Subject Review. Percent Free Prostate-Specific Antigen: Entering a New Era in the Detection of Prostate Cancer

Subject Review Percent Free Prostate-Specific Antigen: Entering a New Era in the Detection of Prostate Cancer ApOORVA R. VASHI, M.D., AND JOSEPH E. OESTERLING, M.D. The introduction of prostate-specific antigen (PSA) testing into clinical medicine in 1986 revolutionized the managementof patientswith prostatecancer. The major limitation of this tumor marker stems from its inability to provide a clear distinction between benign prostate disease and prostate cancer, especially in patients with upper limit of normal or slightly increased PSA values. Recent research has established that PSA exists in the serum in several molecular forms. Patients with benign prostatic hyperplasia have more of the free form, whereas those with prostate cancer have more of a complexed form (PSA covalently bound to (ll-antichymotrypsin). Several investigations have now confirmed that determining percent free PSA (proportion of free PSA to total PSA) enhances the ability of PSA testing to distinguish between prostate cancer and benign prostatic hyperplasia. In addition, percent free PSA seems to have the greatest clinical significance in patients whose total PSA values range from 2.5 or 3.0 ng/ml (lower limit) to 10.0 ng/ml (upper limit). When the total PSA value is in the normal range (2.5 or 3.0 to 4.0 ng/ml), percent free PSA makes PSA a more sensitive test (increases cancer detection). When the total PSA level is minimally increased (4.1 to 10.0 ng/ml), percent free PSA makes PSA a more specific test (eliminates performance of unnecessary prostate biopsies). Although further work remains, it seems that percent free PSA can substantially improve the clinical utility of the PSA test for detecting early, curable prostate cancer. (Mayo Clin Proc 1997; 72:337-344) ACT =ul-antichymotrypsin; Aue =area under the ROC curve; PSA = prostate-specific antigen; PSAD = PSA density; PSAV = PSA velocity; ROC=receiver operating characteristic On the basis ofthe more than 334,000 new cases and 41,800 deaths that are predicted for 1997, prostate cancer is the most commonly detected cancer in men and the second leading cause of death due to cancer.1 In order to decrease the mortality rate associated with this disease, efforts must be focused on early detection of organ-confined cancer in young men; no curative therapy is available for systemic prostate cancer. Since its discovery in 1979,2 prostate-specific antigen (PSA) has become the most clinically useful tumor marker available for the diagnosis and management of prostate cancer.' Studies have demonstrated that PSA testing detects significantlymore cancers than does digital rectal examination.v' as well as a greater proportion of organconfined cancers." Originally, investigators believed that PSA testing might detect clinically insignificant cancers, but current evidence clearly shows that most PSA-detected pros- From The Michigan Prostate Institute, The University of Michigan, Ann Arbor, Michigan, Address reprint requests to Dr. J. E. Oesterling, The Michigan Prostate Institute, The University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI48109. tate cancers have the pathologic features of clinically important, life-threatening tumors."? Although PSA is a powerful clinical tool to monitor disease progression and manage patients with prostate cancer,' in its current form, PSA lacks sufficient sensitivity and specificity to be considered the ideal tumor marker for the early detection of prostate cancer. The use of the traditional cutpoint of 4.0 ng/ml to distinguish between "normal" and "abnormal" PSA values has several limitations. Because PSA is organ specific and not cancer specific, considerable overlap in PSA values exists between patients with prostate cancer and those with benign conditions such as benign prostatic hyperplasia and prostatitis.l''!' In addition, 38 to 48% of patients with clinically significant organ-confined cancer have a normal PSA value of 4.0 ng/ml or less. 12,13 In order to address these concerns, the concepts of PSA density (PSAD),14.15 PSA velocity (PSAV),16,17 and age-specific reference ranges'v'? have been introduced and investigated. In addition, recent studies have demonstrated that PSA is present in the serum in several molecular forms."?' Preliminary investigations have illustrated the potential benefits of using these molecular forms of PSA to enhance the Mayo Clin Proc 1997; 72:337-344 337 1997 Mayo Foundation/or Medical Education and Research

