Free, complexed, and total PSA

Free PSA (fPSA) is a major indicator for the diagnosis and management of prostate cancer. However, within the range of 4-10 ng/mL, in which 75% of men do not have cancer, the fPSA level lacks specificity. At this range, 4 men must undergo biopsy to identify 1 man with cancer. Stenman et al reported that men with prostate cancer had more complexed prostate-specific antigen (cPSA) than fPSA, unlike men with benign prostatic hyperplasia (BPH).[26] After the development of an immunoassay, the investigators demonstrated that the ratio of fPSA to total PSA (tPSA), or f/tPSA, was lower in men with prostate cancer. In the PSA range of 4-10 ng/mL, tPSA segregates adequately between men with or without cancer. The f/tPSA is a more discriminatory indicator. A 7-institution study that investigated 63 men with BPH, 30 men with prostate cancer (prostate size > 40 cm3), and 20 men with small prostates found PSA levels in all the men to be 4-10 ng/mL. The median f/tPSA was 0.188 in BPH patients, 0.159 in prostate cancer patients, and 0.092 in patients with small prostates. These findings imply that prostate size is an important variable in selecting a cutoff value for fPSA. For men whose prostates are smaller than 40 cm3, an f/tPSA of 0.137 or lower is used to detect 90% of the cancers, and 76% of the negative biopsy findings can be eliminated. For men with prostates larger than 40 cm3, a cutoff of 0.205 allows detection of 90% of the cancers, and 38% of the negative biopsy findings can be eliminated. If the patient has a normal-sized prostate on digital rectal examination (DRE), a value of 0.234 is necessary to detect 90% of the cancers, sparing 31.3% of the patients an unnecessary biopsy. Brawer et al, comparing the specificity of tPSA and f/tPSA at various sensitivities, found that at a sensitivity of 80% and a tPSA cutoff of 4.11, the specificity was 35.6%, compared with 46.2% for f/tPSA at a cutoff point of 19%.[27] At a sensitivity of 90% with a tPSA cutoff of 3.4, the specificity was 25.3%, compared with 26.2% for f/tPSA at a cutoff point of 24%. In a large population of men with PSA levels of 4-10 ng/mL and a cutoff point of 25% or less, 95% of the cancers would be detected, and 20% of the patients would be spared a biopsy. Probability of prostate cancer (CaP) in relation to free-tototal prostate-specific antigen (PSA) ratio. Image courtesy of Wikipedia. The fPSA is most useful in men with persistently elevated PSA levels who previously underwent a biopsy with negative findings. As the percentage of fPSA declines, the probability that a cancer is present increases. Conversely, a higher percentage of fPSA indicates a lower probability of cancer. Even with this added information, the decision to perform a biopsy on any given patient ultimately depends on the physicians judgment.

The value of fPSA in the staging of prostate cancer has not been conclusively demonstrated, though several studies indicate that a correlation may exist. In the Baltimore Longitudinal Study of Aging, the f/tPSA significantly segregated those who developed cancer from those who did not up to 15 years before the diagnosis. Twelve men with stage T3 or T4 disease who had Gleason scores of 7 or higher or positive margins after radical prostatectomy had lower f/tPSA values than 8 with less aggressive cancers. tPSA was elevated only 5 years before diagnosis.