Clinical utility of the (-2)proPSA and evaluation of the evidence: a systematic review

Valentina Pecoraro, Laura Roli 3 , Mario Plebanihttp://orcid.org/0000-0002-0270-1711 4 , and Tommaso Trenti 1
  • 1 Clinical Pathology – Toxicology, Nuovo Ospedale Civile Sant’Agostino Estense, Modena, Italy
  • 2 I.R.C.C.S. – Mario Negri Institute for Pharmacological Research, Laboratory of Drug Regulatory Policies, Milan, Italy, Via Pietro Giardini 1355, 41126, Modena, Italy
  • 3 Clinical Pathology – Endocrinology, Nuovo Ospedale Civile Sant’Agostino Estense, Modena, Italy
  • 4 Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy.
Valentina Pecoraro, Laura Roli, Mario PlebaniORCID iD: http://orcid.org/0000-0002-0270-1711 and Tommaso Trenti

Abstract

Background: Diagnostic studies usually provide important information about the analytical and diagnostic performances. We investigated the clinical utility of (-2)proPSA in identifying patients with prostate cancer (PCa).

Methods: We performed electronic searches in five databases as well as a list of reference literature. Studies were included if they evaluated the diagnostic accuracy of (-2)proPSA in men with PSA value ranged from 2.0 to 10 μg/L. We also analyzed data about total PSA (tPSA), %(-2)proPSa, freePSA (fPSA), its percentage (%fPSA) and the prostate health index (phi). The selection of the studies, the screening of the full texts and the data extraction, as well as the assessment of risk of bias using the QUADAS-2 tool were conducted independently by two authors. Grading the quality of the evidence was carried out according to the GRADE method. The random effects model was used for the meta-analyses.

Results: We included 17 studies, including 6912 patients. The pooled sensitivity of (-2)proPSA was 90% and the summary specificity was 13%. The tPSA sensitivity and specificity were 89% and 25%, respectively. Considering (-2)proPSA, 225 men out of 1000 have been identified having PCa true positives (TP). However, 652 persons have been incorrectly identified and undergo biopsy. The majority of studies were judged to carry a moderate risk of bias. Therefore, the overall quality of evidences was deemed to be low.

Conclusions: The (-2)proPSA could be useful to identify men at risk of PCa, but its accuracy still remains uncertain and the level of evidence does not support an improved clinical utility.

Introduction

Prostate cancer (PCa) is the main cause of worldwide death in men and its great prevalence is due to inappropriate life custom and environmental risk factors, as well as genetic factors [1]. Prostate specific antigen (PSA) is the marker used for screening the male population at risk of PCa, although being unspecific for this cancer. PSA levels increase in patients with PCa, independently of the level of PCa aggressiveness. This is especially limiting when the PSA values fall in the diagnostic gray zone, ranging between 2 and 10 μg/L. The clinical significance of the test feels the effect of these limitations, recording a high number of false positives (FP) and therefore an increment in unnecessary prostate biopsies [2]. Considering the limitations unsatisfactory diagnostic accuracy of this molecule, new biomarkers should be developed. Serum contains two forms of PSA, the complex and uncomplex form (free PSA), the combination of which constitute the total PSA (tPSA). The free PSA (fPSA) is enzymatically inactive and is composed of three different types of PSA: benign PSA usually associated with benign prostatic hyperplasia, intact PSA which is similar to the active form, and proPSA usually associated with cancer [3]. Different truncated forms of proPSA have been identified: (-4) and (-2)proPSA are resistant to activation and are biochemical features differentiating from (-5) and (-7)proPSA which are rapidly activated by human kallikrein 2 [4, 5]. Recently, researchers have focused their interest on the (-2)proPSA, because its serum levels seem to be higher in men with PCa compared to men without cancer. Therefore, this molecule appears to be more cancer specific than PSA alone.

To investigate the diagnostic significance of the (-2)proPSA, we performed a methodological assessment, applying the GRADE method [6]. The GRADE approach facilitates the description of the grade of evidence available, based on the quantity of information produced in a study and considering four domains: risk of bias, consistency, directness and precision.

Aim of this paper is the evaluation of the diagnostic accuracy and clinical utility of (-2)proPSA in patients with the PSA value in the gray zone (from 2 to 10 μg/L). We analyzed, also, the diagnostic accuracy of the other available PCa biomarkers.

Materials and methods

We performed a systematic review and meta-analysis according to the recommendations indicated in the Cochrane Handbook for Diagnostic Test Accuracy (DTA) Reviews (http://srdta.cochrane.org/handbook-dta-reviews) and we reported data adapting the preferred reporting items from systematic reviews and meta-analysis (PRISMA) checklist [7] to diagnostic accuracy studies.

Search strategy, eligibility criteria and study selection

A systematic research was performed in five databases: Medline, Embase, Web of Science (WOS), Scopus and The Cochrane Register of Diagnostic Test Accuracy Studies (CRDTAS), to identify all possible eligible studies. The search strategy was carried out using the terms “prostatic neoplasm”, “prostate-specific antigen”, “(-2)pro-prostate-specific antigen”, “proPSA”, “p2PSA”, “sensitivity and specificity” and it was adapted to all databases. Furthermore, we checked the reference list of all selected studies.

