Using PSA Intelligently to Manage Prostate Cancer: Part 1 of 2
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Using PSA Intelligently to Manage Prostate Cancer,
Part 1 of 2

PCRI Insights August, 2003 vol. 6, no. 3
By Jonathan McDermed, Pharm.D., Diagnostic Products Corporation

PSA is the tumor marker of choice to aid in the diagnosis of prostate cancer (PC), to assess prognosis, and to monitor patients treated for this disease. Despite growing evidence supporting the value of PSA testing for the early detection of PC,1 there are a number of physician organizations and government agencies that do not advocate using PSA for routine screening.2-6 This position claims that there is no conclusive evidence that early detection and treatment influences the overall death rate from this disease, and that screening can cause important harms; included among these are frequent false-positive results and unnecessary anxiety, biopsies, and potential complications of treatment of some cancers that may never affect a patient’s health.4-6

Since there is enough evidence to support either of the positions on PC screening in certain patient groups, this controversy will continue for the foreseeable future. What I find troubling is that this discord may explain why many physicians in the U.S. fail to appreciate the importance of early detection and do not routinely recommend PSA testing to their patients. It could also explain why more than half of the American men potentially at risk for PC do not actively participate in PC screening programs today.

Detractors of early PC screening may fail to recognize that the positive biopsy rate in men with PSA levels between 2.5 and 4.0 ng/mL is 22- 25%.7,8 This is very similar to the positive biopsy rate in men having PSA levels between 4.1 and 10.0 ng/mL; and based on current clinical criteria, the majority of cancers identified in this lower PSA range are in fact clinically significant.9 To add more support for earlier PC detection, Walsh and associates clearly showed that approximately 30% of the men diagnosed with a PSA level between 4.1 and 10.0 ng/mL will be found to have extraprostatic extension of PC at the time of radical prostatectomy.10

In this article, I will review literature supporting the concept of PC screening and examine recently published reports describing approaches that utilize PSA intelligently to improve the efficiency of cancer detection. Such approaches target at-risk individuals and can help establish an earlier diagnosis when treatment is more likely to be effective. I also will provide evidence that such approaches may not only save lives, but may also reduce healthcare costs associated with PC screening.

PSA Screening at Earlier Ages

PSA testing is associated with an average lead time of five to six years for PC detection when a PSA level of 4.0 ng/mL is considered the threshold for diagnosis.11,12 However, evidence is available that the standard approach – annual testing beginning at age 50 years – is not the most effective screening strategy.13 PSA levels remain low in younger men without prostatic disease, but gradually increase with age as physiological barriers that keep PSA in the prostatic ductal system become more permeable. Serum PSA levels are even higher in men with benign prostatic hyperplasia (BPH), although the median PSA values from reference range studies are still less than 2.0 ng/mL for men in older age groups.14 As Table 1 shows, the average man in his fourth or fifth decade of life should have a PSA level that is less than 1.0 ng/mL.

Table 1 - Age-Adjusted PSA Reference Range

Several investigators have examined the relationship between PSA levels at an early age and the subsequent development of PC. The richest source of clinical data for this research endeavor has come from the Baltimore Longitudinal Study of Aging (BLSA). This is an ongoing, long-term prospective study of aging conducted by the Gerontology Research Center.15 Since its inception in 1958, a total of 1,722 men have participated in the study for varying lengths of time, returning for follow-up visits at approximately two-year intervals. Serum PSA data is available on more than 1,100 participants. This database has spawned several important papers relevant to the early detection of PC, four of which will be reviewed here.11,16,17,18

PSA Velocity (PSAV)

H. Ballantine Carter, et al at Johns Hopkins University School of Medicine published the first paper involving this database in 1992. This relatively small study described PSA changes over time in three groups of men – normal controls and men diagnosed with either BPH or PC. Levels of PSA (and serum androgens) were examined during the seven to 25 years prior to histologic diagnosis or exclusion of prostate disease. This study showed that changes in serum androgen levels with age were not significantly different between groups and neither were the PSA levels in the men with BPH and PC measured five years before diagnosis. However, the PSA velocity (rate of PSA change over time) in men ultimately diagnosed with PC was significantly greater (0.75 ng/mL/yr.) compared to the men developing BPH. Differences in PSAV have subsequently been confirmed between men with and without PC having initial PSA values between 2.0 and 4.0 ng/mL at the beginning of a 10-year follow-up before diagnosis (Table 2).17

