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Omega-3 Fatty Acids


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The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies sometimes used by patients with cancer. Gary Deng, MD, PhD, and Jyothirmai Gubili, MS, explore the use of omega-3 fatty acids, which have been reported to be associated with health benefits by decreasing inflammation and lowering triglyceride levels. However, evidence to support their use for the prevention or treatment of cancer is not conclusive.

Scientific Name: Omega-3

Common Names: Polyunsaturated fatty acids

Overview

OMEGA-3 FATTY ACIDS (omega-3s) play an important role in many physiologic processes. They are acquired through diet or via supplementation due to the inability of the human body to synthesize them. Fatty fish, some plants, and nut oils are rich in omega-3s. Dietary supplements include fish oil, krill oil, cod liver oil, and algal oil, available in the form of capsules or soft gels. They are widely used for depression, to lower cholesterol, to boost memory, as well as to reduce inflammation and the risk of heart attack.

Alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are among the most studied omega-3s. They are also the commonly used forms in supplements. Following intake, ALA is converted to EPA and DHA, which are readily used by the body. The U.S. Food and Drug Administration recommends limiting the intake of EPA and DHA to 3 g/d.

Omega-3s have been researched extensively, but conclusive data to support their use for disease prevention or treatment are lacking.

The Science

OMEGA-3s HAVE been reported to influence inflammatory responses.1 In a randomized trial of 97 patients with rheumatoid arthritis, 9-month supplementation (cod liver oil containing 2.2 g of n-3 essential fatty acids per day) was shown to reduce the need for daily use of nonsteroidal anti-inflammatory drugs by more than 30% (P = .002).2

Studies also suggest a potential role for omega-3s in the treatment of depression and memory loss. A 2001 Finnish survey, which included 3,204 adults, found that infrequent (less than once a week) consumption of fish was associated with higher likelihood of depressive symptoms.3 When used as adjuvants, omega-3s conferred benefits in patients with major depressive disorders4 and in those with recent-onset psychosis.5 However, a randomized study involving 83 adults receiving standard treatment for major depression did not find any detectable benefit of fish oil supplements (3 g daily for 16 weeks) compared with placebo.6 In another large, 3-year trial of 1,680 elderly individuals with memory complaints, omega-3 supplementation, by itself (P = .812) or in combination with lifestyle interventions (P = .142), did not have a significant effect on cognitive decline when compared with placebo.7

Omega-3s are also widely consumed for preventing cardiovascular disease. Findings indicate that supplementation with omega-3s helps to lower cholesterol levels8; reduce recurrence in patients with a history of stroke receiving low-dose statin therapy9; and improve cardiometabolic profiles in high-risk individuals.10

Gary Deng, MD, PhD. Dr. Deng is Medical Director, Attending Physician, and clinical
member, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.

Gary Deng, MD, PhD. Dr. Deng is Medical Director, Attending Physician, and clinical member, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.

Jyothirmai Gubili, MS. Ms. Gubili is Editor, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.

Jyothirmai Gubili, MS. Ms. Gubili is Editor, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.

However, a meta-analysis of 20 studies involving 68,680 patients did not find any significant association between supplementation with omega-3s (for secondary prevention of cardiovascular disease with a median dose of 1.51 g/d and a median duration of 2 years) and a reduced risk of cardiovascular disease events.11

Investigations into the potential of omega-3s in the prevention of cancer produced mixed results. A large study of 35,016 postmenopausal women reported an association between fish oil supplementation and a decreased risk of breast cancer (hazard ratio [HR] = 0.68; 95% confidence interval = 0.50–0.92).12 Improvements in disease-free and overall survival were also observed in patients with stage III colorectal cancer with wild-type KRAS and mismatch repair–deficient tumors following higher intake of marine omega-3s (median intake of 0.05 g/d in women and 0.06 g/d in men).13 In patients with colorectal cancer undergoing radical resection, postoperative supplementation (1.2 g of lipid/ kg/d for 1 week) resulted in lowering inflammatory response and significantly modulating immune response (increase in CD4-positive/CD8-positive ratio, P = .035; depression in serum tumor necrosis factor–alpha [TNF-a] levels, P = .125) compared with the control group.14

However, data from the SELECT trial indicate an increased risk of prostate cancer in patients with high blood levels of omega-3.15 Furthermore, a randomized trial that included 2,501 survivors of cardiovascular disease, 5 years of daily supplementation (600 mg of EPA and DHA, in a ratio of 2:1) had no impact on cancer outcomes.16 In patients with sporadic colorectal neoplasia, daily EPA supplementation (with 2 g of EPA free fatty acid) for 1 year did not affect reductions in the proportion of patients with at least one colorectal adenoma when compared with aspirin or placebo.17 Also, in the VITAL prevention trial involving 25,871 participants and a median follow-up of 5.3 years, supplementation with omega-3s (1 g/d) did not lower the incidence of invasive cancer or major cardiovascular events compared with placebo.18

OF NOTE

Patients on warfarin or other anticoagulants should be advised about the potential for elevated international normalized ratio and an increased risk of bleeding with omega-3 supplements.

