THE "NEW" PROSTATE CANCER INFOLINK

There has been intense discussion of our report on a recent paper suggesting that there may be heightened risk for prostate cancer diagnosis associated with high levels of consumption of fatty fish (e.g., salmon) and fish oil supplements. The following blog post is written by Jim Waldenfels, who has carried out a detailed analysis of the full text of the original paper by Blasky et al. However, the opinions expressed below are those of the author. They do not necessarily reflect the opinions of The “New” Prostate Cancer InfoLink or its parent organization, Prostate Cancer International.

On July 12, Sitemaster wrote: “Dear Jim: (1) In my experience most men don’t come near to your level of obsession about trying to manage their health.”

With thanks (and apologies) to the creators of the musical My Fair Lady: “I think [he’s] got it! I think [he’s] got it!”. Eliza [Sitemaster] repeats the sentence again and he [Professor Henry Higgins, a.k.a., for this exchange, I] says “By George, [he’s] got it! By George, [he’s] got it!” (From the exchange between Eliza and Professor Higgins in the song “The rain in Spain stays mainly in the plain” with some subtle alterations.)

Not that I haven’t heard the equivalent of that astute assessment of my activities before, chiefly at least once a week at our dinner table.

In all seriousness, having studied this paper, I believe it is more likely than not that the study is picking up not a possible causal connection between increased prostate cancer risks and more marine omega-3 fatty acids coupled with lower omega-6 fatty acids, but rather data associated with increased consumption of marine omega-3s (and perhaps lower consumption of omega-6s) due to heightened concern about developing prostate cancer and awareness of current beliefs about nutrition and prostate cancer risk.  For some of us, including me, concern with lifestyle tactics, including nutrition, to combat the risks of prostate cancer would look at least like strict self-discipline and perhaps like obsession. Sitemaster, I have a hunch that at some level, perhaps even below the level of awareness, you too may be sensing that concern with the risk of prostate cancer, which is perhaps the poorer cousin of obsession (strike that, I mean “high self-discipline” – so much more complimentary), is what is explaining the levels of fatty acids observed in the study. Right up front, let me state that I am far from fully confident of my theory of what is happening, and I do recognize the possibility of some truly increased risk from increased omega-3s/decreased omega-6s as suggested by this paper. I‘m looking forward to some commentary by experts in nutrition and prostate cancer.

What the study reveals to us directly is that men further along the prostate cancer spectrum – a spectrum as reflected in the study spanning: first, some concern but no diagnosis … second, diagnosed prostate cancer that is not “high risk“ … and finally high-risk prostate cancer – consume progressively greater amounts of marine-based omega 3 fatty acids and lower amounts of omega-6 fatty acids. In contrast, the perspective of the authors of the study, and the media take, is that consuming more marine-based omega-3s may increase the risk of getting prostate cancer or its seriousness, and that consuming more omega-6s may decrease these risks, both contrary to conventional wisdom (and most research) until the current and at least two other recent studies. However, at a level a little below the surface details that have been reported, the study also reveals clues to a fair likelihood that this increased consumption is related to the level of personal risk perceived by each participant in the trial and that the increased risks of both getting prostate cancer and developing higher-risk prostate cancer are due to real risk factors behind these perceptions.

Here’s what I think is happening in this trial. (These matters have direct relevance to the details of the trial.) First, the vast majority, perhaps all, of the participants have some heightened concern they will develop prostate cancer, and that supposition is based on the fact that they chose to spend some of their voluntary effort, time, attention, and probably some money in enrollment and participation in a clinical trial for prostate cancer (the SELECT trial), a choice that is quite uncommon for men in the United States. That concern could stem from circumstances as mild as having a friend diagnosed with the disease, or suffering from it, or dying from it, or the concern could stem from more personal and threatening factors.

Second, among all the men with at least that heightened but generalized and non-personal level of concern, many trial participants very likely had even greater concern. We can confidently surmise that having PSA screening results farther from the true norm of less than 1.0 (totally healthy; especially no BPH, no infection, no cancer), or in other words, PSA results closer to exceeding the old biopsy trigger threshold of 4.0 (the upper limit for enrollment in the SELECT trial, coupled with a nonsuspicious DRE), or steadily increasing PSA results, or a post-enrollment suspicious DRE, would increase that concern. We can also confidently surmise that having a “first degree relative” (father or brother) affected by prostate cancer would increase that concern, and the concern would likely also be further heightened if two or more first degree relatives had developed prostate cancer. Having three generations affected by prostate cancer, and having two relatives diagnosed at a young age, especially younger than 55, are additional familial factors that could heighten concern. Simply being African American would likely increase concern in a personal way as the added risk of getting prostate cancer and its seriousness are widely understood in the African American community, I believe.

Third, it’s a safe assumption that men with some concern about prostate cancer risk are more likely to act to try to protect themselves from the risk, and I contend that the likelihood of protective action is typically stronger in proportion to the level of perceived risk. Jonathan’s response of July 15 at 8:26 am to the original discussion is a perfect illustration. His father died from prostate cancer, and his PSA has been elevated for his age. I suspect his father suffered a lingering and often uncomfortable bout with the disease over months or years before dying, which was the case for my own father (and the President’s grandfather, by the way). Unlike the quick death that typifies many cases of heart disease – which, incidentally, is the major risk of mortality for us prostate cancer patients, the prospect of slow decline and death from prostate cancer has an amplified capacity to induce dread and anxiety, and to motivate protective action. Again, Jonathan’s action in seeking out information and taking omega-3s, along with using other health tactics, is an excellent example of the fruits of this motivation, and is so like my own reaction. Here are some examples to show the drastic changes a lot of us make when we confront the risk or actuality of prostate cancer.

