The PCRI Views
Regarding Testing for Prostate Cancer
Using PSA as a Principal Marker

PCRI Insights August 2004 vol. 7, no. 3

PCRI Statement on Annual Testing for PC (The Basics) The Prostate Cancer Research Institute (PCRI) strongly supports annual testing for the early detection of prostate cancer. Effective testing combines both a prostate specific antigen (PSA) blood test and a digital rectal exam (DRE) for men, beginning at: Age 35 – for those have a family history of prostate cancer or who are of African American descent.   Age 40 – for all other men. It is important to note that even elevated PSA levels may indicate the presence of very treatable urinary conditions, such as benign prostatic hyperplasia (BPH) or prostatitis, and do not necessarily indicate that cancer is present in the prostate.

Recent studies published by the New England Journal of Medicine have increased the controversy as to how PSA test results should be evaluated and used. Many experts now suggest that a PSA score of 2.5 nanograms per milliliter (ng/ml) (rather than the current recommendation of 4.0 ng/ml) should be the point at which a doctor considers ordering a biopsy. Other experts disagree, contending that the 4.0 level already results in what they deem to be too many unnecessary biopsies.

The PCRI suggests that the issue is much more complex than simply changing one threshold and using it as an automatic trigger for biopsying men. The following view on a comprehensive approach to testing for prostate cancer was developed by the PCRI staff after a careful review of the literature and was reviewed by members of the PCRI Medical Advisory Board. It was created to help the public understand the importance of regularly monitoring PSA levels in order to accurately detect the presence of prostate cancer (PC), or other conditions such as prostatitis or benign prostatic hyperplasia (BPH), which are normally less serious.

Details on Testing for PC

Effective testing for PC combines both a PSA blood test and a DRE. Hence, prior to having blood drawn for the PSA test, men should take into consideration some of the factors that might cause a variance in the PSA level. This will help men improve their understanding of their PSA values and DRE results, and promote better communication with their physician. Additionally, men are encouraged to be vigilant about getting photocopies of their PSA test results, and also to become familiar with the factors that contribute to being at high-risk for prostate cancer.

1. Though the following factors may not alter the overall PSA level significantly, they may affect PSA rate of increase (PSAV) and PSA doubling-time (PSADT) calculations. (These calculations, and their importance, are explained later.)
   
   Factors that may alter a PSA level include (but are not limited to):
   
   • Digital rectal exam (DRE). May elevate PSA level.1 The duration of elevation may vary, but has been reported to be at least 24 hours in some men.2,3,4 It is recommended that the DRE be performed after blood is drawn for the PSA test in order to obtain an accurate PSA reading.
   
   • Sexual activity. Ejaculation may elevate PSA level for 24 to 48 hours.5
   
   • Different labs or assays use different machines that can produce variable PSA results from the same blood sample.6
   
   • Cystoscopy and/or catheterization. Can elevate PSA level for at least two weeks.3,4,7
   
   • Acute urinary retention. Can elevate PSA for up to two weeks.8
   
   • Prostate biopsy or TURP (transurethral resection of the prostate). Can elevate PSA level significantly for up to six weeks.9
   
   • 5-alpha reductase medications such as Proscar® (finasteride) or Avodart® (dutasteride) can cause a reduction in PSA level of about 50%.10,11
   
2. Men (or their advocates) are strongly encouraged to maintain a log of results and keep photocopies of all reports in order to easily monitor the exact dates and results of their PSA levels and assay and any subsequent pathology reports.
   
3. Men are encouraged to know the risk factors for PC and to understand testing for PC in the context of those factors. Research has shown that patients who make informed testing decisions usually benefit from the results.12,13
   
   Reported high-risk factors for PC include (but are not limited to):
   
   • Being of African American descent.14,15,16
   
   • A family history of prostate cancer, especially in brothers.17,18
   
   • A diet high in saturated fats and red meat.19,20
   
   • Occupations that involve use of pesticides and other chemicals.21,22
   
4. While PSA is a significant indicator in the diagnosis of most forms of PC, there are some extremely aggressive varieties that produce only a small amount of PSA.23 For this reason, PCRI recommends that the DRE as well as the PSA test be done as part of the annual exams.
   