We included studies which respected the following eligibility criteria: i) included male patients with suspicious PCa; ii) included male patients with PSA between 2.0 and 10 μg/L; iii) data about the diagnostic accuracy of (-2)proPSA, tPSA and its derivate [%p2PSA, fPSA, %fPSA, prostate health index (phi)] were reported; iv) published in English, Italian, Spanish, or French. The search strategy was performed by one author (VP). Two independent authors (VP, LR) screened the titles and abstracts, and subsequently reviewed all potentially eligible studies after the removal of duplicates. Disagreements between authors were resolved by consensus.

Data collection

One author (VP) used a standardized data extraction form to collect relevant publication details, regarding, the study methods, and the results, and the second author (LR) checked the data. The authors collected data about: study characteristics (i.e. authors, year of publication, title, reference, study design and inclusion criteria); ii) patient characteristics (i.e. age, number of enrolled patients and number of patients with PCa); iii) detailed information about the index test (i.e. method of assay and cut-off) and reference standard; iv) diagnostic study data (i.e. TP, TN, FP, FN). Disagreements were resolved by discussion. We defined reference standard the test whose results are compared with the index test as reported in the QUADAS-2 tool.

Outcomes

The primary outcome was the diagnostic accuracy of (-2)proPSA defined as the number of TP, FP, false negatives (FN) and true negatives (TN) reported in each study. When these data were not available, they were calculated from sensitivity and specificity data. We evaluated the number of unnecessary prostate biopsies and the number of missed PCa diagnoses. We also considered the changes of tPSA, (-2)proPSA and tPSA concentration in patients with and without PCa.

Assessment of risk of bias

The methodological quality of each selected paper was assessed independently by two reviewers (VP and LR) according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist [8] which considers four domains (patients selection, index test, reference standard and flow and timing), each rated in terms of their risk of bias and applicability to the research question. Risk of bias was judged as “low”, “high”, or “unclear”. If all signaling questions for a domain were answered “yes” then risk of bias was judged “low”. Concerning applicability, the authors recorded the information for which the study did not match the review question. Concerns regarding applicability were rated as “low”, “high” or “unclear”. Any disagreements were resolved through discussion.

Evidence profile using the GRADE approach

We evaluated the evidence using the GRADE approach. Prospective studies were initially considered at high quality but were downgraded according to: their risk of bias, directness of evidence, consistency or imprecision. Directness refers to the link between test of interest and disease or populations evaluated. Consistency concerns the degree of homogeneity (direction and magnitude) of results across the different studies. Precision describes the grade of uncertainty across the effects estimate, in other words the width of confidence intervals for diagnostic accuracy measurement [6, 9].

Statistical analysis

For each study, we constructed two-by-two tables and pooled TP, FP, TN and FN, calculating sensitivity and specificity with 95% confidence intervals. We used the random effects bivariate models to create separate forrest plots. We explored heterogeneity first through visual examination of the forrest plot and then through the analysis of the receiver operating characteristics (ROC) plot. Statistically heterogeneity was measured using I2 tests. All analyses were performed using the Stata 11 and Meta-Disc softwares.

Results

Studies selection

The literature search from Medline, Embase, WOS, Scopus and CRDTAS, after the exclusion of duplicates and irrelevant records, identified 4017 references. Of these, 3987 were discarded because they did not meet the inclusion criteria. Thirty were considered eligible for inclusion and their full texts were evaluated for details. Of these, 13 were excluded because: i) diagnostic accuracy data was not reported (n=7); ii) definition of reference range was not reported (n=2); male patients suspected of PCa were not included (n=3); iii) (-2)pPSA was not considered (n=1). A total of 17 studies [1, 4, 1024] were included in the current analysis (Supplemental Material, Figure 1).

Characteristic of studies

We included 17 cohort studies; 11 of which utilized a prospective design, four retrospective studies and two were defined as prospective and retrospective. Table 1 reports details of the studies selected, including information about the biopsy Gleason score. Overall, 6912 men were enrolled, of these 2993 (43.3%) had PCa. The number of participants ranged from 63 to 1091 and the age ranged from 62 to 68 years old. All trials were conducted between 2003 and 2014 and used immunoassays to quantify the serum markers. All studies used the prostate biopsy to diagnose PCa, and only four studies specified the tPSA as reference standard whose results were compared with the (-2)proPSA. In 15 studies, all patients underwent first serum biomarkers determination and then prostate biopsy [1, 4, 1016, 1824]. One study extended their research through an active surveillance program, of patients with a negative biopsy and with increasing PSA values [17]. All studies reported the performance of (-2)pPSA at 90% sensibility, but not all reported the cut-off values that, when recorded, ranged from 7 to 9 μg/L.

Table 1

Characteristics of included studies.

