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Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers
A meta-analysis and evaluation of national brands
Version of Record online: 21 APR 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 1, pages 150–157, 1 July 2008
How to Cite
Tanvetyanon, T. and Bepler, G. (2008), Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers. Cancer, 113: 150–157. doi: 10.1002/cncr.23527
- Issue online: 20 JUN 2008
- Version of Record online: 21 APR 2008
- Manuscript Accepted: 19 FEB 2008
- Manuscript Revised: 6 FEB 2008
- Manuscript Received: 27 NOV 2007
- lung cancer;
- visual health
Some studies have suggested that beta-carotene supplementation may increase the risk of lung cancer, particularly among smokers or former smokers. Beta-carotene, a provitamin A, is available in multivitamins. In the current study, the authors investigated the risk of lung cancer associated with beta-carotene in smokers or former smokers and surveyed the beta-carotene content in national brand multivitamins.
The authors systemically reviewed the published literature using a search of the MEDLINE database and performed a meta-analysis of large randomized trials that reported on the effect of beta-carotene supplementation on the incidence of lung cancer among smokers or former smokers. A sample of multivitamins was evaluated for their beta-carotene content and the suggested daily dosage.
Four studies contributing 109,394 subjects were available for analysis. The average daily beta-carotene dosage in these trials ranged from 20 to 30 mg daily. Among current smokers, beta-carotene supplementation was found to be significantly associated with an increased risk of lung cancer (odds ratio [OR], 1.24; 95% confidence interval [95% CI], 1.10–1.39). Among former smokers, there was no significant increase noted (OR, 1.10; 95% CI, 0.84–1.45). In a sample of 47 common multivitamins, beta-carotene was present in 70% of the identified formulas. The median dosage of beta-carotene was 0.3 mg (range, 0–17.2 mg) daily. The beta-carotene content was found to be significantly higher among multivitamins sold to improve visual health than among other multivitamins, with a median daily dosage of 3 mg (range, 0–24 mg).
High-dose beta-carotene supplementation appears to increase the risk of lung cancer among current smokers. Although beta-carotene was prevalent in multivitamins, high-dose beta-carotene was observed among multivitamin formulas sold to promote visual health. Cancer 2008. © 2008 American Cancer Society.
Each year in the U.S., more than 200,000 new cases of lung cancer are diagnosed and >150,000 people die of the disease.1 Lung cancer is often diagnosed at an advanced stage, at which time available treatment results in a poor outcome. Over the years, preventive measures have been extensively sought after. This includes chemoprevention by dietary supplements, which has been tested in several randomized trials. Unfortunately, to our knowledge, these trials have failed to identify any agent that reduces the risk of lung cancer. Currently, the American College of Chest Physician recommends that for individuals at risk for lung cancer or those with a history of lung cancer, there are not yet sufficient data to recommend the use of any agent to prevent lung cancer.2
Nevertheless, an important observation has emerged from these chemoprevention trials. Some studies have identified beta-carotene as being associated with an increased risk of lung cancer, especially among participants who are active smokers or have a significant smoking history.3, 4 A previous meta-analysis containing data from 3 large trials has suggested a marginally increased risk of lung cancer associated with beta-carotene supplementation among current smokers or former smokers.5
Although to our knowledge it has no established recommended daily intake dosage, beta-carotene, a provitamin A, is present in many multivitamin formulas. Because approximately one-sixth of Americans regularly consume multivitamins, it is relevant to understand whether and how much beta-carotene exists in national brand multivitamins.6 Although a smaller proportion of smokers consume multivitamins than nonsmokers, some adopt the habit of taking multivitamins as part of a healthier lifestyle.7 Patients with a history of lung cancer, who often have a significant smoking history, as well as their family members, are also more likely to take dietary supplements.8
In this study, we systematically reviewed published randomized controlled trials that reported on the effect of beta-carotene on the incidence of lung cancer. To understand the differential effect of beta-carotene in the high-risk populations who are current smokers or former smokers, we performed meta-analyses in both subgroups separately. In addition, we evaluated the beta-carotene content of a national brand multivitamin sample.
MATERIALS AND METHODS
We searched the PubMed MEDLINE database (1966-2006) for randomized controlled trials in English that compared beta-carotene versus placebo using a search strategy: (cancer and vitamin) AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials [MeSH Terms] OR clinical trial [Publication Type] OR random*[Title/Abstract] OR random allocation [MeSH Terms] OR therapeutic use [MeSH Subheading]). Publications were included for review if outcomes regarding lung cancer and information obtained from among high-risk populations (smokers and former smokers) were reported. Studies were excluded if they were performed in patients with existing lung cancer or a history of lung cancer to avoid the confounding effect of recurrent disease. If multiple publications concerning identical studies existed, data from the most complete report were included. Inclusion criteria, intervention, and outcomes were recorded.
