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Study clarifies role of antioxidants during radiation.

An important paper on the interaction of antioxidants and radiation therapy has been published in the International Journal of Cancer. Despite the importance of its findings, this study has received little attention from the scientific community or the media. As background, in April 2005, Isabelle Bairati, MD, PhD, and colleagues at the Hotel-Dieu de Quebec Research Centre and the Universite Laval completed a ten-year study on the interaction of dietary antioxidants and radiation therapy. This was hailed as the first placebo-controlled, double-blind, randomized trial assessing the effect of supplementation with antioxidant vitamins during radiation therapy. The study concluded that supplements of synthetic beta-carotene (30 mg per day) or alpha tocopherol (400 IU per day) had a harmful effect on cancer patients. In particular, the authors claimed that the cancer recurrence rate was 40% higher among patients who had been randomly assigned to the supplementation arm of the trial. They therefore called on patients and physicians to exert caution in using antioxidants until new evidence could be provided by future trials.

Kedar Prasad, PhD, and other proponents of the concurrent use of antioxidants during cancer treatment criticized the Bairati paper. They were disappointed that Bairati and colleagues had used ordinary alpha tocopherol as their choice of vitamin E when Prasad's previous work had shown that it was not just alpha tocopherol but alpha tocopherol succinate that had the anticancer efficacy. They also felt that natural forms of the vitamin were more effective than synthetic, drug store-type vitamins. But, by and large, the medical world accepted the Bairati trial as definitive proof that antioxidants interfered with radiation therapy. Word spread like wildfire in oncology circles, confirming a long-held belief that antioxidants interfered with standard cancer treatments such as radiation and chemotherapy. The take-away message, as stated in a Universite Laval press release, was that "Supplements May Speed Up Development of Cancer." Advocates of complementary and alternative medicine (CAM) were confounded by this large and impressive study.

But now the other shoe has dropped.

In April 2008, Dr. Bairati and her Quebec colleagues published a major modification of their previous conclusions. Further analysis revealed, they said, that the danger of synthetic antioxidants was limited to one particular sub-population: cigarette smokers--specifically, those who continued to smoke during radiation treatment. The authors analyzed the outcome in 540 patients who had been given radiation for head and neck cancers. During the follow-up period, 119 patients had a recurrence of their disease, and 179 died. Smokers were the group with the worst prognosis. However, astonishingly, smoking in the period leading up to or following radiation therapy did not modify the effects of the two supplements. It was only smoking during the course of radiation therapy that led to a statistically significant increase in the risk of a recurrence. It was a large enough increase to skew the statistics for the group as a whole, leading to the erroneous conclusion that antioxidants interfered with radiotherapy in the general patient population.

Statistically, increased risk is generally expressed as a "hazard ratio" (HR). In this study, current smokers had an HR of 2.41 for recurrence--in other words, more than double the chance of a recurrence compared to the rest of the patient population. The HR for death from any cause was a similar 2.26. But the hazard ratio for dying of their initial head and neck cancer was a whopping 3.38 in patients who got radiation, smoked, and also received a single synthetic antioxidant. "These results could best be explained by the hypothesis that the combined exposures reduced the efficacy of radiation therapy," Bairati and her colleagues now say. "Particular attention should be devoted to prevent patients from both smoking and taking antioxidant supplements during radiation therapy" (Meyer 2008).

According to the National Cancer Institute, 85% of head and neck cancers are linked to tobacco use. (Alcohol use further exacerbates this trend.) This has been widely known for years, and so it is shocking that there are still people so hopelessly addicted to tobacco that they not only continue to smoke after they've been diagnosed with head and neck cancer but also continue to smoke right through their radiation therapy. It was in this subset of particularly unhealthy individuals that antioxidants were associated with an increased risk of disease progression. As Bairati and colleagues suggest, such individuals should definitely not compound their problems by then taking a synthetic antioxidant.

