Beta-carotene: no magic bullet.

"Instead of taking beta-carotene supplements, eat your fruits and vegetables," said Harvard University's Charles Hennekens at a hastily called press conference last January.

The problem: In two major trials--the Physicians' Health Study and the Beta-Carotene and Retinol Efficacy Trial (CARET)--high doses of the popular antioxidant failed to cut the risk of cancer or heart disease, explained Hennekens and others.

Worse yet, the National Cancer Institute (NCI) was halting the CARET trial 21 months early because its beta-carotene-takers--almost all heavy smokers or ex-smokers--were showing a higher risk of lung cancer and heart disease... just like the smokers in a Finnish trial released in 1994.

For years, dozens of multivitamins--and even some breakfast cereals--have boasted "Now with beta-carotene." And now researchers say: "No benefit. Possible harm."

What went wrong?

EARLY EVIDENCE

In one sense, nothing went wrong. "While the results are disappointing," said NCl director Richard Klausner, "the research process, I believe, is working."

Since the 1970s, test tube, animal, and human evidence had mounted that beta-carotene could reduce the risk of cancer and possibly heart disease. In study after study, researchers observed a lower risk of cancer (especially lung cancer) in people (especially smokers) who, on their own, ate a diet rich in beta-carotene--that is, Lots of orange, deep yellow, and green vegetables and fruits.

But the final hurdle was a handful of large "clinical intervention trials," in which researchers randomly assigned thousands of people to take beta-carotene supplements or (look-alike but inactive) placebos and then waited for years to see how many cancers occurred in each group.

"Otherwise, we had no way to know whether it was the beta-carotene or something else in the diet," said Gilbert Omenn, lead investigator of the CARET trial at the Fred Hutchinson Cancer Center in Seattle. It could even have been "something entirely different" about people who eat lots of fruits and vegetables that lowered their risk of cancer in earlier studies.

It was in the intervention trials that beta-carotene started to stumble.

BETA-CAROTENE ON TRIAL

The first hole in the beta-carotene bubble came in April 1994. Stunned NCI researchers reported that in a trial of 30,000 male Finnish smokers, those who were given 20 mg of beta-carotene a day had an 18 percent higher risk of lung cancer and an eight percent higher risk of dying (mostly of lung cancer or heart disease) than those who took a placebo.(1)

Some brushed off the results as a fluke. We didn't. "Shelve the beta-carotene," we wrote in June 1994.

Then, last January, came the news that the NCI was stopping the CARET trial early. "An interim analysis showed that there was a 28 percent increase in the number of lung cancers in the smokers taking 30 mg of beta-carotene and 25,000 IU of vitamin A a day when compared to the smokers taking placebo," said Klausner. The vitamin-takers were also 17 percent more likely to die (mostly of lung cancer or heart disease).

One small consolation: Death rates were only higher in smokers, not ex-smokers. A bigger consolation came from Harvard's Hennekens, who led the longest trial on beta-carotene, one that ended only weeks before the press conference.

The 22, 000 (mostly non-smoking) men in his 12-year Physicians' Health Study had taken 50 mg of beta-carotene every other day to see if it would reduce their risk of any cancer, not just lung cancer.

"Disappointingly, we saw no significant evidence of benefit," said Hennekens. "But reassuringly, there was also no harm of beta-carotene supplementation on cancer or cardiovascular disease."

Why did one study show an increased cancer risk and the other study show none? And, more importantly, why did beta-carotene fail? "The bottom line is, we don't know," says Omenn.

SEARCHING FOR ANSWERS

It's easiest to come up with reason why beta-carotene didn't protect against lung cancer in smokers. "It's possible we launched the intervention too late," says Omenn. "These men and women had an average of 50 pack-years of smoking each." (That's one pack a day for 50 years, two packs a day for 25 years, etc.)

"The ongoing assault by cigarette smoke may be overwhelming any beneficial effect," he adds. It's also possible that in earlier studies, it wasn't the beta-carotene, but something else in fruits and vegetables--or the people who ate them--that lowered the risk.

But why might beta-carotene have raised the risk of cancer and heart disease? So far, researchers can only speculate.

Once a cancer occurs, suggests Omenn, "loading with an antioxidant [like beta-carotene] might protect these abnormal cells from destruction" by the body's immune system.

It's also possible that high doses of beta-carotene could interfere with the body's ability to absorb other things in fruits and vegetables--like other carotenoids--that may reduce the risk of cancer and heart disease.

"We'll be analyzing blood levels to see if there's evidence of interference," said Omenn. So will Hennekens's team.

And then there's the puzzling fact that, unlike the Finnish and CARET trials, Hennekens found no higher risk in beta-carotene-takers.

One explanation is that, for some reason, beta-carotene harms only smokers. Only 11 percent of the men in the Physicians' Health Study smoked, compared to all of the Finns and roughly half of those in the CARET trial.

But, says Hennekens, "if beta-carotene raised the risk of cancer in smokers, I would have expected to see something in the 1,200 smokers who took beta-carotene in our trial."

Another possibility: There may be some (so far unknown) difference between the brand of beta-carotene used by Hennekens and the brand used in the Finnish and CARET trials.

BOTTOM LINE

What do these trials mean for consumers? "Don't start to smoke and if you do smoke, stop," says Hennekens. As for diet, "a beta-carotene supplement neither substitutes for a good diet nor compensates for a bad one," he adds.

There's no evidence that beta-carotene in foods is harmful. On the contrary, says the NCl's Klausner, "the many studies that correlate a healthful diet with a reduced risk stand and remain. But beta-carotene is no magic bullet."

Should people worry about multivitamins or cereals with small amounts of beta-carotene? Klausner refused to say.

But Julie Buring, a colleague of Hennekens who heads the Women's Health Study, was not concerned about RDA-levels--about three milligrams (5,000 IU) a day. "I don't see any evidence that those levels are harmful. That's what people are getting in diets that are beneficial."

To play it safe, though, avoid higher doses. Even if they don't hurt, we can now say that they won't help.

(1) New England Journal of Medicine 320:1029, 1080, 1994.

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