Different prostate-specific antigen assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies

OBJECTIVE: To show the effect of different results for total prostate specific antigen (tPSA) and percentage free/total PSA (%fPSA) obtained with different assays for differentiating between benign and malignant prostate diseases. PATIENTS AND METHODS: Data were used for tPSA and fPSA levels from 596 patients with prostate cancer (314) or no evidence of cancer (282) within the PSA range 0.5-10 ng/mL, analysed with assays from Abbott (AxSYM), Beckman Coulter (Access), DPC (Immulite 2000), and Roche (Elecsys 2010), and with tPSA and complexed PSA (cPSA) assays from Bayer (ADVIA Centaur), as already reported. Receiver operating characteristics (ROC), specificities at assay-dependent and fixed thresholds, and the percentages of correct classification rates of patients were calculated. RESULTS: Whereas the areas under the ROC curves were no different among all tPSA assays, the assay-specific thresholds at 90% sensitivity were 2.5-3.1 ng/mL. When using fixed 2.5 or 4 ng/mL tPSA thresholds there was a wide sensitivity range, with significant differences among almost all assays, resulting in significantly different classification rates of patients. These differences were even larger when using fixed %fPSA thresholds. CONCLUSIONS: The current situation of differences among PSA values measured with different assays do not allow the recommendation of uniform PSA limits as biopsy criteria. For that purpose, better harmonization of PSA values between the different PSA test systems must be realized.     

Derivatives of prostate‐specific antigen as predictors of incidental prostate cancer

OBJECTIVE

To search for an optimal derivative of prostate‐specific antigen (PSA) identifying patients at risk of incidental prostate cancer.

PATIENTS AND METHODS

In all, 693 patients who underwent transurethral resection of the prostate (TURP) with a normal digital rectal examination, no history of prostate cancer and a PSA level of 2.5–10 ng/mL were studied. The total PSA (tPSA), percentage of free/total PSA (%fPSA), complexed PSA (cPSA), PSA density, cPSA density and the ratio of fPSA to cPSA were measured. Specificity, sensitivity, positive and negative predictive values were determined for all possible threshold values indicating the risk of incidental prostate cancer (T1a or T1b). Furthermore, the patients were subdivided according to age and the presence of an indwelling transurethral catheter. The areas under the receiver operating characteristic curves (AUC) were compared.

RESULTS

In the whole sample, the %fPSA was the best test predicting all incidental prostate cancers (AUC 0.618, reference: tPSA 0.494), whereas cPSA density was the best predictor of T1b disease (AUC 0.720, reference: tPSA 0.548). Stratification by age did not meaningfully alter the results, the presence of a transurethral catheter, however, was associated with a superiority of tests based on fPSA (AUC 0.620–0.670) compared with tests based on tPSA or cPSA (AUC 0.421–0.581).

CONCLUSION

Replacing tPSA by PSA derivatives (%fPSA or cPSA density) and stratifying by the presence of an indwelling transurethral catheter may improve the prediction of the risk of incidental prostate cancer and spare unnecessary biopsies before TURP in the tPSA range 2.5–10 ng/mL.     

Assay-specific artificial neural networks for five different PSA assays and populations with PSA 2–10 ng/ml in 4,480 men

Use of percent free PSA (%fPSA) and artificial neural networks (ANNs) can eliminate unnecessary prostate biopsies. In a total of 4,480 patients from five centers with PSA concentrations in the range of 2–10 ng/ml an IMMULITE PSA-based ANN (iANN) was compared with other PSA assay-adapted ANNs (nANNs) to investigate the impact of different PSA assays. ANN data were generated with PSA, fPSA (assays from Abbott, Beckman, DPC, Roche or Wallac), age, prostate volume, and DRE status. In 15 different ROC analyses, the area under the curve (AUC) in the PSA ranges 2–4, 2–10, and 4–10 ng/ml for the nANN was always significantly larger than the AUC for %fPSA or PSA. The nANN and logistic regression models mostly also performed better than the iANN. Therefore, for each patient population, PSA assay-specific ANNs should be used to optimize the ANN outcome in order to reduce the number of unnecessary biopsies.     

