Total Prostate-specific Antigen Assays Research Articles

Do Modifications of Nonequimolar Assays for Total Prostate-specific Antigen Improve Detection of Prostate Cancer?

The major form of prostate-specific antigen (PSA) in serum is complexed to α1-antichymotrypsin (1)(2). This form is present in a higher proportion of men with prostate cancer (PCa) than in men with benign prostate (2). The ratio between the unbound free form of PSA and total PSA is lower in patients with PCa. Assays for total PSA that preferentially detect free PSA overreport the total PSA in sera of patients with benign prostate compared with patients with PCa (3). Thus, it was recommended that assays for total PSA should measure the immunologically detectable forms of PSA on an equimolar basis (4). The clinical relevance of these considerations remains controversial (5)(6)(7)(8)(9)(10)(11), although differences between total PSA assays are well documented (3)(12)(13)(14)(15)(16)(17)(18), but it has yet to be discovered whether the molar response characteristics of total PSA assays have a clinically relevant influence on the clinical diagnostic performance of the assay. Recently, the Assay Comparison Study for PSA of the Working Group on Laboratory Diagnostics of the German Urological Association (19) evaluated 25 total PSA assays and 11 free PSA assays using identical serum samples. During the course of the study, three nonequimolar assays were identified, which subsequently underwent major modifications by the manufacturers, thus challenging us to test the performance before and after modification using aliquots of identical sera. Serum aliquots of 338 men with total PSA concentrations of 2–30 μg/L (mean, 9.2 μg/L; median 7.5 μg/L; SD, 6.6 μg/L) as determined by the Tandem-E® (Hybritech) assay reagent set were selected from the Assay Comparison Study for PSA (19) in accordance with practices and ethical standards of the Committee on Ethical …

WHO First International Standards for Prostate-specific Antigen: The Beginning of the End for Assay Discrepancies?

Despite the success of prostate-specific antigen (PSA) as a tumor marker for the early detection and monitoring of disease in prostate cancer, both clinical and analytical limitations of PSA remain (1). Since the introduction of assays for total PSA in the mid-1980s, assay results have been found to differ among manufacturers (2)(3). Much has been learned in the last two decades about the biology of PSA and the molecular forms of PSA present in serum. Differences among assays still persist, however, even among assays from the same manufacturer that have the same antibodies but different assay formats. With the availability of the First International Standards from WHO, is this the beginning of the end for assay discrepancies? The lack of standardization of PSA was recognized early on as contributing to disparities among assays. Similar to some other tumor markers, a lack of defined antigens, differences in calibrator composition and specific molecular forms, and differences in calibrator assignments as well as the lack of a reference method are some of the issues hampering assay standardization. The lack of standardization of PSA prompted several organizations as well as individual researchers to convene meetings and conferences to address the issue. The Second Stanford Conference on International Standardization of Prostate-specific Antigen (4) was held in 1994. At this conference, the use of a standard, prepared at Stanford by Tom Stamey, consisting of 90% purified PSA-α1-antichymotrypsin (ACT) and 10% free PSA (90:10) on a molar basis was proposed with the rationale that …

Age-related reference intervals for free and total Prostate-specific antigen in a Singaporean population

Cancer of the prostate is the sixth most frequently found cancer in Singapore. Prostate-specific antigen (PSA) is the most clinically useful tumour marker available today for the diagnosis and management of prostate cancer. To enhance the value of PSA as a screening test we developed age-specific intervals for our ethnic population. The measurement of free PSA was included in the study to calculate the free:total ratio which enhances the differential diagnosis of prostate cancer from benign prostatic hyperplasia or prostatitis. The total PSA upper limits of 10-year intervals, beginning at 30-years-old, were 1.4, 1.7, 2.3, 4.0, 6.3 and 6.6 microg/l. Free PSA cut-off limits were 0.4, 0.5, 0.5, 1.0, 1.5 and 1.6 microg/l. The free:total ratio of PSA was not age dependent. Abbott AxSym standardised their calibration material for both free and total PSA assays with the Stanford 90:10 reference material. This laboratory has implemented these age-specific reference intervals and are currently following up their pick-up rate in the detection of prostate cancer.

