Okay....so this is long to post here, but very informative: A Closer Look at Fish Oil and Prostate Cancer - Part 1 Dr. Keith I. Block Fish oil is in the news again, thanks to reports about a research study conducted by Dr Theodore M. Brasky and colleagues linking high blood levels of the fish oil constituents EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) to an increased risk of high-grade prostate cancer in American men. This study has been the subject of a great deal of commentary and criticism, in both mainstream and “alternative medicine” media outlets. Understandably, it has many patients quite concerned, and several have asked if they should discontinue their use of fish oil supplements. Let’s take a look at this study, and some of the concerns that have been raised about the study’s methodology, which are prompting several of us to call its conclusion into question: • It’s important to keep in mind that this was not a randomized study in which men were given fish oil or assigned a high-fish diet. It was an observational study, and while it provides a possible hypothesis for consideration, it does not prove any direct connection between EPA and DHA and prostate cancer. • One single blood sample taken at one point in time may have little relevance to what happens over the next several days and weeks, let alone the next several years, that might increase or decrease risk of prostate cancer. • The patients who had prostate cancer were found to have higher levels of risk factors, such as being overweight or having a family history of prostate cancer. We have no way of knowing how these additional risk factors might have contributed to these patients’ diagnoses. • Brasky and colleagues have no dietary data on these patients, and only a small minority of them were actually taking fish oil, so it’s hard to know how to relate the EPA and DHA contents to what men actually were ingesting. I will go into detail regarding why the lack of dietary data is of considerable relevance later in this blog. • The plasma phospholipid analysis used to determine levels of EPA and DHA in the blood is quite unstable, and variable from day to day. Meaning, had this analysis been done a mere 24 hours later than it was actually done, it might have provided a very different result. • The men in the study were found to have rather low levels of omega-3s to begin with, and the difference between the levels in the high-grade prostate cancer group and the others actually turned out to be very small, 0.02%. The low levels may indicate that these men had diets that were suboptimal in omega-3 content to begin with. • There are also more technical aspects of the study that are concerning. There was no regular schedule of prostate biopsies in the study, so some of those not diagnosed with prostate cancer could actually have had undetected cases. • The assignment of patients to “high” and “low” grades of prostate cancer is questionable at best. Clinically there are three grades of prostate cancer, low, intermediate and high. Some of the intermediate patients were assigned to high grade, and others were assigned to low grade, based on a rationale that has been called into serious question. • Finally, the authors did not present a strong mechanism by which fish oil or fish could increase prostate cancer risk. The subjects in this study were participating in the famous SELECT trial, in which men were given alpha-tocopherol and selenium, which failed to demonstrate any benefits regarding prostate cancer prevention. Brasky and colleagues obtained blood samples taken at the start of the study and compared EPA and DHA levels in study patients who later developed prostate cancer to those men who were also in the study but never got prostate cancer. They tested plasma phospholipid EPA and DHA levels, rather than red blood cells, prostate tissue or other measures that have been used in other studies. Men with high-grade prostate cancer, which has more malignant features than low grade prostate cancer, had levels of EPA and DHA that were a few percentage points higher than those without prostate cancer. However, there was no relationship of EPA and DHA to low-grade, less aggressive types of prostate cancer. Based on this result, the authors cautioned men about using fish oil or eating fish, although they state that these results do not have any direct bearing on what men with prostate cancer should do. The practice of linking blood levels of some natural chemical or physiological variable to later disease risk is widely used in epidemiology, and while it is not considered conclusive in linking disease risk to the natural chemical, it is considered to be a useful piece of information that may – or may not -- alert us to a real relationship. Second, it’s not surprising that the patients with prostate cancer had elevated risk factors for it (at the Block Center, we recommend that anyone at an increased risk of cancer be on an individually tailored prevention regimen). Third, the problem with lack of dietary data is truly significant. The literature on fish consumption and prostate cancer has major studies