Use of the Prostate Health Index and Density in 3 Outpatient Centers to Avoid Unnecessary Prostate Biopsies

Background: Beyond prostate-specific antigen (PSA), other biomarkers for prostate cancer (PCa) detection are available and need to be evaluated for clinical routine. Objective: The aim of the study was to evaluate the Prostate Health Index (PHI) density (PHID) in comparison with PHI in a large Caucasian group >1,000 men. Methods: PHID values were used from available patient data with PSA, free PSA, and [−2]pro­PSA and prostate volume from 3 former surveys from 2002 to 2014. Those 1,446 patients from a single-center cohort included 701 men with PCa and 745 with no PCa. All patients received initial or repeat biopsies. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curves comparing area under the ROC curves (AUCs), precision-recall approach, and decision curve analysis (DCA). Results: PHID medians differed almost 2-fold between PCa (1.12) and no PCa (0.62) in comparison to PHI (48.6 vs. 33; p always <0.0001). However, PHID and PHI were equal regarding the AUC (0.737 vs. 0.749; p = 0.226), and the curves of the precision-recall analysis also overlapped in the sensitivity range between 70 and 100%. DCA had a maximum net benefit of only ∼5% for PHID versus PHI between 45 and 55% threshold probability. Contrary, in the 689 men with a prostate volume ≤40 cm³, PHI (AUC 0.732) showed a significant larger AUC than PHID (AUC 0.69, p = 0.014). Conclusions: Based on DCA, PHID had only a small advantage in comparison with PHI alone, while ROC analysis and precision-recall analysis showed similar results. In smaller prostates, PHI even outperformed PHID. The increment for PHID in this large Caucasian cohort is too small to justify a routine clinical use.

The management of prostate cancer poses difficult challenges, which is largely because we lack the necessary tools to predict its presence, and discern between indolent disease with a small chance of clinical manifestation and aggressive tumours that are more likely to be lethal. Despite the fact that novel blood and urine tests are available, which may predict aggressive disease better than PSA; they are not routinely used due to a lack of clinical validity studies. Tosoian et al. 1 in the present study explored the utility of prostate health index (PHI) density for detection of clinically significant prostate cancer in a contemporary cohort of men presenting for diagnostic evaluation of prostate cancer. Very interestingly the authors hypothesised that, similar to PSA density, PHI density could further improve upon the discriminative ability of PHI to detect prostate cancer. The PHI density calculation was performed using prostate volume, as determined by TRUS. Logistic regression was used to assess the ability of serum markers to predict clinically significant prostate cancer, defined as any Gleason score ≥7 cancer or Gleason score 6 cancer in >2 cores or >50% of any positive core. They showed, albeit in a small sample size, that PHI density could further improve upon the discriminative ability of PHI and appears to be superior to PSA and other PSA derivatives for the identification of clinically significant disease 1. However, it is noteworthy that in all studies on urine or serum biomarkers such as this, the ‘gold standard’ for cancer detection is pathological examination of multiple non-targeted systematic TRUS-guided prostate biopsies, not radical prostatectomy specimens. Intrinsically, this approach implies that no cancer predicted by the biomarker may still mean cancer missed by the biopsy. Recently, the European Association of Urology Guidelines have introduced multi-parametric MRI (mpMRI) as a strongly recommended examination before repeating biopsy when clinical suspicion of prostate cancer persists 2. Indeed, mpMRI is very accurate in detecting clinically significant prostate cancer, with a positive predictive value of 82% and a negative predictive value of >95% for excluding high-risk prostate cancer 3, 4. Introducing mpMRI before prostate biopsy has the potential to improve prostate cancer sampling, because targeted cores contain a more complete pathological representation of the entire tumour, resulting in more personalised treatments for patients 5, 6. However, mpMRI reporting is labour-intensive and time-consuming, requiring experienced radiologists to integrate information from different morphological and functional sequences. The examination is also expensive, due to contrast agent administration and the use of an endorectal coil for imaging acquisition. For these reasons, at the moment, mpMRI is not feasible for screening purposes in the population at risk of prostate cancer, as it would not be sustainable by the National Healthcare System (NHS). Furthermore, ~40% of mpMRI studies are reported as indeterminate, which can lead to repeat examinations or unnecessary biopsy with associated patient anxiety, discomfort, risk and additional costs. A possible solution to the current limitations of mpMRI has been the discovery of new biomarkers to better select the candidates for MRI. Tosoian et al. 1 report that PHI density could be used to avoid 38% of unnecessary biopsies, while failing to detect only 2% of clinically significant cancers. If the specificity of the PHI density score is higher than that of PHI or PSA, then fewer patients will undergo unnecessary MRI, thus increasing the efficiency of the diagnostic pipeline for prostate cancer. Introduction of MRI-targeted biopsy (mpMRI/ultrasonography-fusion biopsy and in-bore biopsy) could further increase PHI density accuracy in detecting tumour and help in implementing a clinical decision support system. In our opinion, to evaluate diagnostic accuracy of biomarkers both prostatectomy and fusion biopsy remain preferable to non-targeted systematic TRUS-guided biopsies, which remains the standard of care in most centres but systematically misses 20–30% of clinically significant cancers, particularly in the anterior gland 5. However, prostate cancer is a complex disease and it is unlikely to be fully characterised with a single fluidic or diagnostic imaging marker tool. A possible scenario in the future should be the clinically validation of a panel of minimally invasive promising blood and urine biomarkers, to better select patients that will benefit from mpMRI. We think that is the most practical way to make mpMRI before biopsy economically viable for universal NHS adoption. The aim should be the development of a clinical decision support system based on mpMRI and circulating biomarkers, as in this case PHI density evaluation, to stratify patients according to their risk of prostate cancer progression, using pathological assessment after prostatectomy as the reference standard. The authors declare no conflicts of interest.

