Preventing Prostate Cancer So Far, No Clear Answers.

The odds aren't good.

One out of six American men will be diagnosed with prostate cancer over the course his lifetime. Every year, the disease kills 31,500 men.

But prostate cancer isn't a universal death threat. For years, researchers have been trying to figure out why the U.S. mortality rate is ten times higher than it is in countries like China. They're still trying.

Now, for the first time, the evidence is strong enough that the National Cancer Institute (NCI) is set to launch a ten-year trial on 32,000 men to see if two supplements--selenium and vitamin E--can cut the incidence of prostate cancer.

"If this study shows a reduction in cancer rates anywhere near what we've seen in earlier trails, it would put a dent in the 200,000 new cases of prostate cancer we see annually," says NCI researcher Demetrius Albanes. But some experts worry that the trial is testing the wrong kind of selenium and vitamin E. "We have to keep our fingers crossed and hope for positive results," says Tim Byers, a professor of preventive medicine at the University of Colorado in Denver. "We could use some.

The death count alone--31,500 lives lost every year--doesn't begin to measure the anxiety, misery, and pain caused by prostate cancer. Yet after years of research, experts don't have many answers for men who want to dodge the disease through diet.

"When you put all the data together, it looks like diet is definitely important," says Edward Giovannucci of the Harvard School of Public Health. "But we can't make any firm recommendations yet."

That's little comfort to men who've seen friends or family members die of the disease or who have a high risk themselves. "So far, we have nothing definite to help men who have a PSA of 8 and have to get a biopsy every six months," says Peter Gann of the Northwestern University Medical School in Chicago. (Doctors use blood levels of PSA, or prostate specific antigen, to screen men for early prostate cancer.)

Nor do researchers have anything definite to help men who face impotence, incontinence, or other side effects from the treatment of prostate cancer. And then there are the men who have succumbed to the disease. Larry Clark was the University of Arizona researcher whose 1996 study found such a remarkable drop in prostate cancer rates that it led the National Cancer Institute (NCI) to mount its new selenium trial. In March 2000, Clark died--of prostate cancer--at the age of 51.

Here's what scientists know so far about diet and the cancer that strikes more American men than any other.

SELENIUM

In the 1980s, when Larry Clark and colleagues assigned 1,300 people to take either 200 micrograms of selenium or a placebo every day, no one suspected that selenium might prevent prostate cancer. Their goal was to see whether it could prevent skin cancer in residents of the Southeast, where the soil and people's diets--are selenium-poor.(1)

"Selenium supplements had no effect on the recurrence of skin cancer," Clark told Nutrition Action Healthletter in 1996. "But the three leading cancers--lung, prostate and colon--all decreased."

Decreased by an unheard-of two-thirds, that is. The researchers had to stop the study three years early because the selenium-takers fared so much better that it would have been unethical to keep people on the placebo.

Still, Clark was cautious about his findings. "Selenium is not going to help everybody, and it's not going to cure all cancer," he explained.

It's possible that selenium only works in people who get too little from their food ... or that Clark's results were a fluke.

But worth another trial? You bet.

The National Cancer Institute (NCI) doesn't expect results from its new trial, called SELECT, for about a decade (see "SELECT One Option," p. 5). Meanwhile, some researchers are worried that SELECT may not be using the right kind of selenium supplement.

Clark's trial used a high-selenium yeast. (SelenoExcell is the brand that is closest to the supplement Clark used--see "The Bottom Line," p. 5.) SELECT will use selenomethionine, which is the most abundant form of selenium found in the yeast. An expert panel recommended selenomethionine instead of yeast because selenium and other constituents of the yeast vary too much from batch to batch, explains the NCI's Demetrius Albanes.

Let's hope it was the right choice.

"I'm concerned that there might be some bioactive compounds in the yeast that aren't in the selenomethionine supplements," says Colorado's Tim Byers, who served on a safety committee for the 1996 study. "If the new study fails, we won't know why."

VITAMIN E

Like selenium, vitamin E's link with the prostate showed up in a clinical trial designed to test something else.

The Alpha-Tocopherol Beta-Carotene (ATBC) study tested a daily dose of 50 International Units (IU) of vitamin E (that's the alpha-tocopherol) on 29,000 male Finnish smokers.(2) It had no impact ... on lung cancer, that is.