To explore the differences between beta-carotene and placebo, a quantitative meta-analytic technique was used to pool data regarding the incidence of lung cancer. The meta-analysis was performed using the random effects model, taking into account both study sample size and between-study variation when weighing study effects. The extent of heterogeneity was quantified using I2 . The summary effect was expressed as the odds ratio (OR). All analyses were performed using REVMAN statistical software (version 1.0.5) by the Cochrane collaboration.9
Evaluation of National Brand Multivitamins
To evaluate national brand vitamins, we sampled multivitamins from several online vitamin stores, including www.gnc.com, www.vitaminshoppe.com, www.iherb.com, and www.drugstore.com all accessed on April 7, 2008. For our review purposes, preparations with iron or calcium as the main ingredient were not considered as multivitamins. The ingredients of the multivitamins were verified from the store or the manufacturers' websites. When necessary, we searched the Micromedex healthcare series or obtained package inserts of the multivitamins from local supermarkets. The dosage of beta-carotene in international units (IU) was converted to mg using the formula: 25,000 IU = 15 mg. The difference in beta-carotene content among general multivitamins and those multivitamins indicated to promote visual health was examined using the exact Wilcoxon rank sum test with normal scores. A P value ≤.05 was considered statistically significant. Descriptive and nonparametric statistics were performed using SPSS software (version 11.5; SPSS Inc, Chicago, Ill).
Our search identified 6 nonduplicative studies for review. Of these, only 4 studies reported on the incidence of lung cancer among high-risk populations and therefore were included for review (Table 1). Of the 2 excluded studies, 1 reported on the incidence of cancer of the respiratory tract, but not specifically discussing lung cancer; the other reported on lung cancer mortality, but not the incidence of lung cancer.
|Reference (Study name)||Subjects, Country||Intervention||Median duration of exposure, years||Effect on lung cancer incidence|
|No authors listed, 19943 (Alpha-Tocopherol, Beta-Carotene Cancer Prevention trial [ATBC])||29,133 male smokers* aged 50–69 y, Finland||Beta-carotene administered as 20 mg daily or vitamin E administered as 50 mg daily||6.1||Increased (P = .04)|
|Hennekens, 199610 (Physician's Health Study)||22,071 male physicians aged 40–84 y, U.S.||Beta-carotene administered as 50 mg on alternate days||12||No significant difference|
|Omenn, 19964 (Beta-Carotene and Retinol Efficacy Trial [CARET])||18,314 ever-smokers† or individuals exposed to asbestos, U.S.||Beta-carotene administered at a dose of 30 mg plus retinol at a dose of 25,000 IU daily||4||Increased (P = .02)|
|Lee, 199911 (Women's Health Study)||39,876 health professionals aged >45 y, U.S.||Beta-carotene administered as 50 mg on alternate days||2.1||No significant difference ‡|
Two trials, the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial and the Beta-Carotene and Retinol Efficacy Trial (CARET), were conducted exclusively among individuals at a high risk for lung cancer.3, 4 In the ATBC study,3 participants were aged 50 to 69 years and smoked ≥5 cigarettes per day at the time of study entry (Table 2). In the CARET study,4 participants had an at least 20-pack-year smoking history and either continued to smoke or had stopped smoking ≤5 years previously. However, in the early part of the CARET study, participants with significant asbestos exposure (after having worked as a plumber, pipe fitter, steamfitter, or shipyard boilermaker for 15 years before study enrollment) were allowed to enroll regardless of smoking history. Nevertheless, only 0.7% of the subjects in the CARET trial were never-smokers.
|Reference (Study name)||Total no. of patients||Total no. of lung cancers||No. of current smokers||Lung cancer in current smokers||No. of former smokers||Lung cancer in former smokers|
|No authors listed, 19943 (Alpha-Tocopherol, Beta-Carotene Cancer Prevention trial [ATBC])||14,560||474||14,560||474||0||0|
|Omenn, 19964 (Beta-Carotene and Retinol Efficacy Trial [CARET])||9420||229||5684||168||3668||61|
|Hennekens, 199610 (Physician's Health Study)*||11,036||82||1230||38||4320||34|
|Lee, 199911 (Women's Health Study)Control arm||19,939||30||2635||15||7088||14|
|Physician's Health Study||11,035||87||1214||41||4364||33|
|Women's Health Study||19,937||21||2600||9||7177||10|
The other 2 trials, the Physicians' Health Study and the Women's Health Study,10, 11 were not conducted exclusively among high-risk individuals, but the incidence of lung cancer among high-risk participants was reported. In the Physicians' Health Study,10 approximately half of the participants were current smokers or former smokers. In the Women's Health Study,11 49% of patients were current or former smokers.
