Take a pill for no more polyps: is it that simple?
Authors: Evelien Dekker, Michal F Kaminski
Journal: The Lancet (2018)

Colonoscopy is regarded as the gold standard for detection of colorectal cancer and its precursors, colorectal adenomas and sessile serrated lesions. This procedure should be able to prevent colorectal cancer by detecting and removing those precursor lesions. After adenoma or sessile serrated lesion resection, individuals are considered to be at high risk of developing metachronous lesions and colorectal cancer, and are therefore advised to undergo surveillance colonoscopy. Despite these preventive measures, post-colonoscopy colorectal cancers (PCCRCs) occur at a frequency of up to 8·6%.1Rutter MD Beintaris I Valori R et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Summary Full Text Full Text PDF PubMed Scopus (137) Google Scholar Chemoprevention has the potential to reduce the occurrence of metachronous adenomas and colorectal cancers. Such an anticolorectal cancer effect is known for aspirin.2Rothwell PM Wilson M Elwin CE et al.Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.Lancet. 2010; 376: 1741-1750Summary Full Text Full Text PDF PubMed Scopus (1046) Google Scholar Furthermore, evidence suggests that fish oils might be useful in the prevention of colorectal cancer, although the mechanism of antineoplastic activity is not fully understood.3Liu M Zhou L Zhang B et al.Elevation of n-3/n-6 PUFAs ratio suppresses mTORC1 and prevents colorectal carcinogenesis associated with APC mutation.Oncotarget. 2016; 7: 76944-76954PubMed Google Scholar The naturally occurring omega-3 polyunsaturated fatty acid C20:5n3 eicosapentaenoic acid (EPA) has clinical proof of concept as a polyp-reducing agent from a randomised controlled trial (RCT) in patients with familial adenomatous polyposis.4West NJ Clark SK Phillips RK et al.Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis.Gut. 2010; 59: 918-925Crossref PubMed Scopus (168) Google Scholar In The Lancet, Mark Hull and colleagues5Hull MA Sprange K Hepburn T et al.Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial.Lancet. 2018; (published online Nov 19.)http://dx.doi.org/10.1016/S0140-6736(18)31775-6Summary Full Text Full Text PDF Scopus (69) Google Scholar aimed to assess the potential of EPA and aspirin for chemoprevention of colorectal adenomas in a high-risk population.5Hull MA Sprange K Hepburn T et al.Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial.Lancet. 2018; (published online Nov 19.)http://dx.doi.org/10.1016/S0140-6736(18)31775-6Summary Full Text Full Text PDF Scopus (69) Google Scholar This population was defined as patients who underwent colonoscopy with polypectomy of at least three adenomas if one was at least 10 mm in size, or at least five small adenomas at colonoscopy. In a multicentre, double-blind RCT in 53 Bowel Cancer Screening Programme (BCSP) centres in England, high-risk individuals were allocated to receive EPA 2 g per day (either as free fatty acid or triglyceride), aspirin 300 mg per day, or both, or neither, for 12 months. Nearly 5 years were required to enrol 709 participants, who were allocated in a 1:1:1:1 ratio to one of the four treatment groups. Adenoma outcome data were available for 640 (90%) participants. The primary endpoint was the adenoma detection rate (ADR; the percentage of participants with any adenoma) at 1 year surveillance colonoscopy, which was 62% overall, with no evidence of an effect of EPA (risk ratio [RR] 0·98, 95% CI 0·87–1·12) or aspirin (RR 0·99, 0·87–1·12). Although ADR was not reduced in individuals using EPA or aspirin, on the basis of the secondary analyses, the authors concluded that this study does provide evidence of chemopreventive activity of both agents, which was colorectal adenoma subtype selective and site selective. Aspirin was effective at reducing the mean total number of adenomas per participant (MAP; incidence rate ratio [IRR] 0·78, 95% CI 0·68–0·90), and the number of adenomas in the right-sided colon. EPA resulted in a reduced MAP in the left colorectum compared with placebo (IRR 0·75, 0·60–0·94) but not total MAP (IRR 0·91, 0·79–1·05). The authors suggest that these results could translate into a clinically meaningful decrease in long-term colorectal cancer risk. ADR is a quality parameter that, when increased by regular feedback as an incentive, reduces subsequent colorectal cancer risk.6Kaminski MF Wieszczy P Rupinski M et al.Increased rate of adenoma detection associates with reduced risk of colorectal cancer and death.Gastroenterology. 2017; 153: 98-105Summary Full Text Full Text PDF PubMed Scopus (255) Google Scholar In this study, the study drugs did not have a significant effect on this quality measure, and the effect of MAP reduction on future risk of colorectal cancer is unknown. Both measures are surrogates of colorectal cancer incidence and mortality, which should be considered ultimate endpoints for chemoprevention trials. This last point is of paramount importance because, at least in patients with Lynch syndrome, the effect of aspirin on cancer development might not be primarily mediated through adenoma prevention.7Burn J Gerdes AM Macrae F et al.Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.Lancet. 2011; 378: 2081-2087Summary Full Text Full Text PDF PubMed Scopus (746) Google Scholar The exact impact on clinical practice is as yet unclear. The use of chemoprevention medications in high-risk populations could potentially be useful either to reduce the PCCRCs or to reduce the burden of surveillance colonoscopies. However, most PCCRCs seem to result from missed lesions or incompletely resected lesions,1Rutter MD Beintaris I Valori R et al.World Endoscopy Organization consensus statements on post-colonoscopy and post-imaging colorectal cancer.Gastroenterology. 