Klein et al’s recent publication of their analysis of SELECT trial data suggests that taking daily doses of vitamin E or selenium reduces risk of prostate cancer.  Taking vitamin E may actually increase risk.  This has me questioning some of the basic assumptions I make about cancer prevention and our use of nutritional supplements.

Before drifting off into the murky realms of my ruminations, it is appropriate to briefly review Klein’s study.  From August 2001 to June 2004, a total of 35,533 men were randomized into one of four groups. One group of 8,752 men took selenium (200 μg/d from L-selenomethionine).  A second group of 8,737 men took vitamin E (400 IU/d of all rac-α-tocopheryl acetate). A third group consisting of 8,702 men received both vitamin E and selenium.  The remaining 8,696 men received only placebo.  At the start of the study, the men were healthy with no sign of prostate cancer (PSA levels  =/<4.0 ng/mL and normal digital rectal exam). Data were collected until July 2011.  The main outcome measure was whether the men were diagnosed with prostate cancer during the course of the trial.

The study yielded unexpected results. Of the men taking placebo, only 529 developed prostate cancer but 620 of those taking vitamin E did.  Taking vitamin E was associated with a statistically significant 17% increase in risk of prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008).  More men in the selenium and the selenium plus vitamin E groups were also diagnosed with cancer but these increases did not reach statistical significance.  In the selenium group, 575 were diagnosed with prostate cancer (HR, 1.09; 99% CI, 0.93-1.27; P = .18). In the selenium plus vitamin E group 555 were diagnosed (HR, 1.05; 99% CI, 0.89-1.22, P = .46).

This is not what the researchers were hoping to see.  Their assumption was that both vitamin E and selenium would lower risk.

Klein’s study isn’t the only recent publication to suggest vitamin E acts differently than predicted. Last June Fleshner et al writing in the Journal of Clinical Oncology reported on their work using vitamin E, soy and selenium or a combination of these supplements on high-grade prostatic intraepithelial neoplasia (HGPIN). This condition is considered the precursor of invasive prostate cancer.  Three hundred men were followed for three years in a randomized phase III double-blind study comparing the effects of daily soy (40 g), vitamin E (800 U), and selenium (200 μg) versus placebo.  Slightly more than a quarter of the study participants developed invasive prostate cancer.  The hazard ratio of those taking the supplements was 1.03(95% CI, 0.67 to 1.60; P = .88).  This was not significantly different than those taking placebo.

Thus in the last six months we have two fairly solid clinical trials telling us that two things that we were fairly sure would be of benefit do no good.

We’ve been in a similar quandary before.  This SELECT study is another well-designed study on antioxidants and cancer that produced the opposite result of what was expected. Instead of lowering risk, the supplements increased risk.

This feels remarkably like the CARET study that rather than prove that beta-carotene and vitamin A lowered risk lung cancer in smokers but found the opposite.

Back in 1991 when the CARET study first got underway, the theory was simple.  People who eat more fruits and vegetables have a lower risk of developing cancer.  It was assumed that the beta-carotene in these foods provided protection.   The trouble was that the study participants who took the 30 mg/day dose of beta-carotene had a 36% higher relative risk of getting lung cancer than those taking placebo. (95% [CI] = 1.07-1.73; P = .01)  Relative risk of dying from lung cancer increased by 59% (95% [CI] = 1.13-2.23; P = .01).

Our learned colleagues have already looked at these current results from the SELECT study and found excuses for the failure to find benefit. [see Geo Espinosa in NMJ]  Back in the days of the CARET study, we pointed out that the betacarotene chosen was synthetic, not natural. In this SELECT study, we can now excuse the failure because the wrong isoform of vitamin E was used; participants took alpha-tocopherol instead of gamma- tocotrienols .

Though these are plausible explanations, I have another explanation, which may border on blasphemy. Instead of finding excuses for studies that don’t support what we believe, let us ponder some of our basic assumptions.

Our basic assumption is that oxidative damage to DNA leads to cancer and preventing this from occurring should prevent cancer.  From there it’s a short leap to the idea that daily doses of antioxidant vitamins will prevent cancer. That short leap is where we may have stumbled.

In the SELECT study, participants took 400 IU of vitamin E per day, in the Fleshner study, twice that amount. These are large amounts of vitamin E, more than a person would ever get from a healthy diet.

Wheat germ oil is the most concentrated dietary source of dietary vitamin E with levels as high as 1276 mcg/gram.    To obtain 400 IU of vitamin E, a person would need to consume more than a cup of wheat germ oil per day.

While it makes sense that a vitamin E deficiency may leave the cells more vulnerable to oxidative damage, where did the idea to employ megadoses like these come from?  This approach sounds more pharmaceutical than naturopathic. We have no naturopathic principle that says, “More melius: More is Better.”   Why would we think these doses of vitamin E that would stimulate the Vis Medicatrix Naturae?  Why are we defending their use?

While we still may want to believe that vitamin E and selenium should prevent prostate cancer, a review in the June issue of Family Practice concludes, “There is no convincing evidence that the use of supplemental multivitamins or any specific vitamin affects the occurrence or severity of prostate cancer.”

