ABSTRACT: Despite the impact of prostate-specific antigen (PSA) testing on the detection and management of prostate cancer, controversy about its usefulness as a marker of disease activity continues. This review, based on a recent roundtable discussion, examines whether PSA measurements can be used rationally in several clinical settings. Following radical prostatectomy and radiation therapy, prediction of survival by PSA level is most reliable in high-risk patients. PSA doubling time after radiation therapy is the strongest predictor of biochemical failure. PSA measurements have been associated with inconsistent results following hormonal treatment; reduced PSA levels may result from antiandrogen treatment, which decreases expression of the PSA gene, and therefore, the level of PSA production. In the setting of primary and secondary cancer prevention, PSA is important in risk stratification when selecting patients for studies. Part 1 of this two-part article, which concludes in the September issue, focuses on the physiology of PSA, its measurement and use in clinical practice, and its predictive value following radical prostatectomy and radiation therapy. [ONCOLOGY 16:1024-1051, 2002]
Prostate-specific antigen (PSA) testing has changed early detection and management of prostate cancer dramatically since its introduction into clinical practice in the early 1980s. Nevertheless, its usefulness as a marker of disease activity and its correlation with survival remain controversial because, in some disease settings, definitive data are lacking for its rational use. This review defines the clinical settings in which PSA can be rationally used as an indicator of disease activity and therapeutic effectiveness.
Because the natural history of prostate cancer can be long—20 to 50 years in some cases—it is impractical to use survival as the only test of a therapy’s usefulness in clinical trials. This is especially true of chemopreventive agents that are active at the earliest stages of a disease that may not be detectable for as long as 20 years. Even the longest-running trial of a potential chemopreventive therapy—the Selenium and Vitamin E Cancer Prevention Trial (SELECT)—is slated for only 12 years.
Using a marker of disease activity as an end point to demonstrate therapeutic efficacy is imperative for trials at various stages of the disease process. Because patients are encouraged to participate in early-detection programs for some cancers at age 40, the time from early detection to clinical diagnosis of recurrent disease may be as long as 10 years, and the time from diagnosis to death may be another 20 to 30 years after definitive therapy—timelines that would pose practical impossibilities for clinical trials.
In the Johns Hopkins series reported by Patrick C. Walsh, MD, and colleagues, the time from surgery to biochemical recurrence as measured by PSA ranged from 2 to 16 years, and from PSA recurrence to metastases averaged 8 years; the median time from metastases to death was 5 years (Figure 1). Chemoprevention aside, these intervals are too long when planning clinical trials to evaluate the effectiveness of therapies for prostate cancer. There is a need for markers as surrogate end points, and PSA has the potential to fill such a role.
The purpose of this review is to define the physiology and clinical use of PSA, and to determine whether PSA measurements can be used rationally as a marker of disease activity in the following clinical settings (Table 1):
• post-radical prostatectomy
• after radiation therapy for local disease
• during hormonal and other drug therapies
• in primary and secondary chemoprevention.
Part 1 of this two-part review, which concludes in the September issue, looks at the physiology of PSA and how its measurement can predict time to disease recurrence and, in a limited setting, survival of patients following radical prostatectomy and radiation therapy.
PSA is a serine protease in the kallikrein family of proteases; it is also called human kallikrein 3 (hK3). Produced in high concentrations by prostatic epithelium, PSA is secreted mainly into seminal fluid, where it dissolves the gel that forms after ejaculation by digesting the major gel-forming proteins, thereby resulting in increased sperm motility.
PSA is not a traditional tumor marker that is produced only by malignant tissue. Normal prostate tissue as well as hyperplastic and neoplastic tissue express PSA and, in fact, often produce more PSA protein than malignant prostate tissue. In prostate cancer, however, the architecture and polarization of epithelial cells are deranged, disrupting normal secretory pathways and causing PSA to "leak" or to be actively secreted into extracellular space and escape into the circulation. As a result, PSA is found in the serum in concentrations 30 times higher per unit weight of cancerous tissue than of normal tissue, and 10 times higher per unit weight of cancerous tissue than of the epithelial tissue in benign prostatic hyperplasia (BPH).[3,6,7]
This is the basis for the use of PSA levels in the detection of prostate cancer. However, there is much overlap between PSA values in BPH and prostate cancer, and various refinements have been made to improve the diagnostic value of this test. Some of these modifications will be considered later.
