The incidence of PCa has increased in the 1990’s, due to increased awareness and prolific Prostate Specific Antigen (PSA) screening. Although in the United States this trend has partly reversed, PCa is still the most common cancer in men representing 21% of cancer cases and it is estimated that 180,890 men will be diagnosed with PCa in United States in 2016 [
1]. In Europe the incidence has increased, with 417,00 new PCa diagnoses in 2012 [
2]. According to current standards, patients with a clinical suspicion of PCa based on elevated serum PSA and/or digital rectal examination should undergo 10–12 systematic transrectal ultrasound (TRUS)-guided prostate biopsies to confirm the diagnosis [
3]. These systematic “blind” prostate biopsies lead to a considerable rate of overdiagnosis of clinically insignificant PCa as well as underdiagnosis and undergrading of significant PCa [
4]. Image - guided targeted biopsy approaches have been proposed to address these problems [
5]. Prostate cancer imaging has thus far developed on two platforms: MRI and Ultrasound. On the MRI platform, multiparametric MRI(mpMRI) in which diffusion - weighted MRI and dynamic contrast- enhanced MRI sequences are added to anatomical T2-weighted imaging has become the standard for PCa imaging [
6]. A 2015 systematic review on the accuracy of mpMRI for the detection of prostate cancer found 12 studies and reported a negative predictive value for the detection of clinically significant prostate cancer between 63 and 98% and positive predictive values of 34–68% [
7]. However, these results should be interpreted with caution since several used biopsy pathology as the reference standard to calculate sensitivity and specificity. Several meta-analyses have addressed the value of mpMRI - targeted biopsy cores and these show an improved per-core detection rate and a beneficial increased per-patient detection rate in patients with a persistent clinical suspicion after prior negative biopsies [
5,
8]. The 2016 update of the EAU (European Association of Urology) guidelines on PCa now recommends performing mpMRI in these patients. However, at this point, the value of using mpMRI and MRI-targeted biopsies at initial biopsy in biopsy-naïve patient is debated [
3]. Even though high negative predictive values for detecting significant prostate cancer have been reported, significant disease can still be missed by MRI - targeted biopsy. Furthermore, considerable heterogeneity and risk of selection bias of published results exists. [
8,
9]. The EAU guidelines therefore recommend combining systematic and targeted biopsies [
3]. The review by Van Hove et al. shows a 1–43% absolute and 2–430% relative increase in per-patient detection rate can be achieved by adding mpMRI - targeted cores to systematic cores [
9]. Several methods of using the information obtained by mpMRI to target the region of interest with prostate biopsies exist: in cognitive targeting, the operator makes a visual estimation of where the MRI lesion is located during a TRUS-guided biopsy procedure. Taking in-bore biopsies during MRI scanning reduces the risk of targeting error but due to its magnet time consuming and therefore costly nature, it is not used often. Fusion devices have been developed that register the MRI images and US together, guiding the observer towards the MRI lesion during the TRUS procedure [
10,
11].
Prostate cancer may be visible on standard B-mode TRUS. However, the sensitivity is generally reported to be around 11–35% and the positive predictive value is often cited to be between 17 and 57%, although some studies have shown slightly better numbers [
12,
13]. Hence, B-mode ultrasound is widely regarded as insufficiently accurate for tumor detection making systematic ultrasound-guided biopsies necessary. A conclusion that is supported by the guidelines [
3,
14]. Contrast - Enhanced Ultrasound (CEUS) has been proposed to improve the accuracy of TRUS to detect Prostate Cancer. In CEUS, an intravascular Ultrasound Contrast Agent (UCA) is used to visualize the changes in vascularity that are typical for significant PCa, particularly angiogenesis. It has been demonstrated that angiogenesis is essential for prostate tumors to progress from small indolent lesions below 2 mm in size to clinically significant disease [
15]. The UCA’s consist of gas-filled micro bubbles of 1–10 μm with a lipid or protein shell that have an intravascular lifespan of several minutes. A systematic review on CEUS demonstrated a sensitivity and specificity of 70 and 74% or PCa detection. It must be noted that this meta-analysis contains a mixture of biopsy - controlled studies and prostatectomy - controlled studies as well as different variants of CEUS. Of particular interest is the analysis by van Hove et al. that shows a 2–8% absolute or 7–35% relative increase in per-patient detection rate was attained by adding CEUS - targeted cores to systematic biopsy protocols [
9]. This analysis indicates improved per-patient detection rates can be achieved with adding CEUS-targeted cores, however CEUS-targeted biopsy at this point cannot replace systematic biopsy. Traditional drawbacks of CEUS are its user-dependency, the limited number of planes that can be visualized in one setting, and the fact that the cues that signify a suspicious focus are subtle and present in the image studies in a matter of seconds. To overcome these drawbacks, computer-aided quantification, a relatively new method to analyze CEUS recordings, is used to assist in the CEUS interpretation [
16]. In the present trial, we will use the Contrast Ultrasound Dispersion Imaging (CUDI) method with computer-aided quantification developed at the Eindhoven University of Technology [
17]. In short, this method entails constructing per-pixel Time-Intensity-Curves (TICs) during the UCA inflow phase of CEUS recordings. Several parameters calculated from the spatiotemporal distribution of these TICs have shown very promising results in predicting PCa presence with Area Under the Curve (AUC) values reaching up to 0.88–0.89 [
17,
18]. These results were obtained by estimating how well CUDI could predict whether pixels belonged to a benign or malignant region of interest using radical prostatectomy specimens as the reference standard. In the present study we will evaluate the value of targeted biopsy procedures with mpMRI and CEUS + CUDI quantitative imaging by performing both procedures with systematic biopsies in the same patients scheduled for initial prostate biopsies. This way we will be able to determine how successful these tools can be used for targeting biopsies and how these targeting procedures compare to each other and to systematic biopsies. Additionally, we will analyze to what extent the imaging tools overlap in the tumors they detect or miss, and therefore to what extent they can be used complementary to each other.