Prostate-specific antigen (PSA) is an established tumour marker for prostate cancer (PCa). Serum thymidine kinase 1 is a possible new marker for the detection of PCa. The aim of the study was to investigate the diagnostic value of the AroCell TK 210 enzyme-linked immunosorbent assay (ELISA) together with free PSA, [-2]proPSA, and Prostate Health Index (PHI) in differentiating PCa from benign urological conditions. Serum samples from 140 patients with PSA values in the range between 2 and 10 µg/L were collected at the Ljubljana University Medical Centre and the Maribor University Medical Centre. Thymidine kinase (TK1) protein levels were determined using the AroCell TK 210 ELISA and PSA-related parameters analysed with commercial assays. Serum TK1 protein, total and free PSA, proPSA, PSA density (PSAD), and PHI levels in patients with confirmed PCa were significantly higher than in patients with benign urological conditions (P < 0.05). Overall, the AroCell TK 210 ELISA results showed a significant correlation with PHI ( r = 0.25, P = 0.0031). Receiver-operating characteristic curve analyses were used to compare the area under the curve (AUC) of TK 210 ELISA, PHI, and PSA density. For PHI, the AUC was 0.73, comparable to those of TK 210 ELISA (0.67) and PSAD (0.66), with no significant differences in pairwise comparisons (PHI vs TK 210 ELISA P = 0.32, PHI vs PSAD P = 0.24, and TK 210 ELISA vs PSAD P = 0.95). The AUC for the combination of TK1 plus PSAD was significantly higher than those for the individual PSA-related biomarkers and marginally PHI, while the AUC for the combination of TK1 plus PHI was significantly higher than those for the individual PSA-related biomarkers except for PHI and marginally for PSAD. Total PSA concentration was the only marker, that was significantly higher in patients with an increasing Gleason grade. These results suggest that TK1 protein determinations together with PHI or PSAD could be a valuable additional tool in PCa management.