AuthorsStudy designInclusion criteriaMethod assayAge of patientsa, yearsPatients, nPatients with cancer, nGleason scoreReference standard
6≤7≥8
Catalona et al. [10]RetrospectiveIncl: patients undergo prostate biopsy, PSA range 4–10 ng/mLImmunoassay631091456n.a.n.a.n.a.Not define
Catalona et al. [11]Prospective and retrospectiveIncl: patients >50 years of age, no PCa history, non suspicious DRE, pre study PSA 1.5 to 11 ng/mL, 6-core or greater biopsy, histological diagnosis from prostate biopsy

Excl: previous prostate surgery, urinary tract infection, no blood or biopsy draw at the appropriate time, previous androgen therapy
Beckman Coulter Immunoassay62.8±7892430n.a.n.a.n.a.Not define
Filella et al. [12]Prospective and retrospectiveIncl: patients selected for biopsy because of an elevated serum PSA level and/or abnormal DRE, as well as patients diagnosed of Pca

Excl: medical therapy to affects PSA serum levels, prostatitis, urinary tract infection, invasive treatment
Beckman Coulter Immunoassay68 (38–88)354175825921Not define
Guazzoni et al. [13]ProspectiveIncl: PSa range 2–10 ng/mL, negative DRE, patients with suspected PSA

Excl: prostatitis, previous prostate surgery, use of drugs may alter PSA levels
Beckman Coulter Immunoassay63.3±8.22681075552tPSA

fPSA

%fPSA
Ito et al. [14]ProspectiveIncl: PSA range 2–10 ng/mLBeckman Coulter Immunoassay66 (37–82)2395312334Not define
Jansen et al. [15] (site 1)ProspectiveIncl: patients >50 years of age, tPSA range 2–10 ng/mL, TRUSPB, histologically confirmed diagnosisBeckman Coulter Immunoassay66 (55–75)405226168122Not define
Jansen (site 2)Excl: history of PCa, prostatitis, urinary tract infection, prostate surgery, use of drugs may akter PSA levelsBeckman Coulter Immunoassay60 (50–77)3511745548Not define
Khan et al. [16]ProspectiveIncl: tPSa range 4–10 ng/mL

Patients with suspected PCa
Beckman Coulter Immunoassayn.a.9341n.a.n.a.n.a.Not define
Lazzeri et al. [17]ProspectiveIncl: negative first biopsy, elevated PSA, suspicious DRE, atypical small acinar proliferation

Excl: man received dutasterine or finasteride, previous invasive treatment, urinary tract infection
Beckman Coulter Immunoassay63.9±7.122271n.a.n.a.n.a.tPSA

fPSA

%fPSA
Lazzeri et al. [18]ProspectiveIncl: patients >45 years of age, PSA range 2–10 ng/mL

Excl: prostatitis, previous prostate surgery, renail failor or other condition may alter PSA values
Beckman Coulter Immunoassay64.2±7.5646264125139tPSA,

fPSA,

%fPSA
Le et al. [19]ProspectiveIncl: PSA range 2.5–10 ng/mL, nonsospicious DREBeckman Coulter Immunoassay6563261911Not define
Mearini et al. [20]ProspectiveIncl: tPSA 2.0–10 ng/mL

Excl: prostatitis, precious prostate surgery, use of drug may alter PSA levels
Beckman Coulter Immunoassay65.4±6.8275866026tPSA

%fPSA

PSAD
Mikolajczyk et al. [4]RetrospectiveIncl: PSA range 4–10 μg/L patients undergo prostate biopsyBeckman Coulter Immunoassay66380238n.a.n.a.n.a.Not define
Miyakubo et al. [1]ProspectiveIncl: PSa range 2–10 ng/mLBeckman Coulter Immunoassayn.a.23953n.a.n.a.n.a.Not define
Ng et al. [21]RetrospectiveIncl: tPSA 4–10 ng/mL, negative DRE

Excl: history of TRUSPB,
Beckman Coulter Immunoassay65.7 (50–84)23021n.a.n.a.n.a.Not define
Sokoll et al. [23]RetrospectiveIncl: man with an indication for prostate biopsy, No prior prostate cancer historyBeckman Coulter Immunoassay62.2±8.212363n.a.n.a.n.a.Not define
Sokoll et al. [22]ProspectiveIncl: Patients >40 years of age, No prior prostate surgery, biopsy or history pf PCa, No use of 5-α reductase inhibitorsBeckman Coulter Immunoassay61.7±8.65662451079642Not define
Stephan et al. [24]ProspectiveIncl: patients referred to the department of urology for suspected PCaBeckman Coulter Immunoassayn.a.475264Not define

n, number; n.a., not available; Incl, inclusion; Excl, exclusion; DRE, digital rectal examination; TRUSPB, transrectal ultrasonography prostatic biopsy; aage reported as mean±SD or median (range).

(-2)pPSA, fPSA and phi levels were slightly higher in PCa patients than in men without PCa in all studies. Results for values of serum biomarkers in patients with or without PCa are shown in Supplemental Table 1.

The evidence profile

The results of the methodological quality of the included studies were shown in Supplemental Table 2. Four studies were retrospective, nine studies (53%) enrolled consecutive patients presenting to the urology department and in three studies the enrolment was unclear. The authors were blinded about the results of index test and reference standards in seven studies and the markers cut-off value were defined in 10 studies only. The majority of studies (n=11, 65%) reported that the blood samples were collected before any prostate manipulation. In all studies all patients received the same reference standard.

Table 2

Evidence profile of the (-2)proPSA accuracy to identify patients with PCa using GRADE approach.

