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Value of Prostate-Specific Antigen: Are Higher Levels Meaningful?

F. B. Dunn

In 1987, Stanford University’s Thomas Stamey, M.D., published a seminal study in the New England Journal of Medicine that concluded that, as prostate tumors worsened, prostate-specific antigen levels rose in sync. Based on this and supporting reports, PSA testing gained fame, exploding to several million tests per year by the mid-1990s.



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Dr. Thomas Stamey

 
But, like a rueful parent reflecting on childhood transgressions, Stamey wishes he knew then what he knows now. In January of this year, he published what again may turn out to be an influential report. This paper, carried in the Journal of Urology, concludes that PSA is "clinically useless" in staging prostate cancer or predicting surgical cures.

"I removed a couple of hundred prostates I wish I hadn’t," he said in an interview.

In particular, he now asserts that, when diagnosing prostate cancer, PSA levels between 2 ng/ml and 9 ng/ml provide no reliable information. (A level lower than 4 ng/ml is generally considered normal, although it varies by age.) "I can’t honestly tell a man with a PSA of 2 to 3 that he has a better chance than someone else with [PSA level] 8 to 9," said Stamey.

The article has triggered intense responses from both sides of a deep clinical rift.

"I don’t want to use the word dangerous, but my concern about this article is the bottom line message of not worrying about PSA until it is in the 7 to 9 range," said William Catalona, M.D., a noted prostate surgeon at Washington University, St. Louis, who biopsies patients with PSA levels as low as 2.5 ng/ml.

On the other hand, epidemiologists maintain that PSA screening has not been proven to decrease death rates, the most important measure of medical benefit. Instead, they say, widespread PSA screening leads to overdiagnosis and overtreatment of many slow-growing, harmless tumors.

Mounting data back up the claim. In the United States, prostate cancer incidence skyrocketed in the early 1990s as PSA screening permeated clinics and hospitals. During the same time in Britain—where PSA tests are relatively uncommon—prostate cancer rates also rose, but not as dramatically. Throughout the early and mid-1990s, the death rate in both countries remained virtually identical, suggesting that in the United States, harmless tumors were being diagnosed.

A second line of evidence from autopsy studies yields consistent results. Up to one-third of men who die from other causes have large prostate cancers visable at autopsy.

"The [Journal of Urology] article suggests that we end up diagnosing a lot of cancers because PSA is secreted not by the cancer but by benign tissue," said Otis Brawley, M.D., assistant director for cancer control at Emory University, Atlanta, and former researcher at the National Cancer Institute.

These divergent views fall on either side of a PSA fault line. Surgeons, who deal with prostate cancer patients as individuals, tend to prefer routine testing. Population researchers, who survey the oncological landscape, remain unconvinced about the balance of benefits versus harms of routine testing.

To reach their conclusions, the Stanford team examined all of the prostates removed at Stanford between 1984 and 1997. After limiting the sample to cancers confined to the prostate, discovered by a digital rectal exam or PSA testing followed by biopsy, they detailed the pathology of some 875 tumors; each was preserved in 3 millimeter sections at the time of surgery. The team then correlated preoperative PSA values with tumor volume and other variables that can predict potential for a surgical cure, including Gleason score and width of surgical margins.

A trend immediately caught the researchers’ attention. As PSA levels ranged from 2 to 9 the morphological measures varied, with little connection to PSA level. These wide variations in tumor aggressiveness per each PSA level emphasizes "the serious limitations of PSA as a predictor of prostate cancer," wrote the team in the report’s abstract. The team illustrates the message with clouds of data points, arranged with no apparent pattern.

Catalona, though, is troubled by the study’s relatively short follow-up. He said a longer study would have uncovered a different trend. If the data were "really mature," with a minimum of 7 to 9 years of follow up, he said, "fewer [patients] in the 2 to 4 range would have had recurrence." Stamey agreed that a longer study would have been better, but declined to speculate on what such a study would reveal.

Still, an estimated 32,000 men will die from prostate cancer in 2002. Many will die despite surgery or other treatments. "Those [against routine testing] say, ‘We aren’t 100% sure that surgery saves lives, but we’re 100% sure that it causes incontinence and impotence,’" said Catalona, who has had vigorous discussions on the topic with Stamey, both in the literature and at conferences. "Stamey talks about the advantages of waiting [for treatment] until PSA is high, that it may allow a man to enjoy his prostate for a few more years," said Catalona. "But what does that matter if he dies from an aggressive tumor?"

With that rhetorical question hanging, Catalona said that he recommends biopsies for men with PSAs above 2.5, marking him as perhaps the most aggressive advocate of early treatment.

If patients wait longer, until PSA is in the 7 to 9 range, about 30% of men will have cancer, Catalona said, citing a 1997 study he published in the Journal of the American Medical Association. "I operate on these men every day and wish I had gotten to them earlier." Of every 10 prostatectomy patients he sees, Catalona said he finds 2 or 3 with diffuse cancers. "A lot of these men had a history of PSAs between 2 and 8 and it [cancer] wasn’t picked up until PSA was quite high."

Of all cancers, the variations seen in prostate tumors are perhaps the widest. All sides agree that a wealth of other evidence from the lab and the clinic, now bolstered by the Stanford study, illustrate a vital point: Whereas a certain PSA score signals danger for one man, it may not for another. Without a clear-cut way to distinguish the two, clinicians are left to sort out a confounding array of recommendations.

The American Cancer Society, for instance, recommends regular PSA testing for men 50 and older. Other groups, including the American Medical Association and the U.S. Preventive Services Task Force, state that widespread screening is unwarranted.

In other words, positions along the PSA testing spectrum depend as much on personal philosophy as it does on the state of the ever-changing science. Until better screening tests for prostate cancer appear, that situation is unlikely to change.



             
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