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Prostate-specific antigen (psa) exists in the serum in two clinically important molecular forms: free PSA and PSA complexed to alpha-antichymo-trypsin. Total PSA approximates the sum of the free and complexed forms. Preliminary investigations have illustrated the potential benefits of using percent-free PSA to enhance the clinical utility of PSA in distinguishing benign prostate disease from prostate cancer. A recent study from Vashi and colleagues defines the optimal range of total PSA for measuring percent-free PSA (reflex range) and generates appropriate cut-off points for percent-free PSA within this range.
The authors studied a total of 413 patients225 (54%) with a benign prostate disease (mean age, 67 years) and 188 (46%) with prostate cancer (mean age, 66 years)who had PSA values between 2.0 and 20.0 ng/mL. Percent-free PSA was calculated for all patients. Receiver operating characteristics (ROC) curves were generated for various ranges of total PSA to determine the reflex range that maximized the increase in sensitivity and specificity of percent-free PSA over total to be used in clinical practice.
The authors found that the appropriate reflex range for the usefulness of percent-free PSA was 3.0-10.0 ng/mL. The appropriate cut-off point for percent-free PSA (when total PSA value was 3.0-4.0 ng/mL) to achieve 90% sensitivity for the detection of prostate cancer was 0.19. This approach resulted in a biopsy rate of 73% and a cancer detection rate of 44% in men with a total PSA value between 3.0 and 4.0 ng/mL. The appropriate cut-off point for percent-free PSA (when the total PSA value was 4.1-10.0 ng/mL) to ensure 95% sensitivity for detection of prostate cancer was 0.24. Within the range of 4.1-10.0 ng/mL, this approach resulted in 13% fewer negative biopsies and failure to detect 5% of the cancer.
Vashi et al conclude that percent-free PSA should be used in patients with a total serum PSA value between 3.0 and 10.0 ng/mL. In patients with a total PSA value between 3.0 and 4.0 ng/mL, percent-free PSA enhanced the detection of prostate cancer (improving sensitivity). In patients with a total PSA concentration ranging from 4.1 to 10.0 ng/mL, negative biopsies were eliminated, improving specificity.
This study does indicate that one can improve the usefulness of the PSA by adding the free PSA determination. This still does not help with the dilemma that the existing data fail to show significantly longer life spans as a result of treating prostate cancer.
In a previous review on the subject (Intern Med Alert 1994;16:161-162), Bruce Hillner, a decision analysis investigator, concluded as follows: "I will restrict my use of PSAs to those requesting it and only after a conversation about the pros and cons."
The test has been improved; the treatment has not. For more information, see the American College of Physicians’ position paper on prostate cancer detection in the Annals of Internal Medicine (1997;126:465).
Having had a slightly elevated PSA determination and a negative prostate biopsy, I personally am unsure whether I’ll ever have my PSA measured again.
Physicians should be aware, however, that the lay magazines, such as Fortune,1 have published sophisticated reviews of prostate cancer screening and treatment. These reviews have emphasized that men should request both total and free PSA. They have also noted that blacks and older men may have larger prostates and that a PSA of 4 ng/mL is not the cut-off point for benign vs. malignant PSA numbers.
Another point to be aware of is that there is a biological variation in some studies of 13% for the free PSA and 5.6% for the total PSA.2
1. Grove. Fortune 1996;May 13:55-74.
2. Nixon RG. Arch Pathol Lab Med 1997;121:385-391.