Published 2016

Collaborative Initiative of the American Urological Association and the Society of Abdominal Radiology’s Prostate Cancer Disease-Focused Panel

Workgroup Members:

SAR: Andrew B. Rosenkrantz, MD; Sadhna Verma, MD; Peter Choyke, MD; Steven C. Eberhardt, MD; Masoom A. Haider, MD; Daniel J. Margolis, MD

AUA: Samir S. Taneja, MD; Krishnanath Gaitonde, MD; Scott E. Eggener, MD; Leonard S. Marks, MD; Peter Pinto, MD; Geoffrey A. Sonn, MD

Introduction

While a large number of template prostate biopsies are performed annually in biopsy-naïve patients in the United States, a majority of the biopsy results are benign¹, and a considerable fraction of tumors are missed². Thus, the subsequent management of patients with a prior negative biopsy represents a common and challenging clinical problem, especially if the PSA continues to rise. Although general guidelines exist regarding the need for repeat biopsy following a negative initial biopsy, well-recognized consensus guidelines are lacking, and decisions are often driven by individual or local practice patterns.

The primary motivation for an immediate or short-term repeat biopsy is concern that a clinically significant cancer was missed on the initial biopsy. The typical scenario is one in which the serum PSA continues to increase after the negative biopsy³. Trans-perineal and trans-rectal extended saturation biopsy schemes can be used in this setting, yet these approaches have potential side effects and may continue to miss significant cancers.^{2, 4, 5} The risk of cancer must be balanced against the cost, discomfort, anxiety, and potential complications of prostate biopsy, including hematuria, urinary retention, infection, and sepsis.⁶ A variety of biomarkers, including PSA derivatives such as the prostate health index (PHI) and 4K score, the urinary prostate cancer gene 3 (PCA3) test, and the epigenetic assay ConfirmMDx have been validated as methods to stratify such patients according to their risk of harboring clinically significant cancer. The efforts to develop new biomarkers reflect the importance of improving patient selection for repeat biopsy. Other management strategies, including administration of the 5-α reductase inhibitor dutasteride,⁷ have been used to mitigate the potential risks of missed cancers. However, equally important to improved patient selection is improving the diagnostic yield of significant cancers at the time of repeat biopsy. While blood, urine and tissue based biomarkers may improve patient selection for repeat biopsy, they do not help to improve the diagnostic yield of the biopsy itself. Only imaging has the potential to both improve patient selection and the yield of repeat biopsy.

Prostate MRI has undergone substantial technological improvement over the last ten years. Meanwhile, radiologists and urologists are gaining experience and training in prostate MRI, and uniform reporting standards are being established.^{8, 9} New technologies have been developed to facilitate the performance of biopsies targeting MRI-defined lesions.¹⁰ As a result, an increasing number of urological practices are incorporating prostate MRI into the routine care of selected patients with a prior negative biopsy. Specifically, prostate MRI is increasingly used to identify patients warranting repeat biopsy, to identify specific anatomic targets in those who do undergo repeat biopsy, and to direct biopsies to these abnormal areas under image guidance. A growing body of literature has emerged, demonstrating the value of MRI-targeted biopsy in the repeat biopsy setting. In this white paper, we evaluate the contemporary peer-reviewed literature on this subject as a basis for generating a summary consensus statement regarding the utilization of prostate MRI and MRI-targeted biopsy in patients with prior negative biopsy. 

Current Guidelines

Current AUA guidelines provide indications for the performance of prostate biopsy solely for the initial biopsy setting.¹¹ The National Comprehensive Cancer Network (NCCN) (version 2.2015) advises repeat biopsy after a negative biopsy if any of several criteria are met:¹² (1) initial biopsy demonstrating atypia or other findings suspicious for cancer, in which case an extended pattern re-biopsy is advised within six months, including increased sampling of the affected site and adjacent areas; (2) multifocal (>2 sites) of high-grade prostatic intraepithelial neoplasia (PIN), in which case a similar extended pattern re-biopsy within six months is advised; (3) focal high-grade PIN, in which case PSA and DRE are advised at a 1-year follow-up interval and consideration of repeat biopsy based on risk; and (4) benign initial biopsy not meeting any of the above criteria, in which case repeat biopsy is advised based on follow-up in 6-12 months using PSA/DRE or percent free PSA, 4K score, prostate health index (PHI), or PCA3. In the repeat biopsy setting, the NCCN guidelines advise that MRI with additional MRI-targeted cores be considered after at least one negative biopsy, although it does not explicitly recommend MRI be routinely performed.

The 2013 update of the European Association of Urology guidelines lists the following indications for repeat biopsy: rising and/or persistently elevated PSA, suspicious DRE, atypical small acinar proliferation, and multifocal high-grade PIN¹³. The EAU guidelines indicate the optimal timing of the repeat biopsy is uncertain and if there is persistent clinical suspicion despite negative biopsies, then MRI with MRI-targeted cores may be performed to rule out an anteriorly located tumor.

