Table of Contents for this page.

Physiology and Epidemiology

Biochemical Characteristics of Prostate-Specific Antigen (PSA)

Screening for Prostate Cancer with Total PSA 

Improving the Specificity of Total PSA as a Prostate Cancer Screen 

Improving Specificity of Prostate Cancer Detection with PSA Isoforms

Staging Prostate Cancer with PSA

Use of PSA in Monitoring Treated Prostate Cancer Patients

The Clinical Utility of Prostate-Specific Antigen By André Valcour, PhD

Physiology and Epidemiology

The prostate is a small gland that, in young adult men, is about the size and shape of a walnut. This gland is responsible for producing approximately 50 percent of the fluid that combines with sperm to make up the ejaculate. During sexual intercourse, this thick fluid protects the sperm from the acidic conditions of the vagina.

The prostate is located under the bladder behind the pubic bone and in front of the rectum. The gland wraps around the urethra, the tube that carries both urine and ejaculate through the penis and out of the body. The gland typically grows during two stages in a man's life. During puberty, the gland grows as part of the normal sexual maturation process. Beginning at middle age, many men experience prostate growth, resulting in a common condition called benign prostatic hypertrophy (BPH).

The prostate is made up of four distinct regions, or zones. The peripheral zone is closest to the rectum and is the region in which most prostate cancers occur. Physicians commonly probe this zone by means of a digital rectal exam (DRE) to feel for early warning signs of prostate cancer. The transition zone normally represents less than 5 percent of the prostate volume, but may become greatly enlarged in men with BPH. The fibromuscular stroma at the front of the prostate controls urination by means of the urethral sphincter and is not generally associated with enlargement or cancer. The seminal vesicles that produce fluids that make up semen connect to the prostate in the central zone.

The most common prostate complaint in younger men is inflammation of the prostate, or prostatitis. This condition is frequently caused by bacterial infection and can be treated with antibiotics or anti-inflammatory drugs. As they become older, many men will develop BPH. As the prostate grows, it becomes restricted by surrounding tissue and packs inward. This can choke the urethra and interfere with both urination and ejaculation. In many cases, BPH can be treated either with medications that cause the prostate to shrink or with surgery.

A third common affliction of the prostate is prostate cancer. Prostate cancer is second only to lung cancer as the leading cause of cancer death among males in the United States.1-3 There are approximately 200,000 new cases diagnosed annually, resulting in more than 30,000 deaths per year. Prostate cancer represents 36 percent of all cancers in men in the United States and leads to 13 percent of all cancer-related deaths. The incidence of prostate cancer in black men is 66 percent higher than in Caucasian men. Nineteen percent of all cancer-related deaths among black men are associated with prostate cancer.1

Biochemical Characteristics of Prostate-Specific Antigen (PSA)

PSA, first identified and purified in 1979,4 is a 28 kDalton glycoprotein (237 amino acids) that is produced by prostate ductal epithelium of the seminal vesicles.4,5 PSA is a serine protease (i.e., an enzyme that breaks down proteins at serine amino acid residues). Chymotrypsin, an enzyme produced by the pancreas to break down proteins in food, is also a serine protease. PSA breaks down proteins of the seminal coagulum to release spermatozoa. The predominant clinical utility of PSA measurement in blood is associated with its production by the prostate; however, PSA is also produced by the periurethral, anal and apocrine sweat glands and has been measured in breast milk. PSA elevation has been observed in patients with breast cancer and patients with salivary gland neoplasms.6

In general, serum PSA levels increase due to physical changes to prostate architecture caused by trauma, infection, inflammation, prostate manipulation, BPH or malignancy. The sensitivity of PSA levels to these changes serves as the basis for the clinical use of the test. The PSA concentration in the serum of healthy men is a million-fold lower than that in seminal fluid. PSA in seminal fluid is predominantly free or uncomplexed. In serum, the majority of PSA is bound to proteinase inhibitors, including *1-antichymotrypsin (ACT) and *2-macroglobulin (A2M). The complexing inhibitors prevent the PSA from digesting proteins in the blood. Measured total PSA consists of free PSA (fPSA) and ACT-bound PSA, since PSA complexed to A2M is not immunologically detectable.

