The Facts About Omega-3 Fatty Acids and Increased Prostate Cancer Risk

A study released this week, “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial,” published in the Journal of the National Cancer Institute (JNCI)) suggests that the omega-3 essential fatty acids EPA, DPA, and DHA - but not the omega-3 fatty acid ALA, found in flax, chia, hemp seeds, and nuts that have repeatedly been shown to lower prostate cancer rates - are somehow associated with increased risks of high-grade prostate cancer. At the same time, higher amounts of normally harmful trans fats in these subjects were associated with lower rates of advanced prostate cancer. [1] Because of the known limitations of this particular kind of study, all of these reported results were completely unproven, highly questionable, and highly unlikely to be true.

What kind of study was this? It is data mining of a previously published population study in which important variables and endpoints for fish oil's relationship to prostate cancer were not controlled, nor any cause and effect demonstrated. Because it is a secondary analysis of a largely epidemiological (population) study, it represents the lowest level of evidence in human studies because most relevant variables, confounding factors, and clinical endpoints are not systematically collected for proper analysis as they would be in an actual controlled clinical trial. Instead, the limited goal was to look for possible associations that were admittedly not rigorous enough to be considered as actual evidence of a causal relationship. As a preliminary study, it was consciously designed only to raise questions, rather than to provide answers, and it did accomplish that goal but also created a messy splash of misleading and over-emphatic headlines inaccurately suggesting that this one study somehow trumps many more robust clinical trials. So much for the media knowing of and respecting the Scientific Method. [2]

Dr Marilyn Glenville PhD, the UK’s leading nutritionist specializing in women’s health and former President of the Food and Health Forum at the Royal Society of Medicine, has noted some deficiencies in the current JNCI report; some examples: [3]

• “This is not a randomised controlled trial but a trial comparing Omega 3 levels in men with prostate cancer with healthy men. The men with prostate cancer had higher levels of Omega 3. But you cannot extrapolate cause and effect from this finding. It is like saying that if the majority of men with prostate cancer played tennis compared to healthy controls then tennis could trigger prostate cancer.”
• In 2009 the Harvard School of Public Health reported that “Omega 3 deficient diets cause up to 96,000 preventable deaths a year in the US. The researchers estimated the number of deaths resulting from 12 preventable causes and Omega 3 deficiency ranked as the sixth highest killer of Americans. A deficiency in these fats was classed as a bigger killer than high intake of trans fats.” [4]
• “…there are many cultures such as the Japanese who eat high amounts of oily fish containing Omega 3 fatty acids and yet have one of the lowest prostate cancer death rates in the world.”

Duffy MacKay, N.D., vice president, scientific and regulatory affairs of the Council for Responsible Nutrition, also noted some concerns with the report: [5]

• “Hundreds of studies over the past two decades have shown omega-3 fatty acids to have positive effects associated with cardiovascular health, perinatal health, inflammation, cognitive function, or cancer. Collectively, this body of research serves as the basis for numerous recommendations from respected organizations, scientific boards and healthcare practitioners that Americans get omega-3 fatty acids in their diets.”
• “While we encourage researchers to continue to study omega-3 fatty acids with an open mind, it is counterproductive when studying nutrition for researchers to promote their study as if it were the only piece of research that counts. In this case in particular, it is especially disingenuous for the researchers to make the kinds of assertions we've seen in the press, given their results are in stark contrast to previous epidemiologic studies that not only demonstrate no correlation between omega-3 consumption through fish and/or supplementation and the risk of prostate cancer, but in many cases also showed a protective effect against prostate cancer.”
• “One should also consider whether this study could have simply been measuring a biomarker reflecting recent intake of fish or fish oil supplements in a group of high risk cancer patients that had been told to increase their EPA and DHA levels, as compared to a group of non-cancer patients that had not been told to consume more EPA and DHA. Plasma levels of EPA and DHA reflect very recent intake and are considered a poor biomarker of long term omega-3 intake especially when compared to red blood cell levels, which reflect medium term intake. A single fish oil dose (or hearty serving of fish at lunch) results in >100 percent increase in plasma omega-3 levels. So looking at plasma levels in healthy and sick people may only provide insight into the recent habits of these individuals.”
• “The American Heart Association, the World Health Organization (WHO), the U.S. Institute of Medicine’s Food Nutrition Board (IOM FNB) and the 2010 Dietary Guidelines all have current policies advising Americans to eat more fatty fish to get the benefits of omega-3 fish oils. It is highly unlikely this one study will change that advice. Omega-3s can also be obtained by taking one of the many supplement products on the market. For those consumers who have concerns about prostate cancer or other questions about omega-3 fatty acids, we recommend speaking with your doctor or other healthcare practitioner.”

