Supplements and cancer prevention

The bloggers here have been very critical of a law passed nearly 20 years ago, commonly referred to as the DSHEA of 1994. The abbreviation DSHEA stands for about as Orwellian a name for a law as I can imagine: the Dietary Supplement Health and Education Act. Of course, as we’ve pointed out time and time again, the DSHEA is not about health, and it’s certainly not about education. Indeed, perhaps my favorite description of this law comes from our very own Peter Lipson, who refers to it as a “travesty of a mockery of a sham.” Rather, it’s about allowing supplement manufacturers and promoters of so-called “complementary and alternative medicine” (CAM, with or without a preceding “s,” depending on your taste) who do not want pesky things like government laws and regulations to interfere with their selling of pseudoscience to market various compounds as “dietary supplements” with near-impunity. As Harriet Hall put it so accurately, the DSHEA is “a stealth weapon that allows the sale of unproven medicines just as long as you pretend they are not medicines.”

The DSHEA accomplishes this by making a seemingly reasonable distinction between food and medicine and twisting it in such a way that allows manufacturers to label all sorts of botanicals and various other compounds, many of which have substances in them with pharmacological activity, and sell them as “supplements” without prior approval by the FDA before marketing. As long as the manufacturer is careful enough not to make health claims that are too specific, namely that the supplement can diagnose or treat any specific disease, and sticks to “structure-function” statements (“it boosts the immune system!”), almost anything goes, particularly if a Quack Miranda Warning is included.

Not surprisingly, given what a big business supplements have become in this country largely due to the DSHEA, manufacturers and CAM advocates fight tooth and nail against any attempt to update the DSHEA to correct some of its more unfortunate consequences. Led by Utah Senator Orrin Hatch and Iowa Senator Tom Harkin, who together make up a bipartisan tag-team in defense of the supplement industry and do their best to block any effort to increase its regulation by the FDA. We saw that most recently when Arizona Senator John McCain, of all people, introduced a bill in 2010 to try to tighten up the DSHEA and was thoroughly slapped down by Orrin Hatch. More recently, not satisfied with how good things are for the supplement industry, another Utah Representative Jason Chaffetz reached across the aisle to Jared Polis, teaming up to introduce the Free Speech About Science Act, which basically seeks to allow the supplement industry to make more liberal claims about its products. All it will need is a “peer-reviewed” paper to support it (Mark and David Geier would do!), and you can claim almost anything. Anything to grow the supplement industry, which is currently around $30 billion a year.

That’s why it’s critical, from time to time, to look at actual evidence, and just last week Maria Elena Martinez, PhD, of the University of California San Diego, and co-authors did in a commentary published online in the Journal of the National Cancer Institute entitled Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms.

As several of us have pointed out before, there are science-based roles for supplementation. For instance, in the case of nutritional deficiencies, and Martinez et al point out the very same thing:

Clearly, dietary supplements are useful for the treatment of nutrient deficiencies; however, with the exception of select subgroups (2,3), such deficiencies are relatively uncommon in the United States and most industrialized countries today.

Of course, if you listen to CAM promoters and supplement manufacturers, you’d think that supplements are absolutely essential to preventing cancer. While it is true that there is increasing evidence that diet has a significant effect on our risk for various cancers, this evidence is nothing new. We’ve simply concentrated on it more in recent years, and a new generation of “natural health” advocates, such as Dean Ornish, have attributed near magical powers to diet as a tool for preventing cancer. As a byproduct of increasing evidence that cancer risk is influenced by lifestyle choices, it is understandably tempting to think that we could somehow “bottle” what’s in various foods as supplements that could reverse or ameliorate diet-associated cancer risks. Ironically, although CAM advocates would never concede it, this sort of thinking is the sort of thinking they themselves decry in conventional medicine when they make the exaggerated charge that all doctors do (or want to do) is to prescribe a pill to deal with health issues. Think about it: Even is supplement did what is claimed for them, is there any real difference between just prescribing a supplement to decrease cancer risk rather than recommending much harder lifestyle interventions and prescribing a statin to prevent heart disease rather than recommending much harder lifestyle interventions?

