© 1996 by Oxford University Press
Journal of the National Cancer Institute, Vol. 88, No. 21, 1560-1570,
November 6, 1996
© 1996 Oxford University Press
-Tocopherol and 
-Carotene Supplements and Lung Cancer Incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: Effects of Base-line Characteristics and Study Compliance
Division of Cancer Prevention and Control, National Cancer Institute Bethesda, MD
Department of Public Health, University of Helsinki Finland
National Public Health Institute Helsinki, Finland
Information Management Services, Inc. Silver Spring, MD
Department of Diseases of the Chest, Turku University Hospital Finland
Finnish Cancer Registry Helsinki
Department of Pathology, The Johns Hopkins School of Medicine Baltimore, MD
University of Helsinki School of Medicine Baltimore. MD
Demetrius Albanes, M.D., National Institutes of Health, Executive Plaza North, Rm. 211, Bethesda. MD 20892-7326.
Background: Experimental and epidemiologic investigations suggest that 
-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and 
-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received -carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of -carotene and vitamin A. Purpose: We examined the effects of -tocopherol and -carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. Methods: A total of 29 133 men aged 50–69 years who smoked five or more cigarettes daily were randomly assigned to receive -tocopherol (50 mg), -carotene (20 mg), -tocopherol and -carotene, or a placebo daily for 5–8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of -tocopherol and -carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. Results: No overall effect was observed for lung cancer from -tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87–1.13; P =.86, logrank test). -Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02–1.33; P =.02, logrank test). The -carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07–1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76–1.23) and in those with a higher alcohol intake (
11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01–1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85–1.24). Conclusions: Supplementation with -tocopherol or -carotene does not prevent lung cancer in older men who smoke. -Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. Implications: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose -carotene supplementation. [J Natl Cancer Inst 1996; 88: 1560–70]
CiteULike 
Connotea 
Del.icio.us What's this?
Online Perspectives about this Classic Article
-
-Carotene and Lung Cancer: A Lesson for Future Chemoprevention Investigations?
- Peter Greenwald
J Natl Cancer Inst 2003 95: 1E.[Extract] [Full Text]
-
CORRESPONDENCE: Re: -Carotene and Lung Cancer: A Lesson for Future Chemoprevention Investigations?
- Daniel O. Stram and Anna H. Wu
J Natl Cancer Inst 2003 95: 4E.[Extract] [Full Text]
This article has been cited by other articles:
|
|
 |
|
  C. G. Slatore, A. J. Littman, D. H. Au, J. A. Satia, and E. White Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer Am. J. Respir. Crit. Care Med., March 1, 2008; 177(5): 524 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Cassileth, G. E. Deng, J. E. Gomez, P. A. S. Johnstone, N. Kumar, and A. J. Vickers Complementary Therapies and Integrative Oncology in Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition) Chest, September 1, 2007; 132(3_suppl): 340S - 354S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Anderson, C. Kooperberg, N. Geller, J. E. Rossouw, M. Pettinger, and R. L. Prentice Monitoring and reporting of the Women's Health Initiative randomized hormone therapy trials Clinical Trials, June 1, 2007; 4(3): 207 - 217. [Abstract] [PDF]
|
|
|
|
 |
|
 S. C. Moore, M. F. Leitzmann, S. J. Weinstein, K. Snyder, D. Albanes, J. Virtamo, B. I. Graubard, S. T. Mayne, H. Yu, U. Peters, et al. Insulin Resistance-Related Gene Polymorphisms and Risk of Prostate Cancer Cancer Epidemiol. Biomarkers Prev., June 1, 2007; 16(6): 1315 - 1317. [Full Text] [PDF]
|
|
|
|
|
|