suggesting that high fish intakes are associated with lower prostate cancer risk – although there are some others that suggest no association, and yes, there have been some that suggest high fish intake is associated with higher prostate cancer risk. However, as I’ll explain below, there are mitigating factors in these studies that suggest the fish itself may not be the problem. Fourth, the analysis by Brasky et al relies on a blood measurement that has its limitations. But as I will detail later in this blog, there are other studies that have found somewhat similar results using different methods of analyzing EPA and DHA levels. Nevertheless the idea that fish consumption increases prostate cancer risk is still questionable. Intriguingly, though, these studies do point out a few cautions about fish consumption and fish oil supplements that may be helpful in prostate cancer prevention. To summarize, the study by Brasky and colleagues finds a statistical association between relatively elevated (but still rather low) levels of EPA and DHA, which come from fish, and high-grade prostate cancer. Because of the numerous limitations and flaws in the study’s methodology that I just reviewed, all the study can really do is suggest a possible correlation that needs substantially more investigation before we can rely on it to make any choices about diet and supplementation. In addition, it is important to remember that the majority of studies, some with considerable rigor, demonstrate both fish and fish oil as a beneficial prevention therapy. Tomorrow’s blog will take a look at some interesting findings from other studies that looked at fish consumption and prostate cancer, as well as delve into the background of this study, which also uncovered some interesting findings about fish and prostate cancer. A Closer Look at Fish Oil and Prostate Cancer – Part 2 Yesterday’s blog post looked at the study by Thomas Brasky and colleagues, which suggested that men who had high-grade prostate cancer had slightly higher blood levels of the omega-3 molecules from fish, EPA and DHA. Based on this result, the authors cautioned men about using fish oil or eating fish. I reviewed the quite substantive criticisms of the article, but also mentioned that looking into the background of this study uncovered some other potentially useful insights about fish and prostate cancer. My staff and I also examined the literature in this area and came across some surprising findings from other studies. One of the major issues with Brasky’s study is the lack of dietary data in the study, since it only examined levels of omega-3s in the blood. In 2010, a meta-analysis was published by Symanski and colleagues that analyzed the relationship between fish consumption and prostate cancer. In a meta-analysis, researchers gather all the human studies on a specific topic. The studies can be either clinical trials or epidemiological studies. The data from all the studies are grouped together statistically and analyzed to answer the question at hand. This gives a much more comprehensive and unbiased view of a subject than simply gathering whatever studies you happen to know about, or collecting only the studies that support your own position. In the case of the fish and prostate cancer meta-analysis, researchers found that, based on multiple epidemiological studies of different designs, the amount of fish that men consumed did not predict whether they were going to get prostate cancer. However, they also found that higher fish consumption was linked to lower mortality rates for prostate cancer, suggesting that fish consumption might be beneficial for men who already had prostate cancer. They could not analyze the relationship between fish and incidence of high-grade or advanced prostate cancer, because there were too few studies to draw conclusions. But along with this study indicating that fish does not increase prostate cancer risk is another meta-analysis, by Chua and colleagues, in which studies similar to that of Brasky and colleagues were collected and analyzed together. Yes, there have been other studies like that of Brasky – they just have not caught the attention of the press the way this one has! The 12 studies analyzed in this meta-analysis explored the relationship of EPA and DHA in blood plasma or serum or in red blood cells to prostate cancer occurrence. This gives us a broader picture than Brasky’s study, which only analyzed one possibly questionable blood component. What this study found was that blood levels of EPA and DHA were not related to overall prostate cancer risk (although, interestingly, a minor fish oil constituent called DPA, was related to lower prostate cancer risk). This is similar to the results of Szymanski’s meta-analysis on fish consumption. However, Chua found that levels of EPA and DHA may be linked to slightly higher rates of high-grade prostate cancer. This result is a little questionable, though, because they had to exclude one study (the Physician’s Health Study) from the analysis because it was quite different from the other studies and did not account for the prevalence of risk