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Date: Thurs., Jan. 18, 1996 For Release: 12:00 p.m. EST Contact: NCI 301)496-6641 or Fred Hutchinson Cancer Center (206) 667-2896
Beta Carotene and Vitamin A Halted in Lung Cancer Prevention Trial Investigators conducting the Beta Carotene and Retinol Efficacy Trial (CARET), a large study of the combination of beta carotene and vitamin A as preventive agents for lung cancer in high-risk men and women, terminated the intervention last week after an average of four years of treatment and told the 18,314 participants to stop taking their vitamins. Interim study results indicate that the supplements provide no benefit and may be causing harm.
Investigators in another trial, the Physicians' Health Study, said today that their study of 22,071 U.S. male physicians ended on schedule, Dec. 31, 1995, after more than 12 years of treatment. The study showed no significant evidence of benefit or harm from beta carotene on cancer or cardiovascular disease.
Both studies have been funded by the National Cancer Institute (NCI) of the National Institutes of Health (NIH). The Physicians' Health Study was also funded by NIH's National Heart, Lung, and Blood Institute.
CARET's lead investigator, Gilbert S. Omenn, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center and the University of Washington School of Public Health in Seattle, explained that regular independent review of the study data showed that lung cancer incidence was unlikely to be reduced by the daily intervention of 30 milligrams (mg) of beta carotene and 25,000 international units (IU) of vitamin A by the scheduled end of the study and that there was a substantial possibility that the supplements might be harming the participants, who are smokers, former smokers, and men exposed to asbestos on the job.
CARET results to date, including 388 people diagnosed with lung cancer and 974 deaths from all causes, showed 28 percent more lung cancers and 17 percent more deaths in participants taking beta carotene and vitamin A. While these interim results are not significant evidence of harm from a statistical standpoint, they are similar to the results of the Alpha-Tocopherol, Beta-Carotene (ATBC) Lung Cancer Prevention Trial published in 1994, which showed 18 percent more lung cancers and 8 percent more deaths in the portion of the 29,133 male smokers in Finland who took 20 mg of beta carotene daily for five to eight years.
Letters asking the 18,314 CARET participants to stop taking their vitamin supplements or placebos were mailed Jan. 13. Investigators plan to follow the participants for at least five more years to determine the long-term effects of the intervention, which was interrupted 21 months early. Omenn said that CARET data also raise the possibility that former smokers, who comprised 34 percent of the participants when recruited, may respond more favorably to vitamin A and beta carotene than current smokers, but that the data are too limited to draw any conclusions at this time. Results from the Physicians' Health Study, the trial of 22,071 U.S. male physicians taking 50 mg of beta carotene or a placebo every other day for 12 years, showed that beta-carotene supplements had no significant effect -- positive or negative -- on cancer or cardiovascular disease in this population of mostly nonsmokers (11 percent are current smokers while 51 percent smoked at some time in their life). Charles H. Hennekens, M.D., Dr.P.H., of Harvard Medical School and Brigham and Women's Hospital, Boston, headed this study, which showed in 1988 that low-dose aspirin reduces the risk of a first heart attack.
In response to the lack of benefit seen in CARET, the Physicians' Health Study, and the ATBC trial, another ongoing trial is removing beta carotene supplements from its intervention. The Women's Health Study, a trial of 40,000 female health professionals, headed by Julie Buring, Sc.D., of Harvard Medical School and Brigham and Women's Hospital, began in 1992. The study will continue to evaluate every-other-day doses of 600 IU of vitamin E and 100 mg of aspirin or placebos.
The results of CARET and the Physicians' Health Study provide strong evidence of no benefit from beta carotene supplements and raise questions about their safety for the general public. "The National Cancer Institute has never had a recommendation for Americans to take supplements," said Peter Greenwald, M.D., Dr.P.H., director of NCI's Division of Cancer Prevention and Control. "The best advice for smokers who want to reduce their risk of lung cancer is still the most direct: Stop smoking. Results from CARET and the ATBC Trial do suggest, however, that smokers should avoid beta carotene supplements."
