What is the significance of elevated total Prostate-Specific Antigen (PSA) and normal free Prostate-Specific Antigen (PSA)?

From the Guidelines

A high total PSA with normal free PSA levels may indicate an increased risk of prostate cancer, but the decision to proceed with further evaluation should be based on a shared decision-making approach, considering the patient's age, risk factors, and potential harms of screening, as recommended by the American College of Physicians 1.

Key Considerations

• The percentage of free PSA relative to total PSA is often more informative than either value alone, with a low free PSA percentage (below 25%) suggesting a higher risk of prostate cancer.
• Other factors that can elevate PSA include recent ejaculation, urinary tract infections, prostate inflammation, or even vigorous exercise, and should be considered in the interpretation of results 1.
• The American College of Physicians recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer, and base the decision to screen on the risk for prostate cancer, a discussion of the benefits and harms of screening, the patient's general health and life expectancy, and patient preferences 1.

Recommendations

• If you have a high total PSA with normal free PSA levels, you should schedule an appointment with a urologist to discuss your individual risk factors and determine the best course of action.
• The urologist may recommend additional tests such as a digital rectal exam, prostate MRI, or possibly a prostate biopsy, depending on your age, family history, and other risk factors.
• It is essential to consider the potential harms of screening, including false-positive results, overdiagnosis, and overtreatment, and to weigh these against the potential benefits of early detection and treatment 1.

Important Factors to Consider

• Laboratory variability can range from 20-25% depending on the type of standardization used, and it is necessary to use the same assay for longitudinal monitoring 1.
• The interpretation of PSA results should always be done in the context of your complete clinical picture, rather than as isolated numbers.
• Clinicians should help men judge the balance of benefits and harms and discuss whether the harms outweigh the potential reduction in prostate cancer mortality in their particular cases 1.

From the FDA Drug Label

1. 1 Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection In clinical studies, finasteride tablets reduced serum PSA concentration by approximately 50% within six months of treatment. The ratio of free to total PSA (percent free PSA) remains constant even under the influence of finasteride tablets.

The patient's high total PSA and normal free PSA may indicate the presence of prostate cancer, and should be evaluated further, even if PSA levels are still within the normal range for men not taking a 5α-reductase inhibitor 2.

• A new PSA baseline should be established at least six months after starting treatment with finasteride tablets.
• Any confirmed increase from the lowest PSA value while on finasteride tablets may signal the presence of prostate cancer.
• The ratio of free to total PSA remains constant, so no adjustment to its value appears necessary.

From the Research

High Total PSA and Normal Free PSA

• A high total PSA level with a normal free PSA level can be an indicator of prostate cancer, but it is not a definitive diagnosis 3.
• The ratio of free-to-total PSA can be useful in distinguishing between prostate cancer and benign prostatic hyperplasia (BPH) 3, 4.
• Studies have shown that digital rectal examination (DRE) and prostate biopsy can affect PSA levels, including free and total PSA 5, 6.
• The free-to-total PSA ratio can be altered by prostatic manipulation, such as DRE and biopsy, which can lead to misleading results 5, 6.
• Multivariate algorithms that incorporate total PSA, free PSA, DRE, and prostate volume can reduce false-positive PSA results in prostate cancer screening 7.

Reference Ranges for PSA

• The normal distribution of PSA values and reference ranges for free, complexed, and total PSA have been established 3.
• The recommended age-specific reference ranges for free, complexed, and total PSA are:
  • 0.5,1.0, and 2.0 ng/mL for men 40-49 years old
  • 0.7,1.5, and 3.0 ng/mL for men 50-59 years old
  • 1.0,2.0, and 4.0 ng/mL for men 60-69 years old
  • 1.2,3.0, and 5.5 ng/mL for men 70-79 years old 3
• The upper limit of normal for the free-to-total PSA ratio is greater than 0.15, and the complexed-to-total PSA ratio is less than 0.70 3.

Clinical Implications

• Phlebotomy should precede DRE in the clinical and research setting to avoid misleading results 5.
• The PSA response to manipulation may be different in patients with prostatic malignancy 5, 6.
• Multivariate algorithms can be used to reduce unnecessary prostate biopsies in screening, but they require updating as clinical practice develops over time 7.