It is possible that PSA itself plays a modulating role in prostate cancer. Recent studies have suggested that men with high plasma levels of insulin growth factor (IGF)-I may have an increased risk of developing prostate cancer. IGF-I in the circulation is complexed to IGF-binding proteins, which also influence the biological activity of IGF. The major IGF binding protein is IGFBP-3, and it has been shown that PSA digests IGFBP-3. This may result in higher-concentrations of IGF-I and, consequently, stimulation of cancer growth.[10,11] On the other hand, PSA may suppress tumor growth by inducing formation of angiostatin.
PSA is also expressed in far lower concentrations by tissues other than prostate epithelium, including the periurethral glands, endometrium, normal breast tissue, breast tumors, breast milk, adrenal neoplasms, parotid gland, and renal cell carcinomas. Nevertheless, in the sera of women, concentrations detected by ultrasensitive assays are rarely higher than 0.5 ng/mL and usually range from 0 to 0.2 ng/mL.[13,14]
Much of the PSA released into the circulation forms complexes with protease inhibitors in plasma. Between 50% and 90% (typically 70% to 85%) of the total assayed PSA in the circulation is complexed to alpha-1-chymotrypsin. Trace amounts complex with an alpha-1-protease inhibitor and alpha-2-macroglobulin[16,17]; the remaining serum PSA is unbound or free. The proportion of complexed PSA delivered by cancerous tissue is higher than that of BPH tissue, possibly because PSA reaching the bloodstream directly can easily form complexes, whereas PSA that reaches circulation through extracellular space is susceptible to extensive proteolysis (it is then said to be "nicked" or "clipped") and is less likely to be bonded by endogenous protease inhibitors.
For this reason, the percentage of free PSA has been used to help increase the sensitivity of cancer detection when PSA is in the normal range (4.0 ng/mL or less) and the specificity when PSA is in the "gray zone" (4.1 to 10.0 ng/mL).[4,8] In this context, use of the ratio of "free PSA to total PSA" has increased the specificity of total PSA levels up to 20 ng/mL without undue loss of sensitivity.
Prostate-specific proteins were identified by several groups in the 1970s. In 1979, Wang and colleagues, who purified the antigen from prostatic tissue and demonstrated its relationship to prostate cancer, were the first to call the protein PSA.
Soon after PSA assays were developed, total serum PSA was shown to detect residual disease after radical prostatectomy and recurrence of tumor on long-term follow-up. In light of such evidence, PSA assays received approval from the US Food and Drug Administration (FDA) for monitoring therapy, and by 1988, PSA became widely used as a marker for prostate cancer. In the context of monitoring, the patient provides his own reference for the assay, but in the detection of prostate cancer, interassay variability became a concern.
The first widely used assay in the United States, Tandem-R (Hybritech), established a reference range for PSA—4.0 ng/mL or less—which was found in 97% of 207 apparently healthy men aged 40 years and older. This and subsequent studies confirming the validity of this reference range[21,22] provided the basis for the commonly used cutoff of 4.0 ng/mL as the normal total PSA in men age 40 years and older.
Most other tests were interpreted on the basis of this reference range, but not all assay methods measure the same PSA concentration, and each assay has its own reference range. Even when reference ranges are similar, tests differ greatly in their upper limits for BPH. The only two assays available in the United States until 1991—the monoclonal Tandem-R and the polyclonal Pros-Check (Yang Laboratories)—differed considerably, sometimes by a factor of two. Since that time, most assays have been thoroughly evaluated and modified to use reference samples as a standard.