Interventions and the duration of exposure in these studies varied (Table 1). The averaged dose of beta-carotene in these trials ranged from 20 to 30 mg daily (33,333–50,000 IU) and the median duration of intervention ranged from 2 to 12 years. Briefly, in the ATBC study, a 2 × 2 factorial design was used and approximately half of the participants who received beta-carotene also received alpha-tocopherol.3 In the CARET study, participants who received beta-carotene also received retinyl palmitate at a dose of 25,000 IU daily.4 In the Physician's Health Study, a 2 × 2 factorial design of beta-carotene and aspirin was used in the initial phase; however, the aspirin arm was terminated early, leaving the beta-carotene intervention continuing alone until completion of the study.10 Finally, in the Women's Health Study, a 2 × 2 × 2 design of aspirin, vitamin E, and beta-carotene was used in the initial phase; however, the beta-carotene arm of the study was terminated early, resulting in a median duration of beta-carotene exposure of only 2.1 years (range, 0–2.7 years).11
Study Results and Meta-analysis
The ATBC and CARET studies3, 4 reported a statistically significant increase in the incidence of lung cancer among subjects who received beta-carotene compared with those who did not. The Physicians' Health Study10 and Women's Health Study11 did not report a significant difference. In the ATBC study,3 an excess cumulative incidence of lung cancer was observed after 18 months of intervention and was noted to increase progressively thereafter. This time-course observation was not specified in other studies.
The 4 studies contributed 109,394 participants (54,955 in the intervention groups and 54,439 in the control groups). Lung cancer occurred in 815 participants in the intervention groups and in 669 participants in the control groups. Meta-analysis of the results from all participants indicated that the incidence of lung cancer was significantly increased in the intervention groups (OR,1.21; 95% confidence interval [95% CI], 1.09–1.34) (Fig. 1).
When considering the subgroup of participants who were current smokers, the OR of lung cancer among participants who received beta-carotene increased even more (OR, 1.24; 95% CI, 1.10–1.39) (Fig. 2). However, when considering the subgroup of participants who were former smokers, there was no statistically significant difference noted with regard to the incidence of lung cancer between participants who received beta-carotene and those who did not (OR, 1.10; 95% CI, 0.84–1.45) (Fig. 3). In the subgroup of participants who were nonsmokers, there was also no difference noted with regard to the incidence of lung cancer between participants who received beta-carotene and those who did not (OR, 0.73; 95% CI, 0.33–1.59).
Evaluation of National Brand Multivitamins
We identified a sample of 24 brands of multivitamins. Each brand may have several formulas. In all, 47 formulas were identified (Table 3). The suggested daily dosages of beta-carotene issued by the manufacturers varied. We could not verify the exact beta-carotene content in 11 formulas. In all, 33 of 47 formulas (70%) were found to contain beta-carotene. The median dosage of beta-carotene was 0.3 mg (range, 0–17.2 mg) daily. The formula with the highest beta-carotene content was sold to promote visual health. Because of this, we specifically examined additional samples of multivitamin brands that were sold to promote visual health.
