ANTIOXIDANT SUPPLEMENTS & PROSTATE CANCER
We are seeing a trend toward retrospective analyses of clinical trial data. Such a procedure is frequently the only manner in which some things can be discovered. The overriding advantage is its ability to provide access to a large number of patients. But there are perils that we civilians should understand. The first is that the patients are “virtual”. They cannot be prior selected, interviewed or screened. Their existence is in the past memory of recorded information.
There is an interesting and valuable editorial in the Journal of the American Medical Association: Peter Gann, “Randomized Trials of Antioxidant Supplementation for Cancer Prevention” (January 7th, 2009). It is readily available and I recommend that you download it and study the message. Let’s just take a glimpse:
“Randomized Trials of Antioxidant Supplementation for Cancer Prevention
First Bias, Now Chance-Next, Cause”
Peter H. Gann, MD, ScD http://jama.ama-assn.org/cgi/content/full/301/1/102
In 1996, a wave of hope arose when the Nutritional Prevention of Cancer Trial reported a 65% reduction in prostate cancer incidence in men receiving selenium supplementation. This came only 2 years after the ATBC Cancer Prevention Trial had reported a 35%reduction in prostate cancer occurrence among men taking vitamin E supplements. Suddenly, it appeared to make sense that this cancer could be prevented by bolstering antioxidant defenses in middle-aged and older men. Prostate cancer was not a pre-specified end point in either trial, and although both results were based on post hoc analysis, randomization had worked and it seemed unlikely that the encouraging findings were due to confounding bias. Indeed, confounding stood as the likely explanation for discordance between the earlier beta carotene trials that failed to demonstrate any benefit and numerous observational studies reporting that men who consumed beta carotene-containing foods were at lower risk for developing cancer, particularly those of the respiratory tract.
Now, 12 years later, comes the disappointing news that two major trials conceived during the wave of hope found that neither selenium nor vitamin E supplementation, alone or in combination, produced any reductions in prostate cancer or cancer of any type. The results of these important studies, the SELECT (Selenium and Vitamin E Cancer Prevention Trial) by Lippman and colleagues and the Physicians’ Health Study (PHS) II by Gaziano and colleagues, are reported in this issue of JAMA.
Despite the null findings, it is important to recognize what these trials have accomplished. SELECT had a simple, cost effective design, completed accrual of more than 35 000 participants ahead of schedule-making it the largest individually randomized cancer prevention trial ever conducted- and maintained high rates of adherence and retention for 4 to 7 years. Given its statistical power, it is unlikely that the study missed detecting a benefit of even a very modest size…..
Epidemiology teaches that every statistical association has only 3 possible explanations: bias, chance, and cause. Regarding nutritional prevention of prostate cancer, first generation phase 3 trials were too reliant on biased interpretation of prior research; second-generation trials may have been too reliant on chance; yet there is every reason to believe that the next generation will have a firmer basis for causal hypotheses. Until then, physicians should not recommend selenium or vitamin E-or any other antioxidant supplements-to their patients for preventing prostate cancer.
The topic centers on nutritional prevention of cancer by antioxidant supplementation of the diet. But there are two threads of the discourse:
- If we expect to see major gains through dietary or other lifestyle choices, then we need first to discard those things about the modern Western social construct that are absolutely proven to be worsening our health and wellness. About dietary intervention, Gann says “If it requires whole foods, extracts, or dietary patterns, it may be necessary to give up the reductionist need to know which molecule is most responsible and perhaps…starting exposure early in life and sustaining it for decades…” So there is an inconvenient truth we should address first of all!
- The overt theme is simply that you cannot trust what you read to be either complete or simple. Many factors impose on every circumstance in life. If two events can be correlated, they might only do so when some other set of factors is constant. In most real cases there is a whole gaggle of interacting forces – big, small and some embarrassing. Still further, correlations might simply be a matter of chance or bias, much as can be seen in the faces of ardent players at a Casino. Analysis in retrospect (post hoc trials) does not allow the investigator to touch the canvas and test those things that paint the scene. Thus, the risks of unfortunate error are magnified – perhaps the conclusions are quite invalid.
So be cautious and inquisitive about revelations from the past in conventional medicine as well as any other field. Errors come from placing heavy reliance on data extracted from campaigns that were conceived, designed and implemented in the past to test one or more hypotheses inevitably different from ours here in the present.
Sir Macfarlane Burnet enjoyed the image of people who studied the natural decomposition of deceased wild dogs across the seasons of each year – only to conclude that it is the sun in particular that brings forth maggots in summer. His point was always that trial results and models must follow an unending tension as we seek to refine ideas and push to know what is just beyond our full understanding as any time.
Be well, try to be wise