analysis showed that aspirin protected against the primary endpoint of colorectal cancer (HR=0.65 [95% CI 0.43–0.97], p=0.035). Negative binomial regression, considering all primary cancer diagnoses in the cancer spectrum of Lynch syndrome found similar evidence of aspirin protection (incidence rate ratio 0.58, 95% CI 0.39–0.87, p=0.0085). For those who took aspirin for the planned minimum 2 years, the effect was similar; HR 0.56, CI 0.34–0.91, p=0.019. There were half as many endometrial cancers in the aspirin group but, overall, non-colorectal cancer Lynch syndrome cancers did not significantly differ over longer follow-up. In the second decade, there was some evidence of a decline in non-Lynch syndrome cancers that did not reach statistical significance.

Implications for colorectal practice

Two standard dose aspirins per day for 2 years results in a significant reduction in colorectal cancer incidence in Lynch syndrome carriers; this persists for over a decade but does not become apparent until about 5 years from commencement. During intervention, serious adverse events did not differ significantly from the placebo group in this relatively young group.

The ongoing CaPP3 Study is a dosing non-inferiority trial which will inform optimal dose for cancer prevention versus adverse events. There is now a strong case for prescribing aspirin to young adult carriers of a germline DNA mismatch repair gene defect.

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