5. There is a small minority of patients who present with disease at an earlier age than indicated by these screening guidelines.24 Patients are encouraged to research their particular situation and pursue testing for PC, if so desired. Any presentation of urinary symptoms (frequency, hesitation, dribbling, pain, incomplete emptying) should be investigated for possible BPH, prostatitis, or PC.

Making the Decision to Biopsy

It has been estimated that only 25-35%25 of prostate biopsies each year in the U.S. find PC. Hence, since prostate biopsies involve excising cores of tissue from the prostate with needles inserted through the rectum, they should not be performed unless there is a persuasive indication that cancer may be present. One such indication is an abnormal DRE (a nodule, hardness, or other irregularity). This, with or without an elevated PSA level, may warrant the need for a biopsy.

The standard for an elevated PSA has until recently been a PSA level of 4.0 ng/ml. However, there is a growing body of research to support that lowering the threshold of the PSA level to 2.5 ng/ml will significantly increase prostate cancer detection. However, it may also increase the proportion of “unnecessary” biopsies.27,28

Prior to taking a PSA test, it should be understood that the PSA test measures an individual’s prostate-specific antigen level, and is not a prostate-CANCER-specific antigen level. Hence, an elevated PSA level can indicate prostatitis (inflamed prostate), BPH (non-malignant enlarged prostate), or prostate cancer. Both prostatitis and BPH are conditions, not diseases, that are usually more easily treated, yet whose symptoms may be similar to those of cancer. Therefore, a needle biopsy may or may not necessarily be the next reasonable step.

The following should be considered before the decision whether or not to biopsy is made:

1. Rule out prostatitis. With the use of a urine culture, antibiotics, and the uPM3 urine test, it may be possible to rule in or rule out prostatitis. If prostatitis is detected, treatment choices should be discussed by the patient and physician.
   
2. Rule out BPH. This can be done (1) by calculating prostate size with the ultrasound measurement of the prostate, (2) by using the uPM3 urine test, and/or (3) with the use of the free PSA percentage.
   
   Free PSA is a sub-type of PSA that is associated with benign prostatic cell proliferation; the free PSA percentage is equal to the free PSA divided by the total PSA, multiplied by 100. A free PSA percentage of less than 10% (after prostatitis has been ruled out) should be considered a possible “ flag” for PC, and biopsy would be warranted.29 If BPH is found, treatment choices should be discussed and considered jointly by patient and physician.
   
3. PSA tests should be repeated regularly and the results should be followed over time so that the PSA velocity, or PSAV (rate of increase in PSA levels in succeeding PSA tests), can be accurately calculated. A PSAV of 0.75 ng/ml/year or higher has been reported to be an indicator of possible PC.30 An increase greater than 2 points in a single year has been shown to correlate with a greater probability of aggressive PC,31 and a biopsy should be considered.
   
4. Following PSA results over time also enables the accurate calculation of the PSA doubling time, or PSADT (the rate of doubling time of PSA level). Estimates vary, but a PSADT of 10 years or less can relate to a greater probability for prostate cancer, and a biopsy should be considered.32
   
5. Measurements made with Transrectal Ultrasound to determine the prostate gland volume can also influence the decision as to whether or not to biopsy. Since the predicted PSA is equal to the gland volume times 0.068,26 the expected tumor volume can be calculated and located.

A Note About Biopsies

The biopsy is used to determine if a man has PC or a pre-cancerous condition. The biopsied tissue provides valuable information about the grade and aggressiveness of the cancer and is also helpful in predicting if the cancer has spread beyond the prostate gland. The most commonly used grading system was developed by pathologist Donald Gleason, MD. The Gleason grading system consists of primary and sceondary grades, each ranked in aggressiveness from 1 to 5. The Gleason score indicates these two grades in the format of primary grade, secondary grade, e.g., 3,4. (See the Jan. 2001 issue of PCRI Insights for details.)

