Prostate cancer screening that is focused only on total prostate-specific antigen (PSA) levels leads to many false-positive results, with unnecessary biopsies and emotional distress. The current total PSA cutoff level also produces many false-negative results. Lowering the cutoff level would detect more early cancers but increase the rate of false-positive results. Other methods, including age-specific cutoffs, analysis of PSA change over time, and the ratio of PSA-to-prostate volume on ultrasonography, have been tried without any clear benefit. The use of serum-free PSA has been proposed, based on the higher protein-bound PSA levels in men with prostate cancer and the higher free PSA in men with benign prostatic hyperplasia. Preliminary studies indicate that measuring the percent of free PSA in men with mildly elevated PSA can decrease unwarranted biopsies without missing a substantial number of cancers. The optimal way to incorporate free PSA testing into prostate cancer screening protocols has not yet been determined. Gann and associates used a case-control analysis of PSA and free PSA results from blood collected between 1982 and 1983, before any case of prostate cancer was detected to compare efficacy.

The Physicians' Health Study analyzed 430 patients with prostate cancer and 1,642 control patients to identify a strategy to decrease the number of unnecessary biopsies while minimizing undetected cancers. Most study subjects were older than 50 years of age when the blood samples were taken. Any percent free PSA cutpoint between 17 and 22 percent used in men with total PSA levels between 3 and 10 ng per mL decreased the biopsy rate and increased the number of true cancers detected. Cancers missed by a formula of combined total and free PSA probably take longer to develop than detected cancers. However, multiple population factors that might affect estimates of free PSA testing benefits include patient age, race, and finasteride use.

The authors conclude that combined free and total PSA testing can maximize cancer detection while minimizing unneeded biopsies. The specific guidelines have yet to be determined, but men with total PSA levels of 4 to 10 ng per mL would have a 0.75 probability of not having cancer without knowing the free PSA and a probability of 0.92 if the free PSA is found to be 27 percent or greater. Men with this same level of total PSA have a cancer probability of 0.25, while adding the criterion of a percent free PSA level of 17 percent or less increases the cancer probability to 0.45. The optimal strategy may be to combine these results with serial blood testing and digital rectal examination.