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PSA for the Primary Care Physician

Prostate specific antigen (PSA) is a protein that is produced by the prostate and is usually only detectable at very low levels in the blood of healthy men. PSA is produced by the epithelial cells in the prostate gland and is normally secreted into the semen or lost in the urine. The only known function of PSA is in male fertility to hydrolyze the coagulum of the ejaculate.¹

PSA has served as a useful tumor marker for prostate cancer. However, there is no unanimity on ordering this test for all men who are at risk for prostate cancer. At the present time, screening for prostate cancer is controversial.^2,3This article reviews the application of PSA as a screening test for prostate cancer and discusses the use of PSA for treating men with benign prostatic hyperplasia (BPH), as well as the use of PSA to monitor men who have been treated for prostate cancer.

PSA was discovered to be a component of healthy human prostate tissue in 1970 and found to be present in human seminal fluid in 1971. In 1986, PSA testing became clinically available. Because of its specificity for prostatic tissue, PSA is the best tumor marker available for this type of cancer.⁴

The two most commonly used assays in the United States are Tandem-R and Pros-Check. There is a close correlation between the two assays, but they have distinctly different normal ranges Pros-Check values are 1.4 to 1.8 times higher than those from the Tandem-R. Therefore, it is the responsibility of each physician to know the performance characteristics of the assay being used so that the results can be interpreted in a meaningful manner.

A Screening Test for Prostate Cancer

Prostate cancer is the most common non-skin cancer affecting men. It is most prevalent in men who are 60 years and older, but it is occasionally found in men in their 40s. Prostate cancer is twice as common in men of African-American descent, and it is more likely to be present at an advanced stage in these men. It is the third most common cause of cancer death in American men, surpassed only by lung and colon cancer. Prostate cancer detection has been enhanced by the introduction of the PSA blood test in the late 1980s. Evidence strongly suggests that the dramatic increase in detection of cancer in the early 1990s, followed by a subsequent decline, is best explained by detection of most of the early small tumors using the PSA blood test. Because of the effectiveness of PSA detection, there are now fewer men with clinically significant cancers to detect. Although more men die with prostate cancer rather than of it, the cancer will kill approximately one in 11 men in the United States. Only 60% of newly diagnosed prostate cancers are clinically localized and curable by currently available treatments. Therefore, if we are to decrease the mortality rate from prostate cancer, it will be necessary to detect these cancers when they are still confined to the prostate gland.

On average, serum PSA levels increase by 0.3 ng/mL/g of BPH tissue. Therefore, the larger the prostate gland in men with BPH, the larger the PSA value. However, larger increases in PSA are usually seen in patients with clinical prostate cancer. Elevated serum PSA levels (> 4.0 ng\mL Tandem-R) occur in about 25% or more of men with BPH, as well as in men with significant volume prostate cancer. PSA therefore is not a specific diagnostic test for prostate cancer, but it does afford an estimation of the probability of prostate cancer being present. Conditions and situations other than BPH and prostate cancer associated with an increase in the PSA level include acute prostatitis, prostate infarction following urethral instrumentation, such as cystoscopy and prostate biopsy, and prostatic intraepithelial neoplasia. This condition may be associated with a disorganization of the epithelial cell layer and a disruption of the epithelial basement membrane, which allows the PSA molecule to diffuse more easily from the acini of the epithelial glands to the adjacent capillary and thus have access into the blood stream.⁵ Finally, a prostate massage and even ejaculation may minimally elevate the PSA. It is for that reason that men are requested to abstain from intercourse or masturbation for 48 hours prior to venipuncture; blood should also be drawn before the digital rectal examination.

In using the serum PSA as a screening tool, several assumptions must be made: the disease being searched for is common in the population; an effective treatment is available that will result in decreased mortality and morbidity; and the test is safe and inexpensive. The PSA test to detect prostate cancer fulfills all three criteria. However, the test is not specific for prostate cancer, and there is a significant overlap in patients with an elevated PSA who have either BPH or prostate cancer. The reported positive predictive value of PSA in screening studies is 28% to 35%, which means that one-third of men with elevated PSA levels (> 4 ng\mL) will be found to have prostate cancer and two-thirds will not (i.e., false-positive results).⁶

The digital rectal examination alone is a poor screening method for prostate cancer. It is difficult to palpate small tumors at the periphery of the prostate gland (2 to 3 cc volume) or even larger tumors that are in the interior of the prostate gland and not amenable to the examining finger in the rectum. This examination is highly subjective, and there is variability in tactile discrimination even among urologists. It is less sensitive than the PSA in detecting prostate cancer, and many of the cancers diagnosed by the rectal examination may have grown and spread beyond the confines of the prostate gland. If the prostate cancer is diagnosed only by the digital rectal examination, only one-third of the cases will have organ-confined disease at the time of diagnosis and two-thirds will have metastasized, greatly diminishing or eliminating the potential for cure of the disease.⁷

A Tool for Treatment of BPH

It is an accepted concept that men with symptoms of lower tract obstruction secondary to BPH and who have large prostate glands (> 40 g) should be treated with 5-alpha-reductase inhibitors or finasteride; smaller prostate glands (< 40 g) are best treated with alpha-blockers. The problem is how to determine the size of the prostate gland accurately and within reasonable cost limits.

