Use and Assessment of PSA in Prostate Cancer

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History of PSA

PSA was first described as a marker for prostate cancer in 1987. Higher tumor volumes were shown to correlate with higher PSA levels.3 PSA as a screening test for CaP was first reported in 1991 and quickly became popular, with a cutoff value of 4.0 ng/mL used to distinguish between a negative or positive screening test.4 Since then annual testing has become prevalent and many clinicians now use 2.5 ng/mL as the cut point. As a consequence the number of new cases has increased dramatically.5, 6

Is PSA a good screening test?

Any good screening test should satisfy a few criteria: it should be sensitive, inexpensive, safe, and detect a disease for which early treatment improves survival. It is the final criterion that has been debated extensively since PSA screening became available. At the center of the debate are 2 issues: the natural history of screen detected prostate cancer and the efficacy of treatment.

Natural history of prostate cancer

The clinical aggressiveness of prostate cancer is highly variable. Although some men with high-grade disease (Gleason grade 8, 9, or 10) can progress from localized disease to metastasis to death in a short time period, others with low-grade cancer (Gleason grade 6 and lower) may never have any clinical sequelae, even without treatment. Autopsy studies have found high rates of clinically insignificant CaP in up to 75% of male octogenarians.11 Unfortunately, PSA cannot distinguish between low-

Does prostate cancer treatment improve survival?

Although overall and cancer-specific survival is generally good after treatment, there have been few randomized trials that compared different treatment modalities for prostate cancer. In 2008, Bill-Axelson and colleagues18 published results of a Scandinavian study of 695 men with clinically localized prostate cancer randomized to radical prostatectomy or watchful waiting between 1989 and 1999. Only 12% had been identified by PSA screening. At 12 years, prostate cancer mortality was 12.5% in

Does PSA screening improve survival?

In the spring of 2009, the New England Journal of Medicine published interim results of two highly anticipated randomized trials on PSA screening: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial sponsored by the National Cancer Institute and the European Randomized Study of Screening for Prostate Cancer (ERSPC).20, 21

The PLCO trial recruited 76,693 men at 10 study centers in the United States between 1993 and 2001. Men were randomized to annual PSA determinations for

PSA manipulations

Several manipulations and additional tests have been developed in an attempt to make PSA a more sensitive and specific test for prostate cancer. These tests include PSA density, free PSA, age-adjusted PSA, and PSA velocity.

PSA density is calculated by dividing serum PSA by prostate volume. Because benign enlargement of the prostate can elevate PSA, calculating PSA density can adjust for this, increase specificity, and potentially reduce the number of prostate biopsies.22 However, calculation of

Race and family history

Prostate cancer is most prevalent in northern Europe, North America, and Australia, and less common in Asia and Africa. African American men have the highest incidence of prostate cancer: 1.6 times higher than Caucasian men in the United States.31 African Americans also suffer worse outcomes: 1.8 years shorter survival after prostatectomy, 0.7 years shorter after radiation, and 1.0 year shorter with observation.32 The risk of death from CaP is 2.4 times greater for African Americans than

Limitations of PSA

Although PSA can be used as a cancer marker and a cancer screening test, its main limitation is that it is not specific for prostate cancer. BPH and large prostate size are known to correlate with higher PSA levels. PSA has been shown to be a marker for prostate growth, acute urinary retention, and progressive urinary symptoms related to BPH.34 Treatment of BPH with 5-alpha reductase inhibitors (finasteride and dutasteride) reduces the size of the prostate and lowers serum PSA by 50%.

Other prostate cancer markers

Given the limitations of PSA, screening tests using other markers for CaP are in development. The DiaPat urine test (DiaPat GmbH, Hannover, Germany) analyzes urinary polypeptides and is commercially available. A study of 18 subjects having prostate biopsy revealed that the test could correctly predict the biopsy result only 50% of the time.38

PCA 3 is an untranslated mRNA overexpressed in 90% to 95% of prostate cancers. It can be detected in urine specimens obtained after prostatic massage. PCA

Current recommendations

Screening for prostate cancer with serum PSA remains controversial. The ERSPC and PLCO trials have thus far shown only a modest or no survival benefit to screening, and its utility as a public health policy is uncertain. The AUA recently revised their recommendations on the use of PSA in a best-practice statement.26 Because PSA is the only test easily available to detect CaP, selective screening (especially for those at higher risk) is still encouraged. Because PSA is a continuous variable and

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