Table 2 - Risk of Prostate Cancer in relation to PSAV

PSA Levels in Younger Men

In 1995, Gann et al evaluated the significance of a single PSA measurement in men with and without PC obtained 10 years before a diagnosis was made.11 This study showed that when compared with men with PSA levels below 1.0 ng/mL, men with PSA levels between 2.0 and 3.0 ng/mL were five to six times as likely to be diagnosed with PC in the next 10 years. The subsequent risk was not evaluated, and the mean age at the time of baseline PSA measurement was 63 years. In a follow-up study in younger men, the PC risk was established using PSA values obtained from frozen serum samples taken up to 25 years before a diagnosis was established.18 As shown in Table 3, the risk of developing PC was more than three-fold higher in men with PSA levels above the median value for that age group. Interestingly, the median PSA values for the two decades evaluated were remarkably similar to age-adjusted PSA values in the aforementioned reference range study.14

Table 3. Risk of Developing Prostate Cancer by PSA Level

What Does This All Mean?

It appears that the long-term risk of developing PC in young men during two to three decades before diagnosis is a function of the PSA level, and that the PSAV in cancer cases will be faster than that of patients with BPH or those with no evidence of prostate disease. This suggests that a baseline PSA measurement could be useful to identify men with a higher risk of developing PC in future years and direct such men with higher than average levels into more intensive PSA surveillance. It has been amply demonstrated that treatment outcome with surgery19 and radiation therapy20 is associated with pre-treatment PSA level, with most patients having PSA levels below 4.0 ng/mL faring better than most with PSA levels between 4.1 and 10.0 ng/mL.

Conversely, men with baseline PSA measurements below average could conceivably forego further PSA testing safely for several years. This concept was confirmed by Dr. E. David Crawford et al, who reported their findings at the 2002 Annual meeting of the American Society of Clinical Oncology. This retrospective study involved 27,863 men between the ages of 55 and 74 who were screened at the University of Colorado. They found that 98.7% of men whose initial PSA value was 1.0 ng/mL or less had a reading five years later that was still < 4.0 ng/ml. Similarly, 98.8% of those whose initial reading was between 1.0 and 2.0 ng/mL still had a reading below 4.0 ng/mL two years later. These results suggest that men scoring at the lowest levels on baseline PSA testing could conceivably go as long as five years between tests and that men with intermediate scores could safely schedule repeat testing every other year. Using such a testing algorithm could theoretically reduce the annual number of PSA tests by 50%, saving the health care system as much as $1 billion annually. These findings confirm the cost savings and deaths prevented that have been demonstrated in previously published reports using computer- generated models testing the efficiency of various screening strategies.21,22,23

Since not all PCs diagnosed in younger men will require immediate treatment, a period of “watchful waiting” is normally indicated. During this interval, the biology of the cancer can be determined by serial PSA testing (PSAV), and tissue or serum samples can be checked for the presence of other markers having prognostic significance. Ultimately, the patient should base his choice of treatment or make a decision to forego treatment upon a careful assessment of all of the clinical and laboratory factors that may have an influence on his outcome.

