June 24, 2003 9:46 p.m. EDT
Cancer Prevention, at a Price
Drug Reduces Risk of Prostate Cancer,
But May Cause Worse Tumors in Some
By MARILYN CHASE
Medical researchers have found a drug that sharply reduces the risk of prostate cancer. But their findings present a painful dilemma for men because taking it may cause worse tumors in an unlucky few.
Finasteride, made by Merck & Co. and currently marketed as a treatment for both benign prostate enlargement and baldness, was found to cut the rate of prostate cancer by 25% in a group of men who began taking it with healthy prostates. But in those who did get the disease, it slightly raised the risk of developing a more lethal tumor.
The study paradox -- prevention with a price -- is sure to be hotly debated by men and their doctors in coming days. The drug "may not be right for all men," said Leslie Ford of the National Cancer Institute in a news briefing after the study was released Tuesday. "But we now know it's possible to prevent" prostate cancer.
Others were more pessimistic, contending that the small rise of potentially more virulent tumors kills any hope of developing finasteride as a preventive drug. "That's a worrisome finding," said Peter Scardino, chairman of urology at the Memorial Sloan-Kettering Cancer Center in New York. He wrote an editorial in the New England Journal of Medicine, which is publishing the study results, arguing against recommending the drug for cancer prevention.
"To find a successful preventive agent, you've got to make sure the agent does very little harm," Dr. Scardino said in an interview.
The National Cancer Institute said men should now discuss the potential risks and benefits of the drug, taking into account their individual risks, family history, and ability to tolerate sexual side effects.
Prostate cancer will be diagnosed in about 220,900 American men this year, and 28,900 men are expected to die of it, the American Cancer Society predicts. The risk runs highest in African-American men.
The quest for drugs to prevent cancer, an increasingly hot pursuit, is a long and difficult one. But the results of this study are among the most encouraging to date because they suggest prostate-cancer prevention is possible. Among the few substances that have proved promising are tamoxifen for breast cancer and retinoid compounds for oral cancer. Numerous studies are under way, testing an array of compounds including anti-inflammatory drugs to prevent colon cancer, asthma drugs to prevent lung cancer, and green tea extracts to prevent skin cancer. It may take years, however, to find definitive answers.
The pace of the research is also slowed by the fact that pharmaceutical companies have invested relatively few resources in prevention trials, especially if the product isn't patentable -- as with vitamins -- or doesn't have a huge market potential.
History is full of compounds that failed. The vitamin A precursor beta carotene, tested to prevent lung tumors in Finnish smokers, actually ended up causing more cancer. But the study had a silver lining. Vitamin E appeared to lower prostate risk, an accidental finding that led to a new trial, as yet unfinished, testing vitamin E and selenium as preventatives.
Sponsored by the National Cancer Institute, the $73 million Prostate Cancer Prevention Trial, as the test of finasteride was known, recruited 18,882 men age 55 and older with normal prostate exams to take five milligrams of finasteride or a placebo pill daily for seven years. The study was halted early, after 9,060 patients completed the course, in March.
The results: Prostate cancer developed in 803 men in the finasteride group, and 1,147 men in the control group -- for a reduction in the cancer rate of 24.8%. But tumors with aggressive characteristics occurred in 6.4% of the finasteride group compared with 5.1% of the controls -- an increase of 1.3 percentage points.
Aggressive cancers are generally more likely to spread outside the prostate gland, more likely to require intensive treatment, and more likely to kill. However, it isn't certain the tumors in the finasteride group will behave this way. During the study, the same number of men in each group died: five in each.
A 'Mixed Message'
The overall cancer reduction "blew me away," said Charles A. Coltman Jr., the senior author of the study. Dr. Coltman is chairman of the Southwest Oncology Group and a professor of medicine at the University of Texas Health Science Center in San Antonio. Still, he said, "This was a mixed message."
Finasteride is already marketed as Proscar to treat benign prostate enlargement, and as Propecia to prevent baldness -- products that reap annual sales of $550 million and $215 million, respectively. Merck Vice President for Clinical Development Elizabeth Stoner hailed the study as "a landmark," though the rise in high-grade tumors "clearly requires further study," she said.
The drug also caused some unpleasant side effects. Loss of libido and impotence were more common in men on finasteride. Difficulty urinating was more common in the placebo group.
Further research will determine why drug-treated men got more high-grade tumors and how they survive, and search for genes, proteins and markers of prognosis. Why the finasteride group got more worrisome tumors isn't clear yet. "It could be finasteride induces higher-grade tumors to grow, though we doubt that," said co-author M. Scott Lucia of the University of Colorado at Denver. Another possibility is that the drug simply makes a tumor look aggressive without behaving that way. A third possibility is that the gland-shrinking action of finasteride allowed biopsy needles to detect more high-grade tumor cells.
The risks notwithstanding, "it's exciting to have a study show that prostate cancer prevention is possible," said Peter Greenwald, director of prevention at the National Cancer Institute in Bethesda, Md. Dr. Greenwald, himself, was a study volunteer. "I thought it was important to lead by example," he said. He believes he got finasteride, but did not develop cancer. Others were less fortunate.
By the luck of the draw, volunteer Paul Faidley, a 67-year-old retired aviation safety inspector from De Soto, Texas, got finasteride. Treated at the University of Texas Southwestern Medical Center in Dallas, he developed a high-grade malignancy and underwent surgery to remove his prostate. He says has no regrets. "Absolutely not," he said. "They've done me a favor. I got that sucker out."
Otis Brawley, professor of oncology at Emory University in Atlanta and an adviser to Merck, suggested that finasteride may be more effective in prevention when given to younger men much earlier in the precancerous phase. "If a man is very worried about prostate cancer, then finasteride therapy with appropriate monitoring appears an appropriate option."
For one prominent cancer survivor, the drug's benefits aren't worth the risks. "Nobody understands how the [hormone] receptor works even though hormone therapy has been around for 50 years," said Andrew S. Grove, founder of Intel Corp. who was diagnosed in 1995. For prevention, he quipped, "I think I will stick with tomatoes and fish, even though neither one grows hair."
Numerous studies have been launched in recent years to determine whether various substances are effective in preventing cancer.
Sources: National Cancer Institute (NCI) Web site www.cancer.gov1; Peter Greenwald, director of Division of Cancer Prevention, NCI
Write to Marilyn Chase at email@example.com
Updated June 24, 2003 9:46 p.m.
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