PSA, PSA density, PSA density of 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

Objectives. To enhance the specificity of prostate cancer (PCa) detection and reduce unnecessary biopsies in men with prostate-specific antigen (PSA) levels of 2.5 to 4.0 ng/mL, we prospectively evaluated various PSA-based diagnostic parameters. Methods. This study included 273 consecutive men with serum PSA of 2.5 to 4.0 ng/mL referred for early PCa detection or lower urinary tract symptoms. All men underwent prostate ultrasound and sextant biopsy with two additional transition zone (TZ) biopsies. If the first biopsies were negative, repeated biopsies were performed at 6 weeks. Total PSA, PSA density (PSAD), PSA density of the transition zone (PSA-TZ), free/total PSA ratio (f/t PSA), and PSA velocity (PSAV) were determined, and the sensitivity, specificity, and predictive values of these various parameters were calculated. Results. Of 273 patients, 207 had histologically confirmed benign prostatic hyperplasia (BPH) and 66 had PCa. f/t PSA and PSA-TZ were the most powerful predictors of PCa, followed by PSA, PSAD, and PSAV. Areas under the receiver operating characteristic curves for f/t PSA and PSA-TZ were 74.9% and 70.1%, respectively. With a 95% sensitivity for PCa detection, an f/t PSA cutoff of 41% and a PSA-TZ cutoff of 0.095 would result in the lowest number of unnecessary biopsies (29.3% and 17.2% specificity for f/t PSA and PSA-TZ, respectively) compared with all other PSA-related parameters evaluated. Conclusions. Compared with standard total PSA assays, f/t PSA and PSA-TZ significantly enhance the sensitivity and specificity of PCa detection in a referral patient population with a total PSA of 2.5 to 4.0 ng/mL.

On the standardization of total prostate-specific antigen: an exercise with two reference preparations.

In this study, 112 serum samples were analyzed for total prostate-specific antigen with three well-established assays i.e. Tandem R and Tandem E (both from Hybritech Inc., San Diego, USA) and Prostatus Free/Total from Wallac Oy, Turku, Finland. Thirty-two samples were collected from prostate cancer patients, 32 from patients with benign prostate hyperplasia and 48 from men participating in a screening study for prostate cancer. The aim of the study was to compare the results before and after recalculation with the data obtained with two reference preparations for total prostate-specific antigen: Stanford 90:10 PSA Calibrator and Certified Reference Material 613 Prostate-Specific Antigen. Comparing the actual results revealed almost perfect correlations between Tandem R and Tandem E and between both Tandem assays and Prostatus. We observed statistically significant differences in accuracy between Tandem R and Tandem E: y(Tandem E)= 1.05 x(Tandem R)+0.07 and between Tandem E and Prostatus: y(Prostatus)= 0.94 x(Tandem E)+0.02 In both comparisons prostate-specific antigen values ranged from 0-40 microg/l. Recalculation with both reference preparations did not solve these discrepancies. One exception was the combination Tandem R and Tandem E. The application of either reference preparation solved the differences in accuracy here. In conclusion, even after recalibration, assays for total prostate-specific antigen are still not completely interchangeable.

Prostate-specific antigen ratio correlates with aggressiveness of histology grades of prostate cancer

Objectives: To compare prostate-specific antigen (PSA) ratio to total PSA (tPSA) assay for prostate cancer diagnosis and to study the correlation of PSA ratio with histology grade of prostate cancer. Methods: Among 334 selected cases, 136 had benign prostate diseases and 198 had prostate cancer. All cases underwent transrectal ultrasound (TRUS) and tissue biopsies within 6 months of their tPSA measurements. All of the tPSA levels taken were between 2 and 20 μg/L. The serum tPSA and free PSA were assayed using the Abbott AxSYM immunoassay system (Abbott Laboratories; Abbott Park, IL, USA). The PSA ratios of patients with prostate cancer were compared to those with benign prostate diseases (BPD) using the Student’s t test. Correlation between the histology grades and PSA ratios was calculated by Pearson test. Receiver operating characteristic (ROC) curves were generated from sensitivities and specificity of various PSA ratios and tPSA levels. Results: We found an inverse correlation between PSA ratios and aggressiveness of histology grades ( r = −0.995, p < 0.01). The higher the histology grade, the lower the PSA ratio tended to be, and the more sensitive and specific the PSA ratio was in the diagnosis of prostate cancer. No correlation was found between histology grades and tPSA levels. A PSA ratio of 0.25 diagnosed 93% of patients with Gleason score greater than 7 and 83% of all prostate cancer patients. It would have reduced unnecessary biopsies by 23% compared to the tPSA level of 4 μg/L. Sensitivity of PSA ratios was higher and specificity was lower in high tPSA level group than they were in low tPSA level group. Conclusions: PSA ratio inversely correlates to aggressiveness of prostate cancer and has a potential to predict histology grade of prostate cancer. PSA ratio improves sensitivity and specificity for prostate cancer diagnosis compared to tPSA assay.