Development and Internal Validation of a Prostate Health Index Based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Simple SummaryIn the last decades, the widespread use of PSA as the standard tool for prostate cancer diagnosis led to a high rate of overdiagnosis and overtreatment. More recently, multiparametric magnetic resonance imaging (mpMRI) became part of the diagnostic pathway, and several next-generation PSA-based tests (PHI, PHI density, 4Kscore, STHLM3) have been proposed. The multivariable approach promises to help with a better stratification of PCa patients at initial diagnosis. In this study, we evaluated the performance of the prostate health index (PHI) and mpMRI for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). Our findings suggested that PHI had a better ability than mpMRI to predict positive biopsy, whereas a comparable performance in the identification of pathological aggressive PCa was pointed out. Notably, PHI and PHI density might represent useful biomarkers to recognize high-grade PCa in patients with low or uncertain PI-RADS scores on mpMRI.Widespread use of PSA as the standard tool for prostate cancer (PCa) diagnosis led to a high rate of overdiagnosis and overtreatment. In this study, we evaluated the performance of the prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). To this end, we prospectively enrolled 196 biopsy-naïve patients who underwent mpMRI. A subgroup of 116 subjects with biopsy-proven PCa underwent surgery. We found that PHI significantly outperformed both PI-RADS score (difference in AUC: 0.14; p < 0.001) and PHI density (difference in AUC: 0.08; p = 0.002) in the ability to predict positive biopsy with a cut-off value of 42.7 as the best threshold. Conversely, comparing the performance in the identification of clinically significant prostate cancer (csPCa) at RP, we found that PHI ≥ 61.68 and PI-RADS score ≥ 4 were able to identify csPCa (Gleason score ≥ 7 (3 + 4)) both alone and added to a base model including age, PSA, fPSA-to-tPSA ratio and prostate volume. In conclusion, PHI had a better ability than PI-RADS score to predict positive biopsy, whereas it had a comparable performance in the identification of pathological csPCa.

Commercial biomarkers and multiparametric MRI (mpMRI) have been utilized to triage men with elevated prostate specific antigen (PSA) and determine patients most likely to harbor clinically-significant prostate cancer (csPCa). We studied combinations of mpMRI, PSA-based and novel extracellular vesicle (EV)-based biomarkers to determine the optimal pre-biopsy testing to predict csPCa at biopsy. Men presenting with elevated PSA (≥ 2 ng/mL) were prospectively enrolled and all men underwent clinically indicated mpMRI and blinded study blood draws to determine PSA, prostate health index (PHI) scoring, and EV serum levels. MRI-fusion transperineal prostate biopsy was performed in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed. Bootstrapping analysis was performed to provide more accurate assessment of predictive abilities. Ultimately, 175 consecutive men were prospectively enrolled. Median age in the study population was 65 years. Combinations of biomarkers and MRI demonstrated better predictive ability for csPCa on biopsy than individual modalities. Predictive ability was greatest for PHI density (PHID)-mpMRI with an AUC of 0.86 (95% CI: 0.80-0.92) while combinations of PSA density -mpMRI (AUC: 0.81; 95% CI: 0.73-0.89) and STEAP1-mpMRI (AUC: 0.77; 95% CI: 0.70-0.86) demonstrated similar ability to predict csPCa. The study is limited by small, predominantly white patient cohort and requires external validation. Inclusion of prostate density with biomarkers increases prognostic ability for detecting csPCa. EV density can refine prediction of csPCa and in combination with PHID-mpMRI leads to superior specificity, thereby decreasing unnecessary biopsies.

Our aim was to assess the usefulness of measuring the percentage of free prostate specific antigen (PSA) in serum in relation to reducing the number of prostate biopsies in men with benign prostate examinations and serum PSA levels between 4 and 10 ng/ml. The percentage of free PSA (Immulite) in serum was analyzed prospectively in 500 men, all of whom underwent ultrasound-guided sextant prostate biopsies. Cancer was detected in 21.4% (107/500) of the patients. Using a free PSA cutoff of < or = 23% as a criterion for performing prostate biopsy would have detected 94.4% of cancers, avoided 18.8% of benign biopsies and yielded a positive predictive value of 25.3%. The percentage of free PSA increased with prostate volume. Mean total PSA and mean free percent PSA values increased as patient age increased, influencing the calculation of cutoff values, sensitivity and specificity. PSA density had a sensitivity and specificity not significantly different than the percentage of free PSA. Measurement of the percentage of free serum PSA improves the specificity of prostate cancer detection in patients with elevated total serum PSA levels and benign prostate examinations.

