Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT
Background: The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer (CRC) chemoprevention, aligned with an excellent safety profile. Objectives: The objectives were to determine whether or not EPA prevents colorectal adenomas, e...
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| Format: | Article |
| Language: | English |
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NIHR Journals Library
2019-06-01
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| Series: | Efficacy and Mechanism Evaluation |
| Subjects: | |
| Online Access: | https://doi.org/10.3310/eme06040 |
| _version_ | 1828313789852811264 |
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| author | Mark A Hull Kirsty Sprange Trish Hepburn Wei Tan Aisha Shafayat Colin J Rees Gayle Clifford Richard F Logan Paul M Loadman Elizabeth A Williams Diane Whitham Alan A Montgomery |
| author_facet | Mark A Hull Kirsty Sprange Trish Hepburn Wei Tan Aisha Shafayat Colin J Rees Gayle Clifford Richard F Logan Paul M Loadman Elizabeth A Williams Diane Whitham Alan A Montgomery |
| author_sort | Mark A Hull |
| collection | DOAJ |
| description | Background: The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer (CRC) chemoprevention, aligned with an excellent safety profile. Objectives: The objectives were to determine whether or not EPA prevents colorectal adenomas, either alone or in combination with aspirin, and to assess the safety/tolerability of EPA, in the free fatty acid (FFA) form or as the triglyceride (TG), and aspirin. Design: This was a randomised, blinded, placebo-controlled, 2 × 2 factorial trial. Setting: The NHS Bowel Cancer Screening Programme (BCSP). Participants: Patients (aged 55–73 years) identified as ‘high risk’ (i.e. those who have five or more colorectal adenomas of < 10 mm in size or three or more colorectal adenomas if one is ≥ 10 mm in size) at screening colonoscopy. Interventions: The interventions were capsules containing 2000 mg of 99% EPA–FFA or 2780 mg of 90% EPA–TG (equivalent to 2000 mg of FFA) taken daily, or identical placebo capsules; and 300 mg of aspirin taken daily, or an identical placebo, enteric-coated tablet. Both were taken for ≈1 year until surveillance colonoscopy. All participants and staff were unaware of treatment allocation. Main outcome measures: The primary outcome was the number of participants with one or more colorectal adenomas [adenoma detection rate (ADRa)] at surveillance colonoscopy. Outcomes were analysed for all participants with observable follow-up data by an ‘at-the-margins’ approach, adjusted for BCSP site and by the need for repeat baseline endoscopy. Secondary outcome measures – these included the number of colorectal adenomas per patient [mean adenomas per patient (MAP)], ‘advanced’ ADRa and colorectal adenoma location (right/left) and type (conventional/serrated). Results: Between November 2011 and June 2016, 709 participants were randomised, with 707 providing data (80% male, mean age 65 years). The four treatment groups (EPA + aspirin, n = 177; EPA, n = 179; aspirin, n = 177; placebo, n = 176) were well matched for baseline characteristics. Tissue EPA levels and tolerability were similar for FFA and TG users. There was no evidence of any difference in ADRa between EPA users (62%) and non-users (61%) [risk difference –0.9%, 95% confidence interval (CI) –8.8% to 6.9%] or for aspirin users (61%) versus non-users (62%) (risk difference –0.6%, 95% CI –8.5% to 7.2%). There was no evidence of an interaction between EPA and aspirin for ADRa. There was no evidence of any effect on advanced ADRa of either EPA (risk difference –0.6%, 95% CI –4.4% to 3.1%) or aspirin (risk difference –0.3%, 95% CI –4.1% to 3.5%). Aspirin use was associated with a reduction in MAP [incidence rate ratio (IRR) 0.78, 95% CI 0.68 to 0.90), with preventative efficacy against conventional (IRR 0.82, 95% CI 0.71 to 0.94), serrated (IRR 0.46, 95% CI 0.25 to 0.87) and right-sided (IRR 0.73, 95% CI 0.61 to 0.88) lesions, but not left-sided (IRR 0.85, 95% CI 0.69 to 1.06) adenomas. There was evidence of chemopreventive efficacy of EPA on conventional (IRR 0.86, 95% CI 0.74 to 0.99) and left-sided (IRR 0.75, 95% CI 0.60 to 0.94) adenomas, but not on total MAP (IRR 