If you are a man and believe this report, then you’ll probably want to eat partially hydrogenated artificial trans fats instead of omega-3 fats for prostate health; though that change would greatly increase your risk of suffering far deadlier cardiovascular diseases, based on evidence from many clinical trials. But that would be ridiculous. In fact, many cultures around the world consume far more fish oil than Americans without having increased risks of aggressive prostate cancer; these include the Inuit people ("Eskimos"), Scandinavians, Southeast Asians, Pacific Islanders, Japanese, Filipinos, and others. 

In any case, in the absence of proper controls or any evidence of causation, we actually can’t know what these study results really mean. For example:

• Were DHA levels related to diet, supplementation, or both?
• Were fish and/or fish oils perhaps consumed as a deliberate health choice because of prior knowledge of prostate issues, rather than actually causing or aggravating those issues? In other words, could the consumption represent an attempt to improve a pre-existing condition by improving one’s nutritional status and be unrelated to the disease itself? Perhaps even suggested by medical teams as potentially helpful for patients' diet?
• If they had been collected, what would key inflammatory and oxidative markers, that are much likelier to be related to prostate health problems than long-chain omega-3 fatty acids such as DHA, have told us about these men’s state of health and disease?
• Where is the biochemical evidence that DHA itself may negatively contribute to prostate concerns? None is presented, even theoretically.

The Global Organization for EPA and DHA Omega-3s (GOED) also criticized these and numerous other some aspects of the JNCI report, among them these important points: [6]

• “The difference in mean blood plasma phospholipid fatty acids blood level for omega-3s was 4.66% in the combined cancer group versus 4.48% in the control. They are basing their results on just ca. 0.2% difference in omega-3 levels.”
• “Plasma phospholipid fatty acids as measured in this study are not a good index of long term intake and are influenced dramatically by a single meal, or even timing of a fish oil dose. A single fish oil dose massively increases LC omega 3 (typically increasing levels by 100% or more) in about 4-12 hours and then washes out around 48 hours.”
• “The study was not designed to look at omega-3 and confounded with selenium and Vitamin E used in the treatment arms.”
• “The test cohort included sick and healthy people. It is possible that sick people were taking fish oil supplements at a higher rate than the healthy individuals.”
• “A recent meta-analysis of fish consumption and prostate cancer by Szymanski et al. (2010) reported a large reduction in late stage or fatal prostate cancer among cohort studies." [7]
• "Several population based studies have shown a benefit of increased omega-3 fatty acid intakes to reducing prostate cancer risk.” [8]^, [9]

As I said earlier, this type of study raises questions about possible associations; but due to its built-in limitations, and results conflicting with most other related studies, provides no real answers.  Unfortunately, its counter-intuitive results generate sensational press coverage rarely accompanied by any true perspective on what this new study really means (not much).

In real life, most Americans and others in Western societies no longer consume the ideal amount or ratio of omega-3 fatty acids in their diet as our ancestors did a century or two ago. This reduction reportedly contributes to the large increase in chronic health problems that plague these societies. It is a public disservice to inappropriately scare people away from healthy foods and supplements, which help balance the diet in these many cases where the lack of essential nutrients is actually causing harm, based solely on such flimsy “evidence”. 