The aim of this study was to analyse the individual variations of total and percent free serum prostatic specific antigen (PSA) and to evaluate whether they could change the indication for prostatic biopsy. Prostatic needle biopsy was indicated in 63 patients with serum PSA between 4.0 and 10 ng/ml. A new determination of total and free PSA was done before the biopsy procedure. The time between the determinations ranged from 29 to 59 days. The total and free serum PSA determinations were performed by a double monoclonal antibody radioimmunoassay Tandem and Tandem free PSA. The median coefficient of variation for serum PSA was 12.9 in cancer free patients and 18.8 when cancer was detected, it was 32.6 and 42.2 respectively for percent free serum PSA. A 22.8% rate of discrepancy between the determinations was found when prostatic biopsy was indicated only by percent free PSA lower than 25. Sensitivity ranged from 93.3% to 100, and reduction of unnecessary biopsies between 15.2 and 21.8%. We conclude that individual variations in total and percent free serum PSA could have clinical implications because of the possibility that it changes the indication for a prostatic biopsy.

Prostate cancer (PCa) diagnosis is often hindered by the need to detect clinically significant disease (csPCa) while minimizing unnecessary biopsies. The Prostate Health Index (PHI) and multiparametric magnetic resonance imaging (mpMRI) are promising tools to address these challenges. To develop and internally validate a predictive model for PCa and csPCa by combining PHI and mpMRI in a high-risk population. This retrospective study included 179 patients who underwent prostate biopsy between 2019 and 2023. Inclusion criteria comprised elevated PSA (> 3 ng/mL), suspicious digital rectal examination and/or family history, PHI values, and pre-biopsy mpMRI. Logistic regression models were developed, and model performance was assessed using C-statistics, calibration plots, and decision curve analysis (DCA). PCa was diagnosed in 40.2% of patients, and csPCa in 34.7% of them. A multivariate model including PHI, prostate volume, and mpMRI achieved an AUC of 0.81 for PCa. For csPCa, the best model combined PHI and prostate volume (AUC 0.76). In the PI-RADS 3 subgroup, PHI showed high discriminatory performance (AUC 0.81), surpassing PSA density (PSA-D). The DCA showed a superior net benefit of the multivariable models compared to single-parameter strategies. Integrating PHI and mpMRI improves PCa diagnostic accuracy and clinical decision-making, especially in ambiguous cases such as PI-RADS 3 lesions, and reduces unnecessary biopsies in clinical practice.

Objective: To investigate the value of prostate health index (PHI) in the diagnosis of prostate cancer in patients with total prostate specific antigen (tPSA) <20 μg/L. Methods: Totally 1 135 patients with tPSA<20 μg/L and prostate biopsy indications at Department of Urology, Fudan University Shanghai Cancer Center from March 2013 to April 2016 were enrolled in this study. They were tested for serum tPSA, free prostate specific antigen and prostate specific antigen isoform 2, from which PHI was calculated. Diagnostic efficacy of PHI and tPSA were evaluated using receiver operating characteristic (ROC) curve analysis. The detection rates of prostate cancer were calculated in different ranges of PHI. Subgroup analysis of 716 patients, who were aged 50 or above with tPSA in the range of 4 to 10 μg/L and digital rectal examination negative, was performed. Results: In the biopsied objects with tPSA<20 μg/L, PHI was significantly higher in prostate cancer patients than that in non-cancer patients (48.4(37.4) vs. 26.5(16.9), U=52 674.00, P=0.000), PHI was also significantly higher in high-grade prostate cancer patients than that of low-grade prostate cancer patients (44.5(30.8) vs. 56.4(42.5), U=23 314.00, P=0.000). The area under the curve (AUC) of PHI for diagnosing prostate cancer was significantly higher than that of tPSA (0.771 vs. 0.627, P=0.000). When PHI was in the range of <27, 27 to <36, 36 to <55 and ≥55, the probability of prostate cancer was 9.4% (95%CI: 7.0% to 12.2%), 16.3% (95%CI: 12.2% to 20.8%), 31.0% (95%CI: 25.9% to 37.3%) and 66.4% (95%CI: 58.9% to 74.2%), respectively. Subgroup analysis showed that the AUC of PHI in diagnosing prostate cancer was significantly higher than that of tPSA (0.764 vs. 0.569, P=0.000). When PHI was in the range of <27, 27 to <36, 36 to <55 and ≥55, the probability of prostate cancer was 8.1% (95%CI: 5.4% to 11.3%), 14.0% (95%CI: 9.1% to 19.9%), 30.8% (95%CI: 23.6% to 38.7%) and 78.8% (95%CI: 66.7% to 88.9%), respectively. Conclusion: PHI is superior to tPSA in the diagnosis of prostate cancer in Chinese men with tPSA<20 μg/L.