factors in its study population. So, this study shows us that there is, again, no link of fish constituents to overall prostate cancer risk, but that there is a possible link to high-grade prostate cancer. A possible link to high-grade prostate cancer was also found in another study on fish consumption, published in 2012 by Joshi and colleagues. This study found that advanced prostate cancer was more common in men who ate large amounts of white fish (flounder, halibut, cod, sole) that was cooked using high-temperature cooking methods (grilling, pan-frying, oven-broiling or barbequeing) until it was well-done. Consumption of white fish cooked at low temperatures or cooked until just done was not related to prostate cancer. Nor was consumption of tuna or dark fish (salmon, mackerel and others). While we think of salmon as being the main source of omega-3s, the fact is that flounder, cod, sole and halibut are also rich in omega-3s. And many people eat more of these fish than of salmon, often in the form of fish sticks, fish fries or commercial fried fish sandwiches (one popular brand of fish sandwich uses pollock, another high omega-3 fish). And, all of these are examples of high-temperature cooking, which, can be extremely adverse clinically, with the potential for compromising health consequences, and are quite relevant to the findings of these studies. This study was followed up by a laboratory study led by Dr Chelsea Catsburg, which explored a possible mechanism for the link to prostate cancer. These researchers noted that cooking white fish at high temperatures generates carcinogenic molecules called heterocyclic amines (HAs) and polycyclic aromatic hydrocarbons (PAHs). The exact same phenomenon is seen when red meat is cooked at high temperatures, and is behind the caution against eating grilled, charred meat, also thought to be carcinogenic. HAs and PAHs generate free radicals in the body, which can initiate cancer-causing mutations. Catsburg’s team suspected that variation in genes involved in the detoxification of carcinogens might be involved in the link between overcooked white fish and prostate cancer. They analyzed the genes involved in detoxifying carcinogens in localized prostate cancer patients and advanced prostate cancer patients. They found that men with a particular form of one gene (PTSG2 765 G/C) who ate lots of white fish did, in fact, have a higher risk of having advanced prostate cancer, especially if they ate well-done white fish. Men with other forms of the gene did not have the risk for prostate cancer even if they ate well-done white fish. Catsburg’s study tells us that it may not be the EPA and DHA in fish that is the potential culprit in causing prostate cancer. Instead, it may be the HAs and the PAHs lurking in all the fried white fish consumed by American men. The EPA and DHA may just “be along for the ride!” This issue highlights why the lack of dietary data in Brasky’s study is significant. Were those men with high-grade prostate cancer eating too many fish sticks and fish sandwiches? We just don’t know, since this study has no dietary correlations. Yet this missing information is extremely relevant. In addition, since all of the men in Brasky’s study apparently had rather low omega-3 levels, one suspects that they may have been eating suboptimal diets, perhaps including the regular consumption of fried fish and fish sandwiches. Now let’s take a look at an interesting characteristic of both EPA and DHA. These molecules are prone to getting oxidized – in other words, rancid. Rancid oils from fish and other sources contain damaging free radicals. In fact, one concern with fish oil supplements is that some of them may be partially oxidized; in other words, they may contain damaging free radicals. If this was the case with the fish oils in the Brasky study, for example, it makes sense that this was a contributing factor to the study’s findings. So far then, we have 2 mechanisms by which fish or fish oil may be linked to prostate cancer, though neither implicates the fish itself! One involves the method of cooking – we know that cooking at high temperatures causes the production of carcinogenic chemicals – and the other involves potential rancid fish oil constituents. In addition, there is a THIRD mechanism that has been suggested as possibly being linked to prostate cancer: mercury pollution. Exposure to mercury has been linked to chronic inflammation of the prostate in rats. Inflammation increases the risk for prostate cancer. In tomorrow’s blog, I will detail what I am advising our patients in light of this research, and what we should all be concerned about. A Closer Look at Fish Oil and Prostate Cancer – Part 3 In two previous blog posts I reviewed the current controversy about the study by Thomas Brasky and colleagues, who found that men with high-grade prostate cancer had slightly higher levels of the fish-based omega-3s, EPA and DHA. As I noted, this is a study with many flaws and limitations, which restricts its credibility. In addition, I’ve detailed other variables that may explain the study’s findings – cooking the fish at