After reviewing this study I, a vegetarian, will continue to take my vegan DHA supplement twice a day with absolutely no concerns that it will negatively affect my own prostate health. Why am I not at all concerned? Because there is still no hard evidence explaining how long-chain omega-3 fatty acids like EPA and DHA may promote prostate cancer. There is still no demonstrated mode of action for this concern, and there are still no plausible explanations of any biological mechanisms that could justify the theory that long-chain omega-3 fatty acids may promote prostate cancer. My lack of concern is evidence based, after carefully reviewing the studies in question. Contrast this with the fear-mongering about fish, fish oil, and omega-3 fatty acids in foods and supplements that is overwhelmingly based on speculation, flimsy data, ignorance (on several levels), and maybe even some bias.

By Neil E. Levin, CCN, DANLA

REFERENCES:

[1] http://www.newswise.com/articles/view/605211/?sc=rssn&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+NewswiseScinews+%28Newswise%3A+SciNews%29

[2] http://teacher.nsrl.rochester.edu/phy_labs/appendixe/appendixe.html

[3] http://www.hfma.co.uk/docs/Omega_3_and_Prostate_Risk-July2013.pdf

[4] The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors" study, April 2009, PLoS Medicine

[5] http://www.crnusa.org/CRNPR13-Omega3071113.html

[6] http://us1.campaign-archive1.com/?u=4ae075406cd789efec4e9ff09&id=6f3dc7a018&e=1704ffc192

[7] Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92(5):1223–1233

[8] Terry P, Lichtenstein P, Feychting M, et al. Fatty fish consumption and risk or prostate cancer. Lancet, 2001,357:1764-6.

[9] Lietzman 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;80:204-216.

Beta-carotene risks still unproven!

