Correspondence
Beta Carotene, Vitamin E, and Lung Cancer
N Engl J Med 1994; 331:611-614September 1, 1994
- Article
To the Editor:
The controversy in the lay press after the publication of the findings of the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (April 14 issue)1 was understandable. Clearly, the public was confused by yet another unfulfilled promise of longevity, and both faddists and manufacturers of vitamin supplements found these results inconsistent with their own beliefs, which had been supported by observational data.
What was not comprehensible, and was quite disturbing, was the irresolute manner in which the findings of the study were interpreted by its authors and those of the accompanying editorial2. The authors concluded that no overall reduction in the incidence of lung cancer was found and that the study “raises the possibility that these supplements may... have harmful as well as beneficial effects.” In fact, because of its methodologic rigor, the study clearly demonstrates an increase in the incidence of lung cancer; that increase is probably around 18 percent, and one can be 95 percent certain that it is somewhere between a 3 percent and a 36 percent increase1. The only real question is how far one can extrapolate these findings to people who are not Finnish male smokers.
The editorialists essentially discard this excess cancer incidence and go so far as to say “it may simply have been due to an extreme play of chance, since the finding is so much at variance with the totality of other evidence suggesting a benefit”2. Of course, the statistical analysis had already evaluated the role of chance and found it quite small. Furthermore, with its methodologic superiority, a randomized, double-blind, placebo-controlled clinical trial outweighs previous observational studies, no matter how many. Sackett and colleagues have pointed out the many biases inherent in observational studies of treatment and have recommended “that you discard at once all articles on therapy that are not randomized trials”3. In fact, two of the authors of the editorial have written an excellent textbook of epidemiology that states that “when well designed and conducted, intervention studies can indeed provide the most direct epidemiologic evidence on which to judge whether an exposure causes or prevents a disease”4.
I can only infer that the authors are hesitant to reach the proper conclusion because the facts conflict with their beliefs. This should be the realm of religion, not science.
4 ReferencesPaul R. Marantz, M.D., M.P.H.
Bronx Municipal Hospital Center, Bronx, NY 104611
The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
Full Text | Web of Science | Medline2
Hennekens CH ,Buring JE ,Peto R . Antioxidant vitamins -- benefits not yet proved. N Engl J Med 1994;330:1080-1081
Full Text | Web of Science | Medline3
Deciding on the best therapy. In: Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine. 2nd ed. Boston: Little, Brown, 1991:196.
4
Design strategies in epidemiologic research. In: Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little, Brown, 1987:26-7.
To the Editor:
The article on the effects of vitamin E and beta carotene on lung cancer in smokers has evoked disappointment in some quarters, but the data may provide an explanation of the findings and offer hope. Within the placebo group the incidence of lung cancer among those in the lowest quartile of serum vitamin E or beta carotene was considerably higher than the incidence of lung cancer among those in the highest quartile. There was also an inverse association between the intake of either test substance at base line and the risk of lung cancer during the trial. On the basis of the initial serum levels of either vitamin E or beta carotene, an educated guess implicating the low serum level in the higher incidence of lung cancer would have been correct. One may draw two conclusions from these data: lifetime intake of either substance is more telling than the intake of these substances during a relatively short pharmacologic trial, and it is better to obtain nutritionally active substances such as vitamin E and beta carotene from the grocery store than from the pharmacy.
David Kritchevsky, Ph.D.
Wistar Institute, Philadelphia, PA 19104To the Editor:
The study agents, dl-alpha-tocopheryl acetate and beta carotene, were both synthetic. Most available sources of these antioxidant supplements are natural. Conceivably, the synthetic antioxidants may have resulted in an unfavorable outcome. In addition, all the formulations were colored with quinoline yellow, a cosmetic and drug dye that has not been proved safe in human studies. There were earlier reports that this coloring agent induced tumors in animals, but more recent animal data suggest that it is not tumorigenic in rats and mice1. Nonetheless, extrapolating animal data to humans is problematic2. The capsules in the study were consumed daily by the participants over the five to eight years of the trial. Maybe the long-term ingestion of the quinoline yellow promoted carcinogenesis.
2 ReferencesMark R. Goldstein, M.D.
Crozer-Chester Medical Center, Upland, PA 190131
Food and Drug Administration 2
Lin CS ,Shoaf SE ,Griffiths JC . Pharmacokinetic data in the evaluation of the safety of food and color additives. Regul Toxicol Pharmacol 1992;15:62-72
CrossRef | Web of Science | Medline
To the Editor:
The Finnish study shows that supplementation with 50 mg of vitamin E or 20 mg of beta carotene does not protect lifelong heavy smokers against lung cancer. This is perhaps not surprising, since antioxidants have never been advocated as a treatment for cancer. The three-stage initiation, promotion, and progression model of cancer is well established. Antioxidant nutrients probably retard some types of initiation and quite clearly inhibit the vitally important promotion process1; however, it has never been suggested that radicals are involved in the progression of clonally established cancers1. The latency period of lung cancer is very long, and it is quite likely that all of the men whose cancer was diagnosed during the six years of the study already had undiagnosed cancer, not detectable on chest films, when the study began.