"In the men who took alpha-tocopherol, we saw a one-third reduction in the incidence of, and a 41 percent reduction in the death rate from, prostate cancer over a period of rive to eight years," explains Albanes, one of the ATBC study investigators.

"That's impressive," he adds. "And it wasn't confounded by any other factors because the men were randomly assigned to a supplement or placebo as they walked in the door."

Other studies suggest that vitamin E might protect the prostate, but the ATBC, says Albanes, "is the linchpin for testing it in the upcoming SELECT trial." The NCI has stopped short of advising men to take alpha-tocopherol supplements until the results are confirmed, he adds.

And that's just as well, because last December a report added a new wrinkle to the vitamin E story.

Researchers at The Johns Hopkins School of Hygiene and Public Health found that men with high blood levels of gamma-tocopherol (another form of vitamin E) had only a quarter the risk of prostate cancer over the next eight years compared to men with lower levels.(3) Alpha-tocopherol was also linked to a lower risk, but only in men who also had high blood levels of gammatocopherol.

"The role of gamma-tocopherol is new and it comes from out of the blue," says Giovannucci. And it could simply be a fluke. Two larger studies found no link between gamma-tocopherol and prostate cancer.(4)

But the Johns Hopkins study needs to be followed up, he adds, "because it raises the issue that vitamin E supplements, which are mainly alpha-tocopherol, may not do as much good as some people think, and may even do harm."

The possible harm: "High doses of alpha-tocopherol may suppress the absorption of gamma-tocopherol," explains Giovannucci.

In three studies, alpha-tocopherol was linked to a lower risk of prostate cancer, but only in smokers.(4)

"There was a suggestion of a slightly elevated risk for non-smokers who took at least 100 IU a day, but we have no explanation for it." says June Chan of the University of California at San Francisco.

That means the possible increased risk could b,e due to chance, but it's too early to say. Says Giovannucci: "For non-smokers, there's very little evidence of benefit and some evidence that alpha-tocopherol is deleterious."

LYCOPENE 

Spaghetti sauce and pizza were big news in 1995. That's when Giovannucci's team found that men who consumed tomato sauce two to four times a week had a 34 percent lower risk of prostate cancer than men who ate no tomato sauce.(5)

The possible protector: lycopene, a carotenoid found in tomatoes that's easier to absorb if they're cooked.(6)

"Lycopene scavenges free radicals and suppresses damage due to oxidation in the tissues," explains Northwestern University's Peter Gann. "As an antioxidant, it's more potent than beta-carotene. And it's concentrated in the prostate."

In 1999, Gann, Giovannucci, and their colleagues found a lower risk of prostate cancer in men who had higher blood lycopene levels 13 years earlier.(7)

"Not every study shows a benefit, but the ones that were best able to detect an association found it," says Giovannucci.

Also encouraging: Researchers often wonder if people who take vitamins or eat more fish are more health-conscious, which could confound their results. But there's less reason to think that pizza and spaghetti eaters are more health-conscious. Still, Giovannucci's research is no excuse to load up on lasagna, pizza, or other saturated-fat-laden foods.

"It's not proven, but eating spaghetti sauce twice a week could certainly be part of a healthy diet," says Giovannucci. "Eating ten pizzas a week isn't."

SOY

"There's a strong biological basis for thinking that soy might lower the risk of prostate cancer," says Mark Messina, a soy expert who is an adjunct professor at Loma Linda University in California and a consultant to the soy industry.

Among the promising clues: In Asia, where tofu and other soy foods are a regular part of the diet, prostate cancer rates are low. And the isoflavones in soy foods inhibit the growth of prostate cancer cells in animals and test tubes.

But when it comes to people, the evidence is thin. "You could put all those animal and test-tube studies in a basket and one good human clinical study would outweigh them," says Messina.

Large U.S. studies can't even look at soy because most men don't eat enough of it. That leaves one study in Hawaiians (it found only a weak link) and another in Seventh-day Adventists.(8,9) That study found a lower risk only in men who drank more than one glass of soy milk a day. However, only two percent of the men drank soy milk that often, so the results aren't rock-solid.

Also disappointing: When researchers gave men with elevated PSA levels two daily soy beverages (each with roughly 35 milligrams of isoflavones), their PSAs didn't drop.(10)

"Our study only lasted six weeks," notes investigator Stephen Barnes of the University of Alabama at Birmingham. "So it's difficult to know what might have happened over the long term."

