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, Harsh Sheth, Faye Elliott, Lynn Reed, Finlay Macrae, Jukka-Pekka Mecklin, Gabriela Möslein, Fiona E McRonald, Lucio Bertario, D Gareth Evans, Anne-Marie Gerdes, Judy W C Ho, Annika Lindblom, Patrick J Morrison, Jem Rashbass, Raj Ramesar, Toni Seppälä, Huw J W Thomas, Kirsi Pylvänäinen, Gillian M Borthwick, John C Mathers, D Timothy Bishop

Journal: Lancet (London, England) 2020;395(10240):1855-1863

PMID: 32534647

Free Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. Electronic address: [email protected].; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.; Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, Australia.; Department of Education & Research, Jyväskylä Central Hospital, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.; St Josefs-Hospital, Bochum-Linden, Germany.; National Cancer Registration and Analysis Service, Public Health England, London, UK.; Instituto Nazionale per lo Studio e, la Cura dei Tumori, Milan, Italy.; Division of Evolution and Genomic Medicine, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Universities Foundation Trust, Manchester, UK.; Clinical Genetics, Rigshospital, Copenhagen, Denmark.; Hereditary GI Cancer Registry, Department of Surgery, Queen Mary Hospital, Hong Kong Special Administrative Region, China.; Department of Molecular Medicine & Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Medical Genetics, Queens University Belfast, Belfast City Hospital HSC Trust, Belfast, UK.; Genomic and Precision Medicine Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.; Department of Gastrointestinal Surgery, Helsinki University Hospital, Helsinki, Finland.; St Mark's Hospital, London, UK; Faculty of Medicine, Imperial College London, London, UK.; Department of Education & Research, Jyväskylä Central Hospital, Jyväskylä, Finland.; Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.

DOI: 10.1016/S0140-6736(20)30366-4