Previous studies have demonstrated that the examining finger is a poor judge of the size of the prostate gland. The digital rectal examination underestimates the size of the prostate gland by 25% in the hands or fingers of urologists who perform these examinations on a regular basis.⁸ The use of ultrasound to determine the size of the prostate gland is too costly and also impractical.

Recent studies have shown that the PSA can be effectively used as a predictor of prostate gland size. It is known that PSA increases with age and with the size of the prostate gland. The report reveals that PSA less than 1.6 ng\mL is associated with small prostate glands (< 40 g) and men with PSA values greater than 1.6 ng\mL are likely to have larger prostate glands (> 40 g) (Figure 1). Therefore, the PSA test can be a useful determinant to select the appropriate treatment for BPH.⁹

On the basis of this information, the PSA can help differentiate large from small prostate glands and be used as a guide to treatment in conjunction with the digital rectal examination. The value is slightly age-dependent. For example, a 65-year-old man with a normal examination, PSA of 2.0 ng/mL, and lower urinary tract symptoms sufficient to impact his quality of life would be likely to have a prostate gland 40 g or greater and would thus be a candidate for treatment with finasteride (5 mg/day). If his PSA was less than 2.0 ng\mL, he would be considered to have a small prostate gland and would be treated with one of the three alpha-blockers (terazosin, tamsulosin, or doxazosin) if symptomatic.

PSA also strongly predicts BPH-related outcomes, such as acute urinary retention and the need for BPH-related surgery.¹⁰ It has been shown that prostate volume in men with BPH predicts negative outcomes, such as acute urinary retention and the need for BPH-related surgery, including transurethral resection of the prostate. It has also been shown that men with larger prostate glands (> 40 g) respond more favorably to treatment with the 5-alpha-reductase inhibitor finasteride. Thus, for men with symptoms of urinary tract obstruction and large prostate glands, it might be best advised to undertake active treatment rather than to follow a strategy of watchful waiting, as the latter is more likely to lead to untoward outcomes such as urinary retention or BPH-related surgery. It is important to inform patients with higher PSA values and thus larger prostate glands that they may have a progressive course of the disease and that watchful waiting may not be the best course of action. If these men are advised to take finasteride, the course of the disease may be altered and their risk of acute urinary retention, need for surgery, or both, is significantly decreased. This kind of targeted therapy ultimately should reduce the number of treatment failures and thereby increase treatment efficiency and cost-effectiveness.¹¹ Also, men with more severe lower tract obstructive symptoms and PSAs greater than 1.4 ng\mL are more likely to require BPH-related surgery compared with a group with similar symptoms and PSA values who take finasteride.¹²

Serial PSA determinations after definitive therapy for organ-confined lesions are unsurpassed as a tool to monitor patients for the presence of prostate cancer. Approximately 90% of patients have undetectable serum PSA within one month postsurgery, and 90% have a normal level of PSA 12 months after radiation therapy. An increasing PSA level after radiation therapy or detectable PSA after surgery almost uniformly implies recurrent or persistent disease.

Monitoring Patients with Localized Prostate Cancer after Treatment

Patients treated with surgery (radical prostatectomy) or radiation therapy should be monitored every three months after their surgery with a PSA test. The half-life of serum PSA is two to three days. Because of the relatively long half-life of PSA, reevaluation of serum PSA postsurgery is generally performed after three months.

Prior to 1993, the accepted cutoff level for PSA after a radical prostatectomy was 0.4 ng\mL. Values greater than 0.4 were considered failures of surgery and recurrence could be expected months or years later. In 1993, however, the ultra-sensitive PSA test became available for monitoring patients with prostate cancer treated by radical prostatectomy.¹³ The ultra-sensitive assays are manufactured by Tosoh (South San Francisco, CA), Quest Diagnostics Incorporated (Teterboro, NJ), and Diagnostic Products Corporation (Los Angeles, CA).

It has been demonstrated that ultra-sensitive assays can reliably read values in the range of 0 to 0.1 ng/mL. Values greater than 0.1 ng\mL using the ultra-sensitive assay will detect recurrence a few months and even several years before the then standard assays. The advantage of this early detection of recurrence after prostatectomy is that further therapeutic measures, such as radiation or hormone therapy, may be undertaken earlier.

The rise of the PSA test is also used to monitor patients after radiation therapy. However, the cutoff level is higher, because the prostate gland remains and continues to secrete small amounts of antigen into the bloodstream. The standard cutoff value for biochemical failure is 1.0 ng\mL. The nadir serum PSA levels after radiation therapy appear to be one of the best posttreatment predictors of outcome, with low PSA nadir levels below 1 ng\mL identifying a group of patients with lower risks of disease recurrence.¹⁴ Postradiation therapy patients believed to have local disease progression may undergo salvage radical prostatectomy.