A comparison of three free and total PSA assays.

Prostate-specific antigen (PSA) has emerged as the most predictive test of whether or not a man has prostatic carcinoma. The free to total PSA ratio provides important enhancement in specificity, thus obviating unnecessary negative biopsies. In the absence of an international standard for total PSA, much less free PSA, variation between manufacturers may cause confusing results. We sought to compare three different manufacturer's free and total PSA assays in a population consisting of consecutive patients who had PSA testing in a reference laboratory in Germany. Between April 1994 and July 1996, serum specimens from 240 men were evaluated with three different free and total PSA assays. Indications for PSA determination were based on the referring physician, who also provided the clinical diagnosis. Total and free PSA were measured on the same freeze-thaw cycle with Chiron Diagnostics, Enzymun Boehringer Mannheim, and Hybritech Tandem-R assays. Seventy-nine men had carcinoma of the prostate, 120 had clinical evidence of benign prostatic hyperplasia and 27 were without evidence of prostatic disease. The Chiron ACS: 180 free to total ratio compared very well with the Tandem-R assay at the 95% sensitivity level, affording 17 and 22% specificity respectively. Using the range of total PSA of 4-10 ng/ml, the increase in specificity of the free to total PSA is quite significant, and the specificity of the Enzymun assays is greatly improved. (Specificity of 49%, 29% and 25% at 95% sensitivity for ACS, Enzymun and Tandem respectively.) This data, based on 'real world' clinical experience, shows significant variation between different manufacturers' assays. There was significant equivalence between the Chiron and Hybritech assays. The Enzymun assay performed well only when data from the total PSA range of 4-10 ng/ml was included. Clinicians must be aware of which manufacturers' assays for both the free and total PSA their laboratory staff is utilizing, and laboratory technicians must provide meaningful outcome data based on the patient population they serve with respect to the performance of these assays.

FREE AND COMPLEXED PROSTATE SPECIFIC ANTIGEN IN THE DIFFERENTIATION OF BENIGN PROSTATIC HYPERPLASIA AND PROSTATE CANCER: STUDIES IN SERUM AND PLASMA SAMPLES

Purpose We prospectively evaluated serum and plasma concentrations of total and free prostate specific antigen (PSA), and PSA complexed to alpha 1-antichymotrypsin in 170 patients who underwent biopsy, including 59 with prostate cancer and 111 with benign prostatic hyperplasia. We compared the usefulness of the ratios of free-to-total and complexed-to-total PSA for distinguishing between prostate cancer and benign prostatic hyperplasia, and studied the influence of blood clotting on the ratios. Materials and Methods Blood samples were processed to generate serum and citrated plasma. To calculate complexed-to-total and free-to-total PSA we assayed plasma and serum samples for total and complexed PSA using homemade immunoassays, and total and free PSA using the Immulite* assay. The 2 total PSA assays were compared using the Tandem-E [dagger] PSA assay. Receiver operating characteristics curves were constructed for the total population, and for 2 to 20, 4 to 20, 2 to 10 and 4 to 10 ng./ml. total PSA. Results In all groups complexed-to-total PSA had higher specificity than free-to-total and total PSA, especially at 90 to 100% sensitivity. Generally citrated plasma samples provided higher specificity than serum samples for all sensitivity values. The best performance for complexed-to-total and free-to-total PSA was obtained in the subset of patients in whom total PSA was 2 to 10 ng./ml. Conclusions Our results indicate that the complexed-to-total PSA ratio performed better for classifying disease status than the free-to-total PSA ration in the whole patient population and in the diagnostic gray zone of 2 to 10 ng./ml. In addition, plasma samples should be used to calculate to complexed-to-total and free-to-total PSA ratio.