However, biopsies should be understood in light of their accuracy. Sextant (6 needle) biopsies with grey-scale ultrasound have been shown to produce a false negative rate of 20%33 and the use of this method is waning. Currently, 10 or more biopsies are obtained from different regions of the prostate, and the false negative rate of these biopsy schemes has decreased modestly.25

Specifically, pathology references to hyperplasia (or hypertrophy) usually indicate BPH (an enlarged or enlarging prostate), and references to inflammation usually indicate prostatitis, both of which are non-cancerous urinary tract conditions and possible causes for elevated PSA levels. Conversely, high-grade PIN (prostatic intraepithelial neoplasia) found in biopsy tissue should be considered precancerous cells, and also a flag for PC.34 Additional biopsies should be considered.

Call the PCRI Helpline if you would like help understanding your PSA test or DRE results, or if you are having suspicious urinary tract symptoms that you would like to discuss.

Call the PCRI Helpline Los Angeles: 800-641-7274                      or 310-743-2110 Florida: 239-395-0995 Georgia: 770-632-2899 Hawaii: 808-891-0209

References

1. Lechevallier E, Eghazarian C, Ortega JC et al: Effect of digital rectal examination on serum complexed and free prostate-specific antigen and percentage of free prostate-specific antigen. Urology 54(5):857-861; Nov 1999.

2. Cevik I, Turkeri LN, Ozveri H et al: Short-term effect of digital rectal examination on serum prostate specific antigen levels. A prospective study. Eur Urol: 29(4): 403-6, 1996.

3. Rodriguez-Rubio FI, Robles JE, Gonzalez A et al: Effect of digital rectal examination and flexible cystoscopy on free and total prostate-specific antigen, and the percentage of prostate-specific antigen. Differences between two assays. Eur Urol. 33(3): 255-60; 1998.

4. Dutkiewicz S, Stepien K, Witeska A: Bladder catheterization and a plasma prostate-specific antigen in patients with benign prostatic hyperplasia and complete urine retention: Mater Med Pol 27(2): 71-3: Apr-Jun 1995.

5. Herschman JD, Smith DS, Catalona WJ: Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology 50(2): 239-43; Aug 1997.

6. Link RE, Shariat SF, Nguyen CV et al: Variations in prostate-specific antigen results from 2 different assay platforms: clinical impact on 2304 patients undergoing prostate cancer screening. J Urol. 171(6 pt 1):2234-8;
Jun 2004.

7. Leibovici D, Zisman A, Chen-Levyi Z et al: Elevated prostate-specific antigen serum levels after intravesical instillation bacillus Calmette-Guerin. J Urol. 164(5): 1546-9; Nov 2000.

8. McNeill SA & Hargreave TB: Efficacy of PSA in the detection of carcinoma of the prostate in patients presenting with acute urinary retention. J R Coll Surg Edinb. 45(4): 227-30; Aug 2000.

9. Oesterling JE, Rice DC, Glenski WJ et al: Effect of cystoscopy, prostate biopsy, and transurethral resection of prostate on serum prostate-specific antigen concentration. Urology 42(3): 276-82; Sep 1992.

10. Marks LS, Partin AW, Gormley GJ et al: Prostate tissue composition and response to finasteride in men with symptomatic benign prostate hyperplasia [see comments]. J Urol 157:2171-8, 1997. Comment in SS J Urol SS 160:134, Jul 1998.

11. Narayan P, Tewari A, Jacob G et al: Differential suppression of serum prostatic acid phosphatase and prostate-specific antigen by 5-alpha reductase inhibitor. J Urol 75(5); 642-6; May 1995.

