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Men whose results are normal on a popular screening test for prostate cancer may have cancer nevertheless, a new study finds. The result, medical experts say, raises questions about what a normal test score should be and whether the cancers in these men, discovered with biopsies, are better off left alone or treated.
The study also amplifies a continuing controversy over the test, known as the P.S.A., and whether finding prostate cancer early and treating it by removing or destroying the prostate is helping or harming men.
The P.S.A., for prostate specific antigen, is a blood test that looks for proteins released by prostate cells. When it finds more than 4 nanograms of the protein in a milliliter of blood, doctors usually recommend biopsies, in which needles are inserted into the prostate to withdraw cells for analysis. When a biopsy finds cancer, most men opt for treatment, usually surgery or radiation to destroy their prostate glands.
But the new study, published today in The New England Journal of Medicine, reports that as many as 15 percent of men with P.S.A. levels less than 4 were found to have cancer when their prostates were assessed with biopsies. The study involved 2,940 men aged 62 to 91 who had no signs or symptoms of cancer.
While higher P.S.A. levels confer greater risk, there appears to be no level, not even zero, at which there is no risk of prostate cancer, according to the lead investigator, Dr. Ian M. Thompson, the chief of urology at the University of Texas Health Science Center in San Antonio.
"Now we don't have a clear definition of normal and abnormal," said Dr. Howard Parnes, who directs prostate cancer research in the National Cancer Institute's division of cancer prevention. "Before these data were out, we were comfortable with the notion that 4 is a cutoff between normal and abnormal. Now these data very clearly tell us that 4 is not a cutoff."
The study was not designed to show what cutoff should be used for P.S.A. levels. And there are no easy answers about whether a man with a low P.S.A. level should have a biopsy, said the deputy chief medical officer for the American Cancer Society, Dr. Len Lichtenfeld. It may depend on how old the man is, or his family history, or how frightened he is of prostate cancer. "These are decisions that are going to have to be discussed between people and their health care providers," Dr. Lichtenfeld said.
Dr. Parnes said he worried that men with low P.S.A. levels and their doctors will see the study results and automatically decide that the safest thing to do is to have a biopsy. Since about 90 percent of men have P.S.A. levels that are below 4, that would mean huge numbers of men will have biopsies; huge numbers will be told they have cancer; and huge numbers may opt for treatment that may not have been necessary.
Prostate cancer is exceedingly common. Autopsy studies, in which prostates are examined section by section, find microscopic cancerous cells in most elderly men but the disease tends to smolder silently, never spreading or causing problems in a man's lifetime. Still, it can be deadly.
Prostate cancer kills 30,000 men a year. Currently, there is no way to know for sure if a cancer will spread and kill, so most men opt for treatment, even though it often leads to impotence or incontinence.
To gauge risk, pathologists grade the cancerous cells, assessing how disordered and abnormal they look. Among the men with P.S.A. levels less than 4 whose biopsies showed cancer, 14.9 percent had high grade cancers, in which the cells look aggressive and threatening under the microscope. But even that result is difficult to interpret, Dr. Parnes said, because the association with grade and outcome was based on studies of much larger tumors, in men with much higher P.S.A. levels.
"Most people would assume that the high-grade tumors are going to be significant if you live long enough," Dr. Parnes said. "But because we are diagnosing the cancers so early, we don't know how long they would take to manifest and not everyone is going to live long enough to develop clinically relevant cancer. The lower the P.S.A. threshold, the deeper into the unknown you're going."
Some doctors, like Dr. H. Ballentine Carter, a professor of urology and oncology at Johns Hopkins University, urge caution about conducting biopsies on men with P.S.A. levels below 4.
"We will find a lot of cancer and we will not know what to do about it," Dr. Carter said. "That is very worrisome."
"The reason for caution," he explained, "is because right now we don't have the ability to know who in this low P.S.A. range has a cancer that is likely to be harmful. There is nothing wrong with doing a P.S.A. but we don't need to act on it immediately. We have an out here. We can follow men over time and biopsy those whose P.S.A. goes up."
Dr. Thompson said men need to be counseled about their options. He typically spends two hours with a patient, he said.
"People say, `What's the problem with treating it?' Dr. Thompson said. "But every treatment has side effects. Even watchful waiting comes with a cost."
For now, said Dr. Lichtenfeld, the question will be whether the old P.S.A. cut-off point of 4 should be moved down.
"There's obviously intense discussion," he said. "We may move it down, but we have to weigh the risks and benefits. We will find more prostate cancer and we will find more cancers that didn't need to be found. We will cause some men harm that they didn't need to have."
Some, like Dr. H. Gilbert Welch, a professor of medicine at the Department of Veterans Affairs in White River Junction, Vt., and at Dartmouth College, said the new study should make men reconsider whether they want a P.S.A. test at all.
"The study begins to highlight that we really don't know what we're looking at," Dr. Welch said. "There's a disconnect between the word cancer as most of the public understands it as a very aggressive disease that leads to death if not treated, and the way the pathologist understands it as a few cells that may not be relevant."
It is becoming increasingly clear, Dr. Welch says, that the more pathologists look for cancer, the more they find it, but that does not mean the cancer is worth finding.
"At some point this has got to be crazy," Dr. Welch said. "Everyone can't have prostate cancer."
"Is our goal to get rid of all prostate cancer or is it to maximize the public health?" Dr. Welch said. "This really says we need to figure out better ways to find out who really does have the cancer we care about."
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