very high temperatures, which can generate mutagenic compounds, the tendency of both DHA and EPA to get oxidized (go rancid), and the potential that the fish/fish oil had mercury contamination. So, what can men concerned about preventing prostate cancer do based on the results of these studies? And what do these studies say to men who already have prostate cancer? First, let’s review why it’s important to include fish and fish oil in the diet. In the real world, people aren’t concerned about preventing one disease at a time. We’re concerned about preventing all diseases – heart disease, diabetes, cancer, dementia and many others. While family history may motivate individuals to take special steps against one disease, they still need to be cognizant of the other health risks associated with diet. Recent studies and reviews indicate that fish consumption or fish oil may contribute to the prevention of colorectal cancer (and breast cancer), Alzheimer’s disease, asthma, stroke and coronary heart disease. People may also increase fish consumption or take fish oil to manage various health conditions, including diabetics who have had heart attacks, people with macular degeneration, those with heart failure, men with elevated C-reactive protein, kidney dialysis patients and those with elevated triglycerides. I would note that in all these cases it is the entire diet that is important: if you eat a lot of fish, or take fish oil supplements, but still have a diet that is high in vegetable oils that contain omega-6s, trans fats, refined flours and sugars, or various kinds of junk foods, you are still putting yourself at risk of several diseases. In other words, there is no supplement regimen out there that will compensate for a poor diet! So there are many sound reasons for men to be taking fish oil and eating fish. But the problems raised by Brasky’s study may still be of concern to some patients. Can the possible concerns with fish consumption raised by Brasky’s study and the other studies we mentioned be alleviated? Since there’s no test for the particular gene analyzed by Catsburg’s team, it’s wise for men, as well as women (who might be incurring genetic damage related to some other type of cancer), to limit consumption of white fish that is grilled, pan-fried, oven-broiled, barbequed or otherwise exposed directly to very high temperatures, especially when this results in the fish being overdone. Some of the same precautions that are recommended for avoiding grilled meat can be applied to fish. These include using lower-temperature cooking methods, such as baking or poaching (a wonderful and easy way to cook fish – see the recipe for Poached Peppercorn Salmon that follows this article). You can also gently pre-cook fish before putting it on the barbeque, so that it doesn’t need to be on the grill as long, or remove charred portions of the fish before eating. And don’t overcook fish – it should be cooked until just done, for better taste and texture as well as safety. You can reduce the risk of mercury pollution by limiting intake of predator fish like swordfish, shark, mackerel, marlin, albacore, yellowtail and orange roughy, and not eating canned tuna more than about once a week. If you’re interested in prostate cancer prevention, you don’t have to give these up entirely, and I would urge you, in fact, to continue including them in your diet. But I don’t suggest eating two cans of tuna every day, as some people involved in body-building are rumored to do! High quality fish oil supplements, obtained from deep cold water sources, do not contain mercury. The problem with possible oxidation of fish oil, as well as, to some extent, the free radicals generated when fish is grilled or barbequed, can also be addressed through antioxidants. One of the crucial steps is to ensure that your diet contains sufficient broad-spectrum antioxidants from vegetables and fruits. At the Block Center, we do comprehensive “terrain testing” on our patients, which, among many other things, enable our dietitians to determine if someone’s dietary antioxidant intake is sufficient, and how you can use better food choices and possibly supplementation to reach optimal antioxidant capacity in your blood. Terrain testing will also tell you whether or not you have inflammatory conditions that should be addressed by taking an anti-inflammatory supplement such as fish oil or curcumin, and what dosage level would be needed and suitable for you based on these laboratory findings. Oxidized fish oil can be avoided by using a high quality fish oil product, ideally one that’s undergone independent testing. Products that are molecularly distilled increase the critical anti-inflammatory components, and if they are processed under nitrogen rather than in open air, it is possible to avoid the unnecessary and harmful oxidation that can occur routinely with many fish oils. These procedures are used in the fish oils recommended at the Block Center. Our Arctic Blox fish oil product is tested for mercury and other heavy metals, and does not contain any such contaminants. It also has added tocopherols and rosemary extract that