Do Fish Oil Supplements Cause Prostate Cancer?

Background

Omega-3 fatty acids, primarily in the form of fish oil, are popular supplements taken primarily for cardiovascular health. But in light of studies suggesting a correlation between higher plasma levels of long-chain omega-3 fatty acids and prostate cancer risk, some clinicians wonder if the benefits of fish oil supplementation outweigh the risks. This article provides an overview of these findings, and their potential clinical implications.

Omega-3 Fatty Acid Sources

Omega-3 fatty acids are essential fatty acids; the body cannot synthesize them.¹ Alpha-linonelic acid (ALA) is an omega-3 fatty acid that is sometimes called plant or vegetable omega-3. Vegetable oils such as soy and canola are the primary sources, but flaxseed, walnuts, and other nuts also contain significant amounts of alpha-linolenic acid. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are called marine omega-3s because they are found in fish.^1.2 For this reason, EPA and DHA supplements are sometimes called fish oils. The body can convert tiny amounts of alpha-linolenic acid into EPA and DHA.^3,4 Docosapentaenoic acid (DPA) is another long-chain omega-3 that comes from fish and is found in fish oil supplements, but to a lesser extent than EPA and DHA.^5,6 DPA can be converted to EPA in the body.⁶

Studies Linking Omega-3 Fatty Acids and Cancer

Randomized controlled trials designed to examine the link between omega-3 fatty acid intake and cancer are unavailable. A meta-analysis of 12 published epidemiologic studies found an association between high serum EPA and DHA levels and high-grade prostate cancer.⁶

The SELECT trial was a randomized, placebo-controlled study of selenium, vitamin E, or both for prostate cancer prevention. Plasma levels of omega-3 fatty acids of patients from this study who developed cancer were compared to those of matched study patients who did not develop cancer.⁵ Men with the highest total levels of EPA, DHA, and DPA had a modestly increased risk of low-grade (HR 1.44, 95% CI 1.08 to 1.93) and high-grade (HR 1.71, 95% CI 1.00 to 2.94) prostate cancer. Similarly, in the Prostate Cancer Prevention Trial, a randomized, placebo-controlled study of finasteride for prostate cancer prevention, men with the highest baseline serum DHA levels had an increased risk of higher-grade prostate cancer (OR 2.50, 95% CI 1.34 to 4.65).⁷ (This study was heavily weighted in the Chua meta-analysis described above). In both of these studies, cases without baseline blood samples available for analysis were excluded.^5,7

Commentary

Why might DHA and EPA increase prostate cancer risk? Contaminants in fish might be carcinogenic, or marine fatty acids might affect the amounts and types of androgens produced in the body in a way that increases prostate cancer risk.⁶

Studies correlating serum omega-3 fatty acids with cancer risk do not prove that eating fish or taking fish oil supplements increase cancer risk. Plasma levels only reflect consumption over the previous three weeks and may not be indicative of the patient’s long-term dietary habits.⁸ Furthermore, in the SELECT population, the difference in plasma levels between men who developed cancer and those who didn’t was very small, and the levels were low, indicating low intake of fatty fish or fish oil supplements.^5,8,9 Regardless, taking fish oil supplements has not been associated with prostate cancer.¹⁰ Not all studies have found an association between omega-3 fatty acids and prostate cancer, and some have even found a protective effect.^6,11-13 In fact, countries where the diet is traditionally high in fish (e.g., Japan) have a lower incidence of prostate cancer than Western cultures.¹⁴ In the absence of prospective studies designed to address this clinical question, it is not surprising that contradictory data exists. Multiple factors are involved in cancer development, and fatty acid metabolism is complex.⁶

Epidemiological evidence suggests that a diet high in omega-3 fatty acids has cardiovascular benefits. The amount needed is not definitive. Although fish is part of a healthy diet, make sure that patients taking fish oil supplements actually need them. The American Heart Association (AHA) recommends that everyone eat a three to four ounce serving of fatty fish (e.g., tuna, salmon, etc) twice a week [Evidence level C; Consensus].¹⁵ Canada’s Food Guide also recommends two 75 g servings weekly.¹⁶ For patients with heart disease, the AHA recommends one gram daily of DHA plus EPA from fatty fish (preferred) or supplements with medical supervision [Evidence level C; Consensus].¹⁷ However, the latest evidence does not support efficacy of fish oil supplements for prevention of cardiovascular events in high-risk patients.^18-21 Keep in mind, though, it may benefit patients with heart failure, and fish oil is still an option for treatment of triglycerides over 500 mg/dL (about 5 mmol/L).^22,23,24