PSA complexes are more stable than fPSA,7,8 both in vivo and in vitro. The serum levels of both total and free PSA increase with prostate manipulation, but the free returns to pre-manipulation concentrations quicker.9 Once collected for testing, the fPSA has been shown to be stable for only 24 hours at 4 degrees while total PSA and complexed PSA are stable for several days.10

Screening for Prostate Cancer with Total PSA

The total PSA test has proved to be extremely valuable as an aid in the detection of prostate cancer when used in conjunction with a DRE. The American Cancer Society1 and the American Urological Society2 have recommended that all men older than 50 be tested annually, using a cut-off value of 4.0 ng/mL. They suggest that younger men in high-risk groups, such as blacks or those with strong family history of prostate cancer, be tested earlier.1

PSA screening should be performed in conjunction with DRE, since the combination of the two tests is more sensitive for the early detection of prostate cancer than either test alone.1,2 Using a cut-off of 4.0 ng/mL, total PSA can often identify patients with prostate cancer who have a negative DRE.2,11 This is thought to be due, in part, to the inability of DRE to detect tumors of small volume that are most likely to be confined to the prostate.12

Since patients with small tumors are believed to have the best prognosis, it has been suggested that PSA is more likely than DRE to detect those tumors with the greatest potential for cure.2 The prognosis of prostate cancer patients is related to stage of disease at the time of diagnosis. Use of PSA screening has resulted in what has been referred to as a "stage shift" with an increased proportion of newly diagnosed cases localized to the prostate. Since the onset of PSA use, deaths from prostate cancer have decreased at a rate of 0.5 percent per year. Earlier diagnosis as a result of PSA screening accompanied by improved methods of disease treatment have resulted in a significant improvement in patient mortality.2,3

While PSA testing has proved to be a valuable tool in the early detection of prostate cancer, it is by no means perfect. It is important to realize that a significant percentage of men with PSA levels of less than the cut-off of 4.0 ng/mL may have prostate cancer.1 The proportion of men with prostate cancer has been shown to correlate with the total PSA value and the result of the DRE.13 The results of a multicenter trial involving 6,630 men screened with PSA and DRE demonstrated the limitation of using this combination of tests. The rate of prostate cancer diagnosis for men when various combinations of these indicators are correlated appears in Table 1.13

Several investigators have considered lowering the cut-off used for PSA screening to improve the sensitivity of the test and detect more prostate cancers.14-16 Age- and race- specific reference intervals have also been proposed.2,5 Any choice of PSA cut-off represents a trade-off between increasing the number of cancers detected and decreasing the number of unnecessary prostate biopsies performed. The American Cancer Society,1 the American Urological Society2 and most assay manufacturers (through their FDA-approved package inserts) continue to recommend using 4.0 ng/mL as a cut-off value.

Improving the Specificity of Total PSA as a Prostate Cancer Screen

Total PSA measurement with DRE has proven to be an imperfect method for detecting prostate cancers since PSA is produced by both the normal and malignant prostate. While many cancers are accurately detected, this combination lacks specificity, especially in the diagnostic gray zone between 4.0 and 10.0 ng/mL (Table 1). Seventy-five percent of men with normal DRE and a total PSA in this range will biopsy negative for prostate cancer. Clinicians have tried a number of approaches to improve the specificity of the PSA test for these patients to reduce the number of unneeded biopsies without missing true cancer cases.

The calculation of PSA density has been used by many urologists as a method of improving the specificity of PSA for prostate cancer. This type of approach is based on the fact that for men with the same total PSA concentration, the probability of having prostate cancer will be higher in men with larger prostates. PSA density is defined as total PSA (ng/mL) divided by prostate volume (cc) as determined by ultrasound.

Seaman and coworkers proposed using a cut-off of 0.15 to identify higher-risk patients with moderately elevated serum PSA levels.17 Several early studies found that use of PSA density was of limited clinical utility in identifying prostate cancer in patients with normal or moderately elevated PSA levels and negative DRE.18,19 The negative findings of these early studies may have been, in part, due to limitations of accuracy in the measurement of prostate size by ultrasound in a population of men with relatively small prostates. The measurement of the prostatic transition zone by transrectal ultrasound (TRUS) in order to calculate the PSA density of the transition zone (PSA-TZ) has been shown to enhance the specificity and sensitivity of the test.20 A recent multisite clinical trial demonstrated that the use of PSA density could provide significantly better specificity for prostate cancer than PSA alone.21

PSA velocity, or the rate of change of PSA over time for an individual patient, can enhance the utility of PSA and help differentiate men with prostate cancer from men without disease.22 In this approach, at least three PSA measurements are made during a two-year period. Men with a calculated rate of change in PSA of greater than 0.75 ng/mL per year are considered to be at higher risk for the development of prostate cancer.22 The utility of PSA velocity assessment is limited by the fact that small changes in total PSA values are used in the calculation. Analytical variation in PSA measurement as well as minor physiologic variation in PSA values can make the results difficult to interpret. In many cases, however, PSA velocity can be useful in identifying patients as candidates for biopsy with normal or moderately elevated total PSA values.