Let us return to that original assumption about antioxidants protecting against cancer.  When this idea first appeared, even the concept of apoptosis was still years in the future.  I now view cell chemistry as a constantly shifting balance between reactive oxygen species (ROS) and glutathione.  While ROS can cause damage, ROS also initiate apoptosis and are the agents by which the cell commits suicide.  Without apoptosis, cells that are becoming cancerous cannot self-destruct.  Could vitamin E limit apoptotic cell death? Though an intriguing thought, the medical literature does not support this idea, at least not yet.

But think about it for a moment.  The published research looks at short-term reactions and responses to supplements using in vitro or animal studies.  In cell culture studies, exposure to vitamin E is often for only 48 or 72 hours.   In animal studies, vitamin E dosing may go on for a week or more.  What happens when an organism such as a middle-aged human male is exposed to massive doses of vitamin E for years?  Might the organism adapt to this constant level of vitamin E?

Living things respond and adapt to the conditions in which they live. Living things respond to stress and hardship by becoming hardier and are better able to tolerate these insults. In our practices as naturopathic physicians, we often attempt to trigger these ‘adaptive responses’ for therapeutic benefit. Our therapies, benign as they may seem, trigger physiologic over reactions, stronger adaptive responses than warranted yet leading to greater repair on a cellular level and a restoration of homeostasis on a systemic level. Hydrotherapy, fasting, and botanical medicines, as employed in naturopathic practice all work this way to benefit the patient by eliciting adaptive responses.

Yet adaptive responses work both ways.  Easing the stresses on an organism over the long run may reduce its capacity to respond to stress.  Raise a plant in a controlled environment free of insect attack, with controlled temperatures and plenty of fertilizer and the result will be a larger plant but with lower concentrations of phyto-nutrients.

Could long term high dose antioxidant supplements do the opposite of what we hope for reducing the body’s capacity to respond to oxidative stress?

Extreme exercise is often used as a research model for oxidative stress.  Athletic exertion causes tissue injury and raises ROS in the muscles and body in general. Thus it’s valuable to consider some the studies that have looked at antioxidant supplementation in athletes.

It has been thought that athletes should take antioxidant vitamins to protect their bodies from this damage.  Whether this really makes a difference is now questioned.  In 2003, Urso et al raised the question stating, “Whether strenuous exercise does, in fact, increase the need for additional antioxidants in the diet is not clear.”

McGinely et al also raised this concern in their 2009 review on the use of high dose antioxidants by athletes. “Indeed, antioxidant supplementation may actually interfere with the cellular signaling functions of ROS, thereby adversely affecting muscle performance.”  

Supplementation with antioxidants prior to exercise bouts in some studies does appear to prevent muscle damage and reduce soreness, but less clear is whether this benefits endurance or strength performance.

Reducing oxidative stress from exercise may not be good thing

Regular exercise, at least in rats, upregulates glutathione levels and reduces the generation of reactive oxygen species decreasing oxidative stress. Mild oxidative stress elicited by regular exercise elicits a hormetic effect.  The beneficial actions of exercise may result from it adaptively upregulating various antioxidant mechanisms, including antioxidative enzymes and repair enzymes that protect and repair molecules from damage.  The health benefits of exercise may actually stem from the oxidative damage that exercise causes.

In 2008 Gomez-Cabrera et al suggested that athletes taking vitamin C were hindering the normal increase in mitochondria that was triggered by training triggered oxidative damage and that this prevented their endurance levels from increasing with training. 

[In March 2011, Roberts et al’s tells us that this isn’t true that, “Vitamin C consumption does not impair training-induced improvements in exercise performance.” ]

The ruminating mind should wonder whether if vitamin C could interfere with adaptive responses over the short term, might high doses of vitamin E do something similar over the long run?  In particular might these chronic high doses hinder the triggering of some ROS elicited mechanism that would normally protect against prostate cancer?

Are any of these thoughts true?  Time will tell.  My faith in antioxidants and the idea that more is better has certainly been shaken.  I’m paying attention to which forms patients take and being fussy about it, hoping that therein lies the problem.  In doing so, I have become acutely aware of the prominent place the term “antioxidant” has in public opinion.   If a supplement or food can lay claim to ‘antioxidant’ status it is immediately considered ‘healthy’ and the higher its ORAC score the higher the pedestal we place it on.  What if this veneration is misplaced?  What if the real goal is some in between balance between reactive oxygen species and antioxidants?  Blasphemy it seems, but not really.

While our profession is caught up in antioxidant worship this isn’t really our creed.  Nowhere in the tradition of nature cure or in our principle of practice do we find antioxidants elevated.  This credo is relatively new a theory we took on from medical researchers and theorists.  We should be careful about clinging to it too tightly.

 

Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011 Oct 12;306(14):1549-56.

Fleshner NE, Kapusta L, Donnelly B, Tanguay S, Chin J, Hersey K, et al. Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium. J Clin Oncol. 2011 Jun 10;29(17):2386-90. Epub 2011 May 2.

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