A recent journal article pointed out the widely-reported danger of smokers using beta-carotene, a natural source (provitamin) of vitamin A, as part of their multivitamins. 1 In this meta-analysis (as in common in such analyses) the researchers have neglected to consider pre-existing dietary and serum levels of this nutrient, making their claim to control by placebo inadequate to properly isolate this variable. In fact, this failure to determine the effects of beta-carotene at a dose-dependent plasma level – and by neglecting to measure total beta-carotene intake along with the relevant synergistic antioxidants associated with it, as opposed to simply measuring supplemental intake - raises serious questions about the validity of these results. 2 There is also legitimate scientific debate over the use of trans versus cis forms of this provitamin that may affect the way it is used by our bodies in vivo that dispute whether all forms are equal, which most studies simply do not address (including this meta-analysis). 3 Regarding beta-carotene safety little has been satisfactorily resolved, and the negative studies have been vigorously disputed for these and other reasons. For example, researchers have previously noted in the Journal of the National Cancer Institute that beta-carotene has been shown to not affect the risk of oxidative DNA damage in male smokers, despite its reputation as an antioxidant. But neither did the provitamin A prove to cause oxidative DNA damage. 4 It has become apparent to numerous observers that simply measuring supplementation of beta-carotene is not a good predictor of serum levels or of risk, and that a low level of total antioxidant intake may be a more valid marker in this regard. In fact, the dietary level of several antioxidants has been shown to be an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A recent study reports, "This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk." 2 As the authors (Tanvetyanon, et al) of this current analysis have themselves noted, the Physicians Health Study compared the effects of taking 50 mg of supplemental beta-carotene (over 83,000 IU) every other day to a placebo in 22,071 US male physicians aged 40-84 and found no adverse health effects over a 12-year study period. 5 Likewise, the Women’s Health Study of 39,876 health professionals found no significant difference on lung cancer rates when looking at the effects of 50 mg of beta-carotene administered on alternate days over 2+ years plus a 4-year follow up period, using forms and dosing similar to the Physician’s Health Study to achieve very high serum levels of beta-carotene. 6 In a third study used in the current meta-analysis, The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (ATBC), an antioxidant study in Finland was halted early because of a widely reported small increase in cancer rates among male smokers taking beta-carotene that were only possibly linked to that nutrient. 7 Headlines associated this supplement with cancer risk. Despite objections that the study was flawed, beta-carotene use dropped. This study continues to be widely cited and believed, despite the researchers’ own statements that the results were most likely due to chance. A later analysis published in July 2004 took another look at that same Finnish smokers study’s data, but now taking into account total antioxidant intake, which should have cleared away some of the scientific controversy over beta-carotene safety. The smokers’ risk of getting lung cancer was inversely associated with total antioxidants in the diet, with more total antioxidants resulting in fewer cancers. 8 In this study a composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: a combination of antioxidants lowered lung cancer risk in male smokers. Properly reviewed, beta-carotene was not the culprit; low antioxidant status was the more relevant factor affecting cancer rates, and supplementation with a single antioxidant supplement simply failed to create enough improvement to avert deaths related to oxidative factors. Perhaps the supplementation with beta-carotene was simply a case of "too little, too late", rather than a root cause of a slightly higher lung cancer rate in those smokers. It is notable that Tanvetyanon et al included the ATBC study but failed to even reference the later Wright et al study that largely refuted the alleged harms of beta-carotene shown in ATBC, which were shown to be more likely due to low levels of total antioxidant intake than to excessive beta-carotene intake. This later review of ATBC should be a cautionary tale concerning the lack of proper controls in nutrient studies, especially as compounded by the use of meta-analysis, and should have alerted the current authors to that all-too-common mistake in nutrient study design. Indeed, another large study has noted that high carotenoid intake, confirmed by measures of plasma, was associated with lower mortality rates among the elderly over a ten year period. 9 This model measured results of consuming both supplements and foods, not solely supplement input, and when combined with plasma levels should therefore be regarded as a far more robust type of science for measuring vitamin effects than a meta-analysis of simply supplementation. As in the long-term Physicians Health Study, there was no observable risk of lung cancer noted in this report. The fourth study used in the current meta-analysis used very high doses of both beta-carotene (30 mg, equal to 50,000 IU) plus 25,000 IU of pre-formed vitamin A. 10 These amounts are extremely high; the Upper Limit for vitamin A is 10,000 IU, though there is no official Upper Limit for beta-carotene because of its historic safety record. The amounts of beta-carotene used in the eye vitamins were high only because the authors selected solely formulas designed for eye health that typically provide more beta-carotene than ordinary multivitamins. This distinction is not clear in their calling such formulas "multivitamins", because that name is typically given to full-spectrum formulas containing a full range of the essential vitamins with minerals, not system-specific formulas like those sold for eye health. Such formulas have proved to be beneficial in maintaining eye health and the combination of antioxidants have been stronger antioxidants than beta-carotene, which is potentially a pro-oxidant at times and could thus be used more safely – and effectively - in combination with other antioxidants. 11 That being said, eye formulas with more milligrams of lutein than beta-carotene are probably better formulated than ones with very high beta-carotene because of their competition for absorption. Most importantly, the authors have not shown why they assume that "multivitamin" use would be associated with the supposed risks of beta-carotene used singly, even if those risks for the solo provitamin are assumed to be true. Nor have they adequately demonstrated the alleged dangers of taking eye formula supplements, or even the danger of lung cancer rates increasing in those taking mixtures of beta-carotene combined with other antioxidant nutrients. In the case of multivitamins most studies have shown overwhelmingly positive effects, such as one report evidencing reduced infections in nursing homes with vitamins over placebo (73% vs. 43%). Intervention was with a multivitamin containing beta-carotene. Infection-related absenteeism was higher in the placebo group than in the treatment group (57% vs. 21%). Perhaps most importantly, 93% of participants with diabetes mellitus reported an infection versus only 17% of those receiving supplements. 12 These huge reductions in potentially serious infections among our elderly citizens should be measured against the relatively slight and mostly theoretical risk of increased lung cancer rates associated with beta-carotene supplementation. A study reported in the Journal of the National Cancer Institute looked at death rates in a population given multivitamins or other nutrients. 13 After supplements were given for 5.25 years in the general population trial of 30,000 people, significant reductions in total [relative risk (RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium combined. The same researchers reported on a subgroup of 3,318 persons with esophageal Dysplasia (a precursor to esophageal cancer) that was given either a multiple vitamin-and-mineral supplement or a placebo for 6 years. In this portion of the trial, small reductions in total (RR 0.93) and cancer (RR = 0.96) mortality were observed but were not significant. In any case, no increase in cancer rates was noted in the group taking multivitamins; there was actually a possible small benefit in terms of reducing this risk. The participants getting the multivitamin took a daily beta-carotene capsule along with two multivitamin tablets. This was a group of subjects at high risk of getting throat cancer. 14-15 It is a leap of faith to assume that a single nutrient would have identical effects to a combination of nutrients without substantial supporting evidence, which is still lacking; confounded by conflicting evidence and multiplying variables in meta-analyses. Since nutrients are both synergistic and present in the diet, it is important to factor those known variables into a proper study design. All too often, researchers do not consider this fundamental difference between drug and nutrient research and unwittingly introduce extra variables that undermine their conclusions. 16