Finally, the latest version of imaging recommendations for prostate cancer diagnosis and staging from the American College of Radiology from 2012 considered as “usually appropriate” the use of prostate MRI for men with prior negative biopsies when there was continued clinical suspicion for cancer.¹⁴

Performance, Interpretation, and Reporting of Prostate MRI following a Negative Biopsy

The Prostate Imaging and Reporting Data System (PI-RADS) Version 2 (V2) was released in December 2014,¹⁵ representing the work of an international panel of leaders in the field of prostate MRI. PI-RADS is a comprehensive, publicly available online document that provides guidelines for the acquisition, interpretation, and reporting of prostate MRI. PI-RADS seeks to standardize the technique and interpretation of prostate MRI, reducing variability among readers and centers. The content of PI-RADS reflects the best evidence available at the time of its development, in combination with the expert opinion. It represents an expanded version of a more focused initial version (PI-RADS version 1) published in 2012.¹⁶ While PI-RADS provides guidelines for standardizing prostate MRI, performing consistent state-of-the-art prostate MRI remains challenging. Moreover, it is important for radiology practices performing prostate MRI to engage in continual quality improvement of their imaging and interpretation though adherence to standards and routine correlations of imaging results with histologic findings.

The guidelines provided by PI-RADS V2 for performing and interpreting prostate MRI are comprehensive and only briefly summarized here. PI-RADS V2 does not specifically require prostate MRI be performed either at 3T or using an endorectal coil, noting that clinically efficacious results can be obtained using a modern 1.5T system in combination with a multichannel receiver surface coil.¹⁵ Nonetheless, PI-RADS V2 states most of its authors favor use of a 3T system, when available, or use of an endorectal coil when using older-generation 3T or 1.5T systems. It is recommended to delay MRI at least 6 weeks (if not longer), following biopsy to allow for resolution of post-biopsy hemorrhage, unless earlier diagnosis is deemed imperative. Measures are also encouraged to reduce the presence of feces and/or air in the rectum, which may cause distortion and other artifacts on the DWI portion of the MRI. These include using “minimal preparation” shortly before the MRI for phased-array coil exams, instructions for the patient to evacuate their bladder and bowels prior to the MRI, and use of a small suction catheter to decompress the rectum if initial images show excessive rectal air. In addition, it is considered diagnostically advantageous to have available at the time of MRI interpretation the patient’s PSA history, prior biopsy results, and other relevant clinical history.

It is important that images be obtained in a standardized manner. PI-RADS V2 recommends prostate MRI protocols routinely include (1) multi-planar fast spin-echo or turbo spin-echo 2D T2-weighted imaging; (2) diffusion-weighted imaging (DWI) with a low b-value of 50-100 sec/mm², a high b-value of 800-1000 sec/mm², and possible additional intermediate b-values, in order to generate an apparent diffusion coefficient (ADC) map; and an additional “high” b-value image set using a b-value of at least 1,400 sec/mm² (which may be either directly acquired or calculated from the lower b-values); and dynamic contrast-enhanced (DCE) imaging using a rapid gradient-echo T1-weighted sequence (temporal resolution ≤ 15 seconds and optimally under 7 seconds; total observation time ≥ 2 minutes). MR spectroscopy is no longer considered a routinely acquired sequence. PI-RADS V2 recommends examination results be reported on a per-lesion basis, with lesion location defined on a 39-sector map. Each lesion’s probability of representing clinically significant cancer is stratified on a 1-5 scale (referred to as the PI-RADS assessment category), with 5 indicating the highest likelihood, analogous to previously employed 1-5 Likert scales. Explicit criteria are provided for categorizing findings on T2WI as well as on DWI/ADC from 1-5 in both the peripheral zone and transition zone. Additional criteria are provided for deriving an overall 1-5 assessment category based on the individual sequence scores. The DWI/ADC score serves as the dominant score in deriving the overall assessment category in the PZ, and the T2WI score serves as the dominant score in deriving the overall assessment category in the TZ. PI-RADS simplifies the interpretation of DCE, classifying DCE findings as positive or negative based on a subjective visual evaluation, without requiring advanced software or post-processing to generate kinetic curves or colored pharmacokinetic maps. DCE findings influence the overall assessment category only for lesions that would otherwise be considered equivocal in the PZ based on DWI/ADC findings. An initial study of PI-RADS V2 demonstrated that the likelihood of diagnosing clinically significant (CS) cancers in both the peripheral and transition zones increased with increasing PI-RADS V2 score.¹⁷ 

