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      Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Background

          Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo.

          Methods

          In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990.

          Results

          861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35–1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32–0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19–0·86, p=0·02) and an IRR of 0·37 (0·18–0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups.

          Interpretation

          600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment.

          Funding

          European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

          Related collections

          Most cited references 19

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          Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.

          Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older. Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention. None. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.

            High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour. We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data. In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60-0·96, p=0·02; mortality HR 0·65, 0·48-0·88, p=0·005), but not rectal cancer (0·90, 0·63-1·30, p=0·58; 0·80, 0·50-1·28, p=0·35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28-0·74, p=0·001; 0·34, 0·18-0·66, p=0·001), but not the distal colon (1·10, 0·73-1·64, p=0·66; 1·21, 0·66-2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20-0·63; 0·24, 0·11-0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36-0·92, p=0·02; 0·47, 0·26-0·87, p=0·01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61-2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70-6·05, p=0·15). Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy. None. Copyright © 2010 Elsevier Ltd. All rights reserved.
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              • Record: found
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              New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.

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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet
                Lancet Publishing Group
                0140-6736
                1474-547X
                17 December 2011
                17 December 2011
                : 378
                : 9809
                : 2081-2087
                Affiliations
                [a ]Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
                [b ]Clinical Genetics, Rigshospital, Copenhagen, Denmark
                [c ]Colorectal Medicine and Genetics, Royal Melbourne Hospital, Melbourne, VIC, Australia
                [d ]Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland
                [e ]St Josefs-Hospital, Bochum-Linden, Germany
                [f ]Département d'Oncologie Génétique, Institut Paoli Calmettes, Marseille, France
                [g ]Clinical Genetics Unit, Princess Anne Hospital, Southampton, UK
                [h ]Department of Medical Genetics, St Mary's Hospital, Manchester, UK
                [i ]Medical and Molecular Genetics, University of Birmingham, Birmingham, UK
                [j ]Istituto Nazionale per lo Studio e, la Cura dei Tumori, Milan, Italy
                [k ]Medical Genetics Clinic, ICMM, University of Copenhagen, Hvidovre, Denmark
                [l ]MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
                [m ]Hereditary GI Cancer Registry, Department of Surgery, Queen Mary Hospital, Hong Kong, China
                [n ]St George's Hospital, London, UK
                [o ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
                [p ]International Hereditary Cancer Centre, Szczecin, Poland
                [q ]Department of Medical Genetics, Queens University Belfast, Belfast City Hospital HSC Trust, Belfast, UK
                [r ]Medical Genetics, Yorkhill, Glasgow, UK
                [s ]Division of Human Genetics, University of Cape Town, Observatory, South Africa
                [t ]Department of Clinical Genetics, Churchill Hospital, Oxford, UK
                [u ]Hunter Area Pathology Service, John Hunter Hospital, New Lambton, NSW, Australia
                [v ]St Mark's Hospital, Imperial College, London, UK
                [w ]Netherlands Foundation of the Detection of Hereditary Tumours and Department of Gastroenterology, Leiden University Medical Centre, Leiden, Netherlands
                [x ]Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
                [y ]Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
                [z ]Department of Pathology, Erasmus University Medical Centre, Rotterdam, Netherlands
                [aa ]Department of Preventative Medicine and Public Health, Hereditary Cancer Institute, Creighton University Medical Center, Omaha, NE, USA
                [ab ]Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
                Author notes
                [* ]Correspondence to: Prof Sir John Burn, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK john.burn@ 123456ncl.ac.uk
                LANCET61049
                10.1016/S0140-6736(11)61049-0
                3243929
                22036019
                © 2011 Elsevier Ltd. All rights reserved.

                This document may be redistributed and reused, subject to certain conditions.

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