The more important lesson for patients and practitioners, however, is that antioxidants do NOT generally interfere with the effects of radiation therapy, as was previously suggested. They do NOT increase the risk of a recurrence, of death from head and neck cancer, or of overall mortality in the average patient. In this updated study, the harmful effect of synthetic antioxidants was entirely limited to those relatively few tobacco-addicted patients who continued to smoke during their radiation therapy. Thus, the major premise underpinning oncologists' condemnation of antioxidants during radiation therapy has crumbled, although few seem to have noticed so far.

Zetia Fails Clinical Trial ... Why Was It Ever Approved?

On the heart disease front, in January 2008, scientists announced the result of the long-awaited ENHANCE study of the cholesterol-lowering drug Zetia (ezetimibe). This drug alone or in combination with the popular statin drug Zocor (simvastatin) conveyed no medical benefit to patients. In fact, the company-sponsored study found that the pace at which artery-clogging plaque formed within blood vessels actually doubled in patients taking the two-drug combination.

In one sense, both Zetia and Zocor did what was asked of them. On average, patients in the two-year clinical trial who took Zocor alone reduced their LDL cholesterol by 41%, while patients who took Vytorin reduced their cholesterol by a whopping 58%. Yet, despite the greater reduction in cholesterol, patients taking Vytorin actually had a increased rate -albeit non-statistically significant--in the growth of fatty plaque in their carotid arteries than those who were on Zocor alone.

In 2006, Merck's patent on Zocor ran out, and it has been a relatively inexpensive generic drug since then. In an attempt to recapture their share of the profitable statin market, the company teamed up with Schering-Plough to market Vytorin, which is, in fact, nothing more than a combination of Zocor and Zetia. It thus cleverly rescued Zocor from the generic drug wilderness by repackaging it as a superior two-drug combination, thereby giving Zocor new life as a high-end and patented product. In case you have not been watching much television lately, Vytorin is the subject of a barrage of TV ads about how cholesterol comes from two sources, food and family. In 2005, the advertising budget for Vytorin alone was $161.5 million, third highest for any drug on the market.

"This drug doesn't work. Period. It just doesn't work," said the ever-vigilant Dr. Steven E. Nissen, chairman of cardiology at the Cleveland Clinic. "This is as bad a result for the drug as anybody could have feared. Millions of patients may be taking a drug that does not benefit them, raising their risk of heart attacks and exposing them to potential side effects."

Worldwide, one million prescriptions for Zetia and Vytorin are written each week, and about five million people are taking the drugs. Almost one million of these patients are Americans, and of these, 60% receive Zetia as part of the Vytorin combination. Sales of Zetia and Vytorin totaled more than $5 billion last year, up 33% from the year before. (Advertising pays!) About 70% of Schering-Plough's earnings depend on the drugs, according to The New York Times, and Merck (the company that, incidentally, manufactured the catastrophic anti-arthritis drug Vioxx) is also quite dependent on its earnings from these statins. Schering-Plough's stock fell eight percent with the bad news about the ENHANCE trial.

"This wraps it up," said Dr. Nissen. "That's all there is. There just isn't any evidence that adding ezetimibe [Zetia] to simvastatin [Zocor] produces any advantage." But wrapped up or not, questions remain about the actual effect of this combination on millions of patients and the manner in which it was approved and marketed.

The ENHANCE trial involved 720 patients, all of whom had a genetic condition that caused abnormally high levels of blood cholesterol. As in previous trials, Zetia was found to be successful in lowering levels of LDL or "bad" cholesterol by 15% to 20%. Statin drugs like Zocor and Lipitor also lower LDL cholesterol in the majority of patients. Most cardiologists believe that, by lowering LDL levels, statins reduce the risk of fatal heart attacks and strokes. However, Zetia, which works by a different mechanism to reduce LDL cholesterol, has never actually been shown to reduce heart attacks or save lives.

Thus, while statins may provide benefit by some less obvious mechanism, the ENHANCE study casts doubt on the notion that lowering LDL by itself--at least in this patient population--is the key to heart health. Yet Dr. Howard Weintraub, MD, of New York University Medical Center, New York City, said in reaction to the study: "These results are very important considerations on how we treat patients with elevated cholesterol and will very likely impact the way we choose drugs to lower cholesterol and eliminate plaque."