Improving Specificity of Prostate Cancer Detection with PSA Isoforms

The percent free PSA (fPSA), calculated from the total and the fPSA, has been shown to improve the clinician's ability to differentiate prostate cancer from benign conditions, especially in men with moderately elevated total PSA levels.21,23,24 Men with prostate cancer tend to have lower percent free PSA (fPSA/total PSA) values than men with benign prostate conditions.

The first fPSA assay to gain widespread acceptance was originally produced by Hybritech and is now manufactured and distributed under the Beckman Coulter label. The success of this test was largely based on the results of a multisite clinical trial in which 773 men with normal rectal exam and total PSA values between 4.0 ng/mL and 10.0 ng/mL underwent prostate biopsy. As a result of this extensive study, the researchers recommended using a cut-off of 25 percent fPSA to identify individuals with an increased risk of prostate cancer. They found that 95 percent of the men studied with cancer (as determined by biopsy) had a percent fPSA less than or equal to 25 percent. Their study further indicated that 20 percent of the men who were prostate cancer negative had a percentage of fPSA greater than the 25 percent cut-off. Use of the 25 percent cut-off to identify higher risk patients could eliminate 20 percent of the biopsies as needless.23

Further analysis of the clinical trial data showed that the percentage of fPSA could be used to stratify risk of prostate cancer diagnosis among men in the diagnostic gray zone. The clinician can use the percentage of fPSA to determine the relative risk of prostate cancer in individual men.23 Table 2 lists the probability of prostate cancer for men with nonsuspicious DRE results and total PSA between 4 ng/mL and 10 ng/mL.23

The clinical utility of percent fPSA for improving the specificity of prostate cancer detection has been confirmed with fPSA assays produced by other manufacturers. For example, the results of a multisite clinical trial of the percent fPSA assay determined on the Abbott AxSYM have recently been published.25 This study found that using the percent fPSA cut-off of 26.4 percent would allow for the detection of prostate cancer in 96 percent of men and would eliminate 27.4 percent of unnecessary biopsies. This study's authors were able to stratify the risk of prostate cancer diagnosis with Abbott AxSYM percent fPSA in much the same way as the author's of the Hybritech trial.23

The cut-offs and clinical reference intervals established as the result of any clinical study are directly applicable only to individuals that fall into a similar reference population. In the multisite clinical trials of the Hybritech and Abbott assays,23,25 the authors only made specific recommendations regarding the use of percent fPSA for men with normal rectal exam and total PSA between 4.0 ng/mL and 10.0 ng/mL.23 Several studies have investigated the clinical utility of percent fPSA determination in men with total PSA less than 4.0 ng/mL.20,26 Twenty percent of prostate cancer cases have an initial total PSA concentration in this range.13 Unfortunately, more aggressive investigation of these cases results in a high frequency of unnecessary biopsies. The use of percent fPSA with cut-offs established for this population of men has been shown to improve the specificity for prostate cancer detection.20,26

The importance of using cut-offs developed from the appropriate reference population is underscored in two recent studies comparing the utility of percent fPSA determination in black and white men.27,28 The first study27 consisted of a subgroup analysis by race of the data generated in the multisite clinical trial of the Hybritech fPSA described earlier.23 The population studied in this trial consisted of 79 black men and 647 white men. The statistical analysis indicated that using a cut-off of 25 percent allowed for detection of 95 percent of cancers in both races and avoided 20 percent and 17 percent of the unnecessary biopsies in white and black men, respectively.

These results are inconsistent with a second study in which 222 black men and 298 white men with total PSA values between 2.5 ng/mL and 9.9 ng/mL were biopsied.28 Using a percent fPSA cut-off of 25 percent in this study would have resulted in substantially more missed cancers in black men (32 percent) vs. white men (12 percent). While it is clear that populations in these two studies are substantially different due to the different total PSA criteria, the discrepant results indicate that further research is required to determine the optimal cut-offs for men of different races.