OutcomesStudies, nPatientsa, nFactors that may decrease quality of evidencebOverall qualityf
Risk of biasIndirectnessInconsistencyImprecision
True positive6760SeriouscNoneSeriouseNoneLow
True negative6171SeriouscSeriousdSeriouseNoneVery low
False positive61116SeriouscSeriousdSeriouseNoneVery low
False negative682SeriouscSeriousdSeriouseNoneVery low

an Patients reported by included studies; bdowngrade quality of evidence: none, serious (–1), very serious (–2); csix prospective studies and only one retrospective study; dthere is uncertainty about the consequences for these patients; ethe studies included use different cut-off and the heterogeneity is very high; fquality range: high, moderate, low, very low.

Using the GRADE approach, we assessed the overall quality of the evidence about the levels of (-2)proPSA in patients with PSA levels between 2.0 and 10.0 μg/L. Because some studies were retrospective, the GRADE scores were downgraded for risk of bias for all outcomes. Our meta-analyses did not suffer from serious imprecision. We subtracted one point for inconsistency in meta-analysis showing substantial heterogeneity, and an additional point for indirectness. The quality of evidences was very low for true negative, false positive and false negative patients. Thus, the available evidences suggest that the measurement of (-2)proPSA does not procure substantial clinical utility in identifying patients with PCa. However, it seems more informative than tPSA alone (Table 2).

Valuation of the diagnostic accuracy

The diagnostic accuracy of (-2)proPSA was evaluated in six studies with 2129 patients. The pooled sensitivity was 0.90 (95% CI 0.88–0.92, I2=0%), the polled specificity was 0.13 (95% CI 0.11–0.15, I2=93.1%) and the area under the curve (AUC) was 0.95 (SE=0.03) (Figures 13). Even if the heterogeneity related to specificity was very high, we estimated that 877 of 1000 patients had a positive test results, 225 of these had PCa (TP), while 652 of these people were FP and they were undergo to prostate biopsy. One hundred and twenty three of 1000 patients had no evidence of cancer, 98 of these could have avoided a biopsy, while 25 patients with PCa would have been missed (Table 3). The pooled positive and negative likelihood ratios (LR) were 1.04 and 0.87, respectively.

Figure 1:
Figure 1:

The pooled sensitivity of (-2)proPSA.

Citation: Clinical Chemistry and Laboratory Medicine (CCLM) 54, 7; 10.1515/cclm-2015-0876

Figure 2:
Figure 2:

The pooled specificity of (-2)proPSA.

Citation: Clinical Chemistry and Laboratory Medicine (CCLM) 54, 7; 10.1515/cclm-2015-0876

Figure 3:
Figure 3:

SROC of (-2)proPSA.

Citation: Clinical Chemistry and Laboratory Medicine (CCLM) 54, 7; 10.1515/cclm-2015-0876

Table 3

Summary of meta-analyses table.

TestStudies, nSensitivitySpecificityper 1000aAUC (SE)LR+LR–
Patients, n(95% CI)I2(95% CI)I2TP rateFP rateTN rateFN rate(95% CI)(95% CI)
(-2)proPSA5 (2129)0.90 (0.88–0.92)0%0.13 (0.11–0.15)93.1%22565298250.95 (0.03)1.04 (0.96–1.13)0.87 (0.47–1.61)
tPSA12 (4077)0.89 (0.87–0.9)27.8%0.25 (0.23–0.27)96.9%223562188270.94 (0.03)1.22 (1.10–1.35)0.47 (0.34–0.65)
%p2PSA14 (4566)0.89 (0.88–0.9)11.7%0.32 (0.3–0.34)86.8%223510240270.89 (0.06)1.35 (1.24–1.46)0.34 (0.27–0.43)
fPSA4 (2516)0.92 (0.9–0.93)55.5%0.08 (0.07–0.10)92.9%23069060200.82 (0.09)1.01 (0.96–1.06)0.98 (0.60–1.60)
%fPSA15 (4758)0.89 (0.88–0.9)6.8%0.22 (0.20–0.24)89.3%223585165270.84 (0.05)1.15 (1.09–1.22)0.49 (0.39–0.60)
PHI11 (4184)0.90 (0.89–0.91)0%0.31 (0.29–0.33)89.8%225518232250.95 (0.03)1.35 (1.25–1.46)0.34 (0.29–0.41)

AUC, area under the curve; TP, true positives; FP, false positives; TN, true negatives; FN, false negatives; aassuming a pre-test probability of 25%.

To obtain clinically relevant estimates of the performance of other available PSA serum markers, we conducted a separate meta-analysis for each of them. Twelve studies evaluated tPSA for 4077 patients. The pooled sensitivity and AUC were inferior to those reported for (-2)proPSA: 89%, 0.94 (SE=0.035), respectively. For all other biomarkers (%(-2)pPSA, fPSA,%fPSA, phi) at fixed sensibility of 90% reported in all studies, the connected specificity was very low and the heterogeneity was very high, probably due to different cut-offs used. The results from these meta-analyses are presented in Table 3.