|Brands (Listed Alphabetically)||Suggested no. of doses per day||Total vitamin a dose per day (IU) (beta-carotene)||Beta-carotene dose per day, mg|
|Active Kids One Source||1||2500 (47%)||0.8|
|Centrum Performance||1||5000 (40%)||1.2|
|Centrum Silver||1||3500 (29%)||0.6|
|Flintstones Complete||1||3000 (33%)||0.6|
|Geritol Complete||1||6100 (100%)||3.7|
|Geritol Extend||1||3333 (40%)||0.8|
|Gynovite Plus||6||5000 (0%)||0|
|Hi-Kovite||2||10,000 (NR)||NR (nonzero)|
|Monocaps||1||5000 (NR)||NR (nonzero)|
|Ocuvite Extra||2||2000 (100%)||1.2|
|Olay Vitamins Complete Women's 50+||1||5000 (0%)||0|
|Olay Vitamins Complete Women's||1||5000 (0%)||0|
|Olay Vitamins Daily Energy Pack||1||5000 (0%)||0|
|One-A-Day Women 50+ Advanced||1||2500 (20%)||0.3|
|One-A-Day Men 50+ Advanced||1||2500 (20%)||0.3|
|One-A-Day Active||1||5000 (40%)||1.2|
|One-A-Day All Day Energy||1||3500 (40%)||0.8|
|One-A-Day Cholesterol Plus||1||2500 (30%)||0.5|
|One-A-Day Essential Formula||1||3000 (NR)||NR|
|One-A-Day Maximum Formula||1||2500 (20%)||0.3|
|One-A-Day Men's Health Formula||1||3500 (14%)||0.3|
|One-A-Day Weight Smart||1||2500 (30%)||0.5|
|One-A-Day Women's Formula||1||2500 (20%)||0.3|
|Optivite PMT||2||25,000 (60%)||9|
|PreserVision AREDS (age-related eye study)||2||28,640 (10%)||17.2|
|Quintabs||1||5000 (NR)||NR (nonzero)|
|Quintabs-M||1||10,000 (NR)||NR (nonzero)|
|Strovite Forte||1||4000 (NR)||NR|
|Ultra Freeda Iron Free||1||12,500 (NR)||NR (nonzero)|
|Ultra Freeda with Iron||1||5000 (NR)||NR (nonzero)|
|Unicap M||1||5000 (0)||0|
|Unicap Sr||1||5000 (0)||0|
|Unicap T||1||5000 (0)||0|
|Vi-Daylin F Liquid||1||1500 (NR)||NR|
|Viactiv Multivitamin||1||2500 (0)||0|
|Vicon Forte||1||8000 (NR)||NR|
|Vitacon Forte||1||8000 (NR)||NR|
We obtained an additional sample of 17 formulas of multivitamins indicated to promote visual health (Table 4). The beta-carotene content was available for all formulas but 1, with a median daily dosage of 3 mg (range, 0–24 mg). Of the assessable formulas, all but 3 contained beta-carotene (82%). The beta-carotene content in this group of multivitamins was found to be significantly higher than that in the group of general multivitamins (P < .001). However, overall, only 1 multivitamin formula was found to have a beta-carotene dosage >20 mg daily.
|Brands (Listed alphabetically)||Suggested no. of doses per day||Total vitamin a dose per day (IU) (Beta-carotene)||Beta-carotene dose per day, mg|
|Bilberry Vision Complex||3||12,500 (100%)||7.5|
|Enzymatic Therapy: Doctor's Choice Eye Formula||3||5000 (50%)||1.5|
|Futurebiotics Eyes Bright||3||25,000 (80%)||12|
|Icaps AREDS||4||28,640 (100)||17.2|
|Marine Silver Nature's Vision||2||5000 (0%)||0|
|Megafood Vision Strength||2||NR||NR|
|Now Foods, Eye Support||3||25,000 (100%)||15|
|Nutritional Science, Eye Vitality||2||5000 (100%)||3|
|Ocuvite Extra||2||2000 (100%)||1.2|
|Ocuvite PreserVision||4||28,640 (100%)||17.2|
|Ocuguard Plus with Lutein||4||40,000 (100%)||24.0|
|PreserVision, age-related eye study||2||28,640 (100%)||17.2|
|Puritan Senior Eye Vision||4||16,250 (75%)||7.3|
|Rainbow Light, Complete Eye Care System||2||10,000 (100%)||3|
|Windmill Vision Support||1||5000 (100%)||3|
Our systematic review identified 4 large randomized studies reporting on the effect of beta-carotene and the incidence of lung cancer in high-risk populations. Meta-analysis demonstrated an increased risk of lung cancer associated with beta-carotene supplementation of approximately 24% from the baseline risk noted among participants who were current smokers. Our survey of multivitamins indicated that the majority contained beta-carotene, albeit in small dosages. Multivitamins sold to promote visual health were found to have a significantly higher dosage of beta-carotene. This finding raises the concern that excess lung cancers may potentially result from the regular consumption of certain multivitamin formulas.