338 Mayo Clio Proc, April 1997, Vol 72 PERCENT FREE PROSTATE-SPECIFIC ANTIGEN clinical utility of PSA testing in the early detection of prostate cancer. These studies suggest that the ability to measure these specific forms of PSA in the serum can enhance the capability of PSA to distinguish between patients with prostate cancer and those with benign disease.p:" This represents a major step forward for men with a serum PSA value in the upper limit of normal or a mildly increased level. CURRENT METHODS OF IMPROVING THE PSA TEST The goals of improving the PSA test are twofold: to enhance sensitivity (increase cancer detection) and to improve specificity (eliminate costly and invasive prostate biopsies that show normal results). PSAD, PSAV, and age-specific reference ranges have been proposed to achieve these goals. In 1992, Benson and associates" introduced the concept of PSAD to distinguish PSA increases due to prostate cancer from those due to benign disease. PSAD is the ratio of the serum PSA concentration and prostate volume, as determined by transrectal ultrasonography. These investigators concluded that a PSAD of 0.15 or less was normal. Unfortunately, PSAD is limited by several factors, including the cost and invasiveness of the transrectal prostate ultrasound study and the inaccuracy of ultrasound to determine the precise prostate volume.f" In addition, a large screening study by Catalona and colleagues" showed no benefit of PSAD over a single PSA cutpoint of 4.0 ng/ml. Carter and coworkers'? introduced the concept of PSAV to enhance the clinical utility of the PSA test. They concluded that a PSAV of 0.75 ng/ml or greater per year was a concern for the presence of prostate cancer. In general, the concept is useful; however, it is limited by the intrinsic variability of PSA testing and the fact that the same assay and laboratory should be used for each measurernent.f:" In addition, each serum sample should be obtained under similar conditions to control for variations due to infection, ejaculation, and other prostate manipulations." Thus, PSAD and PSAV have practical limitations that minimize their effectiveness. Age-specific reference ranges, as proposed by Oesterling and associates, i8 represent an effective method of enhancing the clinical utility of the PSA test. These ranges increase the sensitivity of the PSA test in younger men by decreasing the number of false-negative results and improve the specificity in older men by decreasing the number of false-positive results. 18 The recommended age-specific reference ranges (as proposed by Oesterling and colleagues") are as follows: 0.0 to 2.5 ng/ml, for men 40 to 49 years old, 0.0 to 3.5 ng/ml for men 50 to 59 years old, 0.0 to 4.5 ng/ml, for men 60 to 69 years old, and 0.0 to 6.5 ng/ml for men 70 to 79 years old. The concept that the serum PSA concentration correlates directly with the patient's age has been confirmed subsequently in several investigations.v-v-" A limitation of the work by Oesterling and coworkers 18 is that the data were generated from a homogeneous group of white men. Prostate cancer has a lower incidence in Asian men and a higher, more aggressive incidence in black men. 32 33 Oesterling and associates" noted a similar increase in serum PSA with advancing age in a cohort of healthy Japanese men; however, the age-specific reference ranges were lower: 0.0 to 2.0 ng/ml for men 40 to 49 years old, 0.0 to 3.0 ng/ml for men 50 to 59 years old, 0.0 to 4.0 ng/ml for men 60 to 69 years old, and 0.0 to 5.0 ng/ml for men 70 to 79 years 01d. 32 A recent investigation by Morgan and colleagues" examined the utility of age-specific reference ranges in a large group of black men. With use of the traditional age-specific reference ranges determined for white men, 41 % of cancers would have been overlooked in black men. Therefore, although serum PSA correlated directly with patient age, a separate set of age-specific ranges were determined for black men: 0.0 to 2.0 ng/ml for men 40 to 49 years old, 0.0 to 4.0 ng/ml for men 50 to 59 years old, 0.0 to 4.5 ng/ml for men 60 to 69 years old, and 0.0 to 5.5 ng/ml, for men 70 to 79 years old. The recommended agespecific reference ranges for white, Asian, and black men are succinctly summarized in