Omenn underscored the "quit smoking" message by praising the many CARET participants who were smokers at the beginning of the trial and who have quit during the study. Twenty-two percent of those who smoked at the beginning of the trial have quit.
Greenwald continued, "For all Americans who wish to reduce their risk of lung and other cancers, a low-fat diet with plenty of fruits, vegetables, and grains is the choice to make. These studies show nothing to suggest that smokers or nonsmokers might benefit from beta carotene supplements." Hennekens concurred, noting that "taken together, the results of CARET, ATBC, and the Physicians' Health Study clearly tell us that beta-carotene supplementation is not a magic bullet -- it can neither substitute for a good diet nor compensate for a bad one."
NCI Director Richard Klausner, M.D., praised the work of the researchers and participants of CARET and the Physicians' Health Study, as well as applauding the process of science. "Medicine and public health must be based, whenever possible, on evidence. These trials discussed today provide that essential evidence... While the results are disappointing, the research process, I believe, is working."
The study is comprised of two groups: 14,254 current and former smokers with a long history of smoking and 4,060 asbestos-exposed individuals. The total number of participants is 18,314.
Recruited in Seattle, Portland, and Irvine were 14,254 men and women ages 50 to 69 who are current smokers or are smokers who had quit within six years of enrolling in the study. Smokers and former smokers must have had a smoking history of at least 20 pack years (one pack per day for 20 years or two packs for 10 years, etc). These participants are 56 percent male (7,965) and 44 percent female (6,289) and had an average of 50 pack years of smoking. About 34 percent were former smokers when they joined the study. All participants were counseled to quit smoking during their visits to the study centers. The racial distribution of the participants is 95 percent white, 2 percent African-American, 1 percent Hispanic, and 2 percent Asian or other.
At five of the six centers (Irvine, Calif. excluded), 4,060 men ages 45 to 69 years who had been exposed to asbestos while at work were enrolled in CARET. These participants had to have extensive occupational asbestos exposure beginning at least 15 years earlier, determined by either a chest X-ray that showed asbestos exposure or employment for more than five years in trades that carry a high risk of exposure to asbestos: plumbers and pipefitters, steam fitters, shipyard boilermakers, nonshipyard boilermakers, shipyard electricians, shipscalers, insulators, plasterboard workers, or sheetmetal workers. In addition, they had to be either current smokers or had to have quit smoking within the last 15 years. One- half the CARET participants in both groups took a combination of beta carotene and vitamin A and one-half took inactive placebos.
Beta carotene is an antioxidant, a compound that may prevent cancer-causing substances from damaging DNA. Epidemiologic studies have linked high dietary intake of beta carotene and high serum levels of this micronutrient to a reduced risk of cancer, particularly lung cancer. Vitamin A was chosen for study because it is known to play a part in cell differentiation, a process of "maturing" cells that helps prevent them from inappropriate growth, such as the uncontrolled cell growth that is seen in cancer. Vitamin A (retinol) and its analogues have been shown to be effective in preventing cancers in animals exposed to chemicals like those in cigarette smoke. Beta carotene and vitamin A were given as a combination under the hypothesis of a potentially favorable interaction between the two compounds. The dose of beta carotene in CARET was 30 mg/day, which is equivalent to 50,000 IU of vitamin A or about five medium-sized carrots. Vitamin A was given as retinyl palmitate in a dose of 25,000 IU.
The Physicians' Health Study was conducted nationwide among 22,071 U.S. male physicians ages 40 to 84 years, 11 percent of whom were current smokers and 51 percent of whom had smoked at some time in their life when recruited to the study in 1982.
The participants took either 50 mg of beta carotene every other day or a placebo and 325 mg of aspirin or a placebo on the alternate day. The randomized aspirin component ended early, after five years, primarily because a benefit of aspirin on risk of first heart attack was found (a 44 percent reduction was seen in those taking aspirin). The beta carotene treatment continued until its scheduled termination on Dec. 31, 1995. Questions and Answers about these studies follow.