Measurement of complexed PSA improves specificity for early detection of prostate cancer

Objectives. Prostate-specific antigen (PSA) is the most useful of all tumor markers. Although the sensitivity is impressive, low specificity results in a lack of cancer detection in a significant proportion of patients undergoing prostate biopsy. Several recent studies have addressed the need for improved specificity. Of all these approaches, the free/total PSA ratio appears to be the most promising. Given that most circulating PSA is complexed to alpha 1-antichymotrypsin, and that this moiety represents a greater proportion of the total PSA in those men with carcinoma, we set out to determine whether complexed PSA would improve specificity in the detection of men with prostate cancer. Methods. Archival sera were obtained from 300 men, 75 of whom had biopsy-proved prostate cancer. All sera had been previously stored at −70°C for variable periods. An investigative assay for complexed PSA (Bayer) was used. The Tandem-R free and total PSA assays (Hybritech) were used according to the manufacturer’s recommendations. Results. Among all patients, specificities for the total PSA, free/total PSA, and complexed PSA alone were 21.8%, 15.6%, and 26.7%, respectively, at cutoffs yielding 95% sensitivity. Similar equivalence or superior performance, in terms of specificity relative to the free/total PSA ratio, was seen at other sensitivity thresholds and other total PSA ranges. Conclusions. Complexed PSA alone performs better than total PSA or the free/total PSA ratio and obviates the need for a second analyte determination. We believe this marker may offer significant enhancement in PSA testing with significant economic advantages.

Percent free prostate-specific antigen values in men with recurrent prostate cancer after radical prostatectomy

Objectives. Patients with prostate cancer may have more of the complexed form of prostate-specific antigen (PSA) in the serum, whereas patients with benign prostatic hyperplasia have less of this complexed form and thus a higher proportion of the free form. However, the molecular basis for the lower percent of free PSA in patients with prostate cancer remains unknown, and considerable overlap in values exists. We examined this hypothesis in men with recurrent or persistent cancer after radical prostatectomy. These men, who have “pure” cancer in that they have no benign elements to their disease, should have very low percent free PSA values. Methods. Forty-six men with recurrent (persistent) cancer as manifested by rising PSA values (mean [±SD] 2.4 ± 2.5 ng/mL) after radical prostatectomy were available for analysis. Specimens were analyzed with the use of the Abbott AxSYM free and total PSA assays. The Mann-Whitney U test was used to compare percent free PSA values in this recurrent cancer group with values from a previously defined population of 413 men (225 with benign disease and 188 with prostate cancer before prostatectomy). Results. Median values of percent free PSA in the recurrent cancer group (8.4%) were significantly lower than values in the preoperative cancer (11.7%) or benign (17.4%) groups ( P <0.0001 for both comparisons). Among patients in the “pure” cancer group, 30 (65%) had values less than 10%; however, 4 patients (9%) had values from 15% to 19%, and another 4 (9%) had values of 20% or greater. Pathologically, patients with higher values (15% or greater) had aggressive disease. All patients with values of 20% or greater had evidence of seminal vesicle involvement or nodal disease. Conclusions. Although most cancers exhibit low values of percent free PSA, a significant proportion of aggressive tumors will demonstrate high values. Until this latter phenomenon can be explained, the widespread use of percent free PSA to distinguish benign from malignant disease or to stage confirmed malignant disease should be approached with caution.

Free/total prostate-specific antigen ratio can prevent unnecessary prostate biopsies

