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Original Investigation
November 21, 2019

Effect of Supplementation With Marine ω-3 Fatty Acid on Risk of Colorectal Adenomas and Serrated Polyps in the US General Population: A Prespecified Ancillary Study of a Randomized Clinical Trial

Author Affiliations
  • 1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 2Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 3Clinical and Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston
  • 4Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 5Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 6Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 7Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 8Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge
  • 9Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 10Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 11Yale Cancer Center, New Haven, Connecticut
  • 12Department of Medicine, Yale School of Medicine, New Haven, Connecticut
  • 13Smilow Cancer Hospital, New Haven, Connecticut
  • 14Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
JAMA Oncol. 2020;6(1):108-115. doi:10.1001/jamaoncol.2019.4587
Key Points

Question  Does marine ω-3 fatty acid supplementation reduce risk of colorectal cancer precursors in the US general population?

Findings  In this randomized clinical trial that included 25 871 adults, daily supplementation of marine ω-3 fatty acid, 1 g, did not reduce risk of conventional adenomas or serrated polyps. A suggestive beneficial association was observed among individuals with low plasma levels of ω-3 fatty acid at baseline and among African American persons.

Meaning  Daily supplementation with marine ω-3 fatty acids, 1 g, appears not to reduce the risk of colorectal premalignant lesions in the average-risk US population; however, individuals with low plasma levels of ω-3 or African American persons may benefit.


Importance  Marine ω-3 fatty acid has been suggested to protect against colorectal cancer.

Objective  To assess the effect of daily marine ω-3 fatty acid supplementation on the risk of colorectal cancer precursors, including conventional adenomas and serrated polyps.

Design, Setting, and Participants  This study was a prespecified ancillary study of the placebo-controlled randomized clinical trial VITAL (Vitamin D and Omega-3 Trial). An intention-to-treat analysis was used to examine the effect of daily marine ω-3 supplements among 25 871 adults in the US general population (including 5106 African American persons) free of cancer and cardiovascular disease at enrollment. Randomization was from November 2011 to March 2014, and intervention ended as planned on December 31, 2017.

Interventions  Marine ω-3 fatty acid, 1 g daily (which included eicosapentaenoic acid, 460 mg, and docosahexaenoic acid, 380 mg) and vitamin D3 (2000 IU daily) supplements.

Main Outcomes and Measures  Risk of conventional adenomas (including tubular adenoma, tubulovillous adenoma, villous adenoma, and adenoma with high-grade dysplasia) or serrated polyps (including hyperplastic polyp, traditional serrated adenoma, and sessile serrated polyp). In a subset of participants who reported receiving a diagnosis of polyp on follow-up questionnaires, endoscopic and pathologic records were obtained to confirm the diagnosis. Odds ratios (ORs) and 95% CIs were calculated using logistic regression, after adjusting for age, sex, vitamin D treatment assignment, and use of endoscopy. Secondary analyses were performed according to polyp features and participants’ characteristics.

Results  The demographic characteristics of participants at randomization were well balanced between the treatment and placebo groups; for example, 50.6% vs 50.5% were women, and 19.7% vs 19.8% were African American persons were included in each group. The mean (SD) age was 67.1 (7.1) years in the placebo group and 67.2 (7.1) in the ω-3 treatment group. During a median follow-up of 5.3 years (range, 3.8-6.1 years), 294 cases of conventional adenomas were documented in the ω-3 group and 301 in the control group (multivariable OR, 0.98; 95% CI, 0.83-1.15) (1:1 ratio between number of cases and number of participants). In addition, 174 cases of serrated polyps were documented in the ω-3 group and 167 in the control group (OR, 1.05; 95% CI, 0.84-1.29). Null associations were found for polyp subgroups according to size, location, multiplicity, or histology. In secondary analyses, marine ω-3 treatment appeared to be associated with lower risk of conventional adenomas among individuals with low plasma levels of ω-3 index at baseline (OR, 0.76; 95% CI, 0.57-1.02; P = .03 for interaction by ω-3 index). A beneficial association of supplementation was also noted in the African American population (OR, 0.59; 95% CI, 0.35-1.00) but not in other racial/ethnic groups (P = .11 for interaction).

Conclusions and Relevance  Supplementation with marine ω-3 fatty acids, 1 g per day, was not associated with reduced risk of colorectal cancer precursors. A potential benefit of this supplementation for individuals with low baseline ω-3 levels or for African American persons requires further confirmation.

Trial Registration  ClinicalTrials.gov identifier: NCT01169259

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    1 Comment for this article
    It's a Stupid Study Protocol
    Stephen Strum, MD, FACP | Community Practice of Hematology-Oncology
    Look, after all the technological advances in medicine, to perform a study on supplementation with fish oil and omit crucial issues is just not forgivable. What were the baseline levels of EPA and DHA and the associated ratios that correlate with inflammation in the patients studied? This was not addressed. Was any assessment of the patient study group insofar as inflammation addressed? No. Were the doses used correlate with a Biological End Point (BEP) such as levels of EPA and DHA and associated ratios (e.g., AA/EPA, w-6/w-3) or calculations such as Omega-3 Index? No. The total dose of EPA + DHA in this study was 840 mg per day. In my use of fish oil in my oncology practice, obtaining baseline comprehensive fatty acid profile (CFA) levels via Mayo Medical Labs and using the AA/EPA and w-6/w-3 optimal endpoints of 1.5, the average dose of total EPA and DHA per day is approximately 4,000 mg and not 840 mg. And this optimal amount also relates to what the individual patient is eating. Those who eat out and take in a great amount of processed foods will have greater needs of omega-3 fatty acid supplementation to optimize the fatty acid levels and ratios.

    This study empirically used one size to fit all patients. It is a mindless study and one that concluded that there is no benefit to using fish oil in most patients to prevent colorectal adenomas and serrated polyps. But where was the thinking? If the major consideration was " chemopreventive benefit of marine omega-3 fatty acids in the early stage of CRC development, perhaps through an anti-inflammatory mechanism,..." then scientifically use that hypothesis with the appropriate baseline and lab testing. This "study" missed all the important take-home lessons of proving or disproving a medical hypothesis.