provides further antioxidant protection to help keep the fish oil from going rancid. What about men who already have prostate cancer? Dr Brasky specifically noted that the data in his study do not apply to men with prostate cancer. The finding that prostate cancer mortality is lower in men with high fish intake, noted in the meta-analysis by Szymanski and colleagues, still stands and was not contradicted by Brasky’s work or the other studies we have mentioned. In addition, a randomized trial in which men with early prostate cancer either continued their customary diet or switched to a comprehensive lifestyle intervention featuring a low-fat, plant-based diet along with a soy supplement and, importantly, fish oil supplementation, found that significantly fewer men had to undergo further prostate cancer treatment in the lifestyle group than in those following their usual diet. This suggests that fish oil as part of a full integrative program is helpful, not harmful, for prostate cancer patients. Another study randomized prostate cancer patients to eat either a Western-type diet or a low-fat diet supplemented with 5 grams daily of fish oil. This diet was eaten for only about a month, between the patients’ initial biopsies and prostate removal surgeries. The fish oil group had a 32% reduction in Ki-67, an index of prostate cancer cell proliferation. When serum from these patients was applied to prostate cancer cells in the lab, serum from fish oil patients significantly reduced the cancer cell growth, whereas serum from the Western diet patients slightly increased it. We have observed similarly positive results with our integrative program at the Block Center, which regularly includes fish intake and fish oil supplements, even with advanced prostate cancer patients. Since actual randomized trials are finding beneficial results with fish oil supplementation for prostate cancer patients, we do not see any concern for prostate cancer patients taking fish oil. In fact, I recommend and encourage it as part of a comprehensive diet and lifestyle intervention, along with terrain testing, in order to determine appropriate dosages of fish oil and antioxidants, as well as gauging other nutritional needs. The bottom line is that Brasky’s study is interesting, but certainly not alarming, when viewed in the full context of the research in this area, and when one takes a closer look at the study’s methodology. The results of Catsburg’s related work on overcooked and fried fish, and the need for all of us to make sure that we use high quality supplements and maintain adequate antioxidant intake in our diets can serve as good reminders to stick with our integrative dietary goals. Remember that cancer, and health in general, is not about one single lab test, one single food or one single supplement. It’s about all that you do to take care of your health. This is a good opportunity to review what you’re doing with your diet and supplements, to consider terrain testing if you’re concerned, and to remind yourself that it is not a good idea for any of us to become overly upset or anxious over the results of a single scientific study. References Aronson WJ et al. Phase II prospective randomized trial of a low-fat diet with fish oil supplementation in men undergoing radical prostatectomy. Cancer Prev Res (Phila). 2011; 4(12):2062-71. Brasky TM et al. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial. Journal of the National Cancer Institute 2013; published online July 10, 2013. Catsburg et al. Polymorphisms in carcinogen metabolism, fish intake, and risk of prostate cancer. Carcinogenesis 2012; 7:1352-9. Chua ME et al. 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(5-6):E333-43. Frattaroli et al. Clinical events in prostate cancer lifestyle trial: results from two years of follow-up. Urology. 2008;72(6):1319-23. Joshi AD et al. Fish intake, cooking practices, and risk of prostate cancer: results from a multi-ethnic case-control study. Cancer Causes Control. 2012; 23:405-20. Szymanski KM et al. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92(5):1223-33. Recipe: Poached Peppercorn Salmon Poached Peppercorn Salmon Serves 6 1 small onion, sliced 1 medium carrot, chopped 1 celery stalk, chopped 2 bay leaves 6 whole black peppercorns 1/2 cup vegetable broth 6 salmon fillets (4 ounces each) Salt and pepper 1. In a 10-inch skillet, combine onion, carrot, celery, bay leaves, peppercorns, and broth. You may need to add more broth or water to come 1 inch up side of skillet. 2. Bring to a boil; reduce heat, and simmer 15 minutes. Season salmon fillets with salt and pepper; place in skillet. Cover; simmer 5 minutes. Remove from heat; let stand until fillets are opaque, 8 to 12 minutes. Serve warm or chilled. • Bonus recipe – If you have any leftover dark leafy greens like spinach, kale, or collards, coarsely chop the leaves and place them in your hot skillet with the broth after you’ve removed the salmon. Let them steam until wilted, about 10 minutes. Serve as a side dish with your salmon.
Posted on: Mon, 12 Aug 2013 17:35:57 +0000
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