Objectives. To evaluate the ability of free/total prostate-specific antigen (PSA) ratio to improve specificity of prostate cancer detection, compare Diagnostic Products Corporation (DPC) Immulite and Ciba Corning ACS 180 total (t)PSA assay, and define an assay-specific cutoff point and reflex range for DPC PSA ratio (PSAR). Methods. In a prospective study, 206 men were enrolled with measurement of both assays. Group 1 consisted of 173 men with a suspicion of prostate cancer (PCA). Thirteen men with known PCA (group 2) and 20 men younger than 32 years (group 3) were used as control groups. Results. Our results in group 1 (115 with benign prostatic hyperplasia [BPH], 58 with PCA) revealed a sensitivity of 82.7%, a specificity of 45.2%, and an accuracy of 57.8% for the DPC tPSA assay (cutoff point more than 4.0 ng/mL) within the entire PSA range. tPSA values of the ACS 180 assay were 1.97-fold higher. Within the tPSA gray zone of 2.5 to 10 ng/mL (66 BPH, 23 PCA), specificity and accuracy of DPC tPSA can be improved by using the DPC PSAR (cutoff point less than 19%) from 33.3% to 71.2% and 42.7% to 70.8%, respectively, maintaining the same sensitivity level of 69.6%. Conclusions. By combining tPSA testing with PSAR within the gray zone, 39.7% (25 of 63) of unnecessary biopsies can be saved, without missing any additional cancers compared with tPSA testing alone. The optimal reflex range for DPC PSAR is 2.5 to 10 ng/mL and the best PSAR cutoff point for biopsy criterion is less than 19% in our high-risk population, with a cancer yield of 34%. Because we still do not have an international PSA standard, it is important to use assay-specific “normal values” and PSAR cutoff points.

COMPARISON OF 3 INVESTIGATIONAL ASSAYS FOR THE FREE FORM OF PROSTATE SPECIFIC ANTIGEN

Purpose Measuring percent free/total prostate specific antigen (PSA) versus total PSA alone has been shown to enhance the stratification of cases with and without prostate cancer. We compared the diagnostic performance of 3 free PSA assays when values were interchanged over a common total PSA denominator. Materials and Methods Archival sera from 123 consecutively accrued patients (25 with prostate cancer, 98 with no evidence of malignancy) who had pre-biopsy total PSA levels from 2.0 to 20.0 ng./ml. were obtained from our specimen bank. Serum specimens were analyzed using the Hybritech Tandem R, sup [dagger] Dianon Systems sup [double dagger] and Chiron ACS 180 sup [section] free PSA assays. Total PSA was measured using the Hybritech Tandem R total PSA assay. Linear regression was performed to evaluate the correlation and agreement among assays. Sensitivity and specificity of cancer detection were calculated to compare diagnostic performance. Results The required percent free PSA cutoffs were different among the 3 free PSA assays. The cutoffs to ensure a 95% sensitivity of cancer detection were 22, 34 and 34%, and the number of negative biopsies that were prevented at these cutoffs (specificity) was 38, 19 and 33% for the Hybritech, Dianon, and Chiron assays, respectively. Conclusions The results among the different assays were not interchangeable. Clinicians should be aware that different percent free PSA cutoffs need to be used based on the type of free and total PSA assays, and that not all assays diagnostically perform the same.

REPEAT ULTRASOUND GUIDED PROSTATE NEEDLE BIOPSY: USE OF FREE-TO-TOTAL PROSTATE SPECIFIC ANTIGEN RATIO IN PREDICTING PROSTATIC CARCINOMA

Purpose Despite being the most useful tumor marker for the diagnosis of patients with prostate cancer, serum prostate specific antigen (PSA) is still hampered by lack of specificity. A negative prostate biopsy is associated with a 20 to 40% incidence of positive repeat biopsy in men with persistently elevated serum PSA levels. We determine whether the free-to-total PSA ratio could be predictive of prostate cancer in men undergoing repeat biopsy. Materials and Methods Archival sera, drawn before the first biopsy, were gathered from 51 men with a total serum PSA of 2 to 15 ng./ml. who underwent repeat prostate needle biopsy for various indications. The percent free PSA was calculated using the Hybritech Tandem-R [dagger] free and total PSA as well as Dianon Systems free [double dagger] and Hybritech total PSA assays. The free-to-total PSA ratio results between the cancer and noncancer groups were compared using Student's t test. Results The median Hybritech free-to-total PSA ratio was significantly lower in patients with positive repeat prostate needle biopsy compared to those with negative biopsy (14.9 versus 19.4%, p = 0.05). Total PSA as well as the percent Dianon free-to-Hybritech total PSA ratio were not significantly different between the 2 groups of men. Conclusions For total PSA in the range of 2 to 15 ng./ml. Hybritech free-to-total PSA ratio appeared to aid in the prediction of cancer on repeat biopsy.