Initial clinical studies of PSA isoforms focused on the free PSA assays due to technical difficulties in the development of assays for complexed PSA (cPSA), but assays for this isoform are now commercially available. The sum of the cPSA from Bayer and the Hybritech fPSA is equal to the total PSA measured by the Hybritech29 and Bayer methods.30 Several studies have suggested that the cPSA may be slightly more specific for prostate cancer detection than total PSA in men with total PSA levels in the gray zone.29,31 The superiority of cPSA relative to total PSA, however, was not observed in other studies.32,33

The measurement of cPSA may prove to have clinical application in the determination of percent free (or percent complexed) PSA. fPSA, as a percentage of total, is relatively diminished in patients with prostate cancer, and it has been shown that complexed PSA as a percentage of total tends to be increased in these patients.

Analytically, the cPSA may prove to be superior to the fPSA for a couple of reasons. First, cPSA is present at higher concentrations than the fPSA. In the serum of men with low total PSA, the analytic precision of the free PSA measurement can limit the utility of the test, since clinical decisions are made based on small differences in small numbers. A second advantage to the use of cPSA is the greater in vitro stability of this isoform relative to the fPSA. The instability of the fPSA can lead to falsely low results if the sample is stored or transported in a suboptimal manner.

Staging Prostate Cancer with PSA

The likelihood of effective prostate cancer treatment by radical prostatectomy or radiation therapy is dependent on the pathologic stage to which the cancer has developed at the time of treatment. Clinicians have searched for a tool to predict the degree of cancer containment to the prostate without pathological staging of surgical sections.2,5 Some urologists, with patient consultation, might elect not to treat smaller, potentially less aggressive cancers, especially in older men. Clearly, a tool for the accurate assessment of prostate cancer stage would be exceedingly helpful to physicians and patients in making treatment decisions.

Pretreatment total PSA levels have been shown to correlate with the cancer's response to treatment.2 The American Urologic Association has made specific recommendations regarding the need for bone scans, CT or MRI for staging prostate cancer based on pretreatment PSA levels.2 The use of total PSA in predicting the stage of development of prostate cancers is somewhat limited, however, as several studies have indicated that PSA levels alone were not able to predict the final pathologic stage in all patients.5

Several studies suggest that percent fPSA determination may prove to be an even better tool for prostate cancer staging.34,35 A further analysis of the Hybritech fPSA clinical trial data23 indicated that 75 percent of cancers found in patients with percent fPSA greater than 15 percent were organ-confined.34 Only 34 percent of patients with percent fPSA of less than 15 percent had cancers that were confined to the prostate.34

In a separate study of 108 men who were treated for prostate cancer by radical prostatectomy, preoperative percent fPSA was shown to correlate with the cancer's size and capsular penetration.35 These studies suggest that percent fPSA determination may be helpful in staging prostate cancer.

Use of PSA in Monitoring Treated Prostate Cancer Patients

The use of PSA as an aid in the management of prostate cancer patients after treatment has been well documented.2,5,36 The frequency of cancer recurrence correlates with the degree of cancer progression at the time of treatment.PSA levels should drop to undetectable levels within a month after a curative radical prostatectomy.2,36 Initial radiation therapy does not always result in a drop in PSA levels to undetectable levels; however, the PSA nadir (lowest concentration achieved after initial radiation therapy) has been shown to correlate with the probability of disease recurrence.37 Biochemical recurrence, defined as increasing PSA levels after treatment, can be observed much earlier than clinical signs of tumor recurrence.38,39

Persistent elevation of PSA following treatment or an increase in a post-treatment PSA level has been found to be indicative of recurrent or residual disease.36,40,41 The American Society for Therapeutic Radiology and Oncology has established guidelines for use of PSA levels in determining the appropriate points for prostate rebiopsy or for performing salvage radiotherapy.42

The lead time for the detection of prostate cancer recurrence can be increased by months, or even years, through the measurement of ultrasensitive PSA.43,44 The ultrasensitive PSA tests can be used as an aid in the management of patients following surgical or medical treatment for prostate cancer.

