PSA Testing for Cancer of the Prostate

The role of PSA in the screening of men for cancer of the prostate is controversial and confusing, even though the test does detect cancers.¹

To try to sort out this thorny problem I did a Medline search (PSA, Prostate Specific Antigen, 1999 to present), visited the Bandolier web site and reviewed the article, Prostate Specific Antigen Testing for Early Diagnosis of Prostate Cancer by Michael Barry in the New England Journal of Medicine, Vol 344, No 18, May 3, 2001.

The PSA controversy is due in part to the the lack of RCTs showing that early detection of prostate cancer and aggressive treatment of early cancers reduces mortality. Indeed the studies show that many more men are diagnosed with cancer of the prostate than die of it (although as life expectancy increases prostatic cancer will become a more important clinical problem). Moreover, treatment of early cancer is not with out significant complications such as impotence and urinary incontinence.

To complicate things further a negative test does not guarrantee freedom from the disease nor does a positive test necessarily indicate a true cancer. The PSA can be raised by benign prostatic hyperplasia, biopsy of the prostate, transurethral prostatectomy, acute urinary retention, acute prostatitis, and ejaculation.² The digital rectal examination appears to have no clinically important effect on PSA level. To further muddy the waters, there are several PSA kits available and results may vary from kit ot kit, although there is move towards standardization of the commercially available tests.³

Traditionally, a PSA value of 4.0 ng per milliliter has been used as the upper limit of the normal, although 2 studies on men who had biopsies with levels between 2.5 and 4 ng found cancer in 12-23% of the patients.^4,5 When found to be mildly elevated, it is recommended that the test should be repeated, perhaps with a recommendation of sexual abstinence for 48 hours before the test, to ensure that the results are consistent. Levels above 4 ng or an abnormal digital rectal exam warrent further evaluation with transrectal ultrasound-guided biopsy (although even the accuracy of this "gold standard" has been questioned^6,7 as this approach results in a residual probability of cancer of at least 10 percent).

Because 75% of men with a PSA of 4-10 ng will have a negative biopsy there is interest in improving the specificity of the test. Several suggestions have been made but none seems ideal. Using age-specific reference ranges, with a lower threshold for biopsy in younger men and higher in older men can be helpful in deciding who to investigate. The recommended reference range for serum PSA (95^th percentile) for men aged 40 to 49 years is 0.0 to 2.5 ng/mL; for 50 to 59 years, 0.0 to 3.5 ng/mL; 60 to 69 years, 0.0 to 4.5 ng/mL; and 70 to 79 years, 0.0 to 6.5 ng/mL.⁸ Watching the rate of change in the PSA level (more than 0.75 ng per milliliter per year is more suggestive of prostate cancer than of benign prostatic hyperplasia), requires annual testing for at least three years to be of use.

PSA in the blood is found both as Free PSA and as PSA Complexes. For some unknown reason, patients with cancer of the prostate have lower levels of free PSA than do patients with benign prostatic hypertrophy, and this fact can be used to help improve the diagnosis of cancer.^9,10 It has been postulated that patients with a ratio of free PSA to total PSA of greater than 25 do not require biopsy. However using this cut off would still miss approxmately 8% of cancers.

The interval between testing is also in question, as many men are now tested annually. Recent analysis suggests that testing every two years is adequate, although testing might begin at an earlier age and stop at age 75 or even 65 years in men with persistently low levels of PSA (0.5 to 1.0 ng per milliliter).¹¹

So how do we advise our patients? The best option would seem to be having a full discussion with the patient explaining that the test has a number of false positives and negatives and that there is no good evidence that early detection reduces mortality. Moreover the treatments for early cancer of the prostate carry some potentially significant side effects, like impotence and incontinence. There are some groups of men who are at higher risk of cancer (blacks and men with positive family history, especially at a young age). Also it appears that if testing is done, a free/total PSA of less than 25-30% increases the chance that the elevtion is due to cancer.

In the end there appears to be no right answer and the physician and patient will make a decission based on their feelings after examining the data. In my experience, most men who inquire about the test want to have it done.

- John Hickey

Thanks to Dr. David Bell, Associate Professor of Urology at Dalhousie University Medical School, Halifax Nova Scotia, for reviewing the draft copy of his article

1. Hakama M, Stenman UH, Aromaa A, Leinonen J, Hakulinen T, Knekt P. Validity of the prostate specific antigen test for prostate cancer screening: followup study with a bank of 21,000 sera in Finland. J Urol. 2001 Dec;166(6):2189-91; discussion 2191-2. (Level 3 evidence)
    
2. Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology. 1997 Aug;50(2):239-43. (Level 3 evidence)
    
3. Ward AM, Catto JW, Hamdy FC. Prostate specific antigen: biology, biochemistry and available commercial assays. Ann Clin Biochem. 2001 Nov;38(Pt 6):633-51. (review article)
    
4. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination: enhancement of specificity with free PSA measurements. JAMA 1997;277:1452-1455.) (Level 3 evidence)
    
5. Babaian RJ, Johnston DA, Naccarato W, Ayala A, Bhadkamkar VA, Fritsche HA. The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng./ml.: relation to biopsy strategy. J Urol 2001;165:757-760) (Level 3 evidence)
    
6. Djavan B, Zlotta AR, Ekane S, Remzi M, Kramer G, Roumeguere T, Etemad M, Wolfram R, Schulman CC, Marberger M. Is one set of sextant biopsies enough to rule out prostate Cancer? Influence on transition and total prostate volumes on prostate cancer yield. Eur Urol. 2000 Aug;38(2):218-24. (Level 3 evidence)
    
7. Djavan B, Zlotta A, Remzi M, et al. Optimal predictors of prostate cancer on repeat prostate biopsy: a prospective study of 1,051 men. J Urol 2000;163:1144-1149 (Level 3 evidence).
    
8. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA, Girman CJ, Panser LA, Lieber MM. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges. JAMA. 1994 Mar 9;271(10):746-7 (Level 3 Evidence)
    
9. Djavan B, Zlotta A, Kratzik C, Remzi M, Seitz C, Schulman CC, Marberger M. PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5 to 4.0 ng/mL. Urology. 1999 Sep;54(3):517-22. (Level 3 evidence)
    
10. S Egawa, S Soh, M Ohori et al. The ratio of free to total serum prostate specific antigen and its use in differential diagnosis of prostate carcinoma in Japan. Cancer 1997 79: 90-8. (Level 3 evidence)
     
11. Carter HB, Landis PK, Metter EJ, Fleisher LA, Pearson JD. Prostate-specific antigen testing of older men. J Natl Cancer Inst. 1999 Oct 20;91(20):1733-7. (Level 3 evidence)

You can search for abstracts of the above references by following this link: PubMed