Martinez et al then go on to summarize the state of evidence as it currently exists for the use of supplements to prevent cancer. They conclude that there is precious little evidence for efficacy and existing evidence for harm. Their assessment of the evidence for antioxidants is particularly withering:

Several early observational studies (10–13) found that diets high in fruit and vegetables were associated with diminished risk of several cancers, including respiratory and gastrointestinal cancers. The importance of β-carotene and other carotenoids was suggested by both retrospective and prospective studies showing that low levels of β-carotene in the serum were associated with higher subsequent risk for lung cancer (14). At one point, research focused on retinoid supplementation, in light of the finding that β-carotene is converted to retinol (13). It was hypothesized that the lower risk associated with consumption of these foods, and with β-carotene, α-tocopherol, and vitamin C intake, might be attributable to the activity of antioxidants. In vitro and in vivo studies suggested that these compounds encourage growth of normal tissue and block growth of abnormal tissue (2). However, human experimental studies have uncovered the following: β-carotene does not prevent non-melanoma skin cancer recurrence (15); β-carotene and α-tocopherol with vitamin C do not protect against adenoma recurrence (16); β-carotene and vitamin A do not protect against lung cancer incidence (17); α-tocopherol and β-carotene do not prevent lung cancer (18); β-carotene does not prevent lung cancer (19); vitamins C and E do not protect against total cancer incidence (20); and α-tocopherol, vitamin C, and β-carotene do not protect against total cancer or cancer mortality (21). Based on a review of trial data, a Cochrane report (22) concluded that there was no convincing evidence that β-carotene, vitamin A, vitamin C, or vitamin E supplements, given singly or in combination, prevent gastrointestinal cancers.

That’s not all, though. An article such as this can’t go without mentioning the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which was resoundingly negative. Selenium and vitamin E showed no evidence of decreasing the risk of prostate cancer, leading to the trial being halted after approximately 5.5 years of followup. Consistent with the results of SELECT, a Southwest Oncology Group (SWOG) trial showed that selenium supplementation in men with a premalignant precursor of prostate cancer showed no benefit, and another trial showed that selenized yeast does not prevent recurrence of stage I non-small cell lung cancer. As Martinez et al put it, “organic selenium appears to provide no cancer prevention benefit.”

Not every trial was negative. One exception noted by Martinez et al is a 20 year old prevention trial in China consisting of 30,000 subjects. This study showed a 13% reduction in cancer mortality, including a 21% reduction in gastric cancer mortality, compared to placebo controls in a randomized trial testing a combination of β-carotene, vitamin E, and selenium. This is, at best, a modest effect. However, similar studies looking at such cocktails were even less convincing, including a companion study of 3,000 subjects examining a supplement that contained 14 vitamins and 12 minerals, including β-carotene, vitamin E, and selenium. No statistically significant effect on cancer incidence was observed.

The counterweight to the weight of existing high quality evidence looking at antioxidants and cancer, which suggests no benefit in the vast majority of cancers studied this far and equivocal evidence even in the handful of studies that suggest a benefit is a cohort of studies that suggests the real possibility of harm due to antioxidant use:

Several antioxidant trials (17,18,30,31) have actually reported increased risks with supplementation. The most prominent example, β-carotene and lung cancer, was tested in two RCTs (17,18) in high-risk populations of heavy smokers and asbestos-exposed individuals. Individuals randomly assigned to β-carotene in the Beta-Carotene and Retinol Efficacy Trial (CARET) trial had a 39% increase in lung cancer incidence compared with those in the placebo arm (17); the ATBC trial found a 16% increase in risk of lung cancer associated with β-carotene (18). With prolonged follow-up, NPC investigators found that selenium supplementation statistically significantly increased the risk of squamous cell skin cancer by 25% and total non-melanoma skin cancer by 17% (30). The increased risk was particularly marked among individuals in the highest tertile of circulating selenium levels just before the start of the trial. The most recent illustration of the possibility that pharmacological doses of antioxidants may not have the intended effect comes from the extended follow-up in the SELECT trial, which reported that α-tocopherol increased risk of prostate cancer by a statistically significant 17%; these results led the authors to conclude that consumers should be skeptical of health claims related to unregulated over-the-counter products (31).

The authors then looked at folate supplementation. The state of the evidence for whether folate can prevent cancer is similarly disappointing. In fact, it can be described as largely negative. Worse, like the case with antioxidants, contrary to the hypothesized benefit of folic acid supplementation, there is evidence that it can contribute to some cancers. For instance, there is one trial that showed that long-term supplementation with folic acid increases the risk of advanced colorectal adenomas (relative risk = 1.67) and the risk of developing three or more such adenomas (RR = 2.32). An elevated risk of prostate cancer was also observed. These results are consistent with preclinical studies in animals suggesting that folic acid can increase the risk of cancer, as well as observational studies that have linked higher dietary intake with an increased risk of prostate and breast cancer. Ironically, in the U.S. and other countries, the government has mandated folic-acid fortification of the food supply, which makes the question of whether folic acid supplementation is doing more harm than good particularly pertinent. True, there’s strong evidence that folic acid supplementation of the diet in pregnant women can decrease the risk of birth defects, particularly neural tube defects, but that is short term supplementation compared to long term supplementation. The question, then, is, as always: Is the balance of benefit versus risk due to folate supplementation favorable? There’s enough evidence out there to be concerned that the answer to that question might very well be no, except for pregnant women.

