Prostate Cancer and Omega-3 Fish Oils: Beware Conclusions Born of Misinformation

The recent conclusions of Brasky et al must be examined closely as they are not only misleading but potentially dangerous. This statement may appear extreme, but omega-3 fatty acids have been repeatedly shown to protect us against cardiovascular disease (CVD), the leading cause of death in the Western World. Therefore, if men stop eating fish and taking fish oil pills for fear of prostate cancer, they may be putting themselves at risk for CVD, a disorder that kills seven times as many men as does prostate cancer. Such a decision would be not only unwise, but potentially damaging. To better understand this, let’s examine Brasky’s findings in the context of prior data as well as our understanding of the biology of DHA and EPA.

First, many earlier trials have demonstrated a correlation between high fish consumption and low rates of prostate cancer. Some examples are: Lancet, 2001 Terry et al showed a significant correlation between high fish consumption and a low incidence of prostate cancer. The Physician’s Health Study in 2008 revealed a correlation between high fish consumption and improved survival in men with prostate cancer. A 2003 Harvard study of 48,000 men showed a higher intake of fish to be associated with a lower risk of prostate cancer. There are many other examples, but this should suffice.

Second, let’s look at plasma levels of EPA and DHA in Brasky’s trial. The reported EPA+DHA level in the plasma phospholipids was 3.62% in the non-cancer control group and 3.74% in the high-grade cancer group. This difference between controls and the worst cases is extremely small, frankly with no clinical significance.  It is simply within the normal laboratory variation.

Third, is association tantamount to cause? No. Even if there were a clear association between prostate cancer and high EPA and DHA levels, that would not prove causality. Other plausible explanations exist. In fact, this would more likely be a case of reverse causation. We know that two cancer-related phenomena will increase DHA and EPA levels. First, cancerous tissues can upregulate the genes for enzymes that cause long chain fatty acids to “grow” into EPA and DHA – the desaturases and elongases. Second, we know that genetic polymorphisms in the fatty acid desaturases are associated with an increased risk of cancer. So what may be occurring here (if anything is occurring at all) is that cancer-induced changes in desaturases, or cancer-producing genetic polymorphisms in these same enzymes are causing an increase in EPA and DHA. DHA and EPA are not causing the cancers.

Fourth, we are not told the source of omega-3s in this study group. Is it mostly from fish? Some fish have very high levels of PCBs, substances known to be carcinogenic. To conclude that people should stop their fish oil supplements when some supplements are actually far “cleaner” than fish, might therefore be very misguided.

Fifth, let’s examine another population with vastly different omega-3 levels to see whether Brasky’s assertions are relatable to real life. The Japanese consume eight times as much EPA and DHA as do Americans, yet their risk of prostate cancer is about one eighth of ours. If anything, one should conclude that omega-3s are protective here.

Sixth, we can’t ignore the biology of the fatty acids. A plethora of data has demonstrated the anti-inflammatory impact of the omega-3 fatty acids EPA and DHA. Data have also uniformly shown the pro-inflammatory effects of trans-fatty acids. When trial conclusions fly in the face of our understanding of human biology (in this case, trans fats not being harmful while omega-3s causing harm) we must consider them to be highly suspect.

Finally, let’s not forget that EPA and DHA are considered by experts to be “essential” fats. In other words, we must consume them in order to live. Before we discard these indispensable fatty acids, let’s await better clinical trials, and ones that are plausible in the context of prior literature and well-documented pathophysiology.

Additional resource : Dr. Gerald Chodak’s article entitled “Fish Oil’s Link to Prostate Cancer Unproven”  featured on Medscape.

Learn more about the world’s most potent omega-3 fish oil supplement at vitalremedymd.com

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Caution! Always View Clinical Trials with a Healthy Dose of Skepticism

We are barraged by data. In medicine this comes in the form of clinical trials and reviews. In everyday life data from news outlets strike us at every turn. We also have the internet and TV talk shows. Everyone seems to have an opinion about everything. So how do we separate the wheat from the chaff? When it comes to science, this is what I advise.

First, understand that science is not static; it is a process. It is also not black and white; it comes in countless shades of grey. Published studies are attempts to find biologic connections. They are single links in the chain of understanding. They do not stand alone; they always must be viewed in the context of all other clinical trials as well as our understanding of the complexity of human biology. Never though do we gain a hotline to god. Never are we able to say, “this is truth and all else fiction” after the publication of a clinical trial. So if you hear or see someone go to a place of certainty on the basis of a single trial, be very, very skeptical. Even if that individual is a so-called expert. The experts are not gods.

Second, there are levels of importance among the trials; some therefore are “better” than others. Rarely do you hear even the experts on TV speak about this. They typically speak only about the “abstract”, a brief summation at the beginning of every study. This is an area too complex for most clinicians to fully grasp. How then can we expect the lay population to comprehend this nuance?

Third, and probably most important of all, every trial comes with flaws. Sometimes these imperfections entirely devalue the trial’s results; other times they simply raise cause for concern. Regardless, to do a trial justice, one must read it with a fine tooth comb. In fact, when I really need to understand a particular study I spend four or five hours reading and critiquing it. Imagine that; four or five hours for a single trial. How then can I treat patients, teach, write, and still have time to read the many thousands of trials published annually. I can’t.

In sum, be cautious. Do not jump to conclusions when a study is published. Do not panic. Do not stop your medications or supplements until you’ve had the opportunity to discuss the findings thoroughly with your doctor. Always be circumspect and vigilant when learning about a clinical trial. Always maintain a very healthy skepticism. I guess in the final analysis the truth is that you can’t always believe what you read or hear. Competing interests often get in the way of truth. And the truth with clinical trials is that they are not at all about “the truth”. They are simply small cogs in the wheels of discovery.

Learn more about the world’s most potent omega-3 fish oil supplement at vitalremedymd.com

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Omega-3 Fatty Acids and Risk for Prostate Cancer

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.

Table:
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. Read More…

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