Interestingly, a few studies suggest that fish oil supplementation may enhance the effectiveness of chemotherapy, improve survival,19 and help maintain muscle mass20 in patients with non–small cell lung cancer (NSCLC). An EPA-enriched supplement was reported to improve the tolerability of chemotherapy in patients with advanced colorectal cancer.21 Larger studies are needed to resolve the ambiguity and to determine the most effective dosage and duration.

Mechanistic studies show that omega-3s confer cardioprotection likely via their incorporation into atherosclerotic plaques, rendering them more stable, which is associated with fewer fatal and nonfatal cardiovascular events.22 Omega-3s also demonstrated antiarthritic effects in a murine model by inhibiting the production of interleukin-17 and by increasing the expression of FOXP3, which is essential for regulatory T-cell function.23

In other studies, fish oil was shown to inhibit integrin-linked kinase expression through induction of the transcription factor that activates enhanced binding protein AP-2 alpha, resulting in the inhibition of NSCLC growth.24 Dietary omega-3s were shown to modulate the mammary tumor microenvironment impeding tumor growth and decreasing metastases25 as well as to prevent pancreatic carcinogenesis by reducing lesion penetrance via repressing proliferation associated with reduced phosphorylated AKT.26

GUEST EDITOR

Integrative Oncology is guest edited by Jun J. Mao, MD, MSCE, Laurance S. Rockefeller Chair in Integrative Medicine and Chief, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.

Adverse Reactions

CONSUMPTION OF large doses of omega-3s has resulted in a fishy aftertaste,27 loose stools, and nausea.28 Gastrointestinal events (diarrhea, nausea, and abdominal pain) as well as atrial fibrillation have been reported with the intake of EPA in a clinical study.17

Herb-Drug Interactions

Jun J. Mao, MD, MSCE

Jun J. Mao, MD, MSCE

WARFARIN: An elevated international normalized ratio (INR) has been reported when warfarin was taken with fish oil supplements (2 g/d). The INR decreased after reducing the intake of the supplement.29

High-dose omega-3 supplements have been associated with subdural hematoma (6 g/d) requiring craniotomy30 as well as irreversible warfarin-induced coagulopathy after blunt head trauma.31

Glucocorticoids: Omega-3 supplementation increased some of the adverse effects of glucocorticoids in a murine model.32 However, the clinical relevance of this finding is unknown.

Herb-Lab Interactions

IN A STUDY of heart transplant recipients, omega-3 supplementation was found to decrease vitamin E and beta-carotene levels while increasing TNF-a.33

The conclusions of a meta-analysis indicate that high levels of omega-3s may help to reduce triglyceride levels and increase low-density lipoprotein cholesterol levels.11

Doses of omega-3s higher than 3 g/d may increase bleeding time.34

Summary

OMEGA-3s OBTAINED through diet may have health benefits by decreasing inflammation and lowering triglyceride levels. The 2015 to 2020 dietary guidelines35 for Americans recommend that adults consume 8 or more ounces of a variety of seafood (fish or shellfish) per week. However, the evidence to support supplementation with omega-3s for preventing or treating cancer or cardiovascular disease is not conclusive. Patients on warfarin or other anticoagulants should be advised about the potential for elevated INR and an increased risk of bleeding with omega-3 supplements.

DISCLOSURE: Dr. Deng and Ms. Gubili reported no conflicts of interest.

REFERENCES

1. Khorsan R, Crawford C, Ives JA, et al: The effect of omega-3 fatty acids on biomarkers of inflammation: A rapid evidence assessment of the literature. Mil Med 179(11 suppl):2-60, 2014.

2. Galarraga B, Ho M, Youssef HM, et al: Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology (Oxford) 47:665-669, 2008.

3. Tanskanen A, Hibbeln JR, Tuomilehto J, et al: Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 52:529-531, 2001.

4. Jahangard L, Sadeghi A, Ahmadpanah M, et al: Influence of adjuvant omega-3-polyunsaturated fatty acids on depression, sleep, and emotion regulation among outpatients with major depressive disorders: Results from a double-blind, randomized and placebo-controlled clinical trial. J Psychiatr Res 107:48-56, 2018.

5. Robinson DG, Gallego JA, John M, et al: A potential role for adjunctive omega-3 polyunsaturated fatty acids for depression and anxiety symptoms in recent onset psychosis: Results from a 16 week randomized placebo-controlled trial for participants concurrently treated with risperidone. Schizophr Res. September 18, 2018 (early release online).

6. Grenyer BF, Crowe T, Meyer B, et al: Fish oil supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 31:1393-1396, 2007.