Table 1. Although many investigations have confirmed the finding that the serum PSA level increases with advancing age, the use of different study populations has produced slightly different cutpoints for the age-specific reference ranges. In addition, the value of wider reference ranges in older men (those older than 60 years) has been questioned by the strong proponents of prostate cancer screening. In a study of 6,630 men, Catalona and coworkers" concluded that a cutpoint of 4.0 ng/ml, was superior to age-specific ranges in men older than 60 years because of a potential decrease in cancer detection when age-specific ranges are used for such men. Partin and associates" evaluated the pathologic characteristics of prostate tumors detected or overlooked when agespecific reference ranges were used. This investigation supported the use of age-specific reference ranges in men younger than 60 years of age. Failure to detect some organtable l.-age-specific Reference Ranges Based on Race Serum prostate-specific antigen* (ng/ml) Age (yr) Black Asian White 40-49 50-59 60-69 70-79 2.0 4.0 4.5 5.5 2.0 3.0 4.0 5.0 2.5 3.5 4.5 6.5 *Upper limit of normal,

Mayo Clin Proc, April 1997, Vol 72 PERCENT FREE PROSTATE-SPECIFIC ANTIGEN 339 confined tumors in older men (the clinical significance of these small tumors in older men is unknown), however, led these investigators to conclude that age-specific ranges in men older than 60 years should be studied further. Thus, the search for ways to improve the utility of the PSA test in the early detection of prostate cancer continues. MOLECULAR FORMS OF PSA The discovery that PSA exists in the serum in several molecular forms represents an exciting, new approach for improving the clinical utility of the PSA test. The major forms include a noncomplexed or free form and complexes of PSA with the serine protease inhibitors <Xl-antichymotrypsin (ACT) and <X 2-macroglobulin (the latter of which is undetectable with current immunoassaysj.i':" Total PSA is a combination of all immunodetectable forms in serum, primarily free PSA and PSA-ACT, even though trace amounts of complexes with protein C inhibitor, <Xl-antitrypsin, and interalpha-trypsin inhibitor have been reported." The complexed form between PSA and ACT is the predominant form in the serum, and the noncomplexed or free form is present in a smaller fraction" (Table 2). EARLY INVESTIGAnONS OF PERCENT FREE PSA Preliminary investigations have illustrated the potential benefits of using free or complexed PSA (or their proportion to total PSA) to enhance the clinical utility of PSA in the early detection of prostate cancer. In 1991, Stenman and colleagues" demonstrated that PSA complexed to ACT was higher in patients with prostate cancer than in patients with benign disease. They proposed that the complexed-to-total PSA proportion could discriminate between benign and malignant prostate disease and eliminate one-halfof false-positive results ("negative" biopsies). These findings were confirmed subsequently by Christensson and coworkers." These investigators, however, suggested that the free-tototal proportion or percent free PSA, which is lower in patients with cancer, was a more sensitive or accurate means of discriminating between benign and malignant prostate disease. Using a percent free PSA cutpoint of 0.18, Christensson and associates reported an increase in specificity from 55 to 73% with minimal decrease in sensitivity. The major shortcomings of these studies were the relatively small number of patients and the inclusion of patients with a wide range of PSA values. DEFINING A "REFLEX RANGE" FOR USING PER CENT FREE PSA Most investigations of percent free PSA have included patients with minimally increased PSA values and have focused on the ability of percent free PSA to eliminate negative prostate biopsies (improve specificity). The definition of a minimally increased PSA level has been arbitrarily determined, however, ranging from 4.1 ng/ml to 10.0 or even 20.0 ng/ml. In addition, percent free PSA may also be able to improve cancer detection (sensitivity) in patients with PSA values in the normal range (less than 4.0 ng/ml). Therefore, a logical first step would be to define an optimal range of total PSA for the use of percent free PSA (a reflex range). Indeed, several investigators have determined that Formal name Total PSA Free PSA PSA complexes Table 2.