Finally, Martinez et al take on the case of vitamin D and calcium. Anyone who’s been reading CAM-friendly websites these days probably knows that vitamin D is currently viewed by many in the alternative medicine world as some sort of panacea that prevents all cancer. Heck, to listen to some CAM advocates tell it, vitamin D is supposedly so awesome that it prevents influenza more effectively than the influenza vaccine. Of course, as has been discussed on this very blog, the picture is, as is usually the case, more complicated than that, and Martinez et al try to communicate that complexity, referencing the Institute of Medicine’s recent recommendations for vitamin D and calcium intake published in 2011, in which the IOM concluded that there is insufficient evidence to conclude that there is a causal association between low vitamin D intake or low blood 25 hydroxy (OH) vitamin D [25(OH)D] levels and cancer. Martinez et al sum up this data thusly:

There have been many epidemiological investigations of blood 25 hydroxy (OH) vitamin D [25(OH)D] concentrations and cancer-related endpoints (45–49), and meta-analyses of these have shown statistically significant inverse associations between serum 25(OH)D and colorectal adenoma (46,49) and colorectal cancer (45), whereas the results for prostate cancer have largely been null (45,48). For breast cancer, the relationship with serum 25(OH)D levels varies by study design; case-control studies generally demonstrate inverse associations, and prospective studies have been null (45,47,50); because blood levels are collected after the onset of cancer in case-control studies, the potential for bias in these studies must be considered (47,50). Clearly, clinical trials are needed to elucidate any preventive effect of vitamin D (51,52). To date, three short-term RCTs of vitamin D and cancer endpoints (52–55) have been completed; one showed no direct effect of vitamin D supplementation on cancer mortality (53), the second showed no reduction in breast or colorectal cancer incidence by a vitamin D/calcium combination (54,55), and the third showed a reduction in total cancer incidence by a calcium/vitamin D combination vs placebo (56). As concluded in a recent meta-analysis, because of the potential confounding inherent in observational studies and the limited data from clinical trials, evidence is currently insufficient to draw conclusions about the efficacy of vitamin D supplementation for cancer prevention (57).

As far as cancer is concerned, there just isn’t a whole lot of data from well-designed randomized clinical trials testing the effect of vitamin D supplementation on cancer risk to hang one’s hat on. The same is true of calcium supplementation, only more so. Observational studies have, as Martinez et al almost drolly characterize it, “yielded diverse results.” In any case some of the diverse results with respect to vitamin D suggest a correlation between high vitamin D concentrations and pancreatic cancer, while a recent meta-analysis suggests a reduction in risk. In the case of prostate cancer, however, a recently published study suggests a statistically significantly increased risk of prostate cancer (RR = 1.56 for men in the highest quintile) among men who have the highest levels of 25(OH)D, a finding that was more striking for aggressive disease, leading the authors of the study to advise caution in recommending vitamin D for cancer prevention. Puzzlingly, these results are in contrast to a lot of basic science research that supports a beneficial role for vitamin D compounds in prostate cell proliferation and differentiation, prostate cancer cell growth and invasion, and tumorigenesis.

To say that the state of evidence in support of the use of various dietary supplements as cancer preventatives is unsettled is a gross understatement. Martinez et al discussed supplements that have been studied the most and, let’s be frank, that involve the purest supplements, most of which contain only a single ingredient, and they found little evidence of efficacy in preventing cancer but some evidence of potential harm. That’s not even counting the near innumerable supplements now being sold that are not pure substances but some form of extract from plant, fungi, yeast, or even animal origin. As I’ve said before time and time again, supplements that “work” (i.e., have some sort of biological effect) are drugs. They’re impure, adulterated drugs with highly variable potency because of their highly variable content of active ingredient. Obviously, supplements that don’t have such a biological effect are worthless (except for lining the pockets of supplement manufacturers). That’s why supplement manufacturers very much want consumers to believe that their supplements have a whole range of beneficial biological effects, and the DSHEA allows them to imply that, as long as they don’t do it too explicitly.

Martinez et al put the blame squarely where it belongs: On the DSHEA and another law. They also explain how supplement manufacturers get around even the weak prohibitions in the DSHEA:

Even without such direct statements, anticancer effects can be implied. For example, even though the manufacturers of Pill X cannot openly advertise that it prevents prostate cancer, they can create an advertisement that states that prostate cancer is a major health problem, that Pill X has a role to “support prostate health,” and that a particular study found that the compounds in Pill X reduced the growth of prostate cells in culture. Their website can then be accompanied by advertisements for Pill X and can contain links to testimonials that are free to expound the benefits of Pill X as experienced by real people. The absence of credible scientific evidence that taking Pill X confers anti-prostate cancer properties in men can be easily obscured by this constellation of claims that collectively suggest anticancer effects. As a result of limited regulatory authority, manufacturers who cannot overtly claim anticancer benefits of supplements without scientific proof are nonetheless free to imply those benefits in ways that make it difficult for the consumer to discern innuendo from scientific fact (82).

