Questionable Speculations on the Increase in Lung Cancer Risk from Vitamin A and Carotenoids ─ A Comment on the VITAL Study Results

“A recently published evaluation of data from the VITamins And Lifestyle cohort study discusses the connection between antioxidants and the incidence of lung cancer. Although the authors emphasize that the results of their questionnaire evaluation do not allow us to conclude that vitamin A, beta-carotene or other carotenoids in food supplements increase the risk of lung cancer in general, they nevertheless speculate in questionable hypotheses about a possible connection. 

In an article on the VITamins and Lifestyle Cohort Study (1) published in February 2009, Dr. Jessie A. Satia and her team from the University of North Carolina (USA) maintain that ‘Longer duration of use of individual beta-carotene, retinol (vitamin A) and lutein supplements (but not total ten-year average dose) was associated with statistically significantly elevated risk of total lung cancer.’ This risk, while linked to the period over which the products are taken, is not linked to the average highest dose of the micronutrients in the supplements. The authors believe they have evidence that not only high doses but even smaller amounts of the micronutrients increase the risk of lung cancer if they are taken over a long enough period of time. In this they differ from a large number of studies which revealed no such effects even with higher doses over a longer period of time. Therefore, the authors have to go to great lengths in discussing their results to justify their surprising outcomes.

Study design and questionnaire methodology invalid

The obvious weakness of this study lies in its methodology (2): Satia and her colleagues tried to determine by means of a questionnaire what influence the intake of micronutrients – retinol (vitamin A), beta-carotene, lutein and lycopene – up to ten years previously has on the incidence of lung cancer. For this study, participants were asked to give details from memory of food supplements which they had taken in some cases ten years ago. It is hardly conceivable that the subjects were able to remember accurately enough in which sequence, how frequently and in what composition they had taken products containing micronutrients in the previous four or ten years. Thus, the data on the intake of vitamins which the authors gathered from the questionnaires are in some cases very difficult to follow. They talk of ‘multivitamins’, whereby it is not clear whether or not they mean multivitamin preparations containing extra carotenoids. The authors mention the reporting of ‘individual supplements’ in the questionnaires, while at the same time admitting that this is difficult to follow up in some cases, since for the two carotenoids lutein and lycopene in particular only very few individual supplement preparations were used. Other studies which also used the questionnaire methodology showed that the capacity to remember which vitamins had been taken is best for vitamin C, since this is often taken alone, while the capacity to remember multivitamins, in particular antioxidants (like the carotenoids), with regard to dose and frequency of intake was only given when participants were asked about the manufacturer, which was not the case in this study. Moreover, in a cohort from the EPIC study (3) it was discovered that the reliability with which subjects remember the intake of micronutrients from supplements lies between 50 and 60 percent, with recall of the intake of beta-carotene being particularly weak. The validity of the questionnaires used and above all the conclusions drawn from them are therefore questionable.

Questionable statistical evaluations

The authors claim to have discovered for the first time that it is not the absolute dose that increases the risk of lung cancer, but the length of time of use. This is not surprising, since recall of dosages is surely even more dubious than recall of preparations. However, it is exactly this consideration of intake in the more distant past based solely on memory which represents an essential weakness of the VITAL study.

The authors state that their results strongly contradict those of comparable studies which observed no connection between the intake of carotenoids or vitamin A and an increased risk of developing lung cancer. Only the ATBC and CARET studies (4,5), in which heavy smokers took large doses of beta-carotene over an extended period of time, showed a slight rise in the risk of lung cancer. In this instance a high dose over a long period of time may have played a role. Much more important, however, is understanding that an unhealthy lifestyle (smoking for many years) cannot be compensated for by an individual micronutrient. Large studies with more than 40,000 participants given supplements of 50 mg beta-carotene daily for a period of two years showed, in contrast, that there was no increased risk of lung cancer (6).

Speculative explanations

The authors speculate as to how their results came about. Thus, micronutrient supplements could be more bioavailable than the corresponding substances from fruit and vegetables. However, this would mean that especially with long-term use, the high doses in particular should be much more crucial to the development of lung cancer than the low doses which the authors now want to class as risky when taken over a long period of time. That large intakes interfere with the absorption, transport and distribution of other nutrients and could thus possibly have an adverse influence on other micronutrients is difficult to follow, since, according to the study, the incidence of lung cancer was dose-independent and only related to the duration of intake. Furthermore, the hypothesis that too-high doses of antioxidants could interfere with the immune system, which generates reactive oxygen species in order to function, would only be understandable in the context of a discussion of dose, but not in connection with duration of use. Moreover, vitamin A is not an antioxidant and cannot possibly react in this way with the immune system. The carotenoids under discussion are not capable of scavenging the reactive oxygen species formed by immunocompetent cells.

No explanation for the rise in the number of lung cancer cases

Although Satia and her colleagues do not succeed in explaining the slight increase in the incidence of lung cancer in certain groups, they come to the following conclusion: “Although the results do not universally suggest that retinol, beta-carotene and other carotenoid supplements increase lung cancer risk, there is clearly no evidence of protective effect.” A trivial claim, since numerous epidemiological studies confirm a preventive effect for lung cancer from a balanced carotenoid- and vitamin-rich diet. Clearly, however, micronutrients alone cannot compensate for the consequences of harmful actions such as smoking.

Conclusion

• The VITAL study discussed here does not offer evidence for an increase in lung cancer risk due to the intake of beta-carotene, vitamin A or lutein, even for smokers.
• The use of a long-term questionnaire to determine the intake of micronutrients is of only limited use and the results tend to be seriously prone to error. Large American studies have shown that hardly any consumers take a particular food supplement for a period longer than six months. In most cases after this period or even earlier they change to another product which may differ considerably in respect of composition and dosage.
• The results of the VITAL study are not validated and contradict those of other studies.
• The arguments of the authors are speculative and in some cases contradictory.”

Hohenheim, February 2009

1. Satia J. A. et al. Long-term Use of Beta-Carotene, Retinol, Lycopene, and Lutein Supplements and Lung Cancer Risk: Results From the VITamins And Lifestyle (VITAL) Study. Am J Epidemiol, 2009; 169:815–828.
2. White E. et al. VITamins And Lifestyle Cohort Study: Study Design and Characteristics of Supplement Users. Am J Epidemiol, 2004; 159: 83–93.
3. Ocké M. C. et al. The Dutch EPIC food frequency questionnaire. II. Relative validity and reproducibility for nutrients. Int J Epidemiol, 1997; 26(1):49–58.
4. Albanes D. et al. Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst, 1996; 88(21):1560–70.
5. Omenn G. S. et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med, 1996; 334(18):1150–5.
6. Frieling U. M. et al. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physicians’ health study. Arch Dermatol, 2000;136(2):179–84.
7. Block G. et al. Usage patterns, health, and nutritional status of long-term multiple dietary supplement users: a cross-sectional study. Nutr J., 2007; 6:30.