-Molecular Forms of Prostate-Specific Antigen* Common name t-psa f-psa PSA-ACT PSA-MG PSA-PCI PSA-AT PSA-IT *PSA = prostate-specific antigen. Modified from McCormack and associates." By permission. Description All immunodetectable forms in serum, primarily f-psa and PSA-ACT Noncomplexed PSA; may be proteolytically active or inactive in seminal fluid, only inactive in serum PSA covalently bound to al-antichymotrypsin inhibitor; synonymous with PSA complex; major immunodetectable form in serum PSA covalently linked and encapsulated by a 2-macroglobulin; not detected in immunoassays; synonymous with occult PSA PSA covalently bound to protein C inhibitor; minor component in seminal fluid; not detected in serum PSA covalently bound to ai-antitrypsin; trace component in serum PSA covalently bound to inter-alpha-trypsin inhibitor; trace component in serum

340 PERCENT FREE PROSTATE-SPECIFIC ANTIGEN Mayo CIiD Proc, April 1997, Vol 72 percent free PSA is not useful for the whole range of PSA. 2 6,37 We recently conducted an investigation to define this optimal "reflex range.'?" Our investigation involved 413 men: 225 with benign prostate disease and 188 with clinically localized prostate cancer who had serum PSA values in the 2,0 to 20,0 ng/ml range. We plotted receiver operating characteristic (ROC) curves for total PSA and percent free PSA across various ranges of total PSA. Percent free PSA demonstrated maximal improvement over total PSA (in regard to distinguishing benign prostatic hyperplasia from prostate cancer) in the range of 3.0 to 10.0 ng/ml, as determined by the greatest difference in areas between ROC curves (Fig. 1). In this range, the area under the ROC curve (AVC) for percent free PSA was 0.72, whereas the AVC for total PSA was 0.51 (P<O.OO1). A perfect test has an AVC of 1.0, whereas a test with no discriminatory value has an AVC of 0.5. 39 Percent free PSA clearly represents a significant improvementover total PSA. Therefore, on the basis of these data, any patient with a PSA in this reflex range of 3.0 to 10.0 ng/ml should have a percent free PSA determined. Catalona and colleagues" proposed a slightly different reflex range. In a recent study of men with PSA values ranging from 2.6 to 4.0 ng/ml (see subsequent discussion), percent free PSA determination significantly improved cancer detection. Combining this finding with their initial investigation" ofthe utility of percent free PSA in the range of 4.1 to 10.0 ng/ml (see subsequent discussion), they proposed a reflex range of 2.5 to 10.0 ng/ml. Although we agree that a PSA of 10.0 ng/ml should be the upper limit of normal, whether percent free PSA should be used when the total PSA is 2.5 ng/ml or 3.0 ng/ml is debatable. We chose a 3.0 ng/ml cutpoint because a cutpoint of 2.5 ng/ml resulted in a significantly increased number of biopsies with only a minimal increase in cancer detection. Of note, our study group represented a tertiary referral population, whereas Catalona's subjects were from a screening population. A reflex range of 2.5 or 3.0 ng/ml, (lower limit) to 10.0 ng/ml (upper limit) has appropriate clinical applications. Because most clinicians would not hesitate to perform a prostate biopsy when the total PSA value is greater than 10.0 ng/ml, determination of percent free PSA would be unnecessary when the total PSA value is greater than 10.0 ng/ml. In contrast, considerable debate exists over the current "normal" cutpoint for total PSA (4.0 ng/ml). Labrie and coworkers" proposed a cutpoint of 3.0 ng/ml, below which only a 1.4% chance existed of cancer being overlooked. Partin and associates" suggested that a greater proportion of organ-confined cancers could be detected with a level of 2.8 ng/ml. Oesterling and colleagues" use a cutpoint of 2.5 ng/ml in men 40 to 49 years old and a cutpoint of 3.5 ng/ml. in men 50 to 59 years old. Therefore, a lower limit for the reflex range of 2.5 or 3.0 ng/ml seems clinically appropriate to increase cancer detection. 0,23 Improved performance 0.21 of percent free-psa over total 0.19 PSA(%) 0.17 0.15 o-_.f Lower limit of reflex range (ng/ml) 10 Upper limit of reflex range (ng/ml) 6 Fig. 1. Determination of prostate-specific antigen (PSA) reflex range with best performance for percent free PSA. Bar graph illustrates that total PSA range of 3.0 to 10.0 ng/ ml demonstrates maximal improvement of percent free PSA over total PSA. (From Vashi and colleagues." By pennission.)

