Review
A Systematic Review and Meta-analysis of the Diagnostic Accuracy of Prostate Health Index and 4-Kallikrein Panel Score in Predicting Overall and High-grade Prostate Cancer

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Abstract

Markers for prostate cancer (PCa) have progressed over recent years. In particular, the prostate health index (PHI) and the 4-kallikrein (4K) panel have been demonstrated to improve the diagnosis of PCa. We aimed to review the diagnostic accuracy of PHI and the 4K panel for PCa detection. We performed a systematic literature search of PubMed, EMBASE, Cochrane, and Academic One File databases until July 2016. We included diagnostic accuracy studies that used PHI or 4K panel for the diagnosis of PCa or high-grade PCa. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Twenty-eight studies including 16,762 patients have been included for the analysis. The pooled data showed a sensitivity of 0.89 and 0.74 for PHI and 4K panel, respectively, for PCa detection and a pooled specificity of 0.34 and 0.60 for PHI and 4K panel, respectively. The derived area under the curve (AUC) from the hierarchical summary receiver operating characteristic (HSROC) showed an accuracy of 0.76 and 0.72 for PHI and 4K panel respectively. For high-grade PCa detection, the pooled sensitivity was 0.93 and 0.87 for PHI and 4K panel, respectively, whereas the pooled specificity was 0.34 and 0.61 for PHI and 4K panel, respectively. The derived AUC from the HSROC showed an accuracy of 0.82 and 0.81 for PHI and 4K panel, respectively. Both PHI and the 4K panel provided good diagnostic accuracy in detecting overall and high-grade PCa.

Introduction

The widespread use of prostate-specific antigen (PSA) screening and extended prostate biopsy protocols strongly increased the incidence of prostate cancer (PCa) and the detection of low-risk tumors.1 Indication for prostate biopsy is currently mainly based on PSA serum levels and digital-rectal examination (DRE).2 Although the PSA test led to an increased risk of PCa at an early stage of the disease, it has limited specificity for detecting clinically significant PCa, leading to unnecessary biopsies and detection and treatment of some indolent tumors.3 For these reasons, PSA screening is still controversial owing to some limitations of the test, and it is one of the most debated matters,4 especially in the total PSA (tPSA) range between 2 and 10 ng/mL.5 As a consequence, there is a need for more optimal pre-treatment decision tools that aim at reducing unnecessary biopsies and overtreatment of pathologically insignificant disease. Despite the introduction of several PSA derivatives, such as free to total PSA ratio (%fPSA), PSA density (PSAD), or PSA velocity, our ability to determine the presence of PCa at initial prostate biopsy remains limited. In fact, approximately 75% of patients who do not have PCa may receive prostate biopsies.6 On the contrary, several patients may harbor PCa despite low levels of total PSA (tPSA) (or high levels of %fPSA).7 This has led to attempts to increase the specificity of the PSA test, most typically by using other molecular markers. The combination of multiple biomarkers for the detection of PCa has been proposed to improve the accuracy in the detection of PCa in patients with intermediate levels of PSA.8 Recently, prostate health index (PHI) and the 4-kallikrein (4K) panel have been proposed as useful tools in PCa detection. The PHI, by Beckman Coulter, is a recently approved diagnostic blood test, resulting from the combination of tPSA, fPSA, and [−2]proPSA (p2PSA). It has shown valuable results in the detection of PCa, and it significantly improved the accuracy of tPSA and %fPSA in predicting the presence of PCa at prostate biopsy.9 A few prospective multicenter studies demonstrated that the PHI test has an improved prediction of clinically significant PCa as well.10 On the other hand, the 4K panel, a statistical model based on 4 kallikrein markers (tPSA, fPSA, intact PSA, and human kallikrein-related peptidase 2) measured in blood, has demonstrated better accuracy in predicting the incidence of PCa than total PSA alone and in predicting high-grade disease (Gleason score ≥ 7).11 Both PHI and the 4K panel seem to increase predictive accuracy compared with PSA, and both similarly improved discrimination when predicting PCa and high-grade PCa.12

Currently, no consensus has been expressed about the use of PHI and the 4K panel in routinely clinical practice, and any meta-analysis has been conducted to compare and test the usefulness of these tests in the care of patients with PCa. The purpose of our meta-analysis was to assess the diagnostic accuracy of PHI compared with the 4K panel for PCa detection.

Section snippets

Literature Search

This study was conducted according to the preferred reporting items from systematic reviews and meta-analysis (PRISMA) adapted to the study of diagnostic testing.13

We performed a systematic literature search of PubMed, EMBASE, Cochrane, and Academic One File databases using Medical Subject Headings (MeSH) indexes, keyword searches, and publication types until July 2016 for studies evaluating the diagnostic value of PHI and the 4K panel for diagnosing PCa or high-grade PCa. The search query

Literature Search and Study Selection

Our search retrieved 155 unique publications (Figure 1). Of these publications, 47 full-text articles were considered as eligible with 108 exclusions. Finally, we excluded 14 studies for the analysis because 9 did not report specificity or sensitivity for PCa detection, 3 did not report PCa rate, 1 used a not-standard PHI threshold, and 1 was not in the English language. Finally, 33 publications were included, covering a total of 16,762 patients.9, 11, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24

Discussion

Over recent years, a large amount of evidence has discouraged PCa screening in all ages. In fact, a recent United States preventive services task force has rallied against the widespread use of PSA as a PCa marker, suggesting the necessity for more biomarkers.46 It should be also noted that prostate biopsies may be associated with some complications like bleeding, urinary retention, or infections.47 A recent population-based study, the Global Prevalence Study of Infections in Urology (GPIU),

Conclusion

PHI and the 4K panel had a high diagnostic accuracy for overall PCa detection with good sensitivity and specificity. The findings from this meta-analysis revealed that the 4K panel showed similar performance in predicting high-grade PCa (Gleason score ≥ 7) as the PHI. The quality of the available data is moderate with few case-control design studies. Well-conducted longitudinal studies in a screened population could be useful to corroborate such findings.

Disclosure

The authors have stated that they have no conflicts of interest.

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