1. What is a chemoprevention trial?
A chemoprevention trial is a type of clinical trial, which is a research study conducted with people. In a cancer chemoprevention trial, natural or laboratory-made substances are tested to see if they prevent cancer. The people who participate in such a study are healthy or are at risk of developing cancer, or in some studies, people who have been diagnosed with cancer and are at risk of developing a second cancer.
2. What is the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial?
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial or ATBC Trial was conducted by the National Cancer Institute (NCI) in collaboration with the National Public Health Institute of Finland. The purpose of the study was to see if certain vitamin supplements would prevent lung and other cancers in a group of 29,133 male smokers in Finland. The 50 to 69 year old participants took a pill containing either 50 milligrams (mg) alpha tocopherol (a form of vitamin E), 20 mg beta carotene (a precursor of vitamin A), both, or a placebo (inactive pill that looks like the vitamin) daily for five to eight years.
3. What is the Beta Carotene and Retinol Efficacy Trial or CARET?
The Beta Carotene and Retinol Efficacy Trial or CARET is a large chemoprevention trial that is being conducted in six areas in the United States and is funded by NCI. The purpose of the study was to see if the combination of beta carotene and vitamin A (a retinol) supplements would prevent lung and other cancers in men and women who are smokers or former smokers ages 50 to 69 years, and men who have been exposed to asbestos ages 45 to 69 years. The 18,314 participants stopped taking the supplements prior to the completion of the trial.
4. What is the Physicians' Health Study?
The Physicians' Health Study is a chemoprevention trial with 22,071 male U.S. physicians, of which only 11 percent smoked. The purpose of the study was to test whether a beta carotene supplement reduces the risk of cancer and heart disease as well as whether low-dose aspirin reduced the risk of heart disease. The aspirin component was stopped in early 1988 due to a 44 percent reduction in risk of first heart attack among those taking aspirin. The beta carotene component ended Dec. 31, 1995 after more than 12 years of study.
5. What did these trials show?
In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial, 18 percent more lung cancers were diagnosed and 8 percent more overall deaths occurred in study participants taking beta carotene. In CARET, after an average of four years of receiving supplements, 28 percent more lung cancers were diagnosed and 17 percent more deaths occurred in participants taking beta carotene and vitamin A than in those taking placebos. Neither of these studies showed a benefit from taking supplements.
Because the interim results of CARET were similar to the ATBC study, the intervention was stopped 21 months early. Both of these studies involved persons who were specifically invited to participate because of their high risk for developing lung cancer. The Physician's Health Study was completed at the end of 1995 and showed no benefit or harm in people taking beta carotene supplements for more than 12 years.
6. Why did CARET stop early?
The study itself was not stopped, but the participants were told to stop taking the beta carotene and vitamin A or placebos. The Safety and Endpoints Monitoring Committee for CARET and an ad hoc committee assembled by NCI saw that the interim results clearly showed no benefit from the supplements and also showed there was a possibility that they were harming participants. CARET investigators made the decision to stop the intervention, but they will follow the study group for five more years to determine the long-term effects of the intervention.
The intervention was halted on Jan. 11, 1996 by the CARET investigators. Letters were mailed to participants by Jan. 13 and a public announcement made Jan. 18.
7. Who were the participants in CARET?
The study had two groups: 14,254 current and former smokers with a long history of smoking and 4,060 asbestos-exposed individuals. The smokers and former smokers included 14,254 men and women ages 50 to 69 who are current smokers or are smokers who had quit within six years of enrolling in the study. Smokers and former smokers must have had a smoking history of at least 20 pack years (one pack per day for 20 years or two packs for 10 years, etc). These participants are 56 percent male (7,965) and 44 percent female (6,289) and had an average of 50 pack years of smoking. About 34 percent were former smokers when they joined the study. All participants were counseled to quit smoking at their visits to the study centers.