Mayo Clin Proc, April 1997, Vol 72 PERCENT FREE PROSTATE-SPECIFIC ANTIGEN 341 USE OF PERCENT FREE PSA WHEN THE TOTAL PSA IS NORMAL When the total PSA is in the normal range, the objective is to increase cancer detection (sensitivity) with a judicious increase in the number of biopsies performed. Because the traditional cutpoint of 4.0 ng/ml necessitates a prostate biopsy in patients with a PSA value higher than 4.0 ng/ml and observation in those with a level lower than 4.0 ng/ml, we" divided our "reflex" population into two subgroups: those with total PSA values between 3.0 and 4.0 ng/ml, and those with total PSA values between 4.1 and 10.0 ng/ml. ROC curves comparing the ability of percent free PSA and total PSA values in the range of 3.0 to 4.0 ng/ml to distinguish between benign prostate disease and prostate cancer are shown in Figure 2. Percent free PSA demonstrated significant improvement over total PSA (P<O.OI). In this investigation, we" determined that a percent free PSA cutpoint of 0.19 (or lower) detected 90% of all cancers in the 3.0 to 4.0 ng/ml subgroup. When the cutpoint is higher than 0.19, a patient has less than a 15% chance of having cancer if a biopsy is not performed. With use of the cutpoint of 0.19 for percent free PSA, 73% of the men with a total PSA level between 3.0 and 4.0 ng/ml would have undergone biopsy, and the cancer detection rate would have been 44%. Thus, for every 1.7 biopsies performed, 1 cancer is detected. The aforementioned study by Catalona and coworkers'? also supports the ability of percent free PSA to improve cancer detection when the total PSA value is in the normal range. These investigators reviewed the medical records of 120 men with PSA values between 2.8 and 4.0 ng/ml who had undergone prostate biopsy as part of a pilot study. Cancer was detected initially in 7% and in a total of 22% throughout 4 years of serial screening. With use of a cutpoint of 0.23 for percent free PSA, 93% of men with cancer would have been identified, and 28% of negative biopsies would have been eliminated. On the basis of this information, they conducted a prospective study of 217 "screened" volunteers whose total PSA values were between 2.6 and 4.0 ng/ml and who had undergone a prostate biopsy. With use of a percent free PSA cutpoint of 0.25,91% of the cancers were detected, and 26% of the negative biopsies were eliminated. Therefore, it seems that percent free PSA can significantly enhance cancer detection when the total PSA value is in the upper limit of the normal range. Theoretically, this should result in a larger percentage of organconfined cancers being detected. 12,13,41,42 USE OF PERCENT FREE PSA WHEN TOTAL PSA IS BETWEEN 4.1 AND 10.0 NG/ML Within a PSA range of 4.1 to 10.0 ng/ml, the objective is to eliminate unnecessary negative prostate biopsies (improve specificity) without compromising cancer detection. In a screening population, Keetch and associates? determined that 20% of men with a PSA value between 4.1 and 10.0 ng/ ml have cancer. In our study," total PSA between 4.1 and 10.0 ng/ml, in conjunction with an AVC of 0.52 was of no value in distinguishing benign disease from cancer. Percent free PSA, however, exhibited significant improvement over total PSA in this range (P<0.05) (Fig. 3). On the basis of this information, we" determined that the appropriate cutpoint 1.0 0.9 0.8 0.7 0.6 sensitivity 0.5 0.4 n=41...... roo' 1.0 0.9 0.8 0.7 0.6 sensitivity 0.5 0.4 0.3 0.2... Percent free-psa 0.3 0.2 0.1 - TotalPSA 0.1 0.0. j.... l : : ; : = ; : = ; =..., - -.., - -,. - - - 0.0 -, ; - - -. - - - - -. - ~ 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1-speclflclty 1-speclflclty Fig. 2. Receiver operating characteristic curves for distinguishing prostate cancer from benign prostate disease, comparing percent free prostate-specific antigen (PSA) to total PSA in reflex range subset of 3.0 to 4.0 ng/ml. Areas under the receiver operating characteristic curves for percent free PSA and total PSA are 0.78 and 0040,respectively (P<O.OI). (From Vashi and associates." By permission.) Fig. 3. Receiver operating characteristic curves for distinguishing prostate cancer from benign prostate disease, comparing percent free prostate-specific antigen (PSA) to total PSA in reflex range subset of 4.1 to 10.0 ng/ml. Areas under the receiver operating characteristic curves for percent free PSA and total PSA are 0.71 and 0.52, respectively (P<0.05). (From Vashi and coworkers." By permission.)

