Harvard Men's Health Watch

Vitamin E and prostate cancer: Where do we stand?

It seems like ancient history, but only about a decade has elapsed since the peak of the antioxidant vitamin boom. The enthusiasm was certainly understandable. It began with the observation that people who eat lots of fruits, vegetables, and whole grains — all rich in antioxidants — enjoy substantial protection from cancer and heart disease. Next, laboratory and animal experiments showed that antioxidants could protect DNA from damage by oxygen-free radicals, potentially reducing genetic errors that cause cancer. The animal research also showed that antioxidants could protect arteries by preventing the oxidative damage to LDL cholesterol that puts the "bad" into bad cholesterol.

Unfortunately, it didn't take long for the boom to go bust. A series of large randomized clinical trials found that antioxidant supplements do not reduce the risk of cardiovascular disease — and they may even interfere with some cholesterol-lowering medications. Similarly, supplements do not reduce overall deaths from cancer, and one antioxidant, beta carotene, actually increases the risk of lung cancer in male smokers.

After reviewing all the information, the U.S. Preventive Services Task Force recommended against routine vitamin use to prevent cancer and cardiovascular disease. It's a sound recommendation, but a study published just a few weeks later reminds us that the issue is not fully resolved, at least as far as vitamin E and prostate cancer is concerned.

The vitamin pendulum

Until the 1980s, most academic physicians scorned vitamin pills, asserting that their only effect was to produce expensive, vitamin-laden urine. But the purists began to change their tune, and many began to recommend (and take) vitamin supplements.

Now, antioxidants have lost their appeal, and few experts still recommend them. But what about a simple multivitamin? The authoritative U.S. Preventive Services Task Force has advised against the routine use of supplements to prevent cardiovascular disease and cancer. But a daily multivitamin has other things to recommend it.

Vitamin D is needed to absorb dietary calcium. People who avoid sunlight to reduce their risk of skin cancer are at risk of a vitamin D deficiency. That's because it's hard to come by in the diet. The only significant sources are certain fish and fortified dairy products – but it takes at least a quart of milk a day to get the recommended amount of vitamin D.

Vitamin B12 is present in many animal foods. Since it's not present in vegetable foods, however, strict vegetarians should take supplements. And since many older adults don't have enough stomach acid to liberate vitamin B12 from food, they can benefit from the readily absorbed crystalline B12 in supplements.

As things stand, a daily multivitamin still makes sense. Look for an inexpensive preparation that contains 100% of the daily value for vitamin D, vitamin B12, and two other important B vitamins, B6 (pyridoxine) and folic acid. Extra amounts of B12 and folic acid are harmless and may help certain individuals, but extra amounts of other vitamins may do more harm than good. That's particularly true of vitamin A, since studies show that doses above 3,000 units a day that were previously considered safe can increase the risk of hip fractures.

Don't waste your money on high potency, all-natural, or designer vitamins. Vitamin-mineral combinations are also unnecessary. Above all, remember that your daily multivitamin is just an insurance policy — a supplement, not a substitute, for a healthful diet.

The ATBC study: Beta carotene

The Alpha-Tocopherol, Beta Carotene Cancer Prevention trial (ATBC) was one of the first investigations to cast doubt on the value of antioxidants. ATBC was designed to test the belief that antioxidants would protect men from lung cancer. The subjects were 29,133 Finnish male smokers between the ages of 50 and 69. Starting in 1985, the men were randomly assigned to receive one of four regimens: (1) 50 mg of alpha-tocopherol, the most common form of vitamin E, (2) 20 mg of beta carotene, another potent antioxidant, (3) both antioxidant vitamins, or (4) a placebo. The trial concluded in 1993. When the results were announced a year later, they sounded an alarm: Beta carotene produced an 18% increase in the risk of lung cancer and a less significant increase in the risk of prostate cancer.

Other studies of beta carotene

In 1996, a study called CARET confirmed the adverse effect of beta carotene on lung cancer in smokers, but it did not find any effect on the risk of prostate cancer. That same year, Harvard's Physicians' Health Study reported that beta carotene provided no protection against heart disease, but the supplement did not increase the risk of lung cancer, probably because all the subjects were physicians and only 11% were smokers. As in the CARET study, though, beta carotene did not increase the risk of prostate cancer. In fact, it appeared to reduce the risk in men with very low dietary consumption of carotenoids.

It didn't take long for beta carotene supplements to move from the good column to the bad, at least for men who smoke. Indeed, that's where it belongs. But vitamin E has also changed columns. When it comes to heart disease, that shift is justified, but a possible benefit against prostate cancer has not been ruled out.

The ATBC follow-up studies on vitamin E

When ATBC ended in 1993, all the men were advised to stop taking their supplements. But the scientists continued to monitor them. Their second report provides information on an additional six to eight years of data. Beta carotene's adverse effect on lung cancer diminished rapidly; within four years of stopping the supplement, men who had used beta carotene were no worse off than men who had never taken it.

In its first report, ATBC found that five to eight years of daily alpha-tocopherol reduced the risk of prostate cancer by 32%. Using new information, the follow-up study revised the figure slightly, to a 34% reduction. The apparent benefit of alpha-tocopherol diminished rapidly when supplementation was discontinued, but after six years, a 12% trend toward possible benefit was still evident. The scientists speculate that alpha-tocopheral may act on a late stage in the long, slow process that leads to prostate cancer, and that the possible benefit wanes rapidly once the supplement is discontinued.