The asbestos-exposed participants were 4,060 men ages 45 to 69 years who had been exposed to asbestos while at work. These participants had to have extensive occupational asbestos exposure beginning at least 15 years prior to enrollment, determined by either a chest X-ray that showed asbestos exposure or employment for more than five years in trades that carry a high risk of exposure to asbestos: plumbers and pipefitters, steam fitters, shipyard boilermakers, nonshipyard boilermakers, shipyard electricians, shipscalers, insulators, plasterboard workers, or sheetmetal workers. In addition, they had to be either current smokers or had to have quit smoking within the last 15 years.
8. What is beta carotene?
Beta carotene, which is found in plants, is a precursor of vitamin A. The body converts beta carotene to vitamin A. It occurs mainly in fruits and vegetables that are deep yellow, orange, or dark green in color, such as carrots, squash, yams, peaches, apricots, spinach, collard or mustard greens, and broccoli. It is an antioxidant, a compound that may prevent cancer-causing substances from damaging DNA. Epidemiologic studies have linked high intake of foods rich in beta carotene and high serum levels of the micronutrient to a reduced risk of cancer, particularly lung cancer.
9. What is vitamin A?
Vitamin A is a vitamin, a substance found in foods that is necessary for human health. Vitamin A is found in liver, various dairy products with fat, such as milk, cheese, butter and ice cream, and in fatty fish such as herring, sardines, and tuna. It can also be found in the liver oils of shark, cod, and halibut.
Vitamin A is known to play a part in cell differentiation, a process by which cells "mature." Differentiation helps prevent cells from inappropriate growth, such as the uncontrolled cell growth that is seen in cancer. Many studies in animals show that vitamin A and similar compounds decrease the incidence of cancer.
10. Should Americans who smoke avoid taking beta carotene?
The NCI has never had a recommendation for Americans to take supplements. The best advice for smokers who want to reduce their risk of lung cancer is still the most direct: Stop smoking. The results from CARET and the ATBC Trial suggest that smokers should avoid taking beta carotene supplements.
11. Should Americans who don't smoke take beta carotene supplements?
The results of the Physicians' Health Study showed no benefit or harm to nonsmokers who took beta carotene every other day for 12 years. The results from CARET and the ATBC Study do not provide information about the effects of beta carotene supplements on non-smokers. NCI does not recommend that Americans take supplements. For those who wish to reduce their risk of cancer, NCI advises that it is prudent to adopt a low-fat diet containing plenty of fruits, vegetables, and grains.
12. Should Americans stop eating five fruits and vegetables daily (5-A-Day)?
No. 5-A-Day remains a good idea. In both the ATBC Study and CARET, participants with the highest levels of beta carotene in their blood, measured before the study began, went on to have fewer lung cancers. These results are consistent with the possibility that a different compound or compounds in foods that have high levels of beta carotene may be responsible for the protective effect of dietary beta carotene seen in epidemiologic studies. Because these are studies of pills, not food intake, NCI stresses that the study results do not change the results of studies that show that eating a variety of fruits and vegetables each day remains a good way to reduce the risk of some cancers.
13. What other chemoprevention studies are under way with beta carotene?
The NCI has a number of different agents under study, including calcium, fiber, tamoxifen, and others. Only one large-scale study including beta carotene (the Women's Health Study) was ongoing when CARET stopped its intervention, and the beta carotene portion of that study has been halted. Principal investigators of smaller or shorter-term studies including beta carotene were alerted and advised to consider the results of these studies in making decisions about the trials they are conducting.
In the Women's Health Study, sponsored by the National Institutes of Health, 40,000 apparently healthy women health professionals ages 45 and older were being assigned at random to 50 mg beta carotene, 600 IU vitamin E, 100 mg aspirin, and/or placebos every other day. The beta carotene portion of this trial is being dropped. The trial, which will show the balance of benefits and risks of these agents on cancer and cardiovascular disease, began in 1992.
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