The most common prostate-specific antigen (PSA) value used as the cutoff for normal is 4.0 ng per mL, which was designed to balance sensitivity and specificity for prostate cancer screening. More recently, some have questioned whether a lower cutoff value for normal would increase the sensitivity of cancer detection without an undue decrease in specificity. Thompson and others report on the incidence of prostate cancer among persons with PSA values below the traditional 4.0 ng per mL cutoff, using data from the placebo arm of a large study of finaste-ride for prostate cancer prevention.

The placebo group of the Prostate Cancer Prevention Trial comprised 9,459 men; complete data were available at the end of the seven-year study for 8,215 patients (87 percent). The final data analysis excluded 4,647 participants because of a PSA value above 4.0 ng per mL, an abnormal digital rectal examination, surgery for prostate gland reduction, an improperly timed PSA measurement, or prostate biopsies during the study. The trial was designed to include prostate biopsies on all study participants at the end of seven years, but 17 percent of the eligible participants declined consent, leaving a pool of 2,950 men available for final data analysis. Blacks and other minorities were somewhat underrepresented, limiting the generalizability of the study results for these groups.

At the end of the study, prostate cancer was found on biopsies in 449 men (15.2 percent) with PSA values below 4.0 ng per mL. There was a correlation between higher PSA values and a diagnosis of cancer, with 6.6 percent of men having prostate cancer at PSA levels below 0.5 ng per mL compared with 26.9 percent having cancer at PSA values between 3.1 and 4.0 ng per mL. The rate of increase in annual PSA values correlated significantly with the risk of prostate cancer, but the PSA density (ratio of PSA level to estimated prostate volume) did not. A family history positive for prostate cancer and black race were associated with an increased risk of cancer diagnosis on the end-of-study prostate biopsies. More high-grade prostate cancers occurred in men with higher PSA levels, but considerable overlap in PSA values occurred among the cancer grades.

The authors conclude that prostate cancer is not rare among men with PSA values below 4.0 ng per mL, but note that the implications of this finding for prostate cancer screening remain unclear. In an accompanying editorial, Carter discusses the possible risks and benefits of lowering the normal cutoff value for PSA. The author cautions that the 15 percent cancer rate reported in this study is not unexpected, based on the known prevalence of prostate cancer in autopsy studies. He also notes that it has been shown that prostate cancers with lower PSA values are less likely to be clinically significant and may not benefit from earlier detection. Finally, there is no evidence that PSA screening saves lives, even at the present cutoff value. The ongoing Prostate, Lung, Colorectal and Ovarian Cancer Trial is designed to fill this gap in outcome data for cancer screening.