The tests typically have a functional sensitivity of 0.01 ng/mL, which is an order of magnitude greater than that of other conventional assays (0.1 ng/mL). Unfortunately, there is no evidence that the early detection of prostate cancer recurrence that can be achieved with the ultrasensitive assays can prolong patient survival or reduce morbidity. It has been established that the ultrasensitive assays can detect small amounts of PSA originating from extrahepatic sources.45 It is not clear to what extent small elevations observed only by ultrasensitive methods might be caused by events that are unrelated to prostate cancer recurrence. At this point, it seems that more clinical studies are needed to determine whether use of the ultrasensitive PSA assays offers any clear advantage in the monitoring of patients who have been treated for prostate cancer.

Dr. Valcour is the national director of esoteric immunoassay at LabCorp.

References:

1. von Eschenbach A, Ho R, Murphy GP, et al. American Cancer Society guidelines for the early detection of prostate cancer. Cancer 1997;80(9):1805-1807.

2. Prostate-specific antigen (PSA) best practice policy. Oncology 2000;14:267-286.

3. Hankey BF, Feuer EJ, Clegg LX, et al. Cancer surveillance series: interpreting trends in prostate cancer—part I: Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst 1999; 91(12):1017-1024.

4. Sokoll LJ, Chan DW. Prostate-specific antigen. Its discovery and biochemical characteristics. Urol Clin North Am 1997;24:253-259.

5. Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: A decade of discovery-What we have learned and where we are going. Journal of Urology 1999;162:293-306.

6. Yu H, Levesque MA, Clark GM, Diamandis EP. Prognostic value of prostate-specific antigen for women with breast cancer: a large United States cohort study. Clin Cancer Res 1998; 4(6):1489-1497.

7. Woodrum D, French C, Shamel LB. Stability of free prostate-specific antigen in serum samples under a variety of sample collection and storage conditions. Urology 1996; 48(6A):33-39.

8. Woodrum D, York L. Two-year stability of free and total PSA in frozen serum samples. Urology 1998;52(2):247-251.

9. Ornstein DK, Rao GS, Smith DS, et al. Effect of digital rectal examination and needle biopsy on serum total and percentage of free prostate specific antigen levels. J Urol 1997;157(1):195-198.

10. Allard WJ, Cheli CK, Morris DL, et al. Multicenter evaluation of the performance and clinical utility in longitudinal monitoring of the Bayer Immuno 1TM complexed PSA assay. Int J Biol Markers 1999;14(2):73-83.

11. Crawford DE, DeAntoni EP, Etzioni R, et al. Serum prostate-specific antigen and digital rectal examination for early detection of prostate cancer in a national community-based program. Urology 1996;47(6):863-869.

12. Lee F, Littrup, PJ, et al. Prostate cancer: comparison of transrectal US and digital rectal examination for screening. Radiology 1988;168:389.

13. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: Results of a multicenter trial of 6,630 men. J Urol 1994;151:1283-1290.

14. 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. JAMA 1997;277(18):1452-1455.

15. Catalona WJ, Ramos CG, Carvalhal GF and Yan Y. Lowering PSA cutoffs to enhance detection of curable prostate cancer. Urology 2000;55(6):791-795.

16. Carter HB. A PSA threshold of 4.0 ng/mL for early detection of prostate cancer: The only rational approach for men 50 years old and older. Urology 2000; 55(6):796-799.

17. Seaman E, Whang IS, Olsson CA, et al. PSA density (PSAD). Role in patient evaluation and management. Urol Clin N Am 1993;20(4):653.

18. 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 1994;152(6):2031.

19. Brawer MK, Aramburu EAG, Chen GL, et al. The inability of prostate specific antigen index to enhance the predictive value of prostate specific antigen in the diagnosis of prostatic carcinoma. J Urol 1993;150(2):369.

20. Djavan B, Slotta A, Kratzik C, et al. PSA, PSA density, PSA density of the 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;54(3):517-522.

21. Catalona WJ, Southwick PC, Slawin KM, et al. Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging. Urology 2000;56(2):255-260.

22. Carter HB and Pearson JD. Prostate-specific antigen velocity and repeated measures of prostate-specific antigen. Urol Clin North Am 1997;24(2):333-338.

23. Catalona WJ, Partin AW, Slawin KM, et al. Use of percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998;279(19):1542-1547.

24. Basso D, Fogar P, Piva MG, et al. Total PSA, free PSA/total PSA ratio, and molecular PSA detection in prostate cancer: Which is clinically effective and when? Urology 2000;55(5):710-715.