7. Andrieu S, Guyonnet S, Coley N, et al: Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial. Lancet Neurol 16:377-389, 2017.

8. Gunnarsdottir I, Tomasson H, Kiely M, et al: Inclusion of fish or fish oil in weight-loss diets for young adults: Effects on blood lipids. Int J Obes (Lond) 32:1105-1112, 2008.

9. Tanaka K, Ishikawa Y, Yokoyama M, et al: Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: Subanalysis of the JELIS trial. Stroke 39:2052-2058, 2008.

10. Barbosa MM, Melo AL, Damasceno NR: The benefits of ω-3 supplementation depend on adiponectin basal level and adiponectin increase after the supplementation: A randomized clinical trial. Nutrition 34:7-13, 2017.

11. Rizos EC, Ntzani EE, Bika E, et al: Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. JAMA 308:1024-1033, 2012.

12. Brasky TM, Lampe JW, Potter JD, et al: Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) cohort. Cancer Epidemiol Biomarkers Prev 19:1696- 1708, 2010.

13. Song M, Ou FS, Zemla TJ, et al: Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG phase III trial N0147 (Alliance). Int J Cancer. January 8, 2019 (early release online).

14. Liang B, Wang S, Ye YJ, et al: Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol 14:2434-2439, 2008.

15. Brasky TM, Darke AK, Song X, et al: Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst 105:1132-1141, 2013.

16. Andreeva VA, Touvier M, Kesse-Guyot E, et al: B vitamin and/or ω-3 fatty acid supplementation and cancer: Ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Arch Intern Med 172:540-547, 2012.

17. Hull 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 392:2583-2594, 2018.

18. Manson JE, Cook NR, Lee IM, et al; VITAL Research Group: Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 380:23-32, 2019.

19. Murphy RA, Mourtzakis M, Chu QS, et al: Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer 117:3774-3780, 2011.

20. Murphy RA, Mourtzakis M, Chu QSC, et al. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer 117:1775-1782, 2011.

21. Trabal J, Leyes P, Forga M, et al: Potential usefulness of an EPA-enriched nutritional supplement on chemotherapy tolerability in cancer patients without overt malnutrition. Nutr Hosp 25:736-740, 2010.

22. Thies F, Garry JM, Yaqoob P, et al: Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: A randomised controlled trial. Lancet 361:477-485, 2003.

23. Kim JY, Lim K, Kim KH, et al: N-3 polyunsaturated fatty acids restore Th17 and Treg balance in collagen antibody-induced arthritis. PLoS One 13:e0194331, 2018.

24. Han S, Sun X, Ritzenthaler JD, et al: Fish oil inhibits human lung carcinoma cell growth by suppressing integrin-linked kinase. Mol Cancer Res 7:108-117, 2009.

25. Khadge S, Thiele GM, Sharp JG, et al: Long-chain omega-3 polyunsaturated fatty acids decrease mammary tumor growth, multiorgan metastasis and enhance survival. Clin Exp Metastasis 35:797-818, 2018.

26. Ding Y, Mullapudi B, Torres C, et al: Omega-3 fatty acids prevent early pancreatic carcinogenesis via repression of the AKT pathway. Nutrients 10, E1289, 2018.

27. Anti M, Armelao F, Marra G, et al: Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 107:1709-1718, 1994.

28. Fugh-Berman A, Cott JM: Dietary supplements and natural products as psychotherapeutic agents. Psychosom Med 61:712-728, 1999.

29. Buckley MS, Goff AD, Knapp WE: Fish oil interaction with warfarin. Ann Pharmacother 38:50-52, 2004.

30. McClaskey EM, Michalets EL: Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: Case report and review of the literature. Pharmacotherapy 27:152-160, 2007.

31. Gross BW, Gillio M, Rinehart CD, et al: Omega-3 fatty acid supplementation and warfarin: A lethal combination in traumatic brain injury. J Trauma Nurs 24:15-18, 2017.

32. Fappi A, Godoy TS, Maximino JR, et al: The effects of omega-3 fatty acid supplementation on dexamethasone-induced muscle atrophy. Biomed Res Int 2014:961438, 2014.

33. Holm T, Berge RK, Andreassen AK, et al: Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients. Transplantation 72:706-711, 2001.

34. Lewis CJ: Letter regarding dietary supplement health claim for omega-3 fatty acids and coronary heart disease. FDA Docket No. 91N-0103. October 31, 2000. Available at https:// pdfs.semanticscholar.org/5c90/42de155b3c273a5d70c7ed88acb7bb39b2b7.pdf. Accessed February 20, 2019.

35. Dietary Guidelines 2015-2020. Appendix 3. USDA food patterns: Healthy U.S.-style eating pattern. Available at https:// health.gov/dietaryguidelines/2015/guidelines/appendix-3/. Accessed February 20, 2019.


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