Fine Tuning the Accuracy of PSA Tests
At present, most commercial PSA tests are sensitive monoclonal immunoassays that measure PSA-alpha-1-chymotrypsin and free PSA (total PSA). The affinity of the antibodies used in these assays against the different forms of PSA varies, sometimes resulting in a nonequimolar response to free and complexed forms of PSA. Some assays may preferentially detect more free PSA forms and thus overreport percent free PSA levels in patients with BPH, which may limit interpretation. Only assays that have an equimolar reaction with free PSA and PSA complexes show similar measurements. An assay that does not detect all forms of PSA on an equimolar basis is most accurate when it corresponds with a calibration standard.[4,23]
Recognizing these problems, many manufacturers of nonequimolar assays have modified their assays to produce equimolar responses to the complexed and free forms of PSA. In addition, through an international effort, the Expert Committee on Biological Standardization of the World Health Organization recently established standard reference preparations to validate and calibrate PSA assays.[25,26] One reference preparation is a standard containing 1 mg of free PSA, and the other is a preparation containing 1 mg of total PSA, including 0.1 mg free PSA and 0.9 mg PSA complexed with alpha-1-chymotrypsin. This 90:10 proportion is typical of the sera in men with prostate cancer. Applying this 90:10 calibrator to nine different PSA assays reduced the coefficients of variation among them from 28.3% to 9.5%. This standard has been used to calibrate the last five PSA assays approved by the FDA, and most manufacturers now use these standards.
Especially after radical prostatectomy, but also after other definitive treatments such as radiation or hormonal therapy, PSA levels have been found to correlate with disease activity. In early series from several institutions, patients with no detectable PSA postprostatectomy had no evidence of residual disease, whereas detectable postoperative PSA concentrations correlated with subsequent local recurrence or distant metastases—sometimes occurring as long as 1 to 3 years later. Similar findings were made after radiation and hormonal therapy.[13,27]
The limits of PSA detectability have been extended by ultrasensitive PSA assays that can accurately measure serum PSA levels as low as 0.01 to 0.001 ng/mL.[8,28] Ultrasensitive PSA assays have made it more difficult to distinguish between serum PSA concentrations produced by prostate tissue (including regrowth of cancerous prostate cells) and those produced by other tissues. But long-term follow-up of radical prostatectomy patients has indicated that postsurgical PSA levels as low as 0.01 to 0.07 ng/mL may predict recurrence.
In a recent study using PSA thresholds of 0.2, 0.3, and 0.4 ng/mL, the risks of a continued rise in PSA in the next 3 years were 49%, 62%, and 72%, respectively, leading the investigators to conclude that PSA levels of 0.4 ng/mL or greater best defined a recurrence prompting further therapy. Other large series have used 0.2 ng/mL to indicate disease recurrence. These studies have firmly established the clinical utility of PSA in the postoperative setting, and as these and other studies mature with longer follow-up, it is likely that clinical progression will be seen in virtually all patients experiencing any PSA recurrence.
Other PSA-Based Parameters
Additional measures that improve the predictive value of PSA after definitive therapy are the time to PSA recurrence and the rate at which PSA rises. Pound et al found that the timing of PSA recurrence after surgery, along with preoperative PSA level, accurately predicted disease-free survival and the pattern of recurrence—ie, local vs distant disease recurrence.
The concepts of PSA velocity and PSA doubling time have been used to characterize the rate at which PSA rises. PSA velocity requires at least three measurements over a 2-year period, or at least 12 to 18 months apart, to characterize the change in PSA level per unit of time. First introduced to improve the ability of PSA to detect prostate cancer, velocity differences were significant between men with cancer and men with BPH up to 9 years before diagnosis (Figure 2).
• PSA Doubling Time—When PSA becomes detectable after radical prostatectomy, it tends to increase exponentially, so that a plot of log PSA values against time is linear. PSA doubling time is calculated by dividing the slope of this plot into the natural log of 2 (0.693).[2,33] A doubling time of less than 6 months was found to suggest metastatic disease. Patel et al found doubling time to be a better predictor of risk of recurrence and time to clinical recurrence after radical prostatectomy than preoperative PSA, specimen Gleason sum, or pathologic stage.
In a large radical prostatectomy series (1,997 men) at The Johns Hopkins Hospital, the timing and natural history of disease progression of men with an elevated PSA after therapy were studied. The time to PSA elevation, Gleason score, and PSA doubling time were significant predictors of the probability of and time to development of metastases. A doubling time of 10 months provided the most statistically significant predictor of time to distant disease progression after an isolated elevation in PSA (Figure 3).