THE USE OF PERCENT FREE PROSTATE SPECIFIC ANTIGEN FOR STAGING CLINICALLY LOCALIZED PROSTATE CANCER

Purpose The free-to-total serum prostate specific antigen (PSA) ratio (percent free PSA) has been demonstrated to have clinical use for early detection of men with prostate cancer with total PSA levels between 4.0 and 10.0 ng./ml. Several studies evaluating the usefulness of percent free PSA for the staging of clinically localized prostate cancer have provided conflicting results. We further investigate the usefulness of percent free PSA for staging of clinically localized prostate cancer. Materials and Methods In 263 men with clinically localized prostate cancer who underwent radical prostatectomy total PSA and free PSA were measured preoperatively. Pathological stages were classified as organ confined in 134 cases, capsular penetration in 92, seminal vesicle involvement in 7, involvement of the surgical margins in 20 and lymph node involvement in 10. Results Percent free PSA was significantly different between men with organ confined versus nonorgan confined tumors (p <0.0001) and between those with favorable versus unfavorable pathology (p <0.0001). A cutoff of 12% free PSA provided a 72% positive predictive value and 52% negative predictive value for favorable pathology. A cutoff of 15% free PSA provided a 76% and 53% positive and negative predictive value, respectively, for organ confined disease. Conclusions These data demonstrate that the use of percent free PSA may be of additional value for the staging of clinically localized prostate cancer. The recommendations for cutoff levels of percent free PSA for detection and staging of localized prostate cancer are preliminary and can only be given for this particular assay. A large multicenter trial, controlling for age, stage and grade distribution, as well as for a uniform pathological evaluation and comparable total and free PSA assays, is required to elucidate this issue further.

PROSTATIC VOLUME AND RATIO OF FREE-TO-TOTAL PROSTATE SPECIFIC ANTIGEN IN PATIENTS WITH PROSTATIC CANCER OR BENIGN PROSTATIC HYPERPLASIA

Purpose We correlated prostatic volume with the ratio of free-to-total prostate specific antigen (PSA) in serum from patients with prostatic cancer or benign prostatic hyperplasia (BPH) to evaluate how prostatic volume influences the ratio. Materials and Methods We evaluated sera from 395 patients (mean age 65 years, range 45 to 88) with prostate cancer (239) or BPH (156) for total PSA, free PSA and ratio of free-to-total PSA. For detection of total and free PSA we used an Immulite * * Diagnostic Product Corp., Los Angeles, California. free and total PSA assay. Prostatic volume was determined with transrectal ultrasonography. Prostatic volume in BPH and prostate cancer patients was divided into 10 ml. groups, and mean ratio of free-to-total PSA was calculated for each volume group and both diseases. For statistical analysis Mann-Whitney U and Kruskal-Wallis tests were performed in addition to calculation of sensitivity and specificity, and receiver operator curves for prostates 60 ml. or less and greater than 60 ml. Results For BPH patients the mean ratio of free-to-total PSA was 14.64 to 25.14% without a close relation to prostatic volume. In prostate cancer patients a proportional increase from 8.45 to 19.37% in the ratio of free-to-total PSA with volume was found. Mann-Whitney U analysis revealed significant differences in prostate cancer versus BPH only in patients with prostates of 60 ml. or smaller (p = 0.0008 to 0.029). No significant differences were seen when prostate cancer and BPH patients with prostates larger than 60 ml. were compared (p = 0.082 to 0.868). Kruskal-Wallis test confirmed independence of the ratio of free-to-total PSA from prostatic volume in BPH patients (p = 0.285) but dependence in prostate cancer patients (p <0.0001). Sensitivity was higher in patients with prostates 60 ml. or smaller (86.72%) than in patients with prostates larger than 60 ml. (66%), and specificity was lower at 45.78 and 56.16%, respectively. Conclusions We have shown that the ratio of free-to-total PSA is influenced by prostatic volume in patients with prostate cancer. The ratio of free-to-total PSA provides useful information for differentiate BPH from prostate cancer in patients with small prostates but it is less useful in patients with larger prostates, probably because of the larger proportion of benign hypertrophic tissue.