Discussion

PCa is the most common male cancer affecting middle age men older than 50 years. The serum biomarker recommended in most guidelines in the screening phase for patients at risk of PCa is PSA, but its clinical value is questionable due to a lack of specificity. Despite its widespread use, due to the reduced specificity and sensitivity in patients within the PSA grey zone, this test is unable to discriminate between patients with and without PCa, and between aggressive or indolent cancer types. PSA levels can also be effected by benign prostate conditions or prostatitis, prostate manipulations, some inflammatory processes or infections, specific drugs (NSAIDs, statins, thiazide diureticsor finestaride and five alpha reductase inhibitors) and androgen therapy [25], commonly administered to, or present in, middle aged men. All these factors should be taken into consideration when evaluating PSA values.

Recently, to enhance the selection of patients for prostate biopsy, some authors have proposed numerous serum biomarkers with improved PCa specificity, particularly PSA derivatives such as fPSA,%fPSA, PSA density and PSA velocity. However, the precursor of PSA (proPSA) seems to be the most promising among the candidate molecules. There are four types of proPSA in serum which can be differentiated according to the number of amino acids forming the pro-leader peptide sequence [2, 3, 5]. Of these, the (-2)proPSA is localized in the peripheral zone cancer and its serum levels are higher in patients with PCa than patients without cancer [26].

Despite the unsatisfactory accuracy of tPSA and fPSA, we evaluated the diagnostic accuracy of (-2)proPSA and its derivatives, in discerning men at risk of cancer when PSA was within the diagnostic grey zone. The GRADE approach was again applied to assess clinical utility of the serum biomarker determination.

Our meta-analyses showed that at sensibility 90%, the specificity of (-2)proPSA was 13% and its prognostic value was consistent (AUC 0.95). We also report a good specificity of %(-2)proPSA (32%) and phi (31%). We show that (-2)proPSA was equivalent in term of diagnostic accuracy (sensitivity and specificity) compared to other PSA derivatives, but the number of unnecessary biopsies was reduced unsatisfactory, as well as the number of the false negative. These results suggest a limited clinical utility of (-2)proPSA, due to a high rate of FP and low level of evidence.

It is interesting to note that the accuracy of (-2)proPSA is limited by lack of specificity. Furthermore, for (-2)proPSA the authors reported AUC ranging from 0.51 [18] to 0.62 [15], highlighting a better performance for %(-2)proPSA (AUC from 0.63 [4] to 0.78 [24]) and phi (AUC from 0.67 [18] to 0.78 [21]). For these biomarkers, whereby, we report a significantly high accuracy for detecting PCa (AUC 0.89 and 0.95, respectively) and they seem to be of greater clinical interest.

Our results suggest, also that the %(-2)proPSA and phi improve the detection of PCa in patients with PSA in the grey zone, according to previous systematic reviews. A published systematic review including 12 studies [27] reported similar %(-2)proPSA specificity (32.5 % vs. 32%) and phi specificity (31.6% vs. 31%). However, Wang [28] reported, a very high %p2PSA specificity (40% vs. 32%), phi specificity (45% vs. 31%). The authors suggest that %(-2)proPSA and phi have higher diagnostic accuracy rates than other PSA derivatives and seem to be more useful in PCa diagnosis. Additionally, other authors have suggested that these biomarkers may be potential candidates in predicting aggressive PCa in association with the Gleason score, and may help clinicians in guiding the decision to opt for a biopsy and in choosing appropriate treatment [27, 28].

To assessment of clinical utility, the levels of evidence of the included studies were validated by the GRADE approach [6]. From the level of evidence, to the current study sought to determine whether the (-2)proPSA should be introduced as a preferred biomarker in routine laboratory examinations for the identification of patients with PCa. The level of evidence was evaluated as low quality because the studies included in the current analysis have important methodological shortcomings: some studies have a retrospective design, and in others the outcome assessor was not blinded with respect to the reference or standard test. Despite the encouraging results, the clinical significance of serum PSA remain controversial due to different levels of evidence provided by included studies, and as they are enabling which cannot suggest a clear benefit. Nevertheless the majority of the included studies claimed that the (-2)proPSA has a higher accuracy than traditional marker as the tPSA, the valuation of the evidence through the GRADE method shown a questionable clinical application. This approach could be a valid method also for the laboratory professionals to evaluate the evidence, but its implementation is still far.

Our findings are in line with current recommendations in many international guidelines [2932], which do not support the widespread use of (-2)proPSA in identifying patients at risk of PCa. The main American and European urologist associations recommend the consideration of digital rectal examination (DRE) findings, prostate size, ethnicity, age, comorbidity, family history, previous biopsy results, as well as tPSA values before to perform a biopsy. Moreover, at the moment, tPSA is the only biomarker recommended to monitor patients after radical therapy. Other serum biomarkers still require further investigation to establish their clinical usefulness.

As a result of excess detection of non-aggressive PCa from tPSA levels, active surveillance, identifying patients with quick disease progression during the observation time has been proposed as a strategy to reduce the number of negative prostate biopsies [33]. In patients with previous biopsy and who show increasing PSA values throughout follow-up, (-2)proPSA monitoring could assist in any further prostate biopsy decision making processes [3]. The success of this strategy depends on the ability to identify appropriate patients. Many features were investigated to more precisely characterize candidate patients, and only age, race and family history seem to be associated with active surveillance outcomes [34]. Some authors suggest that (-2)proPSA may have a role in stratifying the risk of progression during the active surveillance program and to improve the treatment decisions, identifying patients requiring a second prostatic biopsy, but further studies are needed to confirm the performance of this biomarker throughout the follow-up.