A (-5, -7) proPSA based artificial neural network to detect prostate cancer

OBJECTIVE: The pro-forms of prostate specific antigen (-2,-5,-7 proPSA) and also %free PSA based artificial neural networks (ANN) have been suggested to enhance the discrimination between prostate cancer (PCa) and no evidence of malignancy (NEM). This study reports on the combined use of proPSA within a %free PSA based ANN to enhance specificity of PCa. METHODS: Serum samples from 898 patients with PCa (n=384) or NEM (n=514) within the PSA range 1-10 microg/l were analyzed for PSA, free PSA and (-5,-7) proPSA (Roche assays). Patient data from two centers - taken first from the Swiss site of the ERSPC (Aarau) and from a referral population (Berlin) have been analyzed. Leave-one-out ANN models with the variables PSA, %fPSA, proPSA, prostate volume and status of digital rectal examination (DRE) were constructed and compared by receiver-operating characteristic (ROC) curve analysis. RESULTS: (-5,-7) proPSA was only significantly different between NEM and PCa in the PSA range 4-10 microg/l. Within the PSA range 4-10 microg/l (Berlin group) the ANN including only the two variables %fPSA and proPSA could reach the same performance like the conventional ANN with PSA, %fPSA, age, prostate volume and DRE (both AUCs: 0.84) However, at 95% sensitivity all ANN could not improve specificity compared to %fPSA. CONCLUSIONS: ProPSA as single parameter did not improve specificity over %fPSA whereas proPSA and %fPSA within an ANN in the PSA range 4-10 microg/l substituted prostate volume and DRE. At 95% sensitivity only ANN with prostate volume and DRE perform significantly better than %fPSA.     

Clinical utility of human glandular kallikrein 2 within a neural network for prostate cancer detection

OBJECTIVE

To assess, using artificial neural networks (ANNs), human glandular kallikrein 2 (hK2), prostate‐specific antigen (PSA), and percentage free/total PSA (f/tPSA), for discriminating between prostate cancer and benign prostatic hyperplasia (BPH).

MATERIAL AND METHODS

Serum samples from 475 patients with prostate cancer (n = 347) or BPH (n = 128) within the PSA range of 1–20 ng/mL were analysed for tPSA, fPSA and hK2 (research assay, Toronto, Canada). Data were analysed in the ranges of 1–4, 2–4, 4–10, and 2–20 ng/mL tPSA. Back‐propagation ANN models with the variables PSA, f/tPSA, and hK2, hK2/fPSA and hK2/(f/tPSA) were constructed. The diagnostic validity was evaluated by receiver‐operating characteristic (ROC) curve analysis.

RESULTS

Whereas the median concentration of hK2 was not significantly different between patients with BPH or prostate cancer in any of the tPSA ranges, the f/tPSA, hK2/fPSA and hK2/(f/tPSA), and the hK2‐based ANN outputs were always significantly different between patients with prostate cancer or BPH. Using ROC curve comparison, all variables were significantly better than hK2 in all ranges. The hK2‐based ANN performed better than f/tPSA except in the 4–10 ng/mL tPSA range. At 90% and 95% sensitivity, the hK2‐based ANN was also significantly better than f/tPSA in the 1–4 ng/mL tPSA range. hK2/(f/tPSA) achieved equal results to the hK2‐based ANN except in the range 2–20 ng/mL tPSA.

CONCLUSIONS

The hK2‐based ANN improves the outcome of f/tPSA but not hK2/(f/tPSA) in almost all analysed subgroups. When comparing the results at 90% and 95% sensitivity the hK2‐based ANN only performed significantly better than f/tPSA in the lowest tPSA range. Only in lower tPSA ranges do hK2‐based ANNs show an advantage for further improving prostate cancer detection.

     

Internal validation of an artificial neural network for prostate biopsy outcome

Objectives:   To carry out an internal validation of the retrospectively trained artificial neural network (ANN) 'ProstataClass'.
Methods:   A prospectively collected database of 393 patients undergoing 8–12 core prostate biopsy was analyzed. Data of these patients were applied to the online available ANN 'ProstataClass' using the Elecsys total prostate-specific antigen (tPSA) and free PSA (fPSA) assays. Beside the internal validation of the ANN 'ProstataClass' an additional ANN (named as ANN internal validation: ANNiv) only using the 393 prospective patient data was evaluated. The new ANN model was constructed with the MATLAB Neural Network Toolbox. Diagnostic accuracy was evaluated by receiver operator characteristic (ROC) curves comparing the areas under the ROC curves (AUC) and specificities at 90% and 95% sensitivity.
Results:   Within a tPSA range of 1.0–22.8 ng/mL, 229 men (58.3%) had prostate cancer (PCa). tPSA, %fPSA and the number of positive digital rectal examinations (DRE) differed significantly from the cohort of patients of the ANN 'ProstataClass', whereas age and prostate volume were comparable. AUCs for tPSA, %fPSA and the ANN 'ProstataClass' were 0.527, 0.726 and 0.747 ( P  = 0.085 between %fPSA and ANN). The AUC of the ANNiv (0.754) was significantly better compared with %fPSA ( P  = 0.021), whereas the AUC of two ANN models built on external cohorts (0.726 and 0.729) showed no differences to %fPSA and the other ANN models.
Conclusions:   Significant differences of DRE status and %fPSA medians decrease the power of the 'ProstataClass' ANN in the internal validation cohort. The effect of retrospective data evaluation the 'ProstataClass' cohort and prospective fPSA measurement may be responsible for %fPSA differences. All ANN models built with different PSA and fPSA assays performed equally if applied to the two cohorts.     

Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting

Background

Total prostate-specific antigen (tPSA), ratio of free PSA (fPSA) to tPSA (%fPSA), and PSA density (PSAD) testing have a very low accuracy in the detection of prostate cancer (PCa). There is an urgent need for more accurate biomarkers.

Objective

To compare the diagnostic accuracy of PSA isoform p2PSA and its derivatives in determining the presence of PCa at initial biopsy with the accuracy of other predictors in patients with tPSA 2.0-10 ng/ml.

Design, setting, and participants

We conducted an observational prospective study in a real clinical setting of consecutive men with tPSA 2.0-10 ng/ml and negative digital rectal examination who were scheduled for prostate biopsy at a tertiary academic center.

Intervention

Outpatient transrectal ultrasound-guided prostate biopsies were performed according to a standardized institutional saturation scheme (18-22 cores).

Measurements

We determined the diagnostic accuracy of serum tPSA, %fPSA, PSAD, p2PSA, %p2PSA [(p2PSA/fPSA) × 100] and the Beckman Coulter Prostate Health Index (phi; [p2PSA/fPSA × √tPSA]).

Results and limitations

Overall, 107 of 268 patients (39.9%) were diagnosed with PCa at extended prostate biopsies. Statistically significant differences between patients with and without PCa were observed for age, prostate and transition zone volume, PSAD, %p2PSA, and phi (all p values < 0.05). In univariate accuracy analysis, phi and %p2PSA were the most accurate predictors of PCa (area under the curve: 75.6% and 75.7%, respectively), followed by transition zone volume (66%), prostate volume (65%), patient age (63%), PSAD (61%), %fPSA (58%), and tPSA (53%). In multivariate accuracy analyses, both phi (+11%) and %p2PSA (+10%) significantly improved the accuracy of established predictors in determining the presence of PCa at biopsy (p < 0.001). Although %p2PSA and phi were significantly associated with Gleason score (Spearman ρ: 0.303 and 0.387, respectively; p ≤ 0.002), they did not improve the prediction of Gleason score ≥7 PCa in multivariable accuracy analyses (p > 0.05).

Conclusions

In patients with a tPSA between 2.0 and 10 ng/ml, %p2PSA and phi are the strongest predictors of PCa at initial extended biopsies and are significantly more accurate than the currently used tests (tPSA, %fPSA, and PSAD) in determining the presence of PCa at biopsy.     

Serum Isoform [−2]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2–10 ng/ml: A Multicentric European Study

Background

Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary.

Objective

To test the accuracy of serum isoform [−2]proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests—in discriminating between patients with and without PCa.

Design, setting, and participants

This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa.

Outcome measurements and statistical analysis

The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis.

Results and limitations

Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values.

Conclusions

In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA.

Trial registration

The study is registered at http://www.controlled-trials.com, ref. ISRCTN04707454.     