While not a perfect test, PSA testing can provide a significant “lead time” to facilitate a diagnosis of PC. Using PSA intelligently to stratify risk and thereby determine the appropriate intensity of PC screening seems more rational than the “one size fits all” approach that is used most commonly today. In addition, more education is needed for physicians who do not offer PSA tests, who do not understand or appreciate the importance of a PC diagnosis, or who do not fully inform the diagnosed patient of all of his treatment options. The public needs to be educated about PC and to fully understand the importance of early detection, and women need to get all of the men in their lives to the doctor for just such a purpose. There are several issues that men and their doctors need to know when using PSA in the above manner to detect PC. ‚

Part 2 of 2

Jonathan McDermed, PharmD, currently serves as the Corporate Marketing Manager for Tumor Markers and Bone Metabolism Assays for Diagnostic Products Corp. of Los Angeles, CA, and is responsible for the planning and implementation of activities relating to sales and distribution of his assays. Dr. McDermed earned his PharmD degree from USC’s School of Pharmacy, and he was one of PCRI’s first employees, assisting patients and providing up-todate information regarding the availability of new diagnostic tests and treatments for prostate cancer.

References:

1. American Cancer Society: Prostate cancer and cancer detection guidelines, 1999, Atlanta, GA, American Cancer Society, 1999.

2. US Preventive Services Task Force: Guide to clinical preventive services, 2nd edition. Washington, DC, US Dept. of HHS, PHS, Science, Office of Disease Prevention and Health Promotion, International Medical Publishing, Inc., 1996.

3. Morbidity and Mortality Weekly Report, 49(36), 9/15/00.

4. US Preventive Services Task Force: Guide to Clinical Preventive Services, 3rd Edition. Washington, DC, US Dept. of HHS, PHS, Science, Office of Disease Prevention and Health Promotion, International Medical Publishing, Inc., 2002.

5. Stanford JL, Feng Z, Hamilton AS, et al: JAMA 283: 354-60, 2000.

6. Potosky AL, Miller BA, Albertsen PC and Kramer BS: JAMA 273:548-52, 1995.

7. Catalona, WJ., Smith, DS., Ratliff, TL. et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med, 324: 1156, 1991.

8. Babaian RJ, Johnston DA, Naccarato W, et al. 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 165: 757-60, 2001

9. Stanford JL, Feng Z, Hamilton AS, et al: JAMA 283: 354-60, 2000.

10. Walsh PC, Partin AW and Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 152: 1831-6, 1994.

11. Gann PH, Hennekens CH, and Stampfer MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 273: 289–94, 1995.

12. Carter HB, and Pearson JD: PSA and the natural course of prostate cancer, in Schroder FH (ed): Recent Advances in Prostate Cancer and BPH. New York, Parthenon, 1997, pp 187–93.

13. Ross K, Carter HB, Pearson JD, et al: Comparative efficiency of prostate specific antigen screening strategies for prostate cancer detection. JAMA 284: 1399–1405, 2000.

14. Price CP, Allard J, Davies G, et al. Pre- and post-analytical factors that may influence use of serum prostate specific antigen and its isoforms in a screening programme for prostate cancer. Ann Clin Biochem 38: 188-216, 2001.

15. Shock NW, Greulich RC, Andres R, et al. Normal Human Aging: The Baltimore Longitudinal Study of Aging. November 1984. Washington, DC, US Government Printing Office (NIH Publication No. 84-2450).

16. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 267: 2215- 20, 1992.

17. Fang J, Metter EJ, Landis P and Carter HB. PSA velocity for assessing prostate cancer risk in men with PSA levels between 2.0 and 4.0 ng/mL. Urology 59: 889- 94, 2002.

18. Fang J, Metter EJ, Landis P, et al. Low levels of prostate-specific antigen predict long-term risk of prostate cancer: Results from the Baltimore Longitudinal Study of Aging. Urology 58: 411-6, 2001.

19. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol Clin North Am 20: 713, 1993.

20. Zagars GK and Pollack A. Radiation therapy for T1 and T2 prostate cancer: prostate-specific antigen and disease outcome. Urology 45: 476, 1995.

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

22. Etzioni RA, Cha R, and Cowem ME. Serial prostate-specific antigen screening for prostate cancer: a computer model evaluates competing strategies. J Urol 162: 741-8, 1999.

23. Barry MJ, Fleming C, Coley CM, et al. Should Medicare provide reimbursement for prostate-specific antigen testing for early detection of prostate cancer, IV: estimating the risks and benefits of an early detection program. Urology 46: 445- 61, 1995.