Abstract
BackgroundThe naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC) chemoprevention, alone or in combination with aspirin, which itself has recognized anti-CRC activity. Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials.DesignThe seAFOod Polyp Prevention Trial is a randomized, double-blind, placebo-controlled, 2 × 2 factorial ‘efficacy’ study, which will determine whether EPA prevents colorectal adenomas, either alone or in combination with aspirin. Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period, malignant change in an adenoma, regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs, regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy. Patients are randomized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo, for approximately 12 months. The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy. Secondary end-points include the number of adenomas (total and ‘advanced’) per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as ‘intermediate risk’ for future surveillance. Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs, resolvin E1 and PGE-M in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination, as well as to discover predictive biomarkers of chemopreventive efficacy. The recruitment target is 904 patients.Trial RegistrationCurrent Controlled Trials ISRCTN05926847
Highlights
The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma number and size in patients with familial adenomatous polyposis
The long natural history of human ‘sporadic’ colorectal carcinogenesis, during which tumor initiation and benign adenoma growth precede transformation into a clinically apparent malignant adenocarcinoma over a number of years, has been the basis for colorectal cancer (CRC) prevention strategies aimed at detection and removal of asymptomatic colorectal adenomas in healthy individuals (either directly by colonoscopy- or flexible sigmoidoscopy (FS)-based screening [2], or indirectly via colonoscopy prompted by faecal occult blood testing [1])
The first patient first visit (FPFV) of the Trial was 11th November 2011. It soon became clear from screening logs at individual Bowel Cancer Screening Programme (BCSP) sites that the eligibility rate was 15–20% rather than the 60% that had been predicted in the original sample size calculation
Summary
Colorectal cancer chemoprevention The scientific and clinical rationale for prevention of colorectal cancer (CRC) is firmly established [1]. In order to detect a minimum 18% relative reduction in adenoma risk in each two-arm comparison (less than the 22% reduction in polyp number compared with placebo in the FAP Trial [15] and below the absolute reduction in polyp number at one year [38%] in the aspirin RCTs [22]) from a 60% adenoma recurrence rate (South of Tyne and Tees BCSP data) at surveillance colonoscopy to 49%, 678 evaluable ‘high risk’ individuals need to be randomized to the four treatment arms, with 80% power at a 5% two-sided significance level. The log relative risk will be estimated using a log-binomial regression model with robust standard errors to allow for potential non-independence of observations within a BCSP centre Both interventions will be fitted simultaneously and in a further secondary analysis, adjusted for ‘repeat colorectal endoscopic procedure within 3 months required’ plus any other covariates identified as important from the baseline comparisons. All participants who experience treatment-emergent ADRs will be listed including participant identification, treatment arm, system organ class, preferred term, unexpectedness, seriousness, severity, start and stop dates/times, action taken and outcome
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