0.91, 95% CI 0.79 to 1.05) or serrated (IRR 1.44, 95% CI 0.79 to 2.60) or right-sided (IRR 1.02, 95% CI 0.85 to 1.22) adenomas. EPA and aspirin treatment were well tolerated, with excess mild/moderate gastrointestinal (GI) adverse events (AEs) in the EPA alone group. There were six GI bleeding AEs. Conclusion: EPA and aspirin treatment were not associated with a reduction in ADRa. However, both agents displayed evidence of chemopreventive efficacy, based on adenoma number reduction, which was specific to adenoma type and location, and is compatible with known anti-CRC activity of aspirin. Limitations: Limitations of the trial included the failure to recruit to the target sample size of 853, and an unexpected switch of EPA formulation mid-trial. Future work: A future objective should be to understand the mechanism(s) of action of EPA and aspirin using the trial biobank. Established trial infrastructure will enable future trials in the BCSP. Trial registration: Current Controlled Trials ISRCTN05926847. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership. |
| first_indexed | 2024-04-13T16:36:31Z |
| format | Article |
| id | doaj.art-af6edf38b81a43cabcafa96d83b3782a |
| institution | Directory Open Access Journal |
| issn | 2050-4365 2050-4373 |
| language | English |
| last_indexed | 2024-04-13T16:36:31Z |
| publishDate | 2019-06-01 |
| publisher | NIHR Journals Library |
| record_format | Article |
| series | Efficacy and Mechanism Evaluation |
| spelling | doaj.art-af6edf38b81a43cabcafa96d83b3782a2022-12-22T02:39:26ZengNIHR Journals LibraryEfficacy and Mechanism Evaluation2050-43652050-43732019-06-016410.3310/eme0604009/100/25Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCTMark A Hull0Kirsty Sprange1Trish Hepburn2Wei Tan3Aisha Shafayat4Colin J Rees5Gayle Clifford6Richard F Logan7Paul M Loadman8Elizabeth A Williams9Diane Whitham10Alan A Montgomery11Leeds Institute of Medical Research, University of Leeds, St James’s University Hospital, Leeds, UKNottingham Clinical Trials Unit, Queen’s Medical Centre, School of Medicine, University of Nottingham, Nottingham, UKNottingham Clinical Trials Unit, Queen’s Medical Centre, School of Medicine, University of Nottingham, Nottingham, UKNottingham Clinical Trials Unit, Queen’s Medical Centre, School of Medicine, University of Nottingham, Nottingham, UKNottingham Clinical Trials Unit, Queen’s Medical Centre, School of Medicine, University of Nottingham, Nottingham, UKNorthern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UKSouth Tyneside District Hospital, South Tyneside NHS Foundation Trust, South Shields, UKNottingham Digestive Diseases Centre, Queen’s Medical Centre, University of Nottingham, Nottingham, UKSchool of Pharmacy and Medical Sciences, Institute of Cancer Therapeutics, University of Bradford, Bradford, UKDepartment of Oncology & Metabolism, Human Nutrition Unit, The Medical School, University of Sheffield, Sheffield, UKNottingham Clinical Trials Unit, Queen’s Medical Centre, School of Medicine, University of Nottingham, Nottingham, UKNottingham Clinical Trials Unit, Queen’s Medical Centre, School of Medicine, University of Nottingham, Nottingham, UKBackground: The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer (CRC) chemoprevention, aligned with an excellent safety profile. Objectives: The objectives were to determine whether or not EPA prevents colorectal adenomas, either alone or in combination with aspirin, and to assess the safety/tolerability of EPA, in the free fatty acid (FFA) form or as the triglyceride (TG), and aspirin. Design: This was a randomised, blinded, placebo-controlled, 2 × 2 factorial trial. Setting: The NHS Bowel Cancer Screening Programme (BCSP). Participants: Patients (aged 55–73 years) identified as ‘high risk’ (i.e. those who have five or more colorectal adenomas of < 10 mm in size or three or more colorectal adenomas if one is ≥ 10 mm in size) at screening colonoscopy. Interventions: The interventions were capsules containing 2000 mg of 99% EPA–FFA or 2780 mg of 90% EPA–TG (equivalent to 2000 mg of FFA) taken daily, or identical placebo capsules; and 300 mg of aspirin taken daily, or an identical placebo, enteric-coated tablet. Both were taken for ≈1 year until surveillance colonoscopy. All participants and staff were unaware