Effect of NIH-IV prostatitis on free and free-to-total PSA

OBJECTIVE: To examine the effect of asymptomatic prostatic inflammation (NIH category IV prostatitis) on total PSA (tPSA), free serum PSA (fPSA) and the ratio of free-to-total prostate specific antigen (%fPSA). The role of free and %fPSA as a diagnostic tool for distinguishing between cancer and non-malignant diseases of the prostate was also investigated. MATERIAL AND METHODS: In a retrospective study 1090 prostate biopsies performed between January 2000 and September 2003 were evaluated and the levels of serum total and free PSA as well as the f/tPSA ratio were determined in samples obtained immediately before biopsy. 404 patients with full clinical and histological records were included in the study. All patients underwent 6 or 8 core primary prostate needle biopsies. RESULTS: A total of 404 patients were included in the analysis. 100 prostate cancer (PCa) (24.8%), 137 NIH-IV prostatitis (33.9%) and 143 patients with benign prostatic hyperplasias (BPH) (35.4%) were identified. 24 (5.9%) patients presented with both PCa and prostatitis on histology and were excluded from further analysis. The mean (median) levels of tPSA, fPSA and %fPSA were 11.94 ng/ml (8.0), 1.31 ng/ml (1.07) and 0.15 (0.14) for NIH-IV prostatitis; 11.94 ng/ml (8.35), 1.54 ng/ml and 0.13 (0.11) for prostate cancer; and 8.19 ng/ml (7.0), 1.48 ng/ml (1.03) and 0.18 (0.15) for BPH. No significant difference was found in tPSA levels between PCa and prostatitis (p = 0.32), while the difference in tPSA levels between PCa and BPH was significant (p = 0.007). Free PSA alone had no diagnostic power in distinguishing PCa from prostatitis (p = 0. 37) and BPH (p = 0. 61). By contrast, the f/tPSA ratio showed significant between-group differences (PCa versus prostatitis (p = 0. 011), PCa versus BPH (p = 0.0001). CONCLUSIONS: Chronic asymptomatic prostatitis NIH category IV has similar effects on total PSA and free PSA levels in serum as PCa. fPSA alone cannot distinguish prostate cancer from non-malignant inflammatory disease of the prostate. The ratio of free-to-total PSA is significantly different in PCa and NIH category IV prostatitis.     

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection

Background

Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity.

Objective

To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia–associated PSA (BPHA).

Design, setting, and participants

Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University.

Measurements

BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA).

Results and limitations

The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity.

Conclusions

This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).     

Comparison of the clinical validity of free prostate-specific antigen, alpha-1 antichymotrypsin-bound prostate-specific antigen and complexed prostate-specific antigen in prostate cancer diagnosis

OBJECTIVE: To evaluate the diagnostic utility of free prostate specific antigen (fPSA), alpha-1- antichymotrypsin-bound PSA (PSA-ACT), complexed PSA (cPSA), and including their associated ratios to total PSA (tPSA) in serum for discrimination between prostate cancer (PCa) and benign prostatic hyperplasia (BPH). METHODS: A total of 166 white men (age: 65-88 years) with a tPSA between 2 and 20 microg/l were retrospectively analysed. Serum concentrations of tPSA, fPSA, PSA-ACT and cPSA were measured in 118 untreated PCa patients and 48 patients with BPH. The tPSA and cPSA concentrations were measured with the Bayer Immuno 1 system (Bayer Diagnostics, Tarrytown, USA). The Elecsys system 2010 (Roche Diagnostics, Mannheim, Germany) was used for determination of tPSA and fPSA. The PSA-ACT assay is a newly, developed prototype assay on the ES system (Roche Diagnostics, Mannheim, Germany). RESULTS: For statistical analysis only patients with tPSA between 2 and 20 microg/l were enrolled. The median concentrations of tPSA (Bayer: PCa 7.36 microg/l, BPH 4.03 microg/l; Roche: PCa 7.75, BPH 4.13), PSA-ACT (PCa 6.98, BPH 3.18) and cPSA (PCa 6.46, BPH 3.20) were significantly different. The median ratios of fPSA/tPSA (PCa 12.8 vs. BPH 22.4%), PSA-ACT/tPSA (PCa 89.8 vs. BPH 76.1%) and cPSA/tPSA (PCa 90.5 vs. BPH 81.7%) were significantly different between PCa and BPH patients. Using the areas under the curves, receiver operating characteristics analysis (tPSA: 2-20 microg/l) for discrimination between PCa and BPH showed that the ratios fPSA/tPSA (area under the curve: 0.77), PSA-ACT/tPSA (0.72) and cPSA/tPSA (0.78) were significantly different from tPSA (Bayer: 0.53; Roche: 0.55). PSA-ACT (0.64) and cPSA (0.59) alone were not significantly different from tPSA. The calculated ratios fPSA/tPSA, PSA-ACT/tPSA and cPSA/tPSA were not significantly different. CONCLUSION: The determination of PSA-ACT or cPSA and the associated ratios do not improve the diagnostic impact to discriminate between PCa and BPH compared to fPSA/tPSA ratio. The ratios PSA-ACT/tPSA or cPSA/tPSA can be considered to be alternative tools of fPSA/tPSA.     

Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml

BACKGROUND: We measured serum levels of human glandular kallikrein 2 (hK2) in patients treated with radical retropubic prostatectomy (rrP) for clinically localized prostate cancer (PCa) with a total PSA (tPSA)-level below 10 ng/ml to investigate whether hK2 can be applied to preoperatively distinguish organ-confined (pT2a/b) from nonorgan-confined (> or = pT3a)-PCa more accurately than total PSA. Further, we evaluated hK2, free- and tPSA-concentrations in all pathologic stages of PCa. METHODS: 161 serum samples from men scheduled for rrP were collected 1 day before surgery prior to any prostatic manipulation. Pathologic work-up revealed > or = pT3a-PCa in 48 and pT2a/b-PCa in 113 patients. HK2-levels in serum were measured using an immunofluorometric assay with an analytical sensitivity of 0.5 pg/ml, a functional sensitivity of 5 pg/ml and insignificant cross-reactivity with PSA (< 0.005%). Total (tPSA) and free PSA (fPSA) levels were measured using a commercially available assay from which we calculated %fPSA and an algorithm that combined hK2 and PSA-levels [hK2] x [tPSA/fPSA]. Means, medians, and ranges were calculated for pT2a/b vs. >/= pT3a-PCa and for all pathologic stages. Statistical significance of differences was calculated using Mann-Whitney-U and Kruskal-Wallis tests. Calculation of receiver-operator-characteristic (ROC) curves were performed for hK2, [hK2] x [tPSA/fPSA] and tPSA to compare diagnostic performance. RESULTS: A mean tPSA level in serum of 6.12 ng/ml in > or = pT3a-PCa was not significantly different (P = 0.366) from 5.78 ng/ml in pT2a/b-PCa. Also, there were no statistically significantly different levels of fPSA (P = 0.947) or %fPSA (0.292) for these two groups. By contrast, mean hK2-level in pT2a/b-PCa of 80 pg/ml was significantly different (P = 0.004) from a mean hK2 level of 120 pg/ml in > or = pT3a-PCa as shown by Mann-Whitney-analysis Moreover, the algorithm of [hK2] x [tPSA/fPSA] was significantly lower (P = 0.0004) in pT2a/b-PCa vs. > or = pT3a-PCa. Calculation of areas under curve (AUC) by receiver-operator-characteristics (ROC) demonstrated that the AUC for hK2 (0.64) was larger and the AUC for [hK2] x [tPSA/fPSA] (=0.68) significantly larger (P = 0.007) compared to the AUC of tPSA (0.55). Furthermore, Kruskal-Wallis Test revealed a highly significant correlation to pathologic stage using hK2 (P = 0.008) and [hK2] x [tPSA/fPSA] (P = 0.0015) compared to no significant differences in serum concentration of tPSA (P = 0.296). Also at tPSA-levels from 10-20 ng/ml, the hK2-levels in pT2a/b-PCa were close to significantly different (P = 0.051) from those in men with >/= pT3a-PCa, while the algorithm of [hK2] x [tPSA/fPSA] in that tPSA-range was significantly lower (P = 0.002) in pT2a/b-PCa compared to > or = pT3a0-PCa. CONCLUSIONS: Highly significant differences in serum concentration enable hK2 to be a powerful predictor of organ-confined disease and pathologic stage of clinically localized prostate cancer, especially in the PSA-range below 10 ng/ml. As such, there are important clinical consequences for the application of hK2 for the adequate treatment of prostate cancer patients, i.e., the option of nerve-sparing surgery. (c) 2001 Wiley-Liss, Inc.     

Screening for Prostate Cancer in 2008 II: The Importance of Molecular Subforms of Prostate-Specific Antigen and Tissue Kallikreins

Context

Over the past decades, prostate-specific antigen (PSA), its isoforms, and other members of the tissue kallikrein family have been of continuous interest with regard to early detection and screening for prostate cancer (PCa).

Objective

This review strives to give an overview of the possible clinical utilities of these markers, focused on early diagnostics and PCa screening.

Evidence acquisition

Using the Medline database, a literature search was performed on the role of molecular subforms of PSA and other members of the tissue kallikrein family in PCa detection.

Evidence synthesis

With respect to PSA isoforms, only the combination of the various truncated forms (pPSA) shows additional value over total PSA (tPSA) and free PSA (fPSA) in PCa detection within the range of 2–10 ng/ml tPSA. At a high sensitivity for PCa, the specificity of the ratio of pPSA to fPSA (%pPSA) is, in general, better than that of the ratio of fPSA to tPSA (%fPSA), with a gain of 5–11%. The (−2)pPSA, (−4)pPSA, (−5)pPSA, (−7)pPSA, and benign PSA (BPSA) isoforms generally show no additional value over either pPSA or the existing parameters of tPSA and fPSA. Of the other members of the tissue kallikrein family, most studies on human kallikrein 2 (hK2) show an additional value of the ratio of hK2 to fPSA (%hK2) over %fPSA alone in PCa prediction. Other tissue kallikreins cannot be recommended for diagnosing PCa, due to the lack of additional value over tPSA or fPSA or to insufficient research. Regarding a prognostic role, the value of PSA subforms as well as of other members of the tissue kallikrein family is limited with regard to existing parameters.