Comparison of prostate-specific antigen (PSA) measured by four combinations of free PSA and total PSA assays

We compared prostate-specific antigen (PSA) assay systems [i.e., free PSA (f-PSA) and the corresponding total PSA (t-PSA) assay] from four different manufacturers as well as the f-PSA/t-PSA ratios with regard to their ability to discriminate between benign prostate hyperplasia (BPH) and prostate cancer (PCA). ROC analysis showed similar areas under the curves (AUCs) with different assay systems. For the entire patient population the AUCs of the f-PSA/t-PSA ratio were not or slightly increased compared with the sole measurement of t-PSA (t-PSA, 0.792-0.820; f-PSA/t-PSA ratio, 0.685-0.859). In contrast, for only those patients who showed t-PSA concentrations within the diagnostic gray area of 4-25 micrograms/L t-PSA, the AUCs were greater for the f-PSA/ t-PSA ratio than for measurement of t-PSA alone (t-PSA, 0.608-0.647; f-PSA/t-PSA ratio, 0.690-0.806). These results were confirmed by the predictive values of the negative results (NPVs) of the t-PSA assays and the f-PSA/t-PSA ratios (assay thresholds corresponding to a 95% detection limit). Compared with the sole t-PSA measurement there was no mentionable increase in the NPVs due to the f-PSA/t-PSA ratio for the entire patient population, but an increase up to 49% when limited to t-PSA concentrations within 4-25 micrograms/L. We therefore conclude that the f-PSA/t-PSA ratio may be helpful for differential diagnosis of BPH and PCA within the diagnostic gray area of 4-25 micrograms/L t-PSA.

Analytical performance of the Tandem®-R free PSA immunoassay measuring free prostate-specific antigen

The analytical performance of the Tandem-R free PSA assay available from Hybritech Inc. was evaluated. Comparison of recoveries of purified free (unbound) prostate-specific antigen (PSA) diluted in female serum in the Tandem-R free PSA assay and the Tandem-R (total) PSA assay demonstrated a link in calibration between the assays and an accurate determination of percent free PSA. The cross-reactivity of the assay to purified PSA-alpha 1-antichymotrypsin was determined to be < 1%. The minimum-detectable concentration was < 0.05 microgram/L. The within-run and between-day CVs were < or = 5% for samples with > 0.3 microgram/L free PSA. Dilution and recovery showed no significant deviations from linearity across the assay range. The assay was insensitive to interference from blood components. The Tandem-R free PSA kit was shown to be an accurate, precise, and reliable assay for the measurement of free PSA.

Screening for prostatic carcinoma: case finding is not the problem.

Prostatic cancer (CaP) is a major cause of mortality and morbidity in men. Prostate specific antigen (PSA) can be used to find cases of prostatic cancer, but at some cost. The clinical biochemistry of PSA has been comprehensively reviewed in a recent issue of this journal.' The pros and cons of using PSA as a screening tool for prostatic cancer have also been extensively reviewed.r? Screening for CaP is influenced by technical factors governing test performance, the natural history of the disease, health economic and ethical factors. Purists would argue that screening is something that is applied only to populations, while others would argue that screening is looking for disease in an asymptomatic person. There is potential for conflict in balancing population interests against individual interests. The body of informed opinion is currently against the use of PSA as a screening tool for prostatic cancer. However, the numbers of PSA tests performed in clinical laboratories are rising as evidenced by a 90% increase within the authors' laboratory over the last year. In part this reflects the ad-hoc use of PSA as a screen for CaP, a practice which generally lies outwith a formal population based screening programme and is not a planned healthcare strategy. Virtually all of the prospective trial data on the use of PSA as a screening test has been derived using the Hybritech Tandem total PSA assay. A search for greater diagnostic specificity has lead to the use of PSA density, PSA velocity and, more promisingly, 'free' PSA. However, none of these techniques have been evaluated in prospective trials. In this personal view we discuss the important issues raised by ad-hoc testing, and consider unresolved issues in relation to screening and the potential problems posed by new assays. We offer some advice to the patient or doctor who asks for a PSA test and for the laboratory worker who has to perform the 'gatekeeper' role. The incidence of prostatic cancer is increasing, partly as a result of greater ascertainment but also because of increased longevity. It is second to lung cancer as a cause of mortality and morbidity in men with malignancy. The prevalence of prostatic cancer in postmortem series is reported to be as high as 32·9% compared to the prevalence of clinical disease, which is around 1·2%.5 This implies that most prostatic cancers do not progress to clinical disease. Notwithstanding this, advocates of screening point to the need for detection of localized cancer for early curative treatment. Opponents of screening point to the costs of screening and the uncertainties about the benefits of intervention. However, they do not offer an alternative strategy for reducing the mortality and morbidity associated with this common disease. The rationale for screening for prostatic cancer as with any other screening programme are based on a management strategy in which there are three components. (1) Case finding: how effective will the test(s) be at finding the disease? (2) Prognosis: how good will it be at predicting the natural history of the disease? (3) Treatment: is there an effective and acceptable treatment for the disease?

