Methods to Improve the Performance of Serum PSA Measurement for the Early Detection of Prostate Cancer
As noted above, various approaches aimed at improving the performance of PSA in early cancer detection have been tested. None are clearly more accurate than total serum PSA levels, but these approaches are discussed below.
Complexed PSA and percent-free PSA
Serum PSA exists in both free form and complexed to a number of protease inhibitors, especially alpha-1-antichymotrypsin. Assays for total PSA measure both free and complexed forms. Assays for free PSA are available. Complexed PSA can be found by subtracting free PSA from the total PSA. Several studies have addressed whether complexed PSA or percent-free PSA (ratio of free to total) are more sensitive and specific than total PSA. One retrospective study evaluated total PSA, free/total, and complexed PSA in a group of 300 men, 75 of whom had prostate cancer. Large values of total, small values of free/total, and large values of complexed PSA were associated with the presence of cancer; the authors chose the cutoff of each measure to yield 95% sensitivity and found estimated specificities of 21.8%, 15.6%, and 26.7%. The preponderance of evidence concerning the utility of complexed and percent-free PSA is not clear, however, total PSA remains the standard.
A number of authors have considered whether complexed PSA or percent-free PSA in conjunction with total PSA can improve the latter's sensitivity. Of special interest is the gray zone of total PSA, the range from 2.5 ng/mL to 4.0 ng/mL. A meta-analysis of 18 studies addressed the added diagnostic benefit of percent-free PSA. There was no uniformity of cutoff among these studies. For cutoffs ranging from 8% to 25% (free/total), sensitivity/specificity ranged from about 45%/95% to 95%/15%.
Percent-free PSA may be related to biologic activity of the tumor. One study compared the percent-free PSA with the pathologic features of prostate cancer among 108 men with clinically localized disease who ultimately underwent radical prostatectomy. Lower percent-free PSA values were associated with higher risk of extracapsular disease and greater capsular volume. Similar findings were reported in another large series.
The third-generation (ultrasensitive) PSA test is an enzyme immunometric assay intended strictly (or solely) as an aid in the management of prostate cancer patients. The clinical usefulness of this assay as a diagnostic or screening test is unproven.[54,55]
Because larger prostates caused by increased amounts of transition-zone hyperplasia are known to be associated with higher serum PSA levels, reports have suggested indexing PSA to gland volume, using a measure known as PSA density. PSA density is defined as serum PSA divided by gland volume. Generally, ultrasound is used to measure gland volume. While early studies suggested that this measure may discriminate between patients with cancer and those with benign disease, subsequent evaluations have failed to confirm any clinically useful association.[57,58]