The ATBC study issued a third report in 2005. This time the scientists did not report a clinical follow-up on the entire group but analyzed blood tocopherol levels and the risk of prostate cancer in a subset of the men. Men with the highest blood levels of alpha-tocopherol enjoyed a 51% lower risk of prostate cancer than men with the lowest levels.

Vitamin E and health

Vitamin E supplements have failed to protect against cardiovascular disease, but they may (or may not) have a role in reducing the risk of prostate cancer. How else might vitamin E affect your health?

A 2-year study of 600 people aged 60 and older linked vitamin E in the moderate dose of 200 IU a day to an increased incidence and a greater severity of upper respiratory infections. Even worse, a 2005 meta-analysis of 19 clinical trials reported that high doses of vitamin E (400 IU a day or more) were linked to an increased mortality rate. The apparent risk was small, but it provides a cautionary note about supplements in general and vitamin E in particular. And in 2005 several studies cautioned that vitamin E and other antioxidants might reduce the effectiveness of cancer radiation therapy. But on the positive side, vitamin E is a component (along with vitamin C, beta carotene, and zinc) of the ocular vitamins that can slow the progression of macular degeneration.

It is clear that more research is needed to learn which supplements work, which don't, and which do more harm than good.

Other vitamin E studies

The ATBC research provides some support for vitamin E (alpha-tocopherol), but it's not conclusive. Although it was a well-conducted randomized clinical trial, its primary goal was to evaluate lung cancer, not prostate cancer. To epidemiologists, this takes a bit of the luster off the prostate cancer findings. More important, all the subjects were smokers. When the Harvard Health Professionals Follow-Up Study looked into the matter, it found that although vitamin E supplements were linked to a reduced risk of prostate cancer in smokers, they had no effect in nonsmokers. In 2004, a study of 72,704 men reported that vitamin E supplements did not appear protective in smokers or nonsmokers. And a 2005 randomized clinical trial found that 400 units of vitamin E a day did not reduce the risk of any form of cancer but did increase the risk of congestive heart failure.

The relationship between vitamin E and prostate cancer has yet another complexity. Vitamin E is not a single compound but a family of chemicals known as tocopherols. The most common member of the family is alpha-tocopherol; it's the form that was used in the ATBC trial and that's found in most supplements. But other tocopherols may have an impact on prostate cancer. The latest player is gamma-tocopherol, a form of vitamin E that is found in foods such as soybean and corn oil but not in ordinary supplements. A study of 10,456 residents of Maryland found that men with the highest blood levels of gamma-tocopherol were only 20%–25% as likely to develop prostate cancer as men with the lowest levels. In contrast, high levels of alpha-tocopherol were not protective. These results contrast with the ATBC study that linked high blood levels of alpha-tocopherol to a 51% lower risk of prostate cancer but reported only a 43% lower risk for men with high blood levels of gamma-tocopherol.

Other antioxidants

Antioxidants provide natural defenses against free radicals. There are many free radicals, and there are also many different antioxidants in various foods and in the human body itself. Three groups of antioxidant vitamins get the most attention; they include vitamin A and related carotenoids (such as the beta carotene used in most studies), vitamin E and the tocopherols (such as the alpha-tocopherol used in most studies), and vitamin C. But a mineral, selenium, also has antioxidant activity, and it may have a role in reducing the risk of prostate cancer.

Two studies are noteworthy. In the first, a team of scientists based in Arizona administered either 200 micrograms of selenium or a placebo each day to 1,312 volunteers with an average age of 63. After four and a half years, the men who took the selenium enjoyed a 63% lower risk of dying from prostate cancer than those who took the placebo. More recently, Harvard researchers studied 33,737 male health professionals, comparing their risks of prostate cancer with their selenium consumption when measured by the selenium content of their toenail clippings. The men with the highest selenium levels (a daily intake of about 159 mcg) were only a third as likely to develop advanced prostate cancer as those with the lowest levels (a daily consumption of 86 mcg).

The last word

Should you take antioxidants to reduce your risk of prostate cancer? It's an open question. Despite the ATBC re-sults, there is not enough evidence at present to warrant widespread use of alpha-tocopherol or other forms of vitamin E. The same is true of selenium, but the data are hopeful as of late 2005, and a daily supplement of 200 mcg of the mineral is a reasonable choice for men concerned about prostate cancer.

More research is needed, and several major clinical trials are already under way. The Physicians' Health Study is expected to report its findings on vitamin E in 2008. In addition, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) has recruited 32,400 North American men to assess the ability of these supplements to prevent prostate cancer. SELECT should be the last word — but it may take 12 years or more to yield results.

In the meantime, what should we do about antioxidants? With the possible exception of selenium, supplements don't seem wise — but getting lots of antioxidants from foods seems very wise indeed. Examples include the lycopene in tomatoes, the gamma-tocopherol in soybeans, and the selenium in whole grains. Even in the 21st century, the fundamental things apply: A good diet is the best way to get the nutrients we need to stay well.