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

John Burn,Anne-Marie Gerdes,Alex Boussioutas,Gabriela Möslein,Jem Rashbass,Finlay Macrae,Carole Brewer,Anthony Ellis,Kirsi Pylvänäinen,Jackie Cook,Harsh Sheth,Diana Eccles,Faye Elliott,Lynn Reed,Raj Ramesar,Annika Lindblom,Lucio Bertario,Lucy Side,D Timothy Bishop ,D Gareth Evans ,Patrick J Morrison ,Judy W C Ho ,Jan Lubiński ,Shirley Hodgson ,Toni T Seppälä ,Jukka–Pekka Mecklin∥ ,Fiona E Mcronald ,Huw Thomas ,Gillian M Borthwick ,Mary Porteous ,Eamonn R Maher ,Rodney J Scott ,Julian R Sampson ,John C Mathers

doi:10.1016/s0140-6736(20)30366-4

Abstract

SummaryBackgroundLynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.MethodsIn the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990.FindingsBetween January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43–0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39–0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34–0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31–0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43–0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously.InterpretationThe case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results.FundingCancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

Highlights

In 1988, Kune and colleagues reported an apparent protective effect of aspirin and other non-steroidal antiinflammatory drugs in a colon cancer case-control study.[1]
All data relating to participants, their random assignment and all clinical outcomes in the trial were collected by the local clinical management centre for each participant and sent to the CAPP2 Offices at Newcastle University, UK, where the dedicated CAPP2 study team maintained the information in a TrakGene database
The distribution of time since recruitment was similar between the groups; 58 (14%) of the aspirin group and 67 (15%) of the placebo group had no follow-up after the intervention phase, predominantly because of refusal to consent to long-term follow-up (61%) or loss to follow-up (34%; figure 1)

Summary

Introduction

In 1988, Kune and colleagues reported an apparent protective effect of aspirin and other non-steroidal antiinflammatory drugs in a colon cancer case-control study.[1] In subsequent years, over 100 observational studies have confirmed the cancer preventive properties of aspirin.[2,3] A series of adenoma prevention trials reported a significant but modest effect of aspirin on new polyp formation.[4] Reviews by Rothwell and colleagues of long-term cancer outcomes among participants in trials of the cardio vascular benefits of aspirin revealed a consistent pattern of significant reductions in cancer incidence and mortality among those randomly assigned to aspirin, following a delay of around 3–5 years.[5,6] The Women’s Health Study[7]. 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

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