342 PERCENT FREE PROSTATE-SPECIFIC ANTIGEN for percent free PSA is 0.24 when the total PSA value is between 4.1 and 10.0 ng/ml (that is, all patients with PSA values lower than or equal to 0.24 should undergo biopsy, and those with values greater than 0.24 should not undergo biopsy). This cutpoint maintains a 95% sensitivity for cancer detection and eliminates 13% of the negative biopsies in this range. Thus, for every seven negative biopsies eliminated, one cancer is undetected. Our results correspond with those of previous studies that have addressed the use of percent free PSA in the range of 4.1 to 10.0 ng/ml. 25.26 Catalona and colleagues" determined that a cutpoint of 0.234 maintains a 90% sensitivity for cancer detection and eliminates 31 % of negative biopsies in men with normal findings on digital rectal examination. Catalona and coworkers" also suggested that prostate volume was important in selecting a cutpoint for percent free PSA. In a small subset of the study population that had prostate volumes lower than 40 ml, a percent free PSA cutpoint of 0.137 detected 90% of cancers and eliminated 76% of negative biopsies. Major limitations of this study were the relatively small number of patients (N = 113) and even smaller numbers within the previously mentioned subgroups. In a cohort of 57 patients, Luderer and associates" examined the utility of percent free PSA in the "diagnostic gray zone" of 4.1 to 10.0 ng/ml. These investigators reported that a cutpoint of 0.25 detected all cancers and eliminated 31% of negative biopsies. They suggested a cutpoint of 0.20, which resulted in 88% sensitivity and 50% specificity. Catalona and colleagues" and Luderer and coworkers" have suggested slightly lower cutpoints for percent free PSA. They, however, have accepted a 90% sensitivity, whereas we have preferred a 95% sensitivity for detecting prostate cancer when the total PSA value is 4.1 to 10.0 ng/ml. Failure to detect 10% of cancers in men with PSA values of 4.1 to 10.0 ng/ml, is of some concern because these tumors are potentially curable. Therefore, our cutpoint of 0.24 maintains 95% sensitivity for cancer detection in this subgroup. The actual value of percent free PSA will be known only when an investigation is conducted that involves a large number of men in the appropriate age-group who are at risk for prostate cancer. Such a screening study by Bangma and associates" is under way. On the basis of preliminary data from 1,726 men who underwent rectal examination, transrectal ultrasonography, and PSA testing, 67 prostate cancers were detected. Using a cutpoint of 0.20 for percent free PSA, these investigators were able to eliminate 39% of biopsies but overlooked 11% of cancers. Other studies also have demonstrated the clinical usefulness of percent free PSA.45-48 All have shown that percent free PSA can improve specificity without a decrease in sensitivity when the total PSA values are less than 20 ng/ml. Mayo Clio Proc, April 1997, Vol 72 Cutpoints proposed for percent free PSA have ranged from 0.15 to 0.25, and the number of biopsies that have been eliminated has ranged from 13 to 76%. Although none of these studies specifically determined a "reflex range," the general consensus was that percent free PSA was useful in discriminating between benign and malignant prostate disease in patients with a total PSA value in the upper limit of normal or with minimally increased PSA values. FUTURE DIRECTIONS WITH PERCENT FREE PSA In addition to the search for methods to improve the detection of prostate cancer, the search continues for methods to predict aggressive versus "insignificant" cancers before definitive treatment is administered. In a group of patients with PSA values that ranged from 2.0 to 14.0 ng/ml, Arcangeli and associates" demonstrated that a lower percent free PSA is associated with more adverse pathologic features. These investigators suggested that a percent free PSA higher than 0.20 is associated with potentially insignificant cancers, and 90% of tumors with adverse features are associated with values lower than 0.20. These findings, however, have not been verified in other trials. 