Urology

Edited by: Steve Bunk W.J. Catalona, D.S. Smith, R.L. Wolfert, T.J. Wang, H.G. Rittenhouse, T.L. Ratliff, R.B. Nadler, "Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening," JAMA-Journal of the American Medical Association, 274:1214-20, 1995. (Cited in 89 papers through August 1997) LESS WORK: Measuring free PSA in serum in screening for prostate cancer will necessitate fewer biopsies than will measuring total PSA, says urologist William Catalona. Comments by William J. Catalona, Department of Surgery, Washington University School of Medicine, St. Louis The main problem with the current method of broad-based prostate cancer screenings for older men, say critics in the medical community, is that too many false-positive readings result. This high rate prompts doctors to routinely order biopsies, which often come up negative. Biopsies are costly and uncomfortable, and carry the potential for infection, notes William J. Catalona, a urologist in the department of surgery at Washington University School of Medicine in St. Louis. His team's paper introduces a screening method that minimizes the need for biopsies. The most commonly used screening method is to measure prostate-specific antigen (PSA) concentrations in serum. PSA is the enzyme responsible for liquefying the viscous gel of ejaculate, thus setting free the sperm in a process essential to fertility. High total PSA concentrations in serum are an indicator of prostate cancer, but in order to identify the disease in its curable stages, a relatively low PSA "cutoff" count of 4.0 nanograms per milliliter of serum is generally used. In reality, PSA levels up to 10 ng/ml can still be borderline for prostate cancer diagnosis. "If your PSA is above 10, you ought to be biopsied, because 60 percent of those men will have cancer," explains Catalona. He says the low PSA cutoff in screenings produces numerous false-positive results, which most commonly are caused either by an enlargement of the prostate known as benign prostatic hyperplasia or by prostatitis, an inflammation of the gland. Patients with those noncancerous conditions are the ones usually subjected to biopsies that would have been unnecessary with a higher PSA cutoff. PSA normally binds to protease inhibitors, which break down protein into peptides, but damaged or "nicked" PSA also exists in a free form in serum. For unknown reasons, free PSA concentrations tend to be lower in patients with prostate cancer than in those with hyperplasia. The objective of this study was to determine whether or not measurement of free serum PSA would improve prediction of prostate cancer in cases that are difficult to diagnose, by differentiating patients at true risk from those with hyperplasia. Measuring total serum PSA levels in 10,249 men aged 50 to 90, the researchers eventually narrowed their study group to 113 men whose initial screenings were in the "diagnostic gray zone" of 4.1 ng/ml to 10 ng/ml. This sample was subdivided into three groups: 63 men with benign prostatic hyperplasia, 30 with prostate cancer and an enlarged prostate gland (40 square centimeters or larger, estimated by ultrasonography), and 20 with prostate cancer and a relatively normal-sized gland. Measurements of free PSA in these groups showed that the larger the prostate had become from hyperplasia, the higher the percentage of free PSA. Thus, the researchers were able to set their free PSA cutoff at a relatively high 23.4 percent. They calculated that this would have eliminated 31.3 percent of negative biopsies in their study sample, while maintaining enough sensitivity to detect 90 percent of the prostate cancers. "You can set that sensitivity anywhere you want, at 95 percent or 98 percent," Catalona says. "You can decide how many cancers you are willing to miss, but the more you get, the fewer biopsies you avoid." Catalona surmises that this paper has been frequently cited because it points the way toward fewer biopsies. Since then, his team coordinated multi-institute research throughout the United States for Food and Drug Administration approval and produced similar results. "My guess, when all is said and done, is that the free PSA cutoff used in practice will be 25 percent, with 95 percent of cancers detected," he predicts. The multicenter trials confirmed another finding in the first study, he adds: The lower the free PSA concentration, the more aggressive the cancer tends to be. Therefore, "the very test you use also gives you an indication of the cancer's aggression." Also, the few cancers that are missed are the most indolent ones, and the free PSA levels in these patients can continue to be monitored. A paper on the latest study has been submitted for publication. Catalona is confident of the eventual impact of the free PSA research: "It will save biopsies, and it will aid in predicting cancer."

Urology

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