PROSPECTIVE EVALUATION OF PROSTATE CANCER DETECTION BY PROSTATE SPECIFIC ANTIGEN RELATED PARAMETERS: COMPARISON IN SERUM AND PLASMA SAMPLES

Introduction: Prostate cancer (PCa) is the second most frequent type of cancer in men; diagnosis is reached through prostate biopsy, an invasive procedure, so efforts are made to avoid unnecessary ones by improving them and optimizing current biomarkers. Among existing biomarkers, prostate -specific antigen (PSA) Density (PSAD), a PSA derivative, is considered a feasible biomarker for PCa Objective: This study aimed to evaluate different PSA derivatives as well as determine whether PSAD with a cut-off point of 0.12 was more accurate than the widely used value of 0.15 to recognize patients suffering from prostate cancer. Material and methods: Retrospective study of 391 patients aged 40 years or more, who underwent prostate biopsy at Fundacion Urologica Cordoba para la Docencia e Investigacion Medica (FUCDIM) , from November 2010 to July 2014. Sensitivity and specificity for the PSAD cut-off point of 0.12 were estimated. Diagnostic accuracy was evaluated through Receiver Operating Characteristic (ROC) curves and the Area Under the Curve. PSAD was compared to total PSA, free/total PSA index, and (free/total PSA)/PSAD. Results: Significantly higher mean values were found in terms of total PSA, PSAD, and F/T PSA in patients with confirmed diagnoses of PCa. PSAD with a cut-off point greater than 0.12 detected a significantly higher percentage of cancer, 80%, p=0.0001, compared to the control group. Furthermore, the strength of association determined that patients with PSAD greater than 0.12 were 3 times more likely to belong to the PCa group. Conclusion: Total PSA, PSAD, and F/T PSA in patients with cancer yielded significantly higher mean values. The best biomarker to predict prostate cancer by biopsy was PSAD, with a cut-off point of 0.12. These results indicate the need to develop further investigations in diverse geographic areas to define the best local cut-off points for PSAD. Our results demonstrate that the established cut-off point of 0.15 could be appropriate for European men but appears to be too high for American and low for Asian males.

Among Chinese men with prostate-specific antigen (PSA) 4-20ng/mL scheduled for biopsy,<20% harbor clinically significant prostate cancer (csPCa, International Society of Urological Pathology [ISUP] ≥2); most procedures target non-clinically significant prostate cancer (non-csPCa; ISUP <2) or benign prostatic hyperplasia (BPH). We tested whether prostate-specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) combined with multiparametric imaging and laboratory assays can accurately identify non-csPCa/BPH and safely reduce unnecessary biopsies. We retrospectively enrolled patients from two centers. In the discovery cohort, participants underwent PSA testing, mpMRI, and 68Ga-PSMA-PET/CT, and were assessed for Prostate Imaging Reporting and Data System (PI-RADS) and PRIMARY scores. Receiver operating characteristic (ROC) curves, decision curve analysis, and diagnostic tests compared the efficacy of each indicator for non-csPCa/BPH and established the optimal strategy. The validation cohort independently verified this strategy. Discovery cohort (n =243): PRIMARY score area under the curve (AUC) 0.92 (95% confidence interval [CI]: 0.88-0.95); cutoff ≤3 provided 83.5% sensitivity and 90.9% specificity, outperforming PI-RADS (P =0.002), PSA density (PSAD), free/total PSA (f/tPSA), and total PSA (tPSA) (all P < 0.0001). Combined models: PRIMARY score+PI-RADS AUC 0.95 (0.92-0.97); PRIMARY+PSAD or+f/tPSA both 0.94. A strategy of PRIMARY score ≤3 plus PSAD ≤0.2 achieved 100% specificity and positive predictive value (PPV) for csPCa, sparing 54.1% of unnecessary biopsies with zero csPCa missed - superior to European Association of Urology (EAU)-recommended PI-RADS ≤2+PSAD ≤0.2 (sensitivity 19.6%). External cohort (n =149) validated 100% specificity/PPV, avoiding 69.6% of biopsies while maintaining 0% csPCa miss rate. In men with suspected prostate cancer (PSA 4-20ng/mL or abnormal digital rectal examination), the combined criterion of PRIMARY score ≤3 and PSAD ≤0.2ng/mL/cm3 enabled pre-biopsy triage that safely avoided immediate diagnostic biopsy in more than 50% of patients ultimately found to harbor non-csPCa and BPH in our cohorts, while ensuring that no csPCa was missed. These findings require confirmation in larger prospective, multicenter studies before routine clinical implementation.

