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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

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  • CAPP2 Investigators
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Background: Lynch 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. Methods: In 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. Findings: Between 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. Interpretation: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. Funding: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

TidsskriftThe Lancet
Udgave nummer10240
Sider (fra-til)1855-1863
Antal sider9
StatusUdgivet - 13 jun. 2020

Bibliografisk note

Funding Information:
We dedicate this work to the memory of our friends and colleagues the late Henry Lynch and the late Doug Altman. They made major contributions to the design and analysis of this work. The CAPP2 trial was made possible by the dedicated efforts of Pam Chapman and Gail Barker together with the commitment of the participants and the Research Staff at all of the CAPP2 UK and international sites, with special thanks to Pascale Ives (CAPP2 Australia) and Donna Job for collating the information submitted to Public Health England. The full list of CAPP2 investigators is given in the appendix (p 7). Our thanks to the following investigators, many of whom have now retired: Marie Luise Bisgaard, Carol Chu, Paulo Fidalgo, Steven Gallinger, Tessa Homfray, Pierre Hutter, Julio Leite, James MacKay, Christopher G Marks, Anthony Miles, Vicky Murday, Cristina Oliani, Sylviane Olschwang, Pedro Perez Segura, Gabriella Pichert, Andre-Pascale Sappino, Alfonso Tempesta, and Ian Walpole. We acknowledge the contribution of the late Caroline Langman and Mohammad Movahedi who contributed to the earlier analyses of this cohort. Our thanks to Brian Shand and Andrew Bacon, Public Health England, UK for their expertise in developing the pseudonymisation code. We also acknowledge the contribution of TrakGene Genetics Information Management Solutions for providing the database software supporting this trial.

Funding Information:
DGE reports personal fees and other from AstraZeneca, outside the submitted work. JCM reports grants from MRC and Bayer, during the conduct of the study. TS reports grants from Sigrid Juselius Foundation, Instrumentarium Science Foundation, Emil Aaltonen Foundation, Finnish Medical Foundation and travel expenses from Medtronic Finland Oy (outside the submitted work); and Co-owner of Healthfund Finland Oy. DTB reports grants from Cancer Research UK during the conduct of the study. GM reports having being paid for consultancy by Bayer (more than 3 years ago) plus engagement with non-ASS companies investigating the effect of chemoprevention. FM is supported by Cancer Council of Victoria and NSW; Cancer Australia. J-PM and KP are supported by The Finnish Cancer Foundation & Jane and Aatos Erkko Foundation, Finland. DGE is supported by the all Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). RR is supported by Medical Research Council (MRC) of South Africa. JB received a fee as a speaker at a Bayer workshop in 2010. All other authors declare no competing interests.

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