This current meta-analysis of 4 studies - only one of which unquestionably shows a slight increase in lung cancer risk but does not actually measure isolated beta-carotene risk; two others are well-designed and robust studies looking at serum levels of those taking a high dose of beta-carotene but show no increased risk in lung cancer rates, and the fourth has been largely shown to be moot by a later and more complete re-analysis of the data - does not support the hypothesis that beta-carotene increases rates of lung cancer and that multivitamins are therefore dangerous. Thus, there is no sound basis in the current review for suggesting that warning labels may be needed for multivitamins or eye health supplements containing beta-carotene along with other nutrients that have been shown in well-designed studies to help protect the eyesight – and independence - of our aging population. REFERENCES:

1. Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer. 2008 Jul 1;113(1):150-7. PMID: 18429004
2. Valtueña S, et al. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. Eur J Clin Nutr. 2007 Jan;61(1):69-76. Epub 2006 Jul 12. PMID: 16835597 [Supported by the European Community IST-2001–33204 'Healthy Market', the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.]
3. Andreas Schieber, Reinhold Carle. Occurrence of carotenoid cis-isomers in food: Technological, analytical, and nutritional implications. Trends in Food Science & Technology, Volume 16, Issue 9, September 2005, Pages 416-422
4. van Poppel G, Poulsen H, Loft S, Verhagen H. No influence of beta carotene on oxidative DNA damage in male smokers. J Natl Cancer Inst. 1995 Feb 15;87(4):310-1. PMID: 7707423
5. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1145-9. PMID: 8602179
6. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999 Dec 15;91(24):2102-6. PMID: 10601381
7. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994 Apr 14;330(15):1029-35. PMID: 8127329
8. Wright ME, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004 Jul 1;160(1):68-76. PMID: 15229119
9. Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr. 2005 Oct;82(4):879-86. PMID: 16210720
10. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155.
11. Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt. 2003 Sep;23(5):383-99. Review. PMID: 12950886
12. Liu BA, et al. Effect of multivitamin and mineral supplementation on episodes of infection in nursing home residents: a randomized, placebo-controlled study. J Am Geriatr Soc. 2007 Jan;55(1):35-42. Erratum in: J Am Geriatr Soc. 2007 Mar;55(3):478. PMID: 17233683
13. Blot WI, Li IY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993:8ı:1483-92
14. Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993 Sep 15;85(18):1492-8. PMID: 8360932
15. Blot WI, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995 Dec;62(6 Suppl):1424S-1426S. PMID: 7495242
16. Levin, N. Land of Confusion: How Poor Science and Misleading Media Coverage Create Public Confusion About How Dietary Supplements Affect Health. J App Nutr, Vol 55, No. 1, 2005 8-15