As for protection from that risk, back in 1999/2000 when I was diagnosed, about one year before the SELECT trial kicked off, there was a lot of available information stating the possibility, even the strong supposed likelihood, that nutritional tactics could help protect us against prostate cancer or reduce its seriousness. For example, the page of brief recommendations under the acronym CASTLES had been published by the American Cancer Society, as indicated above. Additionally, the well-known financier/prostate cancer survivor and advocate Michael Milken had published a cook book for prostate cancer patients. Internet and prostate cancer newsletters also contained information advocating consumption of marine-based omega-3s. These are just some of numerous resources then available.

By 2001, there was enough enthusiasm to launch the large and expensive SELECT trial for vitamin E and selenium. A search of http://www.pubmed.gov a moment ago for “prostate cancer AND omega 3″ yielded 169 hits, with 141 of them dating prior to randomization for the select trial in July 2001; this was therefore knowledge that could have been available to trial participants. A popular prostate cancer newsletter headlined one issue “Omega 3 Fatty Acids & Saw Palmetto” (separate discussions) in December 2000, and the article referred to ongoing discussions about the benefits of marine-based omega-3s, risk of plant omega-3 (ALA or α-linolenic acid), risk of fish contaminants, and safe access to marine omega-3s. My impression is that marine omega-3s have continued to grow in popularity since that time.

Is it not likely that many of the motivated participants in the SELECT trial would have been taking marine omega-3 fatty acids? Is it not likely that they would have been more likely to take them and to take higher doses (including fish) as their risk factors increased? I’m convinced the answer is yes, but that needs to be tested. If so, then I suspect the associations reported in the study between higher levels of marine omega-3s, etc., are just caused by higher consumption without causing higher risk. In other words, if that suspicion is true, we are seeing a spurious association and not a causal relationship.

Here are key details of the current study. Two groups were set up, all participants in the SELECT trial, comprising men who, as required by the trial’s eligibility rules, did not have prostate cancer at the start of the SELECT trial, as indicated by their histories, by PSAs not exceeding 4.0, and by the absence of suspicious DREs. One group, 834 in number, was basically all SELECT trial participants who were diagnosed with prostate cancer through July 31, 2009, about a year after the unblinding of the SELECT trial. The “control” group, 1,393 in number, was a randomized selection of men who were not diagnosed with prostate cancer through July 31, 2009, matched by race (black, others) and age, with fairly close equivalence happening to be achieved for education (somewhat higher among those diagnosed), smoking, body mass index, alcohol consumption, finasteride use, aspirin use, SELECT intervention assignment, and history of diabetes.

However, there were two characteristics for which the groups were not well matched at all: the first was PSA level, and the second was proportions in the groups with first degree relatives diagnosed with prostate cancer. That is the smoking gun (at least in my opinion)!

Regarding PSA, we see this:

The results also show that nearly twice as many men in the group that eventually was diagnosed with cancer had at least one first degree relative with prostate cancer, with more than three times as many having two or more such relatives! Again, that is a sharp tilt!

In short, in view of these two key risk factors, we can see that risk was markedly higher in the group that eventually developed prostate cancer. Moreover, both factors were clearly evident to each man, and both were well known and publicized at the time as risk factors. I contend it is a safe bet that the vast majority of men who were at higher risk knew it. I contend it is a safe bet that many of them were motivated by that higher risk to consume more omega-3s. If those contentions are sound, it is quite likely that the results reported here of higher risk associated with omega-3s are simply due to consumption patterns and not because omega-3s are increasing risk! I hope that’s true, as it would leave me with an abundance of research evidence suggesting that marine-based omega-3 consumption decreases prostate cancer risk.

Finally, let’s consider the differences in the amounts of marine-based omega-3s consumed that are being associated with the greater likelihood reported in this study of both diagnosis and “higher risk” disease:

These differences strike me as small. The study tells us that these differences are significant, but that means “statistical significance.” It does not prove medical significance. Moreover, even small differences are more likely to be “statistically significant” when the number of study participants is large, as is the case here. Is it not likely that the substantial differences in the PSA and first degree relative factors, displayed above, are associated with substantially more perceptions of higher risk in the group that was later diagnosed, and that those substantially greater perceived differences in risk therefore account for the relatively small differences in consumption of omega 3s? I suggest that the same line of thought applies to the “higher-grade” cancer results.

Because the data are all available and no doubt computerized, it would be worthwhile and probably technically easy to match marine-based omega-3 results for the cancer group above with results for a group of non-cancerous SELECT trial participants, but this time matching for both PSA level and first degree relatives. In other words, let’s do the matching that was not done in this study. That would presumably equalize average perception of prostate cancer risk in the two groups. My hypothesis is that such a study would result in no significantly increased omega-3 consumption by the diagnosed group. If significant differences still remained, which I doubt, with higher consumption by the diagnosed group, would that not suggest that something other than perception was contributing to the greater consumption and associated risk, such as the causal connection suggested by this study? Again, I doubt that is the case, but let’s put it to the test.

In short, the findings of the study appear to be an artifact and, if so, should not bear on our consumption of marine-based omega-3 fatty acids, but it should not be difficult technically to put this assessment to the test.

Filed under: Diagnosis, Living with Prostate Cancer, Management, Risk, Uncategorized | Tagged: diet, fish, lifestyle, Omega-3 fatty acids, risk |