of treatment allocation. Main outcome measures: The primary outcome was the number of participants with one or more colorectal adenomas [adenoma detection rate (ADRa)] at surveillance colonoscopy. Outcomes were analysed for all participants with observable follow-up data by an ‘at-the-margins’ approach, adjusted for BCSP site and by the need for repeat baseline endoscopy. Secondary outcome measures – these included the number of colorectal adenomas per patient [mean adenomas per patient (MAP)], ‘advanced’ ADRa and colorectal adenoma location (right/left) and type (conventional/serrated). Results: Between November 2011 and June 2016, 709 participants were randomised, with 707 providing data (80% male, mean age 65 years). The four treatment groups (EPA + aspirin, n = 177; EPA, n = 179; aspirin, n = 177; placebo, n = 176) were well matched for baseline characteristics. Tissue EPA levels and tolerability were similar for FFA and TG users. There was no evidence of any difference in ADRa between EPA users (62%) and non-users (61%) [risk difference –0.9%, 95% confidence interval (CI) –8.8% to 6.9%] or for aspirin users (61%) versus non-users (62%) (risk difference –0.6%, 95% CI –8.5% to 7.2%). There was no evidence of an interaction between EPA and aspirin for ADRa. There was no evidence of any effect on advanced ADRa of either EPA (risk difference –0.6%, 95% CI –4.4% to 3.1%) or aspirin (risk difference –0.3%, 95% CI –4.1% to 3.5%). Aspirin use was associated with a reduction in MAP [incidence rate ratio (IRR) 0.78, 95% CI 0.68 to 0.90), with preventative efficacy against conventional (IRR 0.82, 95% CI 0.71 to 0.94), serrated (IRR 0.46, 95% CI 0.25 to 0.87) and right-sided (IRR 0.73, 95% CI 0.61 to 0.88) lesions, but not left-sided (IRR 0.85, 95% CI 0.69 to 1.06) adenomas. There was evidence of chemopreventive efficacy of EPA on conventional (IRR 0.86, 95% CI 0.74 to 0.99) and left-sided (IRR 0.75, 95% CI 0.60 to 0.94) adenomas, but not on total MAP (IRR 0.91, 95% CI 0.79 to 1.05) or serrated (IRR 1.44, 95% CI 0.79 to 2.60) or right-sided (IRR 1.02, 95% CI 0.85 to 1.22) adenomas. EPA and aspirin treatment were well tolerated, with excess mild/moderate gastrointestinal (GI) adverse events (AEs) in the EPA alone group. There were six GI bleeding AEs. Conclusion: EPA and aspirin treatment were not associated with a reduction in ADRa. However, both agents displayed evidence of chemopreventive efficacy, based on adenoma number reduction, which was specific to adenoma type and location, and is compatible with known anti-CRC activity of aspirin. Limitations: Limitations of the trial included the failure to recruit to the target sample size of 853, and an unexpected switch of EPA formulation mid-trial. Future work: A future objective should be to understand the mechanism(s) of action of EPA and aspirin using the trial biobank. Established trial infrastructure will enable future trials in the BCSP. Trial registration: Current Controlled Trials ISRCTN05926847. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.https://doi.org/10.3310/eme06040aspirincolorectal adenomacolorectal cancereicosapentaenoic acidomega-3 polyunsaturated fatty acid |
| spellingShingle | Mark A Hull Kirsty Sprange Trish Hepburn Wei Tan Aisha Shafayat Colin J Rees Gayle Clifford Richard F Logan Paul M Loadman Elizabeth A Williams Diane Whitham Alan A Montgomery Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT Efficacy and Mechanism Evaluation aspirin colorectal adenoma colorectal cancer eicosapentaenoic acid omega-3 polyunsaturated fatty acid |
| title | Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT |
| title_full | Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT |
| title_fullStr | Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT |
| title_full_unstemmed | Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT |
| title_short | Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT |
| title_sort | eicosapentaenoic acid and or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the nhs bowel cancer screening programme the seafood rct |
| topic | aspirin colorectal adenoma colorectal cancer eicosapentaenoic acid omega-3 polyunsaturated fatty acid |
| url | https://doi.org/10.3310/eme06040 |
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