This study was undertaken to determine whether the prostate specific antigen (PSA) density (PSAD) and PSAD of the transition zone (PSADT) are useful in the detection of prostate carcinoma in Japanese men with intermediate levels of serum PSA. Two hundred and eighty-seven Japanese men with intermediate serum PSA levels (2.1 ng/mL to 10 ng/mL) underwent measurement of prostate volume by transrectal ultrasound (TRUS) and systematic biopsy under TRUS guidance. The volume of the transition zone was also measured by TRUS in 134 patients. The PSAD and PSADT were determined for each patient, and their relationship to prostate carcinoma detection was examined. Prostate carcinoma was detected in 30 of 287 patients (10.5%). Although the serum PSA levels were similar in patients with benign and malignant prostate disease (P = 0.541), the prostate volume (P 0.0009) and PSAD (P < 0.0001) differed significantly in the two groups; in the patients with prostate carcinoma, the prostate volume was smaller, and the PSAD higher, than in the patients with benign disease. At the PSAD cutoff value of 0.18 ng/mL/cm3 or greater, the sensitivity was 70% and the specificity was 67% for the diagnosis of prostate carcinoma. The PSAD was found to be significantly better in the differentiation between benign and malignant prostate disease than the serum PSA in the receiver operating characteristic analyses (P = 0.045). However, the receiver operating characteristic curve for PSAD was not significantly different compared with that for PSA in the men with negative digital rectal examination findings. Prostate carcinoma was detected in 9.0% (12 of 134) of the patients who underwent PSADT determination. Receiver operating characteristic analyses showed that PSADT was not superior to PSA in the detection of prostate carcinoma. In Japanese men with intermediate serum PSA concentrations, PSAD offers additional information useful in the detection of prostate carcinoma, but PSADT does not. Although use of PSAD may decrease the number of unnecessary biopsies, a significant number of prostate carcinomas may be overlooked. Therefore, the authors recommend that serum PSA levels continue to be used as an indicator for biopsy in Japanese men.

Objective: Many men with non-clinically significant prostate cancer (N-CSPCa) will not progress to symptomatic forms within their lifetime. So, predicting clinically significant PCa (CSPCa) will prevent unnecessary biopsies, overdiagnoses, and overtreatment of patients. Thus, we aimed at demonstrating the predictive ability of prostate-specific antigen (PSA) density (PSAD) and f/t PSA in revealing CSPCa (Gleason score 7) in patients diagnosed with prostate cancer on biopsy with a PSA level of 2.5-10 ng/mL. Materials and Methods: We evaluated 78 patients with PSA 2.5-10.0 ng/mL who underwent transrectal ultrasound guided (TRUSG)-guided prostate biopsy in our clinic between March 2017 and August 2020 and whose histology reported as prostate adenocarcinoma. In addition to the demographic content of the patients, PSA, free PSA, prostate size (with TRUSG), rectal examination findings, and prostate biopsy results were recorded. Clinically significant prostate cancer was defined as a minimum Gleason score of 7.