1. Brawley OW, Parnes H: Prostate cancer prevention trials in the USA. Eur J
Cancer 36:1312-1315, 2000.
2. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression
after PSA elevation following radical prostatectomy. JAMA 281:1591-1597, 1999.
3. McCormack RT, Rittenhouse HG, Finlay JA, et al: Molecular forms of
prostate specific antigen and the human kallikrein gene family: A new era.
Urology 45:729-744, 1995.
4. Stenman UH, Leinonen J, Zhang WM, et al: Prostate-specific antigen. Semin
Cancer Biol 9:83-93, 1999.
5. Wang MC, Valenzuela LA, Muphy GP, et al: Purification of human
prostate-specific antigen. Invest Urol 17:159-163, 1979.
6. Stamey TA, Yang N, Hay AR, et al: Prostate specific antigen as a serum
marker for adenocarcinoma of the prostate. N Engl J Med 317:909-916, 1987.
7. Stenman UH: Prostate-specific antigen, clinical use and staging: An
overview. Br J Urol 79(suppl 1):53-60, 1997.
8. Polascik TJ, Oesterling JE, Partin AW: Prostate-specific antigen: A decade
of discovery—what we have learned and where we are going. J Urol 162:293-306,
9. Cohen P, Graves HC, Peehl DM, et al: Prostate-specific antigen (PSA) is an
insulin-like growth factor binding protein-3 protease found in seminal plasma. J
Clin Endocrinol Metab 75:1046-1053, 1992.
10. Pollak M, Beamer W, Zhang JC: Insulin-like growth factors and prostate
cancer. Cancer Metast Rev 17:383-390, 1999.
11. Stattin P, Bylund A, Rinaldi S, et al: Plasma insulin-like growth
factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk:
A prospective study. J Natl Cancer Inst 92:1910-1917, 2000.
12. Gately S, Twardowski P, Stack MS, et al: Human prostate carcinoma cells
express enzymatic activity that converts human plasminogen to the angiogenesis
inhibitor, angiostatin. Cancer Res 56:4887-4890, 1996.
13. Oesterling JE, Chan DW, Epstein JI, et al: Prostate-specific antigen in
the preoperative and postoperative evaluation of localized prostate cancer
treated with radical prostatectomy. J Urol 139:766-762, 1988.
14. Filella X, Molina R, Alcover J, et al: Prostate-specific antigen
detection by ultrasensitive assay in samples from women. Prostate 29:311-316,
15. Vessella RL, Lange PH: Issues in the assessment of prostate-specific
antigen immunoassays: An update. Urol Clin North Am 24:261-268, 1997.
16. Stenman UH, Leinonen J, Alfthan H, et al: A complex between
prostate-specific antigen and alpha 1-antichymotrypsin is the major form of
prostate-specific antigen in serum of patients with prostatic cancer: Assay of
the complex improves clinical sensitivity for cancer. Cancer Res 51:222-226,
17. Lilja H: Structure, function, and regulation of the enzyme activity of
prostate-specific antigen. World J Urol 11:188-191, 1993.
18. 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 277:1452-1455, 1997.
19. Christensson A, Bjork T, Nilsson O, et al: Serum prostate-specific
antigen complexed to alpha 1-antichymotrypsin as an indicator of prostatic
cancer. J Urol 150:100-105, 1993.
20. Partin AW, Oesterling JE: The clinical usefulness of prostate-specific
antigen: Update 1994. J Urol 152:1358-1368, 1994.
21. Catalona WJ, Richie JP, deKernion JB, et al: Comparison of
prostate-specific antigen concentration versus prostate-specific antigen density
in the early detection of prostate cancer: Receiver operating characteristic
curves. J Urol 152:2031-2016, 1994.
22. Dalkin BL, Ahmann FR, Kopp JB, et al: Derivation and application of upper
limits for prostate-specific antigen in men aged 50-74 years with no clinical
evidence of prostatic carcinoma. Br J Urol 76:346-350, 1995.
23. Semjonow A, De Angelis G, Oberpenning F, et al: The clinical impact of
different assays for prostate-specific antigen. BJU Int 86:590-597, 2000.
24. Graves H: Issues on standardization of immunoassays for prostate-specific
antigen: A review. Clin Invest Med 16:415-424, 1993.