The Finnish study was designed a decade ago. The assumption then was that the effect of antioxidants would be small, and a high-risk group would be needed to detect an effect. However, we now know that the preventive effect of antioxidants in the general population can be substantial. For example, vitamin E supplementation was shown in two epidemiologic studies to reduce the risk of heart disease by 40 percent,2,3 and supplementation with vitamin E, beta carotene, and selenium reduced mortality from cancer by 13 percent in a vitamin-poor Chinese population4.
4 ReferencesWilliam A. Pryor, Ph.D.
Louisiana State University, Baton Rouge, LA 708031
Pryor WA. The involvement of free radicals in chemical carcinogenesis. In: Cerutti PA, Nygaard OF, Simic MG, eds. Anticarcinogenesis and radiation protection. New York: Plenum Press, 1987:1-9.
2
Stampfer MJ ,Hennekens CH ,Manson JE ,Colditz GA ,Rosner B ,Willett WC . Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-1449
Full Text | Web of Science | Medline3
Rimm EB ,Stampfer MJ ,Ascherio A ,Giovannucci E ,Colditz GA ,Willett WC . Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-1456
Full Text | Web of Science | Medline4
Blot WJ ,Li J-Y ,Taylor PR , et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:1483-1492
CrossRef | Web of Science | Medline
To the Editor:
The undesirable effects of beta carotene reported in the Journal1 were observed in smokers. Since heavy smokers are commonly heavy drinkers, one may wonder whether alcohol abuse was contributory. Although the authors state that they were “aware of no other data at this time... that suggest harmful effects of beta carotene,” the potentiation of toxicity by combining beta carotene with alcohol has been observed previously. In nonhuman primates, alcohol produced a significant slowing in the blood clearance of orally administered beta carotene, with associated increases in liver and plasma levels and exacerbation of the ethanol-induced hepatotoxicity2. These toxic interactions occurred after only one month, at a dose of 20 to 30 mg of beta carotene per day, an amount equivalent to those given in ongoing “preventive” studies in humans. Similar interactions were observed in rats (unpublished data) and in humans. Plasma carotene levels were compared in two groups of alcoholics with daily intakes below or above 200 g of alcohol3. We expected the lowest beta carotene levels in the heaviest drinkers, in view of their smaller dietary intake. Surprisingly, however, this group had significantly higher levels, a finding consistent with the ethanol-induced interference with the disposition of beta carotene observed in baboons2. Thus, in humans as well as in animals, ethanol was found to interact with beta carotene; therefore, one may wonder to what extent the adverse interactions described in smokers1 may have resulted, at least in part, from associated drinking.
3 ReferencesMaria A. Leo, M.D.
Charles S. Lieber, M.D.
Mount Sinai School of Medicine, New York, NY 100291
The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
Full Text | Web of Science | Medline2
Leo MA ,Kim CI ,Lowe N ,Lieber CS . Interaction of ethanol with beta-carotene: delayed blood clearance and enhanced hepatotoxicity. Hepatology 1992;15:883-891
CrossRef | Web of Science | Medline3
Ahmed S ,Leo MA ,Lieber CS . Interactions between alcohol and beta-carotene in patients with alcoholic liver disease. Am J Clin Nutr 1994;60:430-436
Web of Science | Medline
To the Editor:
The dose of alpha-tocopherol used in the study may have been too low, since American health professionals1 reported that a daily dose of 60 to 100 IU was required to correct the relative risk of coronary heart disease. Moreover, smokers are known to have a low vitamin C intake, as well as an increased vitamin C requirement, and correspondingly have notoriously low plasma vitamin C concentrations2,3. Since vitamin C and vitamin E form a complementary antioxidant defense system,4 the lack of supplementation with vitamin C might well limit the effects of alpha-tocopherol.
4 ReferencesPeter E. Ballmer, M.D.
University of Bern, CH-3010 Bern, SwitzerlandHannes B. Stahelin, M.D.
University of Basel, CH-4031 Basel, Switzerland1
Rimm EB ,Stampfer MJ ,Ascherio A ,Giovannucci E ,Colditz GA ,Willett WC . Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-1456
Full Text | Web of Science | Medline2
Bolton-Smith C ,Casey CE ,Gey KF ,Smith WCS ,Tunstall-Pedoe H . Antioxidant vitamin intakes assessed using food-frequency questionnaire: correlation with biochemical status in smokers and non-smokers. Br J Nutr 1991;65:337-346
CrossRef | Web of Science | Medline3
Smith JL ,Hodges RE . Serum levels of vitamin C in relation to dietary and supplemental inhaled vitamin C in smokers and nonsmokers. Ann N Y Acad Sci 1987;498:144-152
CrossRef | Web of Science | Medline4
Niki E . Interaction of ascorbate and alpha-tocopherol. Ann N Y Acad Sci 1987;498:186-199
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In response to Marantz's concern regarding the potential underinterpretation of our data, science requires the replication of results before we presume causality, preventive or otherwise. This is true even for randomized trials, the gold standard of clinical research.