U. Peters, M. F. Leitzmann, N. Chatterjee, Y. Wang, D. Albanes, E. P. Gelmann, M. D. Friesen, E. Riboli, and R. B. Hayes Serum Lycopene, Other Carotenoids, and Prostate Cancer Risk: a Nested Case-Control Study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Cancer Epidemiol. Biomarkers Prev., May 1, 2007; 16(5): 962 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Puntoni, S. Zanardi, D. Branchi, S. Bruno, A. Curotto, M. Varaldo, P. Bruzzi, and A. Decensi Prognostic Effect of DNA Aneuploidy from Bladder Washings in Superficial Bladder Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2007; 16(5): 979 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G Traber How much vitamin E? ... Just enough! Am. J. Clinical Nutrition, November 1, 2006; 84(5): 959 - 960. [Full Text] [PDF]
|
|
|
|
|
|
S. T. Mayne and B. Cartmel Chemoprevention of Second Cancers Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2033 - 2037. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L Halvorsen, M. H Carlsen, K. M Phillips, S. K Bohn, K. Holte, D. R Jacobs Jr, and R. Blomhoff Content of redox-active compounds (ie, antioxidants) in foods consumed in the United States Am. J. Clinical Nutrition, July 1, 2006; 84(1): 95 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Chen and P. G. Wells Enhanced tumorigenesis in p53 knockout mice exposed in utero to high-dose vitamin E Carcinogenesis, July 1, 2006; 27(7): 1358 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Cronin, M. H. Gail, Z. Zou, P. B. Bach, J. Virtamo, and D. Albanes Validation of a model of lung cancer risk prediction among smokers. J Natl Cancer Inst, May 3, 2006; 98(9): 637 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. I. Fenton and N. G. Hord Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research Carcinogenesis, May 1, 2006; 27(5): 893 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Goodman, M. D. Thornquist, C. Edelstein, and G. S. Omenn Biorepositories: Let's Not Lose What We Have So Carefully Gathered! Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 599 - 601. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Delanian, R. Porcher, J. Rudant, and J.-L. Lefaix Kinetics of Response to Long-Term Treatment Combining Pentoxifylline and Tocopherol in Patients With Superficial Radiation-Induced Fibrosis J. Clin. Oncol., December 1, 2005; 23(34): 8570 - 8579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Touvier, E. Kesse, F. Clavel-Chapelon, and M.-C. Boutron-Ruault Dual Association of {beta}-Carotene With Risk of Tobacco-Related Cancers in a Cohort of French Women J Natl Cancer Inst, September 21, 2005; 97(18): 1338 - 1344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Hix, D. A. Frey, M. D. McLaws, M. Osterlie, S. F. Lockwood, and J. S. Bertram Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative Carcinogenesis, September 1, 2005; 26(9): 1634 - 1641. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Williams and N. G. Hord The Role of Dietary Factors in Cancer Prevention: Beyond Fruits and Vegetables Nutr Clin Pract, August 1, 2005; 20(4): 451 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Du, N. K. Altorki, L. Kopelovich, K. Subbaramaiah, and A. J. Dannenberg Tobacco Smoke Stimulates the Transcription of Amphiregulin in Human Oral Epithelial Cells: Evidence of a Cyclic AMP-Responsive Element Binding Protein-Dependent Mechanism Cancer Res., July 1, 2005; 65(13): 5982 - 5988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Han, D. D. Liu, J. J. Lee, J. Kurie, R. Lotan, W. K. Hong, and H.-Y. Lee 9-cis-Retinoic Acid Treatment Increases Serum Concentrations of {alpha}-Tocopherol in Former Smokers Clin. Cancer Res., March 15, 2005; 11(6): 2305 - 2311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Fukumoto, N. Yamauchi, H. Moriguchi, Y. Hippo, A. Watanabe, J. Shibahara, H. Taniguchi, S. Ishikawa, H. Ito, S. Yamamoto, et al. Overexpression of the Aldo-Keto Reductase Family Protein AKR1B10 Is Highly Correlated with Smokers' Non-Small Cell Lung Carcinomas Clin. Cancer Res., March 1, 2005; 11(5): 1776 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Serrano, L. Baglietto, H. Johansson, F. Mariette, R. Torrisi, M. Onetto, M. Paganuzzi, and A. Decensi Effect of the Synthetic Retinoid Fenretinide on Circulating Free Prostate-Specific Antigen, Insulin-Like