Although this systematic review provides useful information, some limitations could be considered. First, many studies did not report the cut-offs utilized, making difficult the generalizability of the results. Second, although the study’s results were accurate, the meta-analyses were affected by high heterogeneity, probably due to the variety of cut-offs used, the difference in the enrolment methods and the number of core obtained during the biopsy. In this, the concept of harmonization should be highlighted, as the differences among decision limits used in the primary studies compromise the result interpretations and the possibly derived recommendations. Third, studies with retrospective design were included.

Furthermore, we conducted a methodological exercise trying to apply the GRADE method also for the evaluation of a diagnostic test. This approach could be a valid method also for the laboratory professionals to evaluate the evidence, but its implementation is still far due to some levels of criticality. The first obstacle is the lack of explicit diagnostic key question and a clear definition of the diagnostic accuracy outcome. The applicability of the GRADE criteria is laborious often due to the poor reporting of the evaluated studies. So, develop a profile defining the sensibility and specificity in term of number of patients that could benefit or not from the evaluated test, helps readers to judge the test validity. Moreover, the further limitation of our work was the difficulty to engage a structured multidisciplinary and multiprofessional panel with GRADE experienced, ensuring the methodological validity and the clinical relevance of the (-2)proPSA.

In conclusion, the current evidences do not support the clinical utility of (-2)proPSA in the diagnostic process. Transparent and explicit method as GRADE could lead the way for the interpretation and implementation of a new test.

Acknowledgments

The authors wish to thank Johanna Chester who assisted with an editorial evaluation of this review, and Dott. Giovanni Castagnetti for his suggestions.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. VP conceived and designed the study. VP and TT wrote the protocol. VP designed and implemented the search strategies. VP and LR selected studies, assessed validity, and extracted data. VP entered and analysed the data. All authors interpreted the data, prepared the full review and contributed to its revision, interpretation of results, and approval.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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    Catalona WJ, Bartsch G, Rittenhouse HG, Evans CL, Linton HJ, Amirkhan A, et al. Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol 2003;170:2181–5.

    • Crossref
    • PubMed
    • Export Citation
  • 11.

    Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 2011;185:1650–5.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Filella X, Foj L, Auge JM, Molina R, Alcover J. Clinical utility of %p2PSA and prostate health index in the detection of prostate cancer. Clin Chem Lab Med 2014;52:1347–55.

    • PubMed
    • Export Citation
  • 13.

    Guazzoni G, Nava L, Lazzeri M, Scattoni V, Lughezzani G, Maccagnano C, et al. 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. Eur Urol 2011;60:214–22.

    • Crossref
    • Export Citation
  • 14.

    Ito K, Miyakubo M, Sekine Y, Koike H, Matsui H, Shibata Y, et al. Diagnostic significance of [-2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0–10.0 ng/mL range. World J Urol 2013;31:305–11.

    • Crossref
    • PubMed
    • Export Citation
  • 15.

    Jansen FH, van Schaik RH, Kurstjens J, Horninger W, Klocker H, Bektic J, et al. Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection. Eur Urol 2010;57:921–7.

    • Crossref
    • PubMed
    • Export Citation
  • 16.

    Khan MA, Partin AW, Rittenhouse HG, Mikolajczyk SD, Sokoll LJ, Chan DW, et al. Evaluation of proprostate specific antigen for early detection of prostate cancer in men with a total prostate specific antigen range of 4.0 to 10.0 ng/ml. J Urol 2003;170:723–6.

    • Crossref
    • PubMed
    • Export Citation
  • 17.

    Lazzeri M, Briganti A, Scattoni V, Lughezzani G, Larcher A, Gadda GM, et al. Serum index test %[-2]proPSA and Prostate Health Index are more accurate than prostate specific antigen and %fPSA in predicting a positive repeat prostate biopsy. J Urol 2012;188:1137–43.

    • Crossref
    • PubMed
    • Export Citation
  • 18.

    Lazzeri M, Haese A, de la Taille A, Palou Redorta J, McNicholas T, Lughezzani G, et al. Serum isoform [-2]proPSA derivatives significantly improve Gm, European study. Eur Urol 2013;63:986–94.

  • 19.

    Le BV, Griffin CR, Loeb S, Carvalhal GF, Kan D, Baumann NA, et al. [-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. J Urol 2010;183:1355–9.

    • Crossref
    • Export Citation
  • 20.

    Mearini L, Ferri C, Lazzeri M, Bini V, Nunzi E, Fiorini D, et al. Evaluation of prostate-specific antigen isoform p2PSA and its derivates, %p2PSA, prostate health index and prostate dimension-adjusted related index in the detection of prostate cancer at first biopsy: an exploratory, prospective study. Urol Int 2014;93:135–45.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Ng CF, Chiu PK, Lam NY, Lam HC, Lee KW, Hou SS. The Prostate Health Index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen levels of 4–10 ng/mL. Int Urol Nephrol 2014;46:711–7.

