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For more than a decade, PSA (prostate specific antigen) has been approved by the US FDA both as an aid to the early detection of prostate cancer and as a means of monitoring for disease recurrence after treatment.

However, PSA elevations can also occur with various benign conditions such as enlarged prostate and infection of the prostate.

Because the initial PSA testing is not necessarily specific to prostate cancer, its use for clinical application, especially biopsy recommendations, has been a topic of debate. But this debate often disregards the new, helpful information from PSA studies that go much beyond total PSA values.

In recent years, variations on the initial PSA measurement have proven extremely useful in prostate cancer detection.

Patients should request results of these variations and understand their functions in the diagnostic process:

1. Proportion of different PSA isoforms (freePSA, complexed PSA, and proPSA)

2. Prostate volume (PSA density)

3. Rate of change in PSA levels over time (PSA velocity and PSA doubling time)

Total PSA

The first clinical application of the PSA test was to monitor for recurrence after treatment. And it is still useful by itself for this purpose.

For men who undergo a radical prostatectomy, the PSA level should be essentially undetectable after surgery. A subsequent increase in PSA is usually the earliest sign of cancer progression.

PSA can also be used to monitor for prostate cancer progression after other forms of treatment; however, because a variable amount of prostate tissue is still present after radiotherapy and endocrine (hormone) therapy, the use of total PSA in these situations is more complicated.

Variations in PSA Value

Now, in addition to the total PSA level, several variations on the PSA measurement are clinically useful. PSA circulates in the bloodstream in both free and complexed forms, each of which can be measured separately.

Evidence suggests that in the presence of malignancy, a greater proportion of PSA is complexed and a lower proportion circulates in the free form.

Free PSA:

Experiments (Stenman and Lilja 1991) showed that PSA exists in several different forms including a free form that does not attach itself to proteins.

Later studies (Catalona) reported that measurements of the percentage free PSA in total PSA scores could improve the accuracy of PSA testing.

In men with a total PSA level between 4.0 and 10 ng/ml, if the percentage of free PSA was greater than 25%, only 8% of patients were found to have cancer on biopsy; whereas, if the percentage of free PSA was less than 10%, 56% of men were found to have cancer.

Furthermore, among men with prostate cancer, 75% of those with a percentage of freePSA greater than 15% had favorable pathology features after a radical prostatectomy, compared to only 34% of men with a lower percentage of free PSA.

Based on these studies, the FDA approved the free PSA test for prostate cancer detection in 1998.

Patients should know their free PSA percentage as well as their total PSA score.

The free to total PSA ratio, or percent free PSA should be more commonly used in daily clinical practice than C(PSA), complexed PSA.


Some forms of free PSA have been evaluated to increase the accuracy of PSA for prostate cancer detection.

Two of these “i” (inactive) PSA and BPSA are increased with enlarged prostate. Pro PSA is present in increased proportions in men with prostate cancer.

Dr. Catalona showed that using the percentage of Pro PSA as a ratio with free PSA could improve the accuracy of prostate cancer detection and decrease the number of unnecessary biopsies in men with total PSA levels between 2 and 4 ng/ml. Other studies have supported this finding.

Now, Dr. Catalona is in the process of providing studies for FDA approval of the Pro PSA test for prostate cancer detection.

Additional research is underway to examine the relationship between these PSA isoforms with prostate cancer aggressiveness and treatment outcomes.

As a result, these additional isoforms will not only be useful for CaP detection but also provide information that should be helpful in treatment and follow-up decisions.

PSA Density

The underlying concept of PSA density (PSAD) is that a given rise in PSA is more likely to be caused by prostate cancer in a patient with a small prostate gland than in one with a large gland.

A study (Veneziano) suggested that the PSA level divided by the prostate volume, as estimated by transrectal ultrasongraphy, would provide a useful way of knowing to what extent the PSA level was merely a reflection of prostate size.

Another study (Benson) showed PSAD could be useful for prostate cancer detection. In their study, prostate volume was determined from the prostatectomy specimen. The mean PSAD was 0.581 in men with prostate cancer compared to 0.044 in men with enlarged prostate.

In a further study (Catalona) showed that significantly more patients with a preoperative PSAD of less than 0.15 had a more favorable postoperative pathology report than those with a higher PSAD.

While PSAD is clearly useful information, its major limitation is that it requires a measurement of prostate volume done traditionally by transrectal ultrasongraphy, which is more time-consuming and more expensive than a simple blood test.

PSA Velocity

PSA velocity is the measurement of the change in PSA values over a period of time.

Recent evidence suggests that a 0.75 ng/ml/year PSAV cutoff for recommending biopsy is useful for men with a total PSA over 4.0 ng/ml.

In men with a lower total PSA, PSAV cutoffs of 0.3 – 0.5 ng/ml/year should be used to recommend a biopsy.

The National Comprehensive Prostate Cancer Network recommends using a PSAV cutoff of 0.5 ng/ml/year for recommending a prostate biopsy.

PSA Velocity has two limitations in its usefulness: One is the fluctuation in PSA levels within an individual and, sometimes, that fluctuation can be even less consistent if different standards or different labs are used in the testing sequence.

The other is that prostatitis causes sudden dramatic increases in PSA in the absence of prostate cancer. Because of this possibility, a repeat PSA test following a trial of antibiotics is a reasonable option to help determine the need for biopsy.

PSA Doubling Time

PSA doubling time is the amount of time it takes a PSA value to double. In pretreatment situations, men would need a baseline PSA for doubling time to be of use and, presently, most men don’t have that age 40 year, baseline PSA record.

So, PSA doubling time is used most frequently in post-treatment settings. For patients with recurrence after radical prostatectomy, it can be difficult to determine if the recurrence is local or metastatic. The PSADT can help in making that determination and therefore helping to decide between treatment by local salvage radiotherapy or hormonal therapy.

Doubling time can also be used to predict the aggressiveness of the recurrent cancer.


Intelligent use of PSA testing combined with expert treatment of appropriately selected patients will continue to reduce the prostate cancer death rates with statistically acceptable side effects.

*Stacy Loeb is a urology resident at Johns Hopkins who also works in Dr. Catalona’s research group with the support of the Urological Research Foundation.
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