Conclusions

pPSA and hK2 are able to improve PCa diagnosis in the range of 4–10 ng/ml tPSA over the existing variables tPSA and fPSA.     

Prostate-specific antigen velocity based risk-adapted discontinuation of prostate cancer screening in elderly men

Study Type – Prognostic (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Currently, the U.S. Preventive Services Task Force (USPSTF) recommends against PSA screening for prostate cancer in men aged ≥75 years as it concluded that “the harm of screening for prostate cancer in men age ≥75 years may outweigh the potential benefits”. Our findings suggest that elderly men with a PSA velocity of ≥0.45 ng/ml/year have higher risk of death from prostate cancer. Continuing PSA testing may be beneficial for these men.

OBJECTIVE

? To evaluate weather prostate‐specific antigen (PSA) velocity could be used to stratify patients at risk of death from prostate cancer (PCa) and be useful in aiding decision making regarding PSA screening in elderly men, as previous studies have shown that PSA velocity can predict PCa risk.

PATIENTS AND METHODS

? The cohort included 3,525 patients aged ≥ 75 years with two or more PSA tests before a diagnosis of PCa. Cox proportional hazard model was used to evaluate which variables at time of last PSA measurement were associated with death from PCa. ? The rates of death from PCa after diagnosis in different PSA velocity groups were calculated. Kaplan‐Meier and log rank test were used to assess the significant difference in death from PCa after diagnosis, stratified by PSA velocity cutoff.

RESULTS

? On multivariate analysis, men with a PSA velocity of PSA velocity ≥0.45 ng/mL/year had a 4.8‐fold higher risk of death from PCa as compared to men with a PSA velocity of <0.45 ng/mL/year (p value = 0.013). After a median 6.5 (up to 16.9) years of follow‐up from diagnosis, 1.4% of the men with a PSA velocity <0.45 ng/mL/year had died of PCa as compared to 8.7% of those with a PSA velocity ≥0.45 ng/mL/year. ? The cumulative rate of death from PCa after diagnosis, stratified by a PSA velocity of 0.45 ng/mL/year, was statistically different (log rank test, P < 0.001).

CONCLUSION

? Men age ≥ 75 years old with a PSA velocity of <0.45 ng/mL/year are unlikely to die of PCa. It may be safe to discontinue PSA screening in these men.     

Outcome prediction for prostate cancer detection rate with artificial neural network (ANN) in daily routine

BackgroundWe evaluated the use of the artificial neural network (ANN) program “ProstataClass” of the Department of Urology and the Institute of Medical Informatics at the Charité-Universitätsmedizin Berlin in daily routine to increase prostate cancer (CaP) detection rate and to reduce unnecessary biopsies.Materials and methodsFrom May 2005 to April 2007, a total of 204 patients were included in the study. The Beckman Access PSA assay was used, and pretreatment prostate specific antigen (PSA) was measured prior to digital rectal examination (DRE) and 12 core systematic transrectal ultrasound (TRUS) guided biopsies. The individual ANN predictions were generated with the use of the ANN application for the Beckman Access PSA and free PSA assays, which relies on age, PSA, percent free prostate specific antigen (%fPSA), prostate volume, and DRE. Diagnostic validity of total prostate specific antigen (tPSA), %fPSA, and the ANN was evaluated by ROC curve analysis.ResultsPSA and %fPSA ranged from 4.01 to 9.91 ng/ml (median: 6.65) and 5% to 48% (median: 15%), respectively. Of all men, 46 (22.5%) demonstrated suspicious DRE findings. Total prostate volume ranged from 7.1 to 119.2 cc (median: 35). Overall, 71 (34.8%) CaP were detected. Of men with suspicious DRE, 28 (60.9%) had CaP on initial biopsy. The ANN was 78% accurate in the original report. The AUC of ROC curve analysis was 0.51 for PSA, 0.66 for %PSA, and 0.72 for the ANN-Output, respectively.ConclusionsOur results in this independent cohort show that ANN is a very helpful parameter in daily routine to increase the CaP detection rate and reduce unnecessary biopsies.     