    • Crossref
    • PubMed
    • Export Citation
  • 22.

    Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, Broyles DL, et al. A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010;19:1193–200.

    • Crossref
    • PubMed
    • Export Citation
  • 23.

    Sokoll LJ, Wang Y, Feng Z, Kagan J, Partin AW, Sanda MG, et al. [-2]proenzyme prostate specific antigen for prostate cancer detection: a national cancer institute early detection research network validation study. J Urol 2008;180:539–43; discussion 543.

    • Crossref
    • PubMed
    • Export Citation
  • 24.

    Stephan C, Kahrs AM, Cammann H, Lein M, Schrader M, Deger S, et al. A [-2]proPSA-based artificial neural network significantly improves differentiation between prostate cancer and benign prostatic diseases. Prostate 2009;69:198–207.

    • Crossref
    • PubMed
    • Export Citation
  • 25.

    Chang S, Harshman L, Presti J. Impact of common medications on serum totla prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J Clin Oncol 2010;28:3951–7.

    • Crossref
    • Export Citation
  • 26.

    Huang YQ, Sun T, Zhong WD, Wu CL. Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer. Am J Clin Exp Urol 2014;2:343–50.

    • PubMed
    • Export Citation
  • 27.

    Filella X, Gimenez N. Evaluation of [-2] proPSA and prostate health index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013;51:729–39.

    • PubMed
    • Export Citation
  • 28.

    Wang W, Wang M, Wang L, Adams TS, Tian Y, Xu J. Diagnostic ability of %p2PSA and prostate health index for aggressive prostate cancer: a meta-analysis. Sci Rep 2014;4:5012.

    • PubMed
    • Export Citation
  • 29.

    Carter HB, Albertse PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, et al. Early detection of prostate cancer: AUA Guideline. J Urol 2013;190:419–26.

    • Crossref
    • PubMed
    • Export Citation
  • 30.

    Horwich A, Parker C, de Reijke T, Kataja V, Group EG. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;suppl 6:vi106–14.

    • PubMed
    • Export Citation
  • 31.

    Mottet N, Bellmunt J, Briers E, van den Bergh RCN, Bolla M, van Casteren NJ, et al. Guidelines on Prostate Cancer. Amsterdam, The Netherlands: European Association of Urology, 2015.

  • 32.

    NICE. Prostate cancer: diagnosis and treatmen. Nice clinical guideline 2014;175.

  • 33.

    Trock BJ. Circulating biomarkers for discriminating indolent from aggressive disease in prostate cancer active surveillance. Curr Opin Urol 2014;24:293–302.

    • Crossref
    • PubMed
    • Export Citation
  • 34.

    Loeb S, Bruinsma SM, Nicholson J, Briganti A, Pickles T, Kakehi Y, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol 2015;67:619–26.

    • Crossref
    • PubMed
    • Export Citation

Footnotes

Supplemental Material

The online version of this article (DOI: 10.1515/cclm-2015-0876) offers supplementary material, available to authorized users.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1.

    Miyakubo M, Ito K, Yamamoto T, Suzuki K. Diagnostic significance of [-2]prPSA, total and transition zone prostate volume adjusted PSA-related indices in Japanese men with total PSA in the 2.0 to 10.0 ng/ml range. Eur Urol Suppl 2011;10:65.

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  • 2.

    Mikolajczyk SD, Leonard SM, Partin AW, Rittenhouse HG. Free prostate-specific antigen in serum is becoming more complex. Urology 2002; 59:797–802.

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    Hori S, Blanchet JS, McLoughlin J. From prostate-specific antigen (PSA) to precursor PSA (proPSA) isoforms: a review of the emerging role of proPSAs in the detection and management of early prostate cancer. BJU Int 2013;112:717–28.

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    Mikolajczyk SD, Catalona WJ, Evans CL, Linton HJ, Millar LS, Marker KM, et al. Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem 2004;50:1017–25.

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    Peyromaure M, Fulla Y, Debre B, Dinh-Xuan AT. Pro PSA: a “pro cancer” form of PSA? Med Hypotheses 2005;64:92–5.

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    Whiting P, Rutjes A, Westwood M, Mallett S, Deeks J, Reitsma J, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011;155:529.

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    Sing S, Chang S, Matchar M, Bass E. Grading a body of evidence on diagnostic tests. J Gen Intern Med 2012;27:S47–55.

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  • 10.

    Catalona WJ, Bartsch G, Rittenhouse HG, Evans CL, Linton HJ, Amirkhan A, et al. Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol 2003;170:2181–5.

    • Crossref
    • PubMed
    • Export Citation
  • 11.

    Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 2011;185:1650–5.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Filella X, Foj L, Auge JM, Molina R, Alcover J. Clinical utility of %p2PSA and prostate health index in the detection of prostate cancer. Clin Chem Lab Med 2014;52:1347–55.

    • PubMed
    • Export Citation
  • 13.

    Guazzoni G, Nava L, Lazzeri M, Scattoni V, Lughezzani G, Maccagnano C, et al. 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. Eur Urol 2011;60:214–22.