25. Stamey TA, Chen Z, Pretigiacomo AF: Reference material for PSA: The IFCC
standardization study. International Federation of Clinical Chemistry. Clin
Biochem 31:475-481, 1998.
26. Rafferty B, Rigsby P, Rose M, et al: Reference reagents for
prostate-specific antigen (PSA): Establishment of the first international
standards for free PSA and PSA (90:10). Clin Chem 46:1310-1317, 2000.
27. Oesterling JE: Prostate-specific antigen: A critical assessment of the
most useful tumor marker for adenocarcinoma of the prostate. J Urol 145:907-923,
28. Ellis WJ, Vessella RL, Noteboom JL, et al: Early detection of recurrent
prostate cancer with an ultrasensitive chemoluminescent prostate-specific
antigen assay. Urology 50:573-578, 1997.
29. Prestigiacomo AF, Stamey TA: A comparison of 4 ultrasensitive
prostate-specific antigen assays for early detection of residual cancer after
radical prostatectomy. J Urol 152(5 Pt 1):1515-1519, 1994.
30. Amling CL, Bergstralh EJ, Blute ML, et al: Defining prostate-specific
antigen progression after radical prostatectomy: What is the most appropriate
cut-point? J Urol 165:1146-1151, 2001.
31. Han M, Partin AW, Pound CR, et al: Long-term biochemical disease-free and
cancer-specific survival following anatomic radical retropubic prostatectomy.
Urol Clin North Am 28(3):555-565, 2001.
32. Carter HB, Pearson JD, Metter EJ, et al: Longitudinal evaluation of
prostate specific antigen levels in men with and without prostate diseases. JAMA
33. Patel A, Dorey F, Franklin J, et al: Recurrence patterns after radical
retropubic prostatectomy: Clinical usefulness of prostate-specific antigen
doubling times and log slope prostate specific antigen. J Urol 158:1441-1446,
34. Danella J, Steckl J, Dorey F: Detectable prostate-specific antigen levels
following radical prostatectomy: Relationship of doubling time to clinical
outcome (abstract). J Urol 149(part 2):447A, 1993.
35. Lange PH, Ercole CJ, Lightner DJ, et al: The value of serum
prostate-specific antigen determinations before and after radical prostatectomy.
J Urol 141:873-879, 1989.
36. Graves HC, Wehner N, Stamey TA: Ultrasensitive radioimmunoassay of
prostate-specific antigen. Clin Chem 38:735-742, 1992.
37. Yu H, Diamandis EP, Wong PY, et al: Detection of prostate cancer relapse
with prostate-specific antigen monitoring at levels of 0.001 to 0.1 µg/L.
J Urol 157:913-918, 1997.
38. Haese A, Huland E, Graefen M, et al: Ultrasensitive detection of
prostate-specific antigen in the follow-up of 422 patients after radical
prostatectomy. J Urol 161:1206-1211, 1999.
39. Wojno KJ, Vashi AR, Schellhammer PF, et al: Percent free prostate
specific antigen values in men with recurrent prostate cancer after radical
prostatectomy. Urology 52:474-478, 1998.
40. Partin AW, Catalona WJ, Finlay JA, et al: Use of human glandular
kallikrein 2 for the detection of prostate cancer: Preliminary analysis. Urology
41. Mikolajczyk SD, Millar LS, Wang TJ, et al: "BPSA," a specific
molecular form of free prostate-specific antigen, is found predominantly in the
transition of patients with nodular benign prostatic hyperplasia. Urology
42. Jhaveri FM, Zippe CD, Klein EA, et al: Biochemical failure does not
predict overall survival after radical prostatectomy for localized prostate
cancer: 10-year results. Urology 54:884-890, 1999.
43. Iselin CE, Robertson JE, Paulson DF: Radical perineal prostatectomy:
Oncological outcome during a 20-year period. J Urol 161:163-168, 1999.
44. Jhaveri FM, Klein EA, Kupelian PA, et al: Declining rates of
extracapsular extension after radical prostatectomy: Evidence for continued
stage migration. J Clin Oncol 17:3167-3172, 1999.