Practical Applications of the PSA Test

PSA continues to be a reliable screening test for prostate cancer. The American Cancer Society recommends that all men over age 50 have an annual digital rectal examination and a PSA test. Testing should begin at age 40 in men at high risk for prostate cancer, which includes men with a blood relative with a history of prostate cancer and all African-American men because of their increased incidence of prostate cancer and onset at an earlier age than Caucasian men. The American Urological Association provides similar recommendations.

A recently published study using a computer model to compare screening and diagnostic resource use in order to prevent cancer deaths with different PSA screening protocols suggests PSA testing and a digital rectal examination at ages 40, 45, and 50, followed by biennial screening after age 50. As a result of using this modified screening protocol, there would be 30% fewer PSA tests and 25% fewer biopsies than done as a result of annual screening.¹⁵

For patients with a PSA between 4 and 10 ng\mL, the use of the free-PSA test is helpful in differentiating BPH from prostate cancer. This test is based on the finding that prostate cancer releases a form of PSA that is bound to proteins into the blood, different from the PSA that is released by prostate glands with BPH, which is free and unattached to circulating serum proteins. The ratio of free or unbound PSA to total PSA expressed as a percentage is a useful determinant for patients in the gray zone of PSA values 4 to 10 ng\mL. Men with free\total PSA values less than 25% should be referred to a urologist for an ultrasound-guided prostate biopsy. If the free\total PSA value is greater than 25%, the risk of prostate cancer may be so low (< 8%) that prostate biopsy can be avoided. The free\total PSA test serves as a basis for improving the sensitivity and specificity of the PSA blood test and reduces unnecessary prostate biopsies by 25%.⁴

We suggest an algorithm as shown in Figure 2 as a cost-effective method of monitoring patients for early detection of prostate cancer. Using this approach, prostate cancer screening allows the diagnosis to be made at a lower PSA and will find the prostate cancer at a lower stage and lower grade of cellular differentiation at the time of diagnosis.

Summary

The PSA test is used mainly for early detection of prostate cancer. It also has value in other situations, including the selection of the appropriate medication for the treatment of BPH. In men known to have prostate cancer, based on their biopsy result, the PSA test can help predict prognosis. Men with very high PSA levels are more likely to have cancer that has spread beyond the prostate and are less likely to be cured by surgery or radiation. The PSA test is also used to monitor the effectiveness of treatments. After surgery, radiation, or hormonal treatment, rising PSA levels can provide an early sign that the cancer is returning or continuing to grow, and may be helpful in offering additional treatments.

By Neil Baum, MD, and Adam Lipp

Dr. Baum is Associate Clinical Professor of Urology, Tulane Medical School, New Orleans, LA.
Mr. Lipp is an undergraduate premedical student, Tulane University.

References

1. Starney TA, McNeal JE. Adenocarcinoma of the prostate. In: Campbell's Urology, 6th ed., vol. 2. Philadelphia, PA: W.B. Saunders, 1992;1159-1221.

2. Chodak GW. Questioning the value for screening for prostate cancer in asymptomatic men. Urology 1993;42:116.

3. Catalona WJ. Screening for prostate cancer: Enthusiasm. Urology 1993;42(2):113-115.

4. Randrup E, Baum N. Prostate-specific antigen testing for prostate cancer. Postgrad Med 1996;99:227-234.

5. Lange PH. Prostatic specific antigen in diagnosis and management of prostate cancer. Urology 1990;36(suppl 5):25-29.

6. Woolf SH. Screening for prostate cancer with prostate-specific antigen. N Engl J Med 1995;333:1401-1404.

7. Chodak GW, Keller P, Schoenberg HW. Assessment of screening for prostate cancer using the digital rectal examination. J Urol 1989;141: 1136-1138.

8. Roehrborn CG, Girman CJ, Rhodes T, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology 1997;49(4):548-557.

9. Roehrborn CG, Boyle P, Gould AL, Walkdstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999;53:581-589.

10. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: Meta-analysis of randomized clinical trials. Urology 1996;48:398-405.

11. Roehrborn CG. PSA: A new role in the assessment and treatment of patients with LUTS and BPH. Reviews in Urology 1999;I(4S):8-13.

12. Kaplan S, Garvin D, Gilhooly P, et al. Impact of baseline symptom severity on future risk of benign prostatic hyperplasia-related outcomes and long-term response to finasteride. The Pless Study Group. Urology 2000;56(4):610-616.

13. Stamey TA, Graves HC, Wehner N, et al. Early detection of residual prostate cancer after radical prostatectomy by an ultra-sensitive assay for prostate specific antigen. J Urol 1993;149(4):787-792.

14. Pollack A, Zagars GK. Serum prostate specific antigen levels three months after radiotherapy for prostate cancer. J Urol 1993;149:395.

15. Ross KS, Carter HB, Pearson JD, Guess HA. Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA 2000;284:1399-1405.

Baum N, Lipp A. PSA for the primary care physician. Clinical Geriatrics 2001;9(8):32-38.

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