In order to determine the long-term effects from vitamin supplements in smokers, ATBC researchers followed the participants for an additional eight years after the trial ended. The findings from this follow-up study, published in the July 23, 2003 issue of the Journal of the American Medical Association, as well as the initial trial results, are summarized in this fact sheet.

1.  What was the purpose and design of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial?

     The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial was a cancer prevention trial conducted by the U.S. National Cancer Institute (NCI) and the National Public Health Institute of Finland from 1985 to 1993. The purpose of the study was to determine whether certain vitamin supplements would prevent lung cancer and other cancers in a group of 29,133 male smokers in Finland. The 50- to 69-year-old participants took a pill daily for five to eight years that contained one of the following: 50 milligrams (mg) alpha-tocopherol (a form of vitamin E), 20 mg of beta-carotene (a precursor of vitamin A), both, or a placebo (inactive pill that looked like the vitamin).

2.  What were the principal findings?

     •  ATBC researchers reported that men who took beta-carotene had an 18 percent increased incidence of lung cancers and an 8 percent increased overall mortality. Vitamin E had no effect on lung cancer incidence or overall mortality. The men taking both supplements had outcomes similar to those taking beta-carotene alone (New England Journal of Medicine 1994;330:1029).

     •  The adverse effects of beta-carotene appeared stronger in men with a relatively modest alcohol intake (more than 11 grams per day; 15 grams of alcohol is equivalent to one drink) and in those smoking at least 20 cigarettes daily (Journal of the National Cancer Institute1996;88:1560).

     •  Participants taking vitamin E had 32 percent fewer cases of prostate cancer and 41 percent fewer deaths from prostate cancer. Death from hemorrhagic stroke (a deficit of blood to the brain due to the rupture of a blood vessel) was also increased by 50 percent in men taking alpha-tocopherol supplements; the increase occurred primarily among men with hypertension. (Journal of the National Cancer Institute 1998;90:440 and Arterioscler Thromb Vasc Biol 2000;20:230).

3.  What were the principal findings of the post-trial follow-up?

     The participants stopped taking the vitamin supplements in April 1993. However, in order to evaluate the long-term effects of the vitamins on cancer incidence, and overall and cause-specific mortality, they were followed after the trial ended using data from the national registries in Finland. The researchers acquired additional data for cancer incidence and mortality related to specific causes through April 1999 (six years beyond the end of the trial), and for total mortality through April 2001 (eight years beyond the end of the trial). The principal findings from the post-trial follow-up are listed below (Journal of American Medical Association 2003;290:476).

     •  In the eight-year follow-up period, the participants taking beta-carotene experienced 7 percent higher overall mortality than men on the placebo. However, this elevation was largely limited to the first four to six years of follow-up; during the last two years, the overall mortality rates were comparable to participants who did not receive beta-carotene.

     •  In the beta-carotene group, the higher mortality during the trial was due to cardiovascular disease and lung cancer. In contrast, the higher mortality during the post-intervention period was due to cardiovascular disease alone.

     •  The increased risks for lung cancer that occurred in participants supplemented with beta-carotene began to fall soon after the men stopped taking the vitamin, and were similar to the placebo group within four years.

     •  The lower prostate cancer incidence rates in participants taking alpha-tocopherol supplements during the trial returned toward normal soon after the trial ended, but remained below the placebo group rates throughout the six-year post-intervention period.

4.  What were the conclusions and recommendations from the post-trial follow-up?(Journal of American Medical Association 2003;290:476)

     •  The adverse effects from beta-carotene and the beneficial effects from supplementation with alpha-tocopherol (vitamin E) largely disappeared during the post-trial follow-up period.

     •  The findings indicate a symmetry in the time course during and after the trial. That is, the time it took for the elevated lung cancer rates and lower prostate cancer rates to occur was similar to the time for these adverse and beneficial effects to disappear.

     •  There were no additional beneficial late effects on cancer or mortality observed after the trial ended.