45. Mettlin C, Murphy GP, Babaian RJ, et al: The results of a 5-year early
prostate cancer detection intervention. Investigators of the American Cancer
Society National Prostate Cancer Detection Project. Cancer 77:150-159, 1996.
46. ASTRO (American Society for Therapeutic Radiology and Oncology) Consensus
Panel: Consensus statement: Guidelines for PSA following radiation therapy. Int
J Radiat Oncol Biol Phys 37:1035-1041, 1997.
47. Hanlon AL, Pinover WH, Horwitz EM, et al: Patterns and fate of PSA
bouncing following 3DCRT. Int J Radiat Oncol Biol Phys 50:845-849, 2001.
48. Critz FA, Williams WH, Benton JB, et al: Prostate-specific antigen bounce
after radioactive seed implantation followed by external-beam radiation for
prostate cancer. J Urol 163:1085-1089, 2000.
49. Preston DM, Bauer JJ, Connelly RR, et al: Prostate-specific antigen
to predict outcome of external-beam radiation for prostate cancer: Walter Reed
Army Medical Center Experience 1988-1995. Urology 53:131-138, 1999.
50. Lee WR, Hanlon AL, Hanks GE: Prostate-specific antigen nadir following
external-beam radiation therapy for clinically localized prostate cancer: The
relationship between nadir level and disease-free survival. J Urol 156:450-453,
51. Pinover WH, Hanlon AL, Horwitz EM, et al: Validating a treatment policy
for PSA failures following 3D-conformal radiation therapy (abstract). Int J
Radiat Oncol Biol Phys 48(3 suppl):206, 2000.
52. Hanlon AL, Hanks GE: Scrutiny of the ASTRO consensus definition of
biochemical failure in irradiated prostate cancer patients demonstrates its
usefulness and robustness. American Society for Therapeutic Radiology and
Oncology. Int J Radiat Oncol Biol Phys 46:559-566, 2000.
53. Russell KJ, Dunatov C, Hafermann MD, et al: Prostate-specific antigen in
the management of patients with localized adenocarcinoma of the prostate treated
with primary radiation therapy. J Urol 146:1046-1052, 1991.
54. Hanlon AL, Hanks GE, Lee WR, et al: PSA doubling time is an independent
predictor for outcome of prostate cancer treated by external- beam radiation
(abstract). Int J Radiat Oncol Biol Phys 32(suppl 1):231, 1995.
55. Hanks GE, Hanlon AL, Lee WR, et al: Pretreatment prostate-specific
antigen doubling times: Clinical utility of this predictor of prostate cancer
behavior. Int J Radiat Oncol Biol Phys 34:549-553, 1996.
56. Hanks GE, Hanlon AL, Pinover WH, et al: Survival advantage for prostate
cancer patients treated with high-dose three-dimensional conformal radiotherapy.
Cancer J Sci Am 5:152-158, 1999.
57. Hanks GE, Hanlon AL, Pinover WH, et al: Dose selection for prostate
cancer patients based on dose comparison and dose response studies. Int J Radiat
Oncol Biol Phys 46:823-832, 2000.
58. D’Amico AV, Hanks GE: Linear regressive analysis using
prostate-specific antigen doubling time for predicting tumor biology and
clinical outcome in prostate cancer. Cancer 72:2638-2643, 1993.
59. Pilepich MV, Krall JM, al-Sarraf M, et al: Androgen deprivation with
radiation therapy compared with radiation therapy alone for locally advanced
prostatic carcinoma: A randomized comparative trial of the Radiation Therapy
Oncology Group. Urology 45:616-623, 1995.
60. Shipley W, Lu JD, Pilepich M, et al: Does neoadjuvant hormone treatment
compromise subsequent androgen suppression in prostate cancer patients who fail
initial radiation therapy: A secondary analysis of RTOG 8610 (abstract). Int J
Radiat Oncol Biol Phys 48(3 suppl):169-170, 2000.
61. Hanks GE, Lu JD, Machtay M, et al: RTOG protocol 92-02: A phase III trial
of the use of long-term total androgen suppression following neoadjuvant
hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the
prostate (abstract). Int J Radiat Oncol Biol Phys 48(3 suppl):112, 2000.