Complexed prostate specific antigen (PSA) reduces unnecessary prostate biopsies in the 2.6-4.0 ng/mL range of total PSA

OBJECTIVE: To compare the performance of complexed prostate-specific antigen (cPSA) to total PSA (tPSA) and percentage free PSA (f/tPSA) in the diagnosis of prostate cancer for the tPSA range 2.6-4.0 ng/mL. PATIENTS AND METHODS: Consecutive men scheduled for prostate biopsy were enrolled prospectively at 14 different sites in two multicentre studies in Europe and the USA. Serum obtained before biopsy was tested with the ACS:180 and Immuno 1 tPSA and cPSA assays (Bayer Diagnostics, Tarrytown, NY, USA) and the Access fPSA and tPSA assays (Beckman, Inc., San Diego, CA, USA). Receiver operating characteristics (ROC) curves were generated to compare the diagnostic performance of tPSA, cPSA and f/tPSA. RESULTS: Of 316 men with a tPSA of 2.6-4.0 ng/mL, 82 (26%) were diagnosed with prostate cancer on biopsy. ROC analysis of all 316 men showed an area under the curve (AUC) for cPSA of 0.63, significantly greater than the AUC for tPSA of 0.56 (P = 0.008). At a sensitivity of 95%, threshold values of 2.3 ng/mL for cPSA and 2.73 ng/mL for tPSA provided specificities of 20.1% and 9.8%, respectively. f/tPSA was only available for 205 of the 316 (65%) men and the AUC for cPSA was 0.63, and did not significantly differ from the f/tPSA AUC of 0.64 (P = 0.58). CONCLUSIONS: As a single test, cPSA provides improved specificity over tPSA and comparable specificity to f/tPSA for detecting prostate cancer, and may reduce the number of unnecessary prostate biopsies in the 2.6-4.0 ng/mL tPSA range.     

Evaluation of the serum testosterone to prostate‐specific antigen ratio as a predictor of prostate cancer risk

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To analyse the ratio of serum testosterone (sT) to prostate‐specific antigen (PSA) as a predictor of prostate cancer risk, as low levels of sT have been related to a greater risk of prostate cancer, and its ratio with serum PSA level was recently proposed as a new tool to increase the specificity of PSA.

PATIENTS AND METHODS

In all, 439 consecutive men with a normal digital rectal examination and a serum PSA level of 4.1–20 ng/mL had a transrectal ultrasonography‐guided biopsy using a 10‐core scheme, with an additional 1–8 cores according to prostate volume and patient age. The sT level was determined before the procedure using a chemiluminescent assay, and the ratio of sT to PSA (sT/PSA) was calculated after transforming sT measurements from ng/dL to ng/mL. The percentage free PSA (%fPSA) and PSA density were also included in this analysis.

RESULTS

The overall cancer detection rate was 42.1%. The median sT level was 469 ng/dL in men with cancer and 499 ng/dL in those without (P = 0.521). The median sT/PSA was 0.68 and 0.74, respectively (P = 0.215). However, the median %fPSA was 14 in men with cancer and 17 in men without (P < 0.001) and the median PSA density was 0.22 and 0.16, respectively (P < 0.001). The multivariate analysis confirmed the independent predictive value only for %fPSA (odds ratio 0.94, 95% confidence interval 0.91–0.98) and PSA density (5.8, 3.42–19.8).

CONCLUSION

These results do not support the use of sT/PSA for predicting the risk of prostate cancer and to increase the specificity of PSA.     

总体和自由型前列腺特异抗原指数在日本人群前列腺癌筛选中的价值和局限性(英文)

目的:在日本某单机构中评定前列腺特异抗原指数(f/tPSA)的价值和局限性,重点在于避免无意义的前列腺组织活检。方法:631名年龄在44-93岁之间(平均年龄69.8岁)的男性,在日本新滹中心医院用能量多普勒超声波图像引导的经直肠10-点前列腺组织活检后发现其 PSA 值增加,用总体前列腺特异抗原 (tPSA)和前列腺特异抗原指数(f/tPSA)观察组织学特征。结果:在134名 tPSA 为26 ng/mL 或更高病人中,126人(94.3%)检测到前列腺癌(PCa),tPSA 为21-25 ng/mL 时的 PCa 检出率是59.4%,16-20 ng/mL 时为39.2%,11-15 ng/mL 时为30.0%,4.1-10 ng/mL 时为20.0%,小于等于4.0 ng/mL 时为7.6%。在任何一个 tPSA 值区间,PCa 组的 f/tPSA 值都明显低于非肿瘤组(平均为0.122vs.0.160,P<0.001)。接收器特性法表明,对于 tPSA 值在3.0-10 ng/mL(P<0.01)之间的病人,f/tPSA(AUC:0.664)比 tPSA(AUC:0.559)更有价值。虽然以 f/tPSA 等于0.250为分界点可能产生1.8%的 PCa 漏诊率,但是这样有可能节约9.2%不必要的组织活检。结论:对预测 PCa 发病率,f/tPSA 比单独的 tPSA 更有价值。因此,对于被称为 tPSA 灰色地带的亚洲男性来说,我们推荐在 PCa 筛查中用0.250作为 f/tPSA分界点。     