Project Leader in preparation of this PL Detail-Document: Melanie Cupp, Pharm.D., BCPS

References

1. Kris-Etherton PM, Taylor DS, Yu-Poth S, et al. Polyunsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 2000;71:179S-88S.
2. Harper CR, Jacobson TA. Beyond the Mediterranean diet: the role of omega-3 fatty acids in the prevention of coronary heart disease. Prev Cardiol 2003;6:136-46.
3. Hussein N, Ah-Sing E, Wilkinson P, et al. Long-chain conversion of [13C]linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. J Lipid Res 2005;46:269-80.
4. Finnegan YE, Minihane AM, Leigh-Firbank EC, et al. Plant- and marine-derived n-3 polyunsaturated fatty acids have differential effects on fasting and postprandial blood lipid concentrations and on the susceptibility of LDL to oxidative modification in moderately hyperlipidemic subjects. Am J Clin Nutr 2003;77:783-95.
5. Brasky TM, Darke AK, Song X, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst 2013 Jul 10 [Epub ahead of print].
6. Chua ME, Sio MC, Sorongon MC, Morales ML Jr. The relevance of serum levels of long chain omega-3 polyunsaturated fatty acids and prostate cancer risk: a meta-analysis. Can Urol Assoc J 2013;7:E333-43.
7. Brasky TM, Till C, White, E, et al. Serum phospholipid fatty acids and prostate cancer risk: results from the prostate cancer prevention trial. Am J Epidemiol 2011;173:1429-39.
8. Garneau V, Rudkowska I, Paradis AM, et al. Omega-3 fatty acids status in human subjects estimated using a food frequency questionnaire and plasma phospholipids levels. Nutr J 2012;11:46.
9. Welch AA, Bingham SA, Ive J, et al. Dietary fish intake and plasma phospholipid n-3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort. Am J Clin Nutr 006;84:1330-9.
10. Brasky TM, Kristal AR, Navarro SL, et al. Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort. Nutr Cancer 2011;63:573-82.
11. Chua ME, Sio MC, Sorongon MC, Dy JS. Relationship of dietary intake of omega-3 and omega-6 fatty acids with risk of prostate cancer development: a meta-analysis of prospective studies and review of literature. Prostate Cancer 2012;2012:826254.
12. MacLean CH, Newberry SJ, Mojica WA, et al. Effects of omega-3 fatty acids on cancer risk: a systematic review. JAMA 2006;295:403-15.
13. Leitzmann MF, Stampfer MJ, Michaud DS, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr 2004;80:204-16.
14. Mori M, Masumori N, Fukuta F, et al. Traditional Japanese diet and prostate cancer. Mol Nutr Food Res 2009;53:191-200.
15. American Heart Association. Fish and omega-3 fatty acids. September 8, 2010. http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyDietGoals/Fish-and-Omega-3-Fatty-Acids_UCM_303248_Article.jsp. (Accessed August 5, 2013).
16. Health Canada. Mercury in fish. February 15, 2008. http://www.hc-sc.gc.ca/fn-an/securit/chem-chim/environ/mercur/cons-adv-etud-eng.php. (Accessed August 5, 2013).
17. Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003;23:e20-30.
18. Studer M, Briel M, Leimenstoll B, et al. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med 2005;165:725-30.
19. Kwak SM, Myung SK, Lee YJ, et al. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med 2012;172:686-94.
20. ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18.
21. Kromhout D, Giltay EJ, Geleijnse JM, et al. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010;363:2015-26.
22. GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372:1223-30.
23. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333.
24. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol 2009;25:567-79.

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Cite this document as follows: PL Detail-Document, Do Fish Oil Supplements Cause Prostate Cancer? Pharmacist’s Letter/Prescriber’s Letter. September 2013.

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