"ENHANCE found that plaque got slightly worse when the drug combination was used," Dr. Weintraub conceded. Then he added the following eye-opener. "But the real take-home message here is that getting LDL down is important, and that's not something that should be lost as a consequence of this study."

I find this odd. It is by no means clear that manipulating risk factors for a disease is always beneficial in terms of outcome. How does this study support the notion that lowering LDL in and of itself is so important, if those who had additional lowering showed no added benefit? Doesn't it, in fact, call into question the whole idea that merely lowering LDL necessarily results in significant patient benefit? As The New York Times article reported, the findings "raise doubts about the current belief that lowering cholesterol is the key to cardiovascular health" (January 16, 2008).

Growing Anger

There is growing anger over the fact that so many people have been prescribed these expensive drugs (Vytorin and Zetia) as opposed to the relatively cheap generic statin Zocor. "If there is no apparent clinical benefit, why take a drug that costs three or four times more?" asked Steven Findlay of Consumer Union, published of Consumer Reports. "Most people do not need that magnitude of cholesterol reduction anyway."

There is also anger over the fact that these results had been known for many months, but the companies apparently sat on the data. The study was completed in April 2006, but the results were only released last week after a 21-month delay. According to a report in the Washington Post, Merck and Schering-Plough had planned to release the data in March 2007, but then continually missed self-imposed deadlines, blaming the delay on "the complexities of necessary data analysis." The New York Times reports that it took pressure from the House Energy and Commerce Committee to get the companies to finally release the results.

"In light of today's results, which were released nearly two years after the ENHANCE trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data," Representative Bart Stupak, Democrat of Michigan, said in a statement. Mr. Stupak is chairman of the committee's Subcommittee on Oversight and Investigations. In fact, the ENHANCE results were not officially released until a cardiology conference in March 2008.

While granting that the clinical trial was relatively small and that the patients were not typical of most potential users, The New York Times article concluded: "The two companies that reap billions from the drug had been cynically sitting on the results for more than a year" (January 16, 2008).

Amazingly, people on Wall Street who follow pharmaceutical stocks seemed unfazed by the latest study. Goldman Sachs analyst James Kelly reaffirmed his "Buy" rating for Schering-Plough, calling the ENHANCE results a "non-event" that does not represent Vytorin's commercial prospects. He said the results reaffirmed the drug's safety, which had been the key concern of the financial community. How one extracts a reaffirmation of Vytorin's safety from the above data is anybody's guess. Wall Street seems to be counting on the public's short memory and on force of habit among cardiologists to keep them prescribing these dubious drugs.

Approval based on surrogate markers is not limited to anticancer drugs. In heart disease treatments, too, it has apparently become the rule rather than the exception. One can only hope that the next president, whoever he or she may turn out to be, will take a fresh look at the FDA and its disturbingly close relationship with those whom it is supposed to regulate.


Anonymous. Merck, Schering: Enhance study misses significance. Reuters News Agency. Jan 14, 2008.

Bairati I, Meyer F, Jobin E, et al. Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer. 2006 Nov 1;119(9):2221-4.

Berenson, Alex. Study reveals doubt on drug for cholesterol. New York Times. January 15, 2008 (front page).

Cholesterol drug bombs [editorial]. New York Times. January 16, 2008.

Meyer F, Bairati I, Fortin A, et al. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int J Cancer. 2008 Apr 1;122(7):1679-83. (The abstract was posted to the Web in December 2007.)

Meyer F, Bairati I, Jobin E, Gelinas M, Fortin A, Nabid A, Tetu B. Acute adverse effects of radiation therapy and local recurrence in relation to dietary and plasma beta carotene and alpha tocopherol in head and neck cancer patients. Nutr Cancer. 2007;59(1):29-35.

by Ralph W. Moss, PhD

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Title Annotation:War on Cancer
Author:Moss, Ralph W.
Publication:Townsend Letter
Geographic Code:1USA
Date:May 1, 2008
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