Growth Factor-I, and Insulin-Like Growth Factor Binding Protein-3 Levels in Men with Superficial Bladder Cancer Clin. Cancer Res., March 1, 2005; 11(5): 2083 - 2088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Moraitis, B. Du, M. S. De Lorenzo, J. O. Boyle, B. B. Weksler, E. G. Cohen, J. F. Carew, N. K. Altorki, L. Kopelovich, K. Subbaramaiah, et al. Levels of Cyclooxygenase-2 Are Increased in the Oral Mucosa of Smokers: Evidence for the Role of Epidermal Growth Factor Receptor and Its Ligands Cancer Res., January 15, 2005; 65(2): 664 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Taylor and P. Greenwald Nutritional Interventions in Cancer Prevention J. Clin. Oncol., January 10, 2005; 23(2): 333 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Mooney, A. M. Madsen, D. Tang, M. A. Orjuela, W.-Y. Tsai, E. R. Garduno, and F. P. Perera Antioxidant Vitamin Supplementation Reduces Benzo(a)pyrene-DNA Adducts and Potential Cancer Risk in Female Smokers Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 237 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Goodman, M. D. Thornquist, J. Balmes, M. R. Cullen, F. L. Meyskens Jr., G. S. Omenn, B. Valanis, and J. H. Williams Jr. The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping {beta}-Carotene and Retinol Supplements J Natl Cancer Inst, December 1, 2004; 96(23): 1743 - 1750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Schabath, H. B. Grossman, G. L. Delclos, L. M. Hernandez, R. S. Day, B. R. Davis, S. P. Lerner, M. R. Spitz, and X. Wu Dietary Carotenoids and Genetic Instability Modify Bladder Cancer Risk J. Nutr., December 1, 2004; 134(12): 3362 - 3369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Port, K. Yamaguchi, B. Du, M. De Lorenzo, M. Chang, P. M. Heerdt, L. Kopelovich, C. B. Marcus, N. K. Altorki, K. Subbaramaiah, et al. Tobacco smoke induces CYP1B1 in the aerodigestive tract Carcinogenesis, November 1, 2004; 25(11): 2275 - 2281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Hu, D. B. Reuben, E. M. Crimmins, T. B. Harris, M.-H. Huang, and T. E. Seeman The Effects of Serum Beta-Carotene Concentration and Burden of Inflammation on All-Cause Mortality Risk in High-Functioning Older Persons: MacArthur Studies of Successful Aging J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2004; 59(8): M849 - M854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Poschl and H. K. Seitz ALCOHOL AND CANCER Alcohol Alcohol., May 1, 2004; 39(3): 155 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Albright, R. I. Salganik, and T. Van Dyke Dietary Depletion of Vitamin E and Vitamin A Inhibits Mammary Tumor Growth and Metastasis in Transgenic Mice J. Nutr., May 1, 2004; 134(5): 1139 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Omenn Human Lung Cancer Chemoprevention Strategies: Parker B. Francis Lecture Chest, May 1, 2004; 125(5_suppl): 123S - 127S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Carbone Lung Cancer: Early Events, Early Interventions: Conference Summary for the 46th Annual Thomas L. Petty Aspen Lung Conference Chest, May 1, 2004; 125(5_suppl): 167S - 172S. [Full Text] [PDF]
|
|
|
|
|
|
A. Svilaas, A. K. Sakhi, L. F. Andersen, T. Svilaas, E. C. Strom, D. R. Jacobs Jr., L. Ose, and R. Blomhoff Intakes of Antioxidants in Coffee, Wine, and Vegetables Are Correlated with Plasma Carotenoids in Humans J. Nutr., March 1, 2004; 134(3): 562 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Murtaugh, K.-n. Ma, J. Benson, K. Curtin, B. Caan, and M. L. Slattery Antioxidants, Carotenoids, and Risk of Rectal Cancer Am. J. Epidemiol., January 1, 2004; 159(1): 32 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bendich From 1989 to 2001: What Have We Learned About the "Biological Actions of Beta-Carotene"? J. Nutr., January 1, 2004; 134(1): 225S - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Russell The Enigma of {beta}-Carotene in Carcinogenesis: What Can Be Learned from Animal Studies J. Nutr., January 1, 2004; 134(1): 262S - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Krone and L. C. Harms Re: Zinc Supplement Use and Risk of Prostate Cancer J Natl Cancer Inst, October 15, 2003; 95(20): 1556 - 1556. [Full Text] [PDF]