Contemporary prostate cancer prevalence among T1c biopsy-referred men with a prostate-specific antigen level < or = 4.0 ng per milliliter

OBJECTIVE: To investigate the prostate cancer (PCa) prevalence and risk factors of men with prostate-specific antigen (PSA) level< or =4.0 ng/ml and an unsuspicious digital rectal examination (DRE) in a large biopsy referral cohort. MATERIALS AND METHODS: Between 1997 and 2005, 855 men underwent initial transrectal ultrasound (TRUS)-guided prostate biopsy at the University Hospital Hamburg-Eppendorf. Patients with any previous surgical or medical treatment were excluded from analyses. Logistic regression analyses were performed to determine risk factors of PCa at biopsy and high-grade PCa defined as biopsy Gleason sum> or =7. RESULTS: Overall PCa detection rate was 23.1%. The majority had a biopsy Gleason sum of 6 (79.5%) and 20.5% had a biopsy Gleason sum> or =7. Total PSA (tPSA) and percentage of free PSA (%fPSA) were statistically significantly different in men with and without PCa (all p<0.001). In tPSA strata < or = 0.5, 0.6-1.0, 1.1-2.0, 2.1-3.0, and 3.1-4.0 ng/ml, PCa prevalence was 4.0%, 10.6%, 14.8%, 24.5%, and 32.1%, respectively. In logistic regression analyses addressing PCa and Gleason sum > or = 7 at biopsy, %fPSA and prostate volume represented independent and most informative risk factors. CONCLUSION: Our data demonstrate that a substantial percentage (23.1%) of men with a PSA< or =4.0 ng/ml and an unsuspicious DRE in a biopsy referral population harbor PCa, with 20.5% being high grade. Low %fPSA and low prostate volume represent important parameters in PCa and in high grade disease detection at biopsy, respectively.     

Multicenter European External Validation of a Prostate Health Index–based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Background

External validation of a prediction tool is mandatory to assess the tool's accuracy and generalizability within different patient cohorts.

Objective

To externally validate a previously developed Prostate Health Index (PHI)–based nomogram for predicting the presence of prostate cancer (PCa) at biopsy.

Design, setting, and participants

The study population consisted of 883 patients who were scheduled for a prostate biopsy at one of five European tertiary care centers. Total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), and [−2]pro–prostate-specific antigen (p2PSA) levels were determined. The fPSA-to-tPSA ratio (%fPSA), p2PSA, and PHI ([p2PSA / fPSA] × √tPSA) were calculated.

Intervention

Extended initial and repeat prostate biopsy.

Outcome measurements and statistical analysis

Logistic regression models were fitted to test the predictors of PCa and to determine their predictive accuracy. A calibration plot was used to evaluate the extent of overestimation or underestimation between nomogram predictions and observed PCa rate. Decision curve analysis (DCA) provided an estimate of the net benefit obtained by using the PHI-based nomogram.

Results and limitations

Of 833 patients, 365 (41.3%) were diagnosed with PCa at extended prostate biopsy. In accuracy analyses, PHI was the most informative predictor of PCa (0.68), outperforming tPSA (0.51) and %fPSA (0.64). The predictive accuracy of the previously developed nomogram was 75.2% (95% confidence interval, 71.4–78.1). Calibration of the nomogram was good in patients at a low to intermediate predicted probability of PCa, while calibration was suboptimal, with a tendency to overestimate the presence of PCa, in high-risk patients. Finally, DCA demonstrated that the use of the PHI-based nomogram resulted in the highest net benefit. The main limitation of the study is the fact that only Caucasian patients were included.

Conclusions

At external validation, the previously developed PHI-based nomogram confirmed its ability to determine the presence of PCa at biopsy. These findings provide further evidence supporting the potential role of the nomogram in the biopsy decision pathway for European men with suspected PCa.

Patient summary

In the current study, we externally validated a Prostate Health Index–based nomogram to predict the presence of prostate cancer (PCa) at biopsy. This tool may help clinicians determine the need for a prostate biopsy in European patients with suspected PCa.