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    Lower PSA threshold may improve test's clinical value

    Seattle-A new study suggests that a lower PSA threshold for considering a prostate biopsy may improve the clinical value of the widely used test. In addition, lowering the threshold for biopsy may be particularly important for men under the age of 60 years, according to researchers from Brigham and Women's Hospital in Boston and Washington University School of Medicine in St. Louis.

    "We were interested in finding out how well this test performs," said lead author Rinaa S. Punglia, MD, MPH, a radiation oncologist at Brigham and Women's Hospital. "When adjusting the numbers to account for bias, we discovered that physicians who use a PSA of >4.0 ng/mL to recommend biopsy, the current standard, may be missing 82% of cancers in men under 60 years of age and 65% in men over 60."

    Dr. Punglia and colleagues also demonstrated that lowering the threshold to 2.6 ng/mL in younger men may double the cancer-detection rate without significantly altering the number of false-positive results. Their study is published in the New England Journal of Medicine (2003; 349:335-42).

    Selection bias in earlier data

    The study is based on computer models, and it is drawn from data on 6,691 men who underwent PSA screening at Washington University from 1995 to 2001. Of these men, 705 (11%) subsequently underwent biopsy.

    Assuming the chance of undergoing biopsy depends on PSA results and other clinical variables, the researchers employed a mathematical model to estimate adjusted receiver-operating-characteristic (ROC) curves. They found that adjusting for verification bias significantly increased the area under the ROC curve of the PSA test compared with unadjusted analysis (0.86 vs.0.69 for men aged <60 years and 0.72 vs. 0.62 for men >60 years).

    "The estimated geometric mean of PSA levels derived from the adjusted ROC curves for men with prostate cancer ranged from 2.1 to 3.9 ng/mL, depending on age and the results of the digital rectal examination," Dr. Punglia and colleagues wrote. "These values are significantly lower than the levels of 6.3 and 7.5 ng/mL reported in a previous study."

    After comparing the unadjusted numbers with the adjusted ones, the team found that selection bias in earlier data had led some researchers to incorrectly assume that PSA screening had near-perfect discriminatory power.

    "The medical community has probably overestimated the sensitivity of this test, and it may be reasonable to lower our threshold from 4.0 to 2.6 ng/mL," Dr. Punglia said. "Although we won't know if PSA testing decreases mortality until the results of randomized clinical trials come in, based on this study, men who undergo screening, along with their physicians, may want to think differently about a PSA of 3.0 ng/mL."

    Press sending wrong message

    Co-author William J. Catalona, MD, formerly of Washington University and currently professor of urology at Northwestern University, Chicago, said he was very disappointed with the way this study was presented in the lay press. He said some urologists are now being inundated with questions about whether the PSA test has any value at all.

    "One of the things that disappointed me about the reaction to this in the press is that the PSA doesn't work," Dr. Catalona told Urology Times. "The message of this paper is that the PSA test is not being used as effectively as it could be. Some of the headlines [in the lay media] suggest that the PSA test is no good because it misses so many cancers, and that was not the message from the study."

    Dr. Catalona said the PSA test "would be really efficient" if 2.5 ng/mL were used as a cutoff. However, an editorial published in the New England Journal of Medicine along with his team's study argued against a lower cutoff (2003; 349:393-5)

    "My feeling is that, eventually, most urologists will accept the lower cutoff for younger patients," Dr. Catalona said. "The most important take-home message to urologists is if the PSA is higher than 2.5 ng/mL, that patient should seriously consider having a biopsy, regardless of age.

    "And if the patient decides after giving it serious consideration to not have it, then he should have the PSA monitored every 12 weeks. Quarterly is what I recommend to see if it is rising."

    Alan W. Partin, MD, PhD, professor of urology at Johns Hopkins Medical Center, Baltimore, said it is clear from the Prostate Cancer Prevention Trial that a large number of men with prostate cancer have a PSA <4.0 ng/mL, but the question still remains whether it is in the patient's best interest to detect and subsequently treat those cancers. Dr. Partin agreed with Dr. Catalona that many men are now questioning whether the PSA test is a valid instrument.

    "I have heard that from a lot of patients," Dr. Partin said. "I don't think the study itself was addressing the utility of the test for screening, but for the cutoff that we presently use. We should not lose faith in this test. PSA still is the best test we have for the early detection of prostate cancer."



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