The role of free prostate-specific antigen in the diagnosis of prostate cancer.

To determine whether the free/total prostate-specific antigen (PSA) ratio can discriminate between patients with prostate cancer or benign prostatic hyperplasia (BPH). A prospective study was conducted using free and total PSA assays in patients who underwent transrectal-ultrasound guided biopsies indicated by a total serum PSA level of > 4 ng/mL and/or a positive digital rectal examination. Sixty-nine men (median age 68 years, range 57-86) who presented to our out-patient department with symptoms of prostatism were included in the study. Blood samples were drawn from all patients before biopsy. Histopathological examination detected prostate cancer in 17 of 69 (25%) patients and 13 of these 17 patients had a free/total PSA ratio of < 0.15; only 12 of 52 (23%) patients with BPH had a ratio of < 0.15. Receiver operating characteristic analysis indicated a threshold free/total PSA ratio of < or = 0.15 was the optimum discriminatory level. In the whole study group, this threshold had sensitivity, specificity, positive- and negative-predictive values of 76%, 77%, 52% and 91%, respectively. There were 40 patients with serum PSA levels of 4-10 ng/mL and 17.5% (7/40) of these were diagnosed with cancer. Using a free/total PSA ratio of 0.15 would have failed to diagnose two patients of seven with prostate cancer but 30 patients would have avoided a biopsy. In this subgroup, the threshold ratio of 0.15 had sensitivity, specificity, positive- and negative-predictive values of 71%, 85%, 50% and 93%, respectively. The rates for a PSA density (PSAD) at a threshold of > or = 0.15 were 71%, 76%, 38%, 93%, respectively. These results indicate that using the free/total PSA ratio gives a significant improvement over PSAD and total PSA values alone in the diagnosis of prostate cancer: its use may also enhance the diagnostic accuracy in patients with intermediate PSA levels.

The ratio of free to total serum prostate specific antigen and its use in differential diagnosis of prostate carcinoma in japan

To improve the clinical usefulness of prostate specific antigen (PSA), unique methods have been proposed. The percentage of free PSA in serum facilitates the distinction between benign histologic conditions and prostate carcinoma while retaining high sensitivity. Using monoclonal antibodies, an AIA total PSA assay system was established that recognized PSA equally in free or complex form. The clinical usefulness of the ratio of two different molecular forms of PSA was investigated using 268 archival serum samples. Men with prostate carcinoma had significantly lower ratios of free to total PSA than those with benign prostatic hyperplasia (BPH) (P = 0.0001). At total PSA levels between 2.1 and 10 ng/mL, medians of total PSA were not significantly different between men with prostate carcinoma and men with BPH. Differences in median percentages of free PSA for these two groups were statistically significant (P = 0.0001). The ratio of free to total PSA was useful for identifying prostate carcinoma in palpably benign glands with total PSA of 2.1-10 ng/mL (P = 0.0001), whereas total PSA was not useful for such identification. When calculated for low total PSA levels between 2.1 and 4 ng/mL, sensitivity and specificity were 91.7% and 72.2%, respectively, with a cutoff value of 17%. This ratio of free to total PSA was as useful as PSA density in receiver-operating curve analysis. The use of the ratio of free to total PSA renders total PSA of greater use of distinguishing prostate carcinoma and is applicable to patients with low total PSA. Elderly men with a clinical diagnosis of BPH who are scheduled for surgery may benefit from the determination of this ratio.