     •  The results of both the trial and post-trial follow-up of the ATBC Study, in conjunction with results from the CARET Study (beta-Carotene and Retinol Efficacy Trial) completed in 1996, continue to support the recommendation that beta-carotene supplementation should be avoided by smokers. The possible preventive effects of alpha-tocopherol on prostate cancer require confirmation in other ongoing trials.

     •  Continued follow-up of the participants will provide unique and valuable information on the duration of trial effects and potential late effects of intervention with these antioxidant vitamins. Further follow-up will also contribute to our understanding of the biological mechanisms through which such hemoprevention agents affect carcinogenesis and human cancer risk.

5.  Why were vitamin E and beta-carotene chosen for this trial?

     Vitamin E and beta-carotene were chosen because epidemiologic studies have linked high dietary intake and high serum levels of these micronutrients to a reduced risk of cancer, particularly lung cancer. Both are antioxidants, compounds that may prevent carcinogens from damaging DNA and other cellular systems.

6. Why was the ATBC Study conducted in Finland in men only?

     The study was conducted in Finland because of the high lung cancer rates in men in that country, which were due primarily to cigarette smoking. Furthermore, Finland had a clinic system for the screening and treatment of lung diseases (mainly tuberculosis) through which the recruited population of smokers could participate in the study. Finland also has a national cancer registry, which keeps track of all the cancer cases identified in that country, a vital measurement for the large trial.

     Finnish women were not included in the study because their rate of lung cancer was substantially lower than the rate for Finnish men. In 1985, the annual age-adjusted lung cancer rate for Finnish men was 67 cases per 100,000 men and for women was eight cases per 100,000 women.

7.  How much did the study cost?

     NCI allocated about $20 million over 10 years for the trial, with a similar sum contributed by the government and research institutions in Finland. In addition, F. Hoffmann-LaRoche Ltd, a pharmaceutical company based in Basel, Switzerland, supplied the 60 million pills the men took during the trial, without charge, at a cost to the company of about $3 million. The cost for the eight-year follow-up was about $3 million.

8.  What are the results from other large-scale prevention studies?

     The Beta-Carotene and Retinol Efficacy Trial (CARET) compared the effects of beta-carotene plus vitamin A (retinyl palmitate) to placebo in 18,314 men and women ages 45 to 74 who were either smokers, former smokers, and/or had been exposed to asbestos. A 28 percent higher lung cancer incidence and 17 percent higher overall mortality occurred in the group taking the vitamin supplementation.

     The Physician's Health Study showed that beta-carotene supplementation had no effect on lung cancer or overall mortality among the 22,071 men ages 40 to 84 followed for an average of 12 years. However, this population was at lower risk for lung cancer compared to the participants in the ATBC or CARET trials.

9.  What other large-scale dietary intervention studies are underway?

     The Selenium and Vitamin E Cancer Prevention Trial (SELECT), sponsored by NCI, began in July 2001, and will determine if these two dietary supplements can protect against prostate cancer. The 32,400 participants will be randomized to receive daily supplements of either: selenium and vitamin E (alpha-tocopherol); selenium and placebo; vitamin E and placebo; two placebos. The trial is expected to end in 2013.

     The Women's Health Study, headed by researchers at Boston's Brigham and Women's Hospital, is evaluating the benefits and risks of low-dose aspirin and vitamin E on cardiovascular disease and cancer among 40,000 female health professionals. When the trial began in 1992, there was a beta-carotene arm, which was dropped when the results from the other beta-carotene trials were announced. The trial is expected to end in August 2004.

     The Physicians' Health Study II, headed by investigators at Harvard Medical School in Boston, is evaluating vitamin E, vitamin C, beta-carotene and a multivitamin for the prevention of cardiovascular disease, total cancer, and prostate cancer among 15,000 male physicians age 50 or older. The trial began in 1997 and is expected to end in December 2007.

For more information about cancer, visit the NCI Web site at cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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