We agree with Kritchevsky that possible interpretations of the contrast between the observational data and the intervention effect in our trial include the view that long-term or lifetime intake is more important than short-term intake and that fruits and vegetables, with their many nutritionally active substances, may be better sources of these substances than pills.
Pryor proposes that the lack of efficacy in our study was due to the long latency period of lung cancer. Although we would agree that longer supplementation may be more likely to reverse long-term processes, even relatively short interventions can influence the incidence of cancer; for example, we observed a lower incidence of prostate cancer in response to vitamin E treatment in the course of our study.
It is unlikely that differences in vitamin formulation influenced the results of our study, as suggested by Goldstein. These same synthetic agents (produced by Hoffmann-La-Roche, the source of the agents in our study) were demonstrated to have efficacy in cancer prevention in the Linxian, China, studies.1 Furthermore, the capsules given to all trial participants contained equal small amounts of quinoline yellow for masking purposes.
The question of whether alcohol abuse contributed to the undesirable effects observed for beta carotene is raised by Leo and Lieber. The strong association between smoking and drinking is well known, and although the hepatotoxicity they observed in their study is not equivalent to carcinogenesis, we have been evaluating the possibility that alcohol influenced the effects of beta carotene.
Although it is possible that a low dose of vitamin E or a relative lack of vitamin C may reduce the effectiveness of vitamin E, as suggested by Ballmer and Stahelin, data from the Linxian trials1 do not support this. Low-dose vitamin E (30 mg daily), in combination with beta carotene and selenium, reduced cancer mortality.1 In addition, among those who received vitamin E, the number of deaths attributed to cancer was essentially the same among those who received vitamin C and those who did not (185 vs. 184).
1 ReferencesOlli P. Heinonen, M.D., Sc.D.
Jussi K. Huttunen, M.D.
National Public Health Institute, SF-00300 Helsinki, FinlandDemetrius Albanes, M.D.
Philip R. Taylor, M.D., Sc.D.
National Cancer Institute, Bethesda, MD 20892for the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group
1
Blot WJ ,Li J-Y ,Taylor PR , et al. Nutrition Intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:1483-1492
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Marantz has taken issue with our interpretation of the results of the Alpha-Tocopherol, Beta Carotene (ATBC) trial and with our statement in the accompanying editorial that the results suggest the benefits seen in earlier observational studies may have been overestimated, or even perhaps that these antioxidant vitamins may have some harmful effects. He concludes that because of its methodologic rigor, the trial clearly demonstrates that beta carotene causes lung cancer.
As with any analytic epidemiologic study, possible alternative explanations for the results of this trial include bias, confounding, and chance.1 No one would disagree that a randomized trial provides a degree of control over bias and confounding that cannot be achieved in an observational study. Nonetheless, the results of randomized trials are still subject to chance. The proper calculation of the P value is easy, but the proper interpretation may not be. In this case, the authors stated in their protocol that the aim of the trial was to test whether beta carotene prevents lung cancer; at no time did they or anyone else state a priori that the aim should be to evaluate whether beta carotene causes lung cancer. This viewpoint was based on the totality of evidence to date, which includes basic research as well as numerous observational epidemiologic studies, the results of most of which are compatible with possible benefits. None of this evidence indicated harm. Thus, the ATBC trial was designed to answer whether there truly was a benefit of beta carotene on lung cancer, and if so, how large.
Although the trial's findings of possible harm may be real, they were totally unexpected, which is why we believe the proper interpretation of the results to be hypothesis-generating, not hypothesis-testing. As such, even a P value as extreme as that seen in the ATBC trial can arise largely or wholly by chance. Furthermore, the most informative data on cancer from this trial will emerge from continued follow-up and not just from the six years of study already reported on. We believe the most plausible interpretation of the data is that they raise the possibility of a harmful effect, which must be corroborated or refuted in other trials. We would disagree strongly with the drawing of any firm conclusions from the unexpected results of a single trial that are contrary to the totality of the evidence.
1 ReferencesCharles H. Hennekens, M.D.
Julie E. Buring, Sc.D.
Brigham and Women's Hospital, Boston, MA 02115Richard Peto, F.R.S.
Oxford University, Oxford OX2 6HE, United Kingdom- Citing Articles (2)
Citing Articles
1
K. Fred Gey. (1998) Vitamins E plus C and interacting conutrients required for optimal health. BioFactors 7:1-2, 113-174
CrossRef2
Jeffrey S Bland. (1995) Oxidants and Antioxidants in Clinical Medicine: Past, Present and Future Potential. Journal of Nutritional and Environmental Medicine 5:3, 255-280
CrossRef