Messina remains optimistic. "There's a consistent story forming," he says. "But it's a story waiting to be confirmed."

SEAFOOD

In Giovannucci's latest study, the men who consumed more fish--especially fatty fish--had a lower risk of prostate cancer. "We saw a benefit for men who eat fish three or four times a week," he explains.

One study is just the beginning. But with recent research finding that seafood may protect the heart, blood vessels, and eyes, why not serve up some fish for dinner? It doesn't have to be fancy.

Says Giovannucci: "Salmon and tuna--two of the most popular fish--are good sources of omega-3 fats and seem to be protective."

THE PRUDENT DIET

It's too early to know whether selenium, vitamin E, lycopene, soy, or seafood can prevent prostate cancer. Nor is there any guarantee that cutting back on red meat or high-fat dairy foods will lower the risk. But men who follow advice for an overall healthy diet can't lose.

"We're not up to the point of giving recommendations on diet and prostate cancer," says the University of California's June Chan. "But it's prudent to eat less meat and animal fat and more vegetables, fruits, and whole grains. There's good reason to believe that a prudent diet is beneficial for heart disease, and it may help for cancer."

THE BOTTOM LINE

While it's too early to say for sure, these steps may reduce the risk of prostate cancer:

* Limit red meat, full-fat cheese, and other fatty animal foods.

* Eat seafood--especially fatty fish like salmon--three or four times a week.

* Eat healthy tomato-rich dishes (spaghetti or other pastas, not lasagna or pizza) at least twice a week.

* Consider taking a daily supplement with 200 micrograms (mcg) of selenomethionine or high-selenium yeast. (If you're looking for SelenoExcell high-selenium yeast, check the ingredient list. It's found in some selenium and multivitamin-and-mineral supplements.)

* Get some gamma-tocopherol in your diet. Soy oil (often used in salad dressings), corn oil, and sesame oil are good sources. (Some vitamin E supplements contain both alpha- and gamma-tocopherol, but many labels don't say how much gamma you're getting.)

* Limit calcium intake from food and pills to 1,200 mg a day and take a standard multivitamin with 400 IU of vitamin D.

SELECT ONE OPTION

This summer, the National Cancer Institute is launching a new 7- to 12-year trial called SELECT (SELenium and Vitamin E Cancer Prevention Trial) to test whether selenium (200 micrograms a day) and/or vitamin E (400 IU of alpha-tocopherol a day) can lower the risk of prostate cancer in healthy men. To volunteer, you must have a PSA no higher than 4 and must be at least 55 years old (at least 50 if you're African American). For more information, call the NCI's Cancer Information Service (1-800-4CANCER).

(1.) J. Amer. Med. Assoc. 276:1957, 1996.

(2) J. Nat. Cancer Inst. 90: 440, 1998.

(3) J. Nat. Cancer Inst. 92:2018, 2000.

(4) J. Nat. Cancer Inst. 92:1966, 2000.

(5) J. Nat. Cancer Inst. 87:1767, 1995.

(6) J. Nat. Cancer Inst. 91: 317, 1999.

(7) Cancer Research 59:1225, 1999.

(8) Cancer Research 49:1857, 1989.

(9) Cancer Causes and Control 9: 553, 1998.

(10) Journal of Urology 165: 294, 2001.

RELATED ARTICLE: POSSIBLE PROMOTERS

"There's a general consensus that saturated fat or red meat is associated with a higher risk of prostate cancer," says June Chan of the University of California at San Francisco. But so far, studies haven't been able to tease out what it is in meats or dairy foods that may cause prostate cells to go haywire. Saturated or animal fat is a leading possibility. Among the others:

* Red meat. In 1993, Harvard researchers reported that men who ate red meat (beef, pork, lamb, or veal) most frequently had more than double the risk of advanced prostate cancer compared to men who ate those meats least often.(1) This year, they updated their findings on the study, which tracks more than 50,000 men.

"Our study still suggests that the less red meat you eat, the better," says Harvard's Edward Giovannucci.

Why red meat? Cooking the meat at high temperatures produces heterocyclic amines, which may promote cancer. "It could also be the animal fat or the high calorie-density of diets rich in red meat," says Giovannucci. "We're not sure which."

If animal fat were a culprit, as some studies suggest, high-fat dairy foods like whole milk and cheese would also put the prostate at risk. But it's also possible that the calcium in dairy foods poses a threat.