25. Vessella RL, Lange PH, Partin AW, et al. Probability of prostate cancer detection based on results of a multicenter study using the AxSYM free PSA and total PSA assays. Urology 2000;55(6):909-914.

26. Catalona WJ, Partin AW, Finlay JA, et al. Use of percentage of free prostate-specific antigen to identify men at high risk of prostate cancer when PSA levels are 2.51-4 ng/mL and digital rectal examination is not suspicious for prostate cancer: An alternative model. Urology 1999;54(2):220-224.

27. Catalona WJ, Partin AW, Slawin KM, et al. Percentage of free PSA in black versus white men for detection and staging of prostate cancer: A prospective multicenter clinical trial. Urology 2000;55(3):372-376.

28. Fowler JE Jr, Sanders J, Bigler SA, et al. Percent free prostate specific antigen and cancer detection in black and white men with total prostate specific antigen 2.5 to 9.9 ng/mL. J Urol 2000;163(5):1467-470.

29. Brawer MK, Grant ME, Meyer JL, et al. Measurement of complexed PSA improves specificity for early detection of prostate cancer. Urology 1998;53(3):372-378.

30. Stamey TA, Yemoto CE. Examination of the 3 molecular forms of serum prostate specific antigen for distinguishing negative from positive biopsy: relationship to transition zone volume. J Urol 2000;163(1):119-126.

31. Brawer MK, Cheli CD, Neaman IE, et al. Complexed prostate specific antigen provides significant enhancement of specificity compared with total prostate specific antigen for detecting prostate cancer. J Urol 2000;163(5):1476-1480.

32. Jung K, Ulrike E, Lein M, et al. Ratio of free or complexed prostate-specific antigen (PSA) to total PSA: Which ratio improves differentiation between benign prostatic hyperplasia and prostate cancer? Clin Chem 2000;46(1)55-62.

33. Okegawa T, Noda H, Nutahara K, Higashihara E. Comparison of two investigative assays for the complexed prostate-specific antigen in total prostate-specific antigen between 4.1 and 10.0 ng/mL. Urology 2000;55(5):700-704.

34. Southwick PC, Catalona WJ, Partin AW, et al. Prediction of post-radical prostatectomy pathological outcome for stage T1c prostate cancer with percent free prostate specific antigen: A prospective multicenter clinical trial. J Urol 1999;162:1346-1451.

35. Arcangeli CG, Humphrey PA, Smith DS, et al. Percentage of free serum prostate-specific antigen as a predictor of pathologic features of prostate cancer in a screening population. Urology 1998;51(4):558-565.

36. Laufer M, Pound CR, Carducci MA, Eisenberger MA. Management of patients with rising prostate-specific antigen after radical prostatectomy. Urology 2000; 55(3):309-315.

37. Critz FA, Levinson AK, Williams WH, et al. Prostate specific antigen nadir achieved by men apparently cured of prostate cancer by radiotherapy. J Urol 1999; 161:1199-1205.

38. Patel A, Dorey F, Franklin J, deKernion JB. Recurrence patterns after radical retropubic prostatectomy: Clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 1997;158:1441-1445.

39. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomical radical retropubic prostatectomy: Patterns of recurrence and cancer control. Urol Clin N Am 1997;24(2):395.

40. Schellhammer PF, El-Mahdi AM, Kuban DA, Wright GL. Prostate-specific antigen after radiation therapy; Prognosis by pretreatment level and post treatment nadir. Urol Clin N Amer 1997;24(2):407-414.

41. American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: Guidelines for PSA following radiation therapy. Int J Rad Oncol Biol Phys 1997;37(5):1035-1040.

42. American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement on radiation therapy of prostate cancer: Guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. J Clin Oncol 1999;17(4):1155-1163.

43. Witherspoon LR, Lapeyrolerie T. Sensitive prostate specific antigen measurements identify men with long disease-free intervals and differentiate aggressive from indolent cancer recurrences within 2 years after radical prostatectomy. J Urol 1997; 157:1322-1328.

44. Yu HE, Diamandis EP, Prestigiacomo AF, Stamey TA. Ultrasensitive assay of prostate-specific antigen used for early detection of prostate cancer relapse and estimation of tumor-doubling time after radical prostatectomy. Clin Chem 1995;41(3):430-434.

45. Diamandis EP, Yu H. Nonprostatic sources of prostate specific antigen. Urol Clin North Am 1997;24(2):275-282.

Page Reviewed and/or Updated:

September 21, 2008