Indeed. Another recent review concluded that, with the possible exceptions of vitamin D and omega-3 fatty acids, there are no data to support the widespread use of dietary supplements in Westernized populations and that such supplements can even be harmful. Another recent study finds no effect from supplements on all-cause mortality and even found a negative effect from folic acid supplementation, consistent with yet another study. The bottom line is that, at present, it is quite probable that most supplements probably do more harm than good.

So why do so many people take supplements? Martinez et al also quite correctly point out:

Undoubtedly, use is driven by a common belief that supplements can improve health and protect against disease, and that at worst, they are harmless. However, the assumption that any dietary supplement is safe under all circumstances and in all quantities is no longer empirically reasonable. Believers in supplements are sometimes quick to discredit caution over supplement use, as they suggest that the tendency of mainstream science to ignore nonconventional evidence is tainted or that mainstream science is somehow corrupted by its link to a medical–industrial complex that seeks to protect profits rather than prevent disease.

Right on cue, our favorite quack apologist and supplement hawker, Joe Mercola, chimed in with an article entitled Over 60 Billion Doses a Year and Not ONE Death, But Still Not Safe? In it, Mercola in his usual frothing-at-the-mouth style (although not nearly as frothy as another favorite quack apologist Mike Adams) rants that a recent survey from the American Association of Poison Control Centers’ National Poison Data System reveals, there were zero deaths linked to nutritional supplements in 2010, amusingly citing the Orthomolecular Medicine News Service as its source. Orthomolecular medicine, you might recall, is a form of supplement quackery originally embraced by Linus Pauling when he concluded that high dose vitamin C was the cure for the common cold and cancer.

Never let it be said that Mercola isn’t good at intentionally confusing short term toxicity with long term effects in his eagerness to attack a straw man. He seems to think that when scientists point out that supplements can be hazardous that they are claiming that supplements will kill you fast when in reality most potential problems with supplements are long term health effects, although, I would point out, certain supplements can certainly cause serious problems more acutely. In any case, when Mercola asks, “Where are the bodies?” I’d answer that if a supplement increases the risk of a common cancer by 25%, that’s a lot of potential bodies. They just won’t be directly linked to supplements. Particularly amusing is Mercola’s outrage that the FDA is trying to impose the same limits on supplements as on aspartame, monosodium glutamate, and sodium nitrate.

What is infuriating Mercola and the supplement industry are draft guidelines from the FDA designed to assess new ingredients in supplements using safety standards similar to what are required for the approval of new food additives, as described in this recent New England Journal of Medicine commentary:

The proposed guidance clarifies the level of evidence the FDA would use to assess safety. Specifically, the safety of supplements would be evaluated according to three key factors: documented history of use (e.g., in foods or in supplements or herbal medicines sold outside the United States), formulation and proposed daily dose (e.g., more or less than was formerly consumed), and the recommended duration of use (e.g., intermittent or long-term). The FDA’s guidance provides a thoughtful framework for evaluating the safety of new ingredients (see table Required Safety Testing for New Dietary Ingredients Labeled for Intermittent Use.), and if implemented it would lead to substantial improvement in safety. For example, the FDA would require in vitro, animal, and tolerability testing for products that would be marketed for consumption at doses greater than those historically ingested.

In actuality, however, even these draft guidelines do not go far enough, and the supplement industry is vigorously opposing them, even though they strike me as an eminently reasonable strategy for trying to address at least one of the shortcomings of the DSHEA. After all, don’t supplement manufacturers themselves claim that their supplements are food, not medicine? Then why not require that new supplement ingredients without documented historical usage be subject to the same requirements for safety as any other food additive?

It’s important to remember that, in the end, supplements that have biological activity are functioning as drugs. As Martinez et al and a number of other studies strongly suggest, there is very little, if any, evidence that supplements improve health, at least in an already well-fed population, with a precious few possible exceptions that are far more narrow than anything CAM advocates or supplement manufacturers claim. Worse, at least as it stands right now, for most supplements, it is disturbingly likely that the harms probably outweigh the benefits for most people. This is one area where we probably do need more studies, but they need to be “strategically designed” studies, as Martinez et al put it, set up in light of existing evidence from previous studies that have been largely negative.

Posted in: Cancer, Herbs & Supplements, Politics and Regulation

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