This article by William S. Harris, PHD was originally published by the Foundation for Health Improvement and Technology’s on the lecturepad.org website.
William S. Harris, PhD
Senior Research Scientist, Health Diagnostic Laboratory, Inc. (Richmond, VA)
Professor, Department of Internal Medicine, Sanford School of Medicine, University of South Dakota
President, OmegaQuant Analytics, LLC (Sioux Falls, SD)
On July 11, 2013 a paper was published online by Brasky et al. in the Journal of the National Cancer Institute entitled, “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial.” The authors found that higher plasma omega-3 fatty acid levels were associated with increased risk for developing prostate cancer. In this study, plasma phospholipid omega-3 levels were measured in 834 men who eventually developed prostate cancer (the time between plasma sampling and diagnosis is not available from the abstract), and 1393 men who did not. Using standard statistical methods, they found that men in the highest quartile of omega-3 had a 43% to 71% increased risk for prostate cancer (depending on severity). This is the same conclusion that the same group reached in 2011 in a study in another cohort entitled, “Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial.”(1) So with two studies reaching the same conclusion, it is important to seriously consider its findings.
I will be the first to admit that had this study turned out the “right” way, I would have embraced its findings and had no criticism of its design or methods. It is disingenuous, therefore, for me to find fault with the way the study was conducted just because I don’t agree with the findings. Nevertheless, we should examine the methods to be clear on the context of the conclusions.
First, the reported EPA+DHA level in the plasma phospholipids in this study was 3.62% in the no-cancer control group, 3.66% in the total cancer group, 3.67% in the low grade cancer group, and 3.74% in the high-grade group. These differences between cases and controls are very small and would have no meaning clinically as they are within the normal variation. Based on experiments in our lab, the lowest quartile would correspond to an HS-Omega-3 Index of <3.16% and the highest to an Index of >4.77%). These values are obviously low, and virtually none of the subjects were in “danger” of having an HS-Omega-3 Index of >8%. In Framingham, the mean Omega-3 Index of participants who were not taking fish oil supplements was 5.2% and for those taking supplements, it was 7.5%.(2) Both of these numbers are considerably higher than the values reported by Braskey et al., even in their highest quartile. Thus, it is extremely unlikely that these patients were taking fish oil supplements. Indeed, the SELECT study (in which all these patients were participants) was a randomized trial of vitamin E and selenium supplements for the prevention of prostate cancer. In the study protocol, it is stipulated that if the subjects wanted to take a multi-vitamin, the study would provide it; nothing is said about fish oil supplements, but it is hard to imagine their use was widespread in this trial.
So to conclude that regular consumption of 2 oily fish meals a week or taking fish oil supplements (both of which would result in an Index above the observed range) would increase risk for prostate cancer is extrapolating far beyond the data. This study did not test the question of whether giving fish oil supplements (or eating more oily fish) increased prostate cancer risk; it looked only a blood levels of omega-3 which are determined by intake, other dietary factors, metabolism, and genetics. The endless repetition of “supplements are dangerous” in the news media is not based on any data from this study.
But even granting that the associations they reported are real, the findings of this study do not mean that EPA and DHA play any role in the development of prostate cancer. Associations do not imply causation. For example, it is possible that some component of whatever fish these patients were consuming was carcinogenic, in which case the serum omega-3 levels were just a marker of fish (i.e., carcinogen) intake.
It is important to put these findings into perspective (which the authors failed to do). First consider the risk of dying from prostate cancer vs. ischemic heart disease (IHD). Based on the National Vital Statistics Report for deaths in the US in males in 2010, (http://www.cdc.gov/nchs/data/dvs/deaths_2010_release.pdf), there were about 28,500 deaths from prostate cancer and 207,500 deaths from IHD: a 7.3x higher rate of death for heart disease. If one assumes (conservatively) that higher fish intake reduces risk for death from heart disease by only 10%, and (liberally) increases risk for death from prostate cancer by 50%, then the chances of dying from coronary heart disease (CHD) are still 4.4x higher than from prostate cancer. This very crude analysis suggests that even in the worst case scenario, the benefit of higher omega-3 intakes/levels still outweighs the risk.
The authors also failed to present the fuller story taught by the literature. The same team reported in 2010 that the use of fish oil supplements was not associated with any increased risk for prostate cancer.(3)A 2010 meta-analysis of fish consumption and prostate cancer reported a reduction in late stage or fatal cancer among cohort studies, but no overall relationship between prostate cancer and fish intake.(4) Terry et al. in 2001 reported higher fish intake was associated with lower risk for prostate cancer incidence and death,(5) and Leitzmann et al. in 2004 reported similar findings.(6) Higher intakes of canned, preserved fish were reported to be associated with reduced risk for prostate cancer.(7) Epstein et al. found that a higher omega-3 fatty acid intake predicted better survival for men who already had prostate cancer,(8) and increased fish intake was associated with a 63% reduction in risk for aggressive prostate cancer in a case-control study by Fradet et al..(9) So there is considerable evidence actually FAVORING an increase in fish intake for prostate cancer risk reduction.