* Calcium. It cuts the risk of osteoporosis and possibly colon cancer. And low-fat milk and other dairy foods can help prevent high blood pressure (though not necessarily because of their calcium).

So how could too much calcium promote prostate cancer? The theory: The active form of vitamin D--which we get mostly from sunlight--may protect the prostate.(2) And calcium lowers levels of active vitamin D in the blood.

Don't panic. Not all studies see a link between calcium and prostate cancer. And most men never reach the "too-much-calcium" range.

"Calcium may really be only a concern for men who get more than 2,000 milligrams a day," says Chan. So it's still safe to shoot for the latest Recommended Dietary Allowances (RDAs)--1,000 mg a day for men 50 or younger and 1,200 mg for men over 50. (That includes what you get from food and supplements.)

The evidence isn't strong enough to recommend that men change their calcium intake, she adds. "But they should be aware of the association between calcium and prostate cancer, because they may be getting calcium from fortified foods and not even know it."

Would it help to simply boost your vitamin D intake?

"Whether vitamin D is related to prostate cancer is still an open question," says Giovannucci. "But it's prudent to get adequate vitamin D from a multivitamin or sunlight." Fatty fish and fortified foods are also sources.

(1) Journal of the National Cancer Institute 385:1571, 1993.

(2) Cancer Research 58: 442, 1998.

RELATED ARTICLE: PC-SPES: SLOWING DOWN DISEASE?

Millions of men who have prostate cancer want to know whether diet or supplements can slow or stop the disease. But so far, research has yielded few answers.

For example, in a Canadian study of 384 men with prostate cancer, those who consumed the most saturated fat were three times more likely to die of the disease over the next rive years than those who consumed the least.(1) But it isn't clear from this less-than-perfect study that saturated fat made the difference.

Researchers are more confident that a mixture of seven herbs called PC-SPES may slow advanced cancer in men who have no other treatments available. But the pricey supplement may be no more safe or effective than taking an ordinary estrogen pill.

"Many of the herbs that my prostate cancer patients take do nothing," says William Oh, a researcher and oncologist at Harvard Medical School and the Dana Farber Cancer Institute in Boston. "PC-SPES has effects that are visible to all doctors who work with it, but whether it is any more effective than giving estrogen, we don't know."

Oh tracked 23 advanced cancer patients who had been taking six capsules (1,920 milligrams) of PC-SPES a day.(2) "Half had more than a 50 percent drop in PSA levels and many had a decrease in symptoms and relief from bone pain," he reports. "If we can reduce PSA levels significantly, we can predict that they'll live longer and better."

But his study and two others like it aren't definitive, in part because they didn't compare PC-SPES to anything else. A new clinical trial will. Oh and colleagues will study men whose cancer is progressing even though they're taking drugs that block testosterone. Half will get PC-SPES; the others will get an estrogen called DES, or diethylstilbestrol.

"We know PC-SPES has hormonal effects like estrogen," says Oh. "We're trying to understand to what extent PC-SPES's effect is due to its estrogen activity."

That's why taking PC-SPES is not a good strategy for men who want to prevent prostate cancer. Like estrogen, PC-SPES can cut testosterone to castration levels. "It's like getting your testicles removed," explains Oh. "Eunuchs don't get prostate cancer, but it's not a price most men are willing to pay."

What's more, PC-SPES isn't as safe as its over-the-counter availability implies. "It has all the side effects of taking estrogen, like nipple tenderness, breast swelling, hot flashes, and fatigue," cautions Oh. "And the most dangerous side effect is blood clots, which occur in an estimated rive to ten percent of patients.

"Clots can stay in the legs or they can break off and go to the lung, which is more serious," he explains. "In men who have underlying heart disease, the clot can get lodged in a coronary artery," causing a heart attack.

Those risks may be worth taking for men who have failed the usual anti-testosterone treatment. In fact, Oh now recommends it to all men in that condition. "Their life expectancy is about 12 months," he says. But a risky supplement that can cost more than $300 a month is not a good gamble for anyone else.

Says Oh: "Right now we have no evidence that PC-SPES prolongs life, but it can reduce the symptoms of cancer and control the disease for some period of time in men who have limited options."

(1) European Urology 35: 388, 1999.

(2) Urology 57:122, 2001.

For links to the most useful Web sites with information on prostate cancer, see www.cspinet.org/nah/07_01/prostatelinks.html