50.51 Additional studies are needed to clarify this observation. Despite the significant improvement of percent free PSA over total PSA, several questions remain unanswered about percent free PSA. Because PSA is age dependent, 14 percent free PSA may also vary with age. Oesterling and colleagues'" demonstrated that, although total, free, and complexed PSA all varied with age, the proportion of free PSA to total PSA (percent free PSA) was independent of age in a community-based population. In a separate study, however, we found that percent free PSA correlates directly with patient age (Vashi AR, Wojno KJ, Oesterling JE. Unpublished data). Controversy also exists about the effect of prostate volume on percent free PSA. Catalona and coworkers" suggested that percent free PSA increases with increasing prostate size. In contrast, Yemoto and associates" observed no correlation between prostate volume and percent free PSA. These relationships must be further examined in larger investigations. CONCLUSION The discovery that PSA exists in the serum in different molecular forms and the development of assays for free PSA represent a major advancement in the diagnosis of early, curable prostate cancer. An algorithm for the diagnosis of prostate cancer with use of percent free PSA is presented in Figure 4. Percent free PSA is significantly lower in patients with prostate cancer and discriminates between benign and malignant disease most effectively when the total serum PSA level is between 2.5 or 3.0 and 10.0 ng/ml. When the total PSA value is in the normal range, percent free PSA

Mayo Clin Proc, April 1997, Vol 72 PERCENT FREE PROSTATE-SPECIFIC ANTIGEN 343 A g e years ~ 5 0 A g e years ~ 4 0if positive family history or if Black Life expectancy of 10-15 years.-----1-------..1 ( ORE and PSA ) If ORE normal and PSA<3.0 ng/ml If PSA 3.0-10.0 ng/ml (Reflex range: % free-psa determination) If ORE suspicious or PSA>10.0 ng/ml If PSA 3.0-4.0 ng/ml and % free-psa:o;o.19 Annual evaluation and PSA velocity TRUS-guided biopsy Fig. 4. Diagnostic algorithm for detecting early, curable prostate cancer by using percent free prostate-specific antigen (PSA). DRE = digital rectal examination; TRUS = transrectal ultrasonographic. improves the sensitivity of the PSA test (improves cancer detection). When the total PSA value is 4.1 to 10.0 ng/ml, percent free PSA improves the specificity of the PSA test (eliminates negative prostate biopsies). Both of these outcomes are clinically desirable. Indeed, a new era in PSA testing is here. REFERENCES 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997. CA Cancer 1 Clin 1997; 47:5-27 2. Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification of a human prostate specific antigen. Invest Urol 1979; 17:159-163 3. Oesterling le. Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. 1 Urol 1991; 145:907-923 4. Brawer MK, Chetner MP, Beatie 1, Buchner OM, Vessella RL, Lange PH. Screening for prostatic carcinoma with prostate specific antigen. 1 Urol 1992; 147:841-845 5. Catalona Wl, Richie IP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. 1 Urol 1994; 151:1283-1290 6. Catalona Wl, Smith OS, Ratliff TL, Basler lw. Detection of organconfined prostate cancer is increased through prostate-specific antigen-based screening. lama 1993; 270:948-954 7. Smith OS, Catalona Wl. The nature of prostate cancer detected through prostate specific antigen based screening. 1 Urol 1994; 152:1732-1736 8. Epstein Jl, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage TIc) prostate cancer. lama 1994; 271:368-374 9. Stormont TJ, Farrow GM, Myers RP, BIute ML, Zincke H, Wilson TM, et al. Clinical stage BO or TIc prostate cancer: nonpalpable disease identified by elevated serum prostate-specific antigen concentration. Urology 1993; 41:3-8 10. Stamey TA, Yang N, Hay AR, McNeal le, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl 1 Med 1987; 317:909-916 II. Monda 1M, Barry MJ, Oesterling JE. Prostate specific antigen cannot distinguish stage Tla (AI) prostate cancer from benign prostatic hyperplasia. J Urol 1994; 151:1291-1295 12. Hudson MA, Bahnson RR, Catalona Wl. Clinical use of prostate specific antigen in patients with prostate cancer. J Urol 1989; 142:1011-1O17 13. Lange PH, Ercole Cl, Lightner 01, Fraley EE, Vessella R. The value of serum prostate specific antigen determinations before and after radical prostatectomy. 1 Urol 1989; 141:873-879 14. Benson MC, Whang IS, Olsson CA, McMahon 01, Cooner WHo The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostate specific antigen. 1 Urol 1992; 147:817-821 15. Seaman E, Whang M, Olsson CA, Katz A, Cooner WH, Benson Me. PSA density (PSAO): role in patient evaluation and management. Urol Clin North Am 1993 Nov; 20:653-663 16. Oesterling JE, Chute CG, lacobsen Sl, Guess HA, Panser LA, Johnson CL, et al. Longitudinal changes in serum PSA (PSA velocity) in a community-based cohort of men [abstract]. 1 Ural 1993; 149(Suppl):412A 17. Carter HB, Pearson JO, Metter EJ, Brant LJ, Chan OW, Andres R, et al. Longitudinal evaluation of prostate-specific antigen levels in

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