12. Lake Hospital Systems, Willoughby, OH: Does patient partnership in continuing medical education (CME) improve the outcome in osteoporosis management? J Contin Educ Health Prof 22(3): 142-151; Summer 2002

13. Bridge PD, Berry-Bobovski L, Bridge TJ et al: Evaluation of a communitybased health education program. J Cancer Educ 17(2): 101-5: Summer 2002.

14. Wilkinson S, List M, Sinner M et al: Educating African-American men about prostate cancer: impact on awareness and knowledge. Urology 61(2): 308-313; Feb 2003.

15. Sellers DB & Ross LE: African American men, prostate cancer screening and informed decision making. J Natl Med Assoc 95(7): 618-625; Jul 2003.

16. Nieder AM, Taneja SS, Zeegers MP et al: Genetic counseling for prostate cancer risk. Clin Genet 63(3): 169-76; Mar 2003.

17. Bruner DW, Moore D, Parlanti A et al: Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis. Int J Cancer 107(5): 797-803; Dec 10 2003.

18. Loman N, Bladstrom A, Johannsson O et al: Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known BRCA1 and BRCA2 mutation status. Breast Cancer Res 5(6): R175-86, 2003.

19. Giovannucci E: Dietary influence of 1,25(OH) 2 vitamin D in relation to prostate cancer: a hypothesis. Cancer Causes Control 9(6):567-582; Dec 1998.

20. Kushi L & Giovannucci E: Dietary fat and cancer. Am J Med;113 Suppl 9B:63S-70S. 2002 Dec 30.

21. Fleming LE, Bean JA, Rudolph M et al: Mortality in a cohort of licensed pesticide applicators in Florida. Occup Environ Med 56(1): 14-21;Jan 1999.

22. Mills PK & Yang R: Prostate cancer risk in California farm workers. J Occup Environ Med 45(3): 249-58; Mar 2003.

23. Alhara M, Lebovitz RM, Wheeler TM et al: Prostate-specific antigen and Gleason grade: an Immunohistochemical study of prostate cancer. J Urol 151(6): 1588-64; Jun 1994.

24. D’Aprile M, Santani D, DiCosimo S et al: A typical case of metastatic undifferentiated prostate carcinoma in a 36 years old man: clinical report and literature review. Clin Ter 151(5):371-4; Sep-Oct 2000.

25. Ornstein DK, Kang J: How to improve prostate biospy detection of prostate cancer. Curr Urol Rep. 2(3): 218-23; Jun 2001.

26. Applewhite J, Hall C: Transrectal Ultrasound and Biopsy in the Early Diagnosis of Prostate Cancer. Cancer Control (8):141-150, 2001.

27. Punglia RS, D’Amico AV, Catalona WJ et al: Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Eng J Med 349(4): 335-42;Jul 24 2003.

28. Thompson JM, Pauler DK, Goodman PJ et al: Prevalence of prostate cancer among men with a prostate-specific antigen =4.0 ng per milliliter. N Eng J Med 350 (22): 2239-46; May 27 2004.

29. Martinez L, Tabernero A; Contrearas T:. Determination of the percentage of free prostate-specific antigen helps to avoid unnecessary biopsies in men with normal rectal examinations and total prostate-specific antigen of 4-10 ng/ml; Eur Urol 2000 Mar;37(3):289-37; Mar 2000.

30. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992; 267:2215-2220.

31. D’Amico AV et al: Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Eng J Med 351:125-35; Jul 8 2004.

32. Raaijmakers R, Wildhagen MF, Ito K et al: Prostate-specific antigen change in the European Randomized Study of Screening for Prostate Cancer, Urology. 63(2):316-20; Feb 2004.

33. Terris MK: Sensitivity and specificity of sextant biopsies in the detection of prostate cancer: preliminary report. Urology. 54(3): 486-9; Sept. 1999.

34. Steiner MS: High-grade prostatic intraepithelial neoplasia and prostate cancer risk reduction. World J Urol: 21(1):15-20; Feb 21, 2003.

 

Prostate Cancer Research Institute (PCRI)

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