In 1996, a large study of smokers and asbestos-exposed workers found that the dietary supplement beta-carotene and retinol (vitamin A) increased lung-cancer risk. Now, a six-year follow-up study has found that the increased risk may persist in participants, especially in women and former smokers, even after discontinuing supplement use. Results of the study were published in the Dec. 1 issue of the Journal of the National Cancer Institute (JNCI).
Additionally, the study found that the overall increased risk of death from cardiovascular disease that had been observed while participants were taking the supplement was found to disappear in men soon after beta-carotene use was stopped, although female smokers appear to have a persistent elevated risk for this side effect as well.
The NCI-funded analysis, part of the Carotene and Retinol Efficacy Trial (CARET), was led by Drs. Gary Goodman and Mark Thornquist of the Public Health Sciences Division and included collaborators in California, Oregon, Michigan, Maryland and Connecticut.
Goodman, also a medical oncologist at Swedish Cancer Institute in Seattle, said that over the six-year follow-up period, women smokers who had received the combination of beta-carotene and vitamin A were about 35 percent to 40 percent more likely to develop lung cancer or to die of any cause than were women who had not received the supplements.
"These findings underscore the importance of long-term follow-up in any type of intervention study," he said. "It's not enough simply to see whether an intervention has an effect over a short duration, because there may be future unforeseen outcomes."
The most striking and unexpected of these, he said, was the observation that while similar increases in risk of lung cancer, death from cardiovascular disease and death from any cause were observed in men and women during the time at which beta-carotene and retinol supplements were administered, only women were found to have a continued increased risk of these outcomes during the post-intervention period.
The researchers are proposing additional follow-up studies to further evaluate why beta-carotene increases lung-cancer risk as well as to shed light on the gender disparity during the post-intervention period.
The CARET study was initiated in 1983, following the publication of several preliminary studies from other groups that suggested that beta-carotene protected individuals against cancer. Beta-carotene, a precursor to vitamin A, is an antioxidant. Antioxidants are thought to prevent the damage to cells and tissues caused by the buildup of molecules called free radicals, which are produced during the course of normal metabolism but may be elevated by exposures such as tobacco or radiation.
CARET involved more than 18,000 current and former male and female smokers and asbestos-exposed males, groups that have a higher risk of developing lung cancer compared to the general population. Participants were either assigned to a placebo group or to a group that received a combination of beta-carotene and vitamin A.
At the time, public enthusiasm for the purported health benefits of beta-carotene was so high, Thornquist said, "people thought it would be unethical to assign participants to the placebo group." But CARET's careful analysis of the supplement soon proved otherwise.
The intervention phase of the study was stopped two years early when it was found that participants who took the supplements had a 28 percent greater incidence of lung cancer and 17 percent more deaths than the placebo group. The risk of dying of cardiovascular disease was 26 percent higher in supplement users compared to that of the placebo group. Another large beta-carotene cancer prevention trial, conducted in Finland, came to similar conclusions.
To determine if the effects of beta-carotene continued after participants stopped taking the supplements, Goodman and colleagues have continued to follow the CARET participants. The published results are for a follow-up period through the end of 2001, six years after the intervention phase of the trial was stopped.
In men, the increased risk of cardiovascular disease mortality quickly disappeared after they stopped taking the supplements. However, women had a higher risk of death from cardiovascular disease or from any cause than men. In addition, the incidence of lung cancer and deaths from all causes decreased but did not disappear completely after the supplementation ceased. The excess risk of lung cancer was restricted primarily to females and former smokers.
Overall among male and female CARET participants, the researchers found a 12 percent greater risk of lung cancer, an 8 percent greater risk of death from any cause and a 2 percent greater risk of death from cardiovascular disease among former supplement users during the follow-up period. These increases were not considered statistically significant. When female smokers were evaluated alone as a subgroup, the increased risk for each of these conditions was 33 percent, 37 percent and 44 percent, respectively.
Goodman said that it is not yet known why beta-carotene increases lung-cancer risk in smokers, although researchers have speculated that the supplement enhances the DNA-damaging effects of tobacco.
"We also don't know why the risk persists after intervention only in women, although we can speculate about some gender differences that may contribute to this effect," he said. "For example, beta-carotene is a fat-soluble compound, and women tend to have higher body-fat percentages than men."
In addition, he said, the female hormone estrogen may play a role. "Estrogen can be a carcinogen depending on how it's metabolized. It's possible that beta-carotene changes the metabolism of estrogen."
Goodman stressed the importance of follow-up studies to assess the long-term impact of medications, particularly as medicine moves more toward preventive practice.
"Historically, medical treatments were evaluated based on whether people lived or died," he said. "Today, millions of people take drugs for years for chronic conditions. When that many people are involved, there are bound to be side effects observed over time."
Thornquist added that this problem presents an extra challenge when dealing with dietary supplements, which by law are not regulated by the Food and Drug Administration.