Another piece of the picture is to compare prostate cancer rates in Japan vs. the US. Here is a quote from the World Foundation of Urology*:
“[Prostate cancer] incidence is really high in North America and Northern Europe (e.g., 63 X 100,000 white men and 102 X 100,000 Afro-Americans in the United States), but very low in Asia (e.g., 10 X 100,000 men in Japan).” (http://www.prostatecancerprevention.net/index.php?p=prostate-cancer)
Since the Japanese typically eat about 8x more omega-3 fatty acids than Americans do and their blood levels are twice as high, you’d think their prostate cancer risk would be much higher… but the opposite is the case.
There is also a wealth of evidence from randomized clinical trials with fish oils in which the incidence of cancer (rarely subsetted) is always tracked as a possible adverse event. The table below shows the findings for the 8 major studies reported to date which included over 78,000 patients. In none of these studies was cancer incidence significantly increased by omega-3 fatty acid supplementation.
Reported incident cancer diagnosis (cancer deaths) Trial
n Dur. (yrs) Placebo N-3
Alpha-Omega(10) (prostate cancer) 4,837 3.4 0.8% 1.4%
Heart Failure(11) (cancer death) 6,975 3.9 3.2% 3.1%
GISSI-Prevenzione(12) 11,320 3.5 2.25% 2.65%
JELIS(13) 18,645 4.6 2.4% 2.6%
SUFOLOM3(14) (cancer death) 2,501 4.2 6.5% 7%
Origin(15) 12,536 6.2 no difference in cancer rate
Risk and Prevention(16) 12,513 5 7.2% 7.9%
Omega(17) 3,851 1 1.4% 1.7
In summary, the work of Brasky et al. does add to the evidence-base for omega-3 fatty acids and prostate cancer, which taken as a whole (not even getting into animal studies which are typically positive) support a neutral, if not beneficial, effect of fish oil in prostate cancer. The RCT data do not support an effect of omega-3 on cancer risk in general, and a 2012 review of omega-3 and prostate cancer concluded, “Thus, epidemiological studies provide inconsistent results, suggesting an inverse association of LC n-3 PUFA.”(18)
There will always be mixed findings in studies of “diet” and “disease” since both predictor and outcome entail so many variables, known and unknown. Higher omega-3 levels are associated with lower rates of death from any cause,19,20 from sudden cardiac arrest,21 and with slower rates of cellular aging.22 The risk benefit for fish oils remains very favorable.
1. He K, Xun P, Brasky TM, Gammon MD, Stevens J, White E. Types of fish consumed and fish preparation methods in relation to pancreatic cancer incidence: the VITAL Cohort Study. Amer J Epidemiol 2013;177:152-60.
2. Harris WS, Pottala JV, Vasan RS, Larson MG, Robins SJ. Changes in erythrocyte membrane trans and marine fatty acids between 1999 and 2006 in older Americans. J Nutr 2012;142:1297-303.
3. Brasky TM, Kristal AR, Navarro SL, Lampe JW, Peters U, Patterson RE, White E. Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort. Nutr Cancer 2011;63:573-82.
4. Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr 2010;92:1223-33.
5. Terry P, Lichtenstein P, Feychting M, Ahlbom A, Wolk A. Fatty fish consumption and risk of prostate cancer. Lancet 2001;357:1764-6.
6. Leitzmann MF, Stampfer MJ, Michaud DS, Augustsson K, Colditz GC, Willett WC, Giovannucci EL. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr 2004;80:204-16.
7. Mina K, Fritschi L, Johnson KC. An inverse association between preserved fish and prostate cancer: results from a population-based case-control study in Canada. Nutr Cancer 2008;60:222-6.
8. Epstein MM, Kasperzyk JL, Mucci LA, Giovannucci E, Price A, Wolk A, Hakansson N, Fall K, Andersson SO, Andren O. Dietary fatty acid intake and prostate cancer survival in Orebro County, Sweden. Amer J Epidemiol 2012;176:240-52.
9. Fradet V, Cheng I, Casey G, Witte JS. Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk. Clin Cancer Res 2009;15:2559-66.
10. Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010;363:2015-26.
11. GISSI-HF I. 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.
12. Investigators G-P. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999;354:447-55.
13. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.
14. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010;341:c6273.
15. Investigators O. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Eng J Med 2012;Published online June 12, 2012.
16. Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med 2013;368:1800-8.
17. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, Gottwik M, Steinbeck G, Del CU, Sack R, Worth H, Katus H, Spitzer W, Sabin G, Senges J. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010;122:2152-9.
18. Gerber M. Omega-3 fatty acids and cancers: a systematic update review of epidemiological studies. BrJ Nutr 2012;107 Suppl 2:S228-S39.
19. Mozaffarian D, Lemaitre RN, King IB, Song X, Huang H, Sacks FM, Rimm EB, Wang M, Siscovick DS. Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med 2013;158:515-25.
20. Pottala JV, Garg S, Cohen BE, Whooley MA, Harris WS. Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: The Heart and Soul Study. Circ Cardiovasc Qual Outcomes 2010;3:406-12.
21. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002;346:1113-8.
22. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA 2010;303:250-7.
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