Avodart may promote some tumor growth

Avodart, a drug now used to shrink enlarged prostates, can suppress slow-growing prostate cancers - but it may also promote the growth of the most threatening tumors, according to a major study sponsored by the drug's maker, GlaxoSmithKline.

The same vexing dilemma emerged seven years ago in a government-funded study of a similar compound, called finasteride, made by Merck & Co. Inc. Marketed as Propecia to fight baldness and Proscar for enlarged prostates, finasteride has not caught on for prostate-cancer prevention, and the idea remains controversial.

Both finasteride and Avodart reduce production of a potent form of testosterone, the male hormone that stimulates the prostate gland. Both drugs also dramatically reduce the gland's secretion of PSA (protein specific antigen), a substance measured in the blood to screen men for prostate cancer.

The new study, published in Thursday's New England Journal of Medicine, is sure to renew debate over the prudence of curbing cancer by interfering with hormonal activity in the prostate. While the researchers wrote that Avodart, known chemically as dutasteride, "may be considered as a treatment option" for men at increased risk for the cancer, Johns Hopkins University urologist Patrick C. Walsh firmly reached the opposite conclusion.

"Dutasteride and finasteride do not prevent prostate cancer, but merely temporarily shrink tumors that have a low potential for being lethal," he wrote in an editorial in the journal. "Furthermore, the use of these drugs for prevention may be somewhat risky."

Countered Thomas Jefferson University urologist Leonard Gomella, a designer of the Avodart study: "With all due respect to Dr. Walsh, whom we all revere, we now have two drugs that show similar reductions in prostate cancer. We have no evidence that these drugs cause high-grade cancers."

Neither is there conclusive evidence that they don't. And the raw numbers don't settle the matter.

After four years, there were 659 prostate cancers among the 3,305 men on Avodart, compared with 858 cancers among the 3,424 men on a placebo. Thus, Avodart cut cancer risk 23 percent - about the same as in the finasteride study.

But a more complex picture emerges from data on the aggressiveness of the cancers - indicated by a "Gleason score" - and when the tumors were detected by biopsy.

Compared with the placebo group, the Avodart group had far fewer nonaggressive cancers, roughly the same number of somewhat-aggressive cancers, but a significantly greater number of extremely aggressive "high-grade" cancers - the kind that are hard to cure.

Over four years, Avodart takers were diagnosed with 29 high-grade cancers, compared with 19 for men on a placebo. The disparity surfaced in the third and fourth years, when men on Avodart had 12 high-grade tumors, while the placebo group had only one.

Another nuance involved the biopsies, in which bits of tissue were removed for microscopic exams. While all the men were automatically scheduled for biopsies in the second and fourth years, only those who developed a sign of cancer, such as a high PSA level, were biopsied in-between.

Among the 810 men biopsied because of a worrisome sign, there was no difference in cancer incidence - 17 percent in each group.

The researchers speculate that the extra biopsies and screening artificially changed the number of high-grade tumors detected late in the study. The logic is that some of the low-grade cancers in the placebo group might have progressed to high-grade cancers if the men had not been diagnosed and treated in the first two years.

But the researchers concede "an alternative explanation" is that the high-grade-cancer disparity was "due in part to dutasteride therapy."

No one questions the value of dutasteride and finasteride in treating prostate enlargement, a benign condition that can cause urinary problems that make men miserable.

But when the goal is warding off a cancer that kills 27,000 U.S. men a year, the value of therapy is debatable. For example, while Walsh sees no victory in reducing cancers that are probably inconsequential, the Avodart researchers argue that those are the very cancers for which most men are being unnecessarily treated.

"We are overdiagnosing and overtreating prostate cancer," said study leader Gerald Andriole, chief of urology at the Washington University School of Medicine. "This is exactly where dutasteride would come in. We reduce the chance of being diagnosed with tumors that are not apt to be of concern. . . . They wouldn't need to undergo aggressive treatment with terrible side effects like impotence and incontinence."

Because Avodart reduces prostate size, it should theoretically make detection of high-grade cancers easier - which might explain why the Avodart group had more of them.

These drugs "are helpful to us in finding the more aggressive cancers. And they make any change in PSA an important change," said Jefferson's Gomella.

But skeptics point out that the PSA test - already controversial because it has led to more cancer diagnoses without a definite reduction in cancer deaths - becomes even trickier with the drugs.

To estimate what the "true" PSA level would be without the PSA-suppressing drug, doctors have to double the measured blood level. Even then, Walsh said, the PSA level may be so low that it gives men taking Avodart "a false sense of security."

"So this guy goes along his way, and nine years down the line, he has incurable cancer," Walsh said. "I've seen a number of patients on Propecia. They walk in with a low PSA, and yet they have high-grade cancer."

Although Avodart in the study had few serious side effects, there was an "unexpected imbalance" in cardiac failure between the two groups. Heart failure developed in 30 Avodart users compared with 16 on placebo.

GlaxoSmithKline this week applied for U.S. Food and Drug Administration approval to market Avodart for prostate-cancer prevention in men at increased risk - like the men in the study - and also for those without clear risk factors, said Roger Rittmaster, executive director of the firm's oncology unit.

The prospect of such advertising worries prostate-cancer survivor Stewart Justman, because studies - and his own experience - show that doctors oversell and oversimplify the PSA test.

Justman, a University of Montana liberal-studies professor, wrote Do No Harm: How a Magic Bullet for Prostate Cancer Became a Medical Quandary, about the finasteride controversy.

Before his cancer diagnosis seven years ago, "all I heard about the PSA test is 'early detection saves lives,' and I didn't know any better. There was no informed consent," Justman said. "So are doctors going to recommend dutasteride for cancer prevention the way doctors recommend the PSA?"

Walsh fears the answer is yes. "Doctors may prescribe this drug to men with slightly elevated PSA levels, as if it's like a cholesterol-lowering drug, without recognizing how closely these men need to be followed."

Gomella's view: "People want the cure-all. But all the things we do in medicine are a double-edged sword. You have to balance the good and the bad."