To understand the magnitude of this risk, it will help to consider that approximately 50 million Americans regularly consume multivitamins.7 Data from the National Health Interview Survey from the Centers for Disease Control and Prevention indicated that approximately 20% of Americans are current smokers.12 By a rough estimate, approximately 10 millions Americans are current smokers who consume multivitamins. On the basis of the National Cancer Institute (NCI)'s Surveillance, Epidemiology, and End Results database, the incidence of lung cancer is approximately 60 per 100,000 in the general population (not necessarily among smokers). Because beta-carotene appears to increase this risk by 24%, an increase in lung cancer incidence of 14.4 per 100,000 population can be expected. If these 10 million people were to consume beta-carotene at the dosage used in the chemoprevention study, this would have resulted in an excess of 1440 lung cancer cases each year. In addition, this number would be higher if one considers that the risk of lung cancer is 22 times higher among male smokers and 12 times higher among female smokers than the risk among their never-smoker counterparts.12
Although the dosages of beta-carotene in the sample of multivitamins in the current study appear to be substantially lower than those used in the chemoprevention study, one cannot rule out a linear dose-risk correlation.3, 4, 10, 11 In a large prospective study among French women, the incidence of lung cancer increased as beta-carotene intake increased, and a modest dosage of beta-carotene supplementation (estimated to be approximately 2.1 mg daily) was found to be associated with an increased risk of tobacco-related cancers.13 In addition, for some people who consume a combination of several multivitamin preparations, the cumulative beta-carotene dosage can increase even further. In addition, prolonged exposure may be significant. The cocarcinogenic effect of beta-carotene appears to stem from its ability to exacerbate DNA oxidative damage and modify p53-related pathways of cell proliferation and apoptosis, leading to the development of cancer.14 Since the late 1990s, a correlation between beta-carotene and lung cancer has been observed.15 An experiment in ferrets who were given beta-carotene supplements and exposed to tobacco smoke also clearly indicated an acceleration in lung tumorigenesis.16
However, beta-carotene does have an efficacy in a dry type of age-related macular degeneration (ARMD). This condition, reported to affect approximately 0.5% of the population, is manifested by a gradual loss of vision and can be diagnosed by a dilated eye examination.17 In the Age-Related Eye Disease Study (AREDS), patients with moderate or advanced ARMD were found to have a lower risk of disease progression when taking antioxidant supplements including beta-carotene at a dose of 15 mg daily.18 However, it is important to address the fact that ARMD is an uncommon cause of visual problems when compared with refractive disorders. In addition, to our knowledge there is no evidence that patients with early ARMD will benefit from beta-carotene supplementation.19 Based on our findings, we believe that the public should be discouraged from taking beta-carotene supplements to improve vision without a recommendation from their ophthalmologists.
The current study has several limitations. First, in the CARET study, participants also received retinyl palmitate in addition to beta-carotene.4 It is possible that retinyl palmitate interfered with the risk estimation of beta-carotene, although it is unlikely that the observed increased risk of lung cancer resulted solely from the administration of retinyl palmitate. In fact, a large randomized study of high-dose retinyl palmitate supplementation among patients with stage I lung cancer who underwent a curative resection indicated that adjuvant therapy with retinyl palmitate significantly decreased the development of a new primary lung cancer.20 Second, in the ATBC study,3 which had a 2 × design, alpha-tocopherol was also administered to approximately half of the participants receiving beta-carotene. An analysis from the ATBC study suggested that alpha-tocopherol had a small effect in reducing the incidence of lung cancer, albeit a statistically insignificant one, and this could result in an underestimation of the risk of lung cancer in our meta-analysis. Third, the sample of multivitamins in the current study was not comprehensive. However, we believe they were representative of other formulas available on the market. Finally, it is important to emphasize that these data apply to vitamin supplementations and that an extrapolation to foods rich in beta-carotene such as fruits and vegetables cannot be made.
After the completion of the CARET and ATBC studies, the excess risk of lung cancer and its associated mortality either persisted insignificantly or decreased to the baseline risk after the discontinuation of beta-carotene.21, 22 The NCI has published its conclusions regarding the beta-carotene chemoprevention trials but to our knowledge has never made recommendations as to whether Americans should take supplements.23 The best advice is to stop smoking. Because physicians often have limited knowledge of what to advise their patients with regard to dietary supplementation,24 perhaps advice regarding beta-carotene and the risk of lung cancer among ongoing smokers should also serve this purpose. During our multivitamin survey, we did not encounter any disclosure of lung cancer risk on any occasion, even among the multivitamin brands containing high-dose beta-carotene.
We thank Dr. I-Min Lee, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, for providing information regarding the Women's Health Study.
- 9The Cochrane Collaboration. Available at http://www.cochrane.org Accessed October 20, 2007.
- 12U.S. Department of Health and Human Service. Sustaining state programs for tobacco control: data highlights 2006. Rockville, MD: Centers for Disease Control and Prevention; 2006. Available at: http://www.cdc.gov/tobacco/ Accessed January 20, 2008.
- 23National Cancer Institute, US National Institutes of Health. Available at: www.cancer.gov/cancertopics/factsheet/Prevention/betacarotene Accessed January 20, 2008.