    • Crossref
    • Export Citation
  • 14.

    Ito K, Miyakubo M, Sekine Y, Koike H, Matsui H, Shibata Y, et al. Diagnostic significance of [-2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0–10.0 ng/mL range. World J Urol 2013;31:305–11.

    • Crossref
    • PubMed
    • Export Citation
  • 15.

    Jansen FH, van Schaik RH, Kurstjens J, Horninger W, Klocker H, Bektic J, et al. Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection. Eur Urol 2010;57:921–7.

    • Crossref
    • PubMed
    • Export Citation
  • 16.

    Khan MA, Partin AW, Rittenhouse HG, Mikolajczyk SD, Sokoll LJ, Chan DW, et al. Evaluation of proprostate specific antigen for early detection of prostate cancer in men with a total prostate specific antigen range of 4.0 to 10.0 ng/ml. J Urol 2003;170:723–6.

    • Crossref
    • PubMed
    • Export Citation
  • 17.

    Lazzeri M, Briganti A, Scattoni V, Lughezzani G, Larcher A, Gadda GM, et al. Serum index test %[-2]proPSA and Prostate Health Index are more accurate than prostate specific antigen and %fPSA in predicting a positive repeat prostate biopsy. J Urol 2012;188:1137–43.

    • Crossref
    • PubMed
    • Export Citation
  • 18.

    Lazzeri M, Haese A, de la Taille A, Palou Redorta J, McNicholas T, Lughezzani G, et al. Serum isoform [-2]proPSA derivatives significantly improve Gm, European study. Eur Urol 2013;63:986–94.

  • 19.

    Le BV, Griffin CR, Loeb S, Carvalhal GF, Kan D, Baumann NA, et al. [-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. J Urol 2010;183:1355–9.

    • Crossref
    • Export Citation
  • 20.

    Mearini L, Ferri C, Lazzeri M, Bini V, Nunzi E, Fiorini D, et al. Evaluation of prostate-specific antigen isoform p2PSA and its derivates, %p2PSA, prostate health index and prostate dimension-adjusted related index in the detection of prostate cancer at first biopsy: an exploratory, prospective study. Urol Int 2014;93:135–45.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Ng CF, Chiu PK, Lam NY, Lam HC, Lee KW, Hou SS. The Prostate Health Index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen levels of 4–10 ng/mL. Int Urol Nephrol 2014;46:711–7.

    • Crossref
    • PubMed
    • Export Citation
  • 22.

    Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, Broyles DL, et al. A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010;19:1193–200.

    • Crossref
    • PubMed
    • Export Citation
  • 23.

    Sokoll LJ, Wang Y, Feng Z, Kagan J, Partin AW, Sanda MG, et al. [-2]proenzyme prostate specific antigen for prostate cancer detection: a national cancer institute early detection research network validation study. J Urol 2008;180:539–43; discussion 543.

    • Crossref
    • PubMed
    • Export Citation
  • 24.

    Stephan C, Kahrs AM, Cammann H, Lein M, Schrader M, Deger S, et al. A [-2]proPSA-based artificial neural network significantly improves differentiation between prostate cancer and benign prostatic diseases. Prostate 2009;69:198–207.

    • Crossref
    • PubMed
    • Export Citation
  • 25.

    Chang S, Harshman L, Presti J. Impact of common medications on serum totla prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J Clin Oncol 2010;28:3951–7.

    • Crossref
    • Export Citation
  • 26.

    Huang YQ, Sun T, Zhong WD, Wu CL. Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer. Am J Clin Exp Urol 2014;2:343–50.

    • PubMed
    • Export Citation
  • 27.

    Filella X, Gimenez N. Evaluation of [-2] proPSA and prostate health index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013;51:729–39.

    • PubMed
    • Export Citation
  • 28.

    Wang W, Wang M, Wang L, Adams TS, Tian Y, Xu J. Diagnostic ability of %p2PSA and prostate health index for aggressive prostate cancer: a meta-analysis. Sci Rep 2014;4:5012.

    • PubMed
    • Export Citation
  • 29.

    Carter HB, Albertse PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, et al. Early detection of prostate cancer: AUA Guideline. J Urol 2013;190:419–26.

    • Crossref
    • PubMed
    • Export Citation
  • 30.

    Horwich A, Parker C, de Reijke T, Kataja V, Group EG. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;suppl 6:vi106–14.

    • PubMed
    • Export Citation
  • 31.

    Mottet N, Bellmunt J, Briers E, van den Bergh RCN, Bolla M, van Casteren NJ, et al. Guidelines on Prostate Cancer. Amsterdam, The Netherlands: European Association of Urology, 2015.

  • 32.

    NICE. Prostate cancer: diagnosis and treatmen. Nice clinical guideline 2014;175.

  • 33.

    Trock BJ. Circulating biomarkers for discriminating indolent from aggressive disease in prostate cancer active surveillance. Curr Opin Urol 2014;24:293–302.

    • Crossref
    • PubMed
    • Export Citation
  • 34.

    Loeb S, Bruinsma SM, Nicholson J, Briganti A, Pickles T, Kakehi Y, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol 2015;67:619–26.

    • Crossref
    • PubMed
    • Export Citation
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