|
|
|
|
 |
|
 The ATBC Study Group Incidence of Cancer and Mortality Following {alpha}-Tocopherol and {beta}-Carotene Supplementation: A Postintervention Follow-up JAMA, July 23, 2003; 290(4): 476 - 485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Goodman, S. Schaffer, G. S. Omenn, C. Chen, and I. King The Association between Lung and Prostate Cancer Risk, and Serum Micronutrients: Results and Lessons Learned from {beta}-Carotene and Retinol Efficacy Trial Cancer Epidemiol. Biomarkers Prev., June 1, 2003; 12(6): 518 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Baron, B. F. Cole, L. Mott, R. Haile, M. Grau, T. R. Church, G. J. Beck, and E. R. Greenberg Neoplastic and Antineoplastic Effects of {beta}-Carotene on Colorectal Adenoma Recurrence: Results of a Randomized Trial J Natl Cancer Inst, May 21, 2003; 95(10): 717 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Crowe, R. Kim, and R. A.S. Chandraratna Retinoic Acid Differentially Regulates Cancer Cell Proliferation via Dose-Dependent Modulation of the Mitogen-Activated Protein Kinase Pathway Mol. Cancer Res., May 1, 2003; 1(7): 532 - 540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Neuhouser, R. E. Patterson, M. D. Thornquist, G. S. Omenn, I. B. King, and G. E. Goodman Fruits and Vegetables Are Associated with Lower Lung Cancer Risk Only in the Placebo Arm of the {beta}-Carotene and Retinol Efficacy Trial (CARET) Cancer Epidemiol. Biomarkers Prev., April 1, 2003; 12(4): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H Halsted Dietary supplements and functional foods: 2 sides of a coin? Am. J. Clinical Nutrition, April 1, 2003; 77(4): 1001S - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Nyberg, S.-M. Hou, G. Pershagen, and B. Lambert Dietary fruit and vegetables protect against somatic mutation in vivo, but low or high intake of carotenoids does not Carcinogenesis, April 1, 2003; 24(4): 689 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Greenwald {beta}-Carotene and Lung Cancer: A Lesson for Future Chemoprevention Investigations? J Natl Cancer Inst, January 1, 2003; 95(1): E1 - E1. [Full Text]
|
|
|
|
 |
|
 G E Goodman Lung cancer * 1: Prevention of lung cancer Thorax, November 1, 2002; 57(11): 994 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Holick, D. S. Michaud, R. Stolzenberg-Solomon, S. T. Mayne, P. Pietinen, P. R. Taylor, J. Virtamo, and D. Albanes Dietary Carotenoids, Serum {beta}-Carotene, and Retinol and Risk of Lung Cancer in the Alpha-Tocopherol, Beta-Carotene Cohort Study Am. J. Epidemiol., September 15, 2002; 156(6): 536 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Hecht, P. Upadhyaya, M. Wang, R. L. Bliss, E. J. McIntee, and P. M.J. Kenney Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination Carcinogenesis, September 1, 2002; 23(9): 1455 - 1461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wolf The effect of {beta}-carotene on lung and skin carcinogenesis Carcinogenesis, August 1, 2002; 23(8): 1263 - 1265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ambati, B. K. Ambati, F. L. Ferris III, A. S. Lindblad, and R. C. Milton Age-Related Eye Disease Study Caveats Arch Ophthalmol, July 1, 2002; 120(7): 997 - 999. [Full Text] [PDF]
|
|
|
|
|
|
K. M. Fairfield and R. H. Fletcher Vitamins for Chronic Disease Prevention in Adults: Scientific Review JAMA, June 19, 2002; 287(23): 3116 - 3126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Partridge, J. Avorn, P. S. Wang, and E. P. Winer Adherence to Therapy With Oral Antineoplastic Agents J Natl Cancer Inst, May 1, 2002; 94(9): 652 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. O. Stram, M. Huberman, and A. H. Wu Is Residual Confounding a Reasonable Explanation for the Apparent Protective Effects of Beta-carotene Found in Epidemiologic Studies of Lung Cancer in Smokers? Am. J. Epidemiol., April 1, 2002; 155(7): 622 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Halvorsen, K. Holte, M. C. W. Myhrstad, I. Barikmo, E. Hvattum, S. F. Remberg, A.-B. Wold, K. Haffner, H. Baugerod, L. F. Andersen, et al. A Systematic Screening of Total Antioxidants in Dietary Plants J. Nutr., March 1, 2002; 132(3): 461 - 471. [Abstract] [Full Text] |