2018; 155: 909-925Summary Full Text Full Text PDF PubMed Scopus (137) Google Scholar which are reasons for emerging interest in colonoscopy quality improvement.8Kaminski MF Thomas-Gibson S Bugajski M et al.Performance measures for lower gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy (ESGE) quality improvement initiative.Endoscopy. 2017; 49: 378-397Crossref PubMed Scopus (328) Google Scholar Instead of aiming to reduce PCCRCs, the study by Hull and colleagues5Hull MA Sprange K Hepburn T et al.Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial.Lancet. 2018; (published online Nov 19.)http://dx.doi.org/10.1016/S0140-6736(18)31775-6Summary Full Text Full Text PDF Scopus (69) Google Scholar aimed to assess the effect of EPA and aspirin on new metachronous adenomas. Although this study was embedded in the quality-assured English BCSP, an ADR of 62% for surveillance 1 year after clearing colonoscopy is remarkably high,9Martinez ME Baron JA Lieberman DA et al.A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.Gastroenterology. 2009; 136: 832-841Summary Full Text Full Text PDF PubMed Scopus (441) Google Scholar even for a high-risk population. This result suggests these adenomas might be mostly synchronous and not newly grown lesions, and could have been detected and resected at baseline colonoscopy as well. Could the results possibly support further lengthening of the colonoscopy surveillance intervals or rather use of aspirin and EPA instead of surveillance colonoscopies? Based on the study results, after 1 year of daily medication use, there was no effect on the schedule of subsequent surveillance colonoscopy. To reduce the risk of metachronous lesions, only in the UK the highest-risk groups are recommended for 1 year surveillance,10Cairns SR Scholefield JH Steele RJ et al.Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).Gut. 2010; 59: 666-689Crossref PubMed Scopus (866) Google Scholar whereas other European Union countries and the USA provide a 3 year recommendation.11Hassan C Quintero E Dumonceau JM et al.Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) guideline.Endoscopy. 2013; 45: 842-864Crossref PubMed Scopus (417) Google Scholar, 12Lieberman DA Rex DK Winawer SJ Giardiello FM Johnson DA Levin TR Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2012; 143: 844-857Summary Full Text Full Text PDF PubMed Scopus (1423) Google Scholar Ongoing trials are assessing potential further extension of the interval up to 5 years.13Jover R Bretthauer M Dekker E et al.Rationale and design of the European Polyp Surveillance (EPoS) trials.Endoscopy. 2016; 48: 571-578Crossref PubMed Scopus (79) Google Scholar Before recommending long-term use of chemopreventive medication, several key questions should be answered. Would patients be willing to take daily medication to prevent precursor lesions and maybe colorectal cancer in the far future? The low inclusion rate (less than three patients per centre per year) suggests this might be questionable. Although EPA and aspirin were generally well tolerated, the proportion of gastrointestinal adverse events (38%) was high in participants receiving EPA alone. Compliance to taking the medications daily in the long run might be relatively low.14Zhao H Hei N Wu Y et al.Initiation of and adherence to tamoxifen and aromatase inhibitor therapy among elderly women with ductal carcinoma in situ.Cancer. 2017; 123: 940-947Crossref PubMed Scopus (14) Google Scholar Besides an appropriate risk-benefit analysis, cost-effectiveness analyses should address the question of whether daily use of aspirin and EPA would be less costly and more effective than regular surveillance colonoscopy. The road to a paradigm shift to taking chemoprevention medications instead of, or alongside, surveillance colonoscopies to prevent colorectal cancer is still long. In the near future, personalised risk stratification and more accurate non-invasive screening tests seem more appropriate measures to reduce the number of unnecessary surveillance colonoscopies. This strategy might help to select only the individuals that need interventional colonoscopies—ideally, only those individuals with colorectal lesions that are on the verge of becoming malignant. ED reports future participation as a Principal Investigator in a study on the use of eicosapentaenoic acid in patients with familial adenomatous polyposis. ED and MRK have previously collaborated with Colin Rees, one of the authors of the Article discussed in this Comment, in several studies and manuscripts. ED is a collaborator on a grant pending with two of the Article authors for the creation of a network of gastrointestinal centres. ED reports receiving equipment from Olympus and FujiFilm, research funding from FujiFilm, honoraria for consultancy from FujiFilm, Tillots, and Olympus, and speaker's fees from Olympus, all outside the area of work discussed here. MFK has received honoraria for consultancy from AlfaSigma and speaker's fees from Olympus and Norgine, outside the area of work discussed here. Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trialNeither EPA nor aspirin treatment were associated with a reduction in the proportion of patients with at least one colorectal adenoma. Further research is needed regarding the effect on colorectal adenoma number according to adenoma type and location. Optimal use of EPA and aspirin might need a precision medicine approach to adenoma recurrence. Full-Text PDF Open Access