Quality Assurance of Prostate MRI Interpretation

A primary barrier to the widespread clinical adoption of prostate MRI has been marked variation not only in image quality, but also in radiologists’ performance in exam interpretation. Prostate MRI image quality is influenced not only by the specific vendor and scanner model, but also by a wide array of acquisition parameters, such that exam quality may vary across centers employing the same MRI system based on the achieved level of scan optimization. Currently, there is no standardization for image quality. Moreover, interpretation of prostate MRI is inherently challenging as a result of a spectrum of diagnostic pitfalls that may result in either a false-positive or false-negative reading and thereby hinder performance. Indeed, the literature has demonstrated improved performance in prostate MRI interpretation among more experienced radiologists.^18-20  For example, one study reported significantly greater diagnostic accuracy among radiologists with dedicated experience in prostate MRI than among radiologists with general expertise in body MRI.¹⁸  Thus, to date, implementation of prostate MRI and MRI-targeted biopsy has remained most heavily concentrated within major academic centers that have developed the necessary radiological experience and expertise to provide high quality MRI interpretations. The successful broader adoption of prostate MRI for patients with a prior negative biopsy requires that radiologists in community settings also receive the appropriate training and experience to provide high-quality interpretations.

As of this writing, there is no formal mechanism for radiologists to become certified in prostate MRI interpretation, nor an established number of examinations that must be interpreted in order for radiologists to achieve sufficient experience. However, various educational opportunities are available to assist radiologists in achieving the appropriate level of interpretive skill. Many hands-on courses and symposia are routinely offered that combine didactic lectures with interactive workshops and supervised case review at workstations,²¹ providing an opportunity for direct feedback from experienced radiologists serving as course guides. For example, one study demonstrated the ability to rapidly achieve significant improvements in radiologists’ tumor detection, reader confidence, and prediction of significant cancer following a targeted educational program in prostate MRI.²²  In addition, regular participation in a local multi-disciplinary conference attended by urologists, radiologists, and pathologists can facilitate dialogues among specialties that may improve the radiologist’s reporting patterns. Perhaps most important, it is critical interpreting radiologists participate in ongoing case review, comparing prospective interpretations with subsequent histological results from targeted biopsy and prostatectomy. This direct feedback is needed to help the radiologist identify and correct systematic causes of false-positive and false-negative interpretations. For example, Akin et al. demonstrated significant improvements in radiologists’ interpretation when receiving individualized feedback comparing earlier interpretations with pathological tumor maps.²³

Given the challenges associated with prostate MRI interpretation, practices seeking to adopt a comprehensive program of diagnostic MRI and MRI-targeted prostate biopsy must actively engage in quality assurance efforts to ensure sufficient accuracy. Specifically, practices should seek to obtain histologic validation of their interpretations before broadly integrating prostate MRI into local practice. Since currently no quality standards or benchmarks for MRI interpretation or MRI-guided biopsies have been established, the authors of this white paper here propose benchmarks based on published reports from expert centers in combination with consensus experience and opinion. Two metrics considered most useful in assessing the accuracy of local prostate MRI interpretation are the cancer detection rate (CDR) at various PI-RADS thresholds as well as the miss-rate of MRI for clinically significant (CS) cancer. It is suggested that targeted biopsy of highly suspicious (PI-RADS 4) lesions yield GS≥3+4 tumor in ≥30% of patients, and of very highly suspicious (PI-RADS 5) lesions yield GS≥3+4 tumor in ≥70% of patients. In addition, it is suggested that MRI-targeted cores detect ≥80% of GS≥3+4 tumors present on either radical prostatectomy or concurrently performed template or saturation biopsies.

The clinical statements in the remainder of this white paper are contingent upon the availability of quality prostate MRI image acquisition and interpretations by individuals with sufficient experience and skill in the area, as well as of experience by the operators in performing the MRI-targeted biopsy. Provided sufficient expertise in prostate MRI interpretation and MRI-targeted biopsy, prostate MRI use can benefit the management of patients with a prior negative biopsy. Conversely, if expertise is lacking and the suggested benchmarks cannot be met, the clinical utility of prostate MRI proposed in this white paper is unlikely to be achieved and indeed misleading information and harmful consequences are possible. In this context, the authors of this paper strongly entreat radiologists interpreting MRI to pursue routine quality assessments, as well as education and other measures to improve the quality of their MRI interpretations.

Literature Review Goals and Methodology

We performed a review of the literature aimed at the following questions:  

• What is the impact of MRI following a negative prostate biopsy on the detection of CS cancer? Related to this, which patients should be offered prostate MRI following a negative biopsy?
• Is there an optimal approach to performing repeat biopsies when a pre-biopsy MRI has been obtained? Related to this, are advanced technologies for targeting suspicious regions on MRI required or recommended, and is there still a need to perform repeat standard systematic sampling at the time of repeat MRI targeted biopsy?
• Can repeat biopsies be safely deferred based on a negative MRI? If so, what is the appropriate clinical follow-up in such patients and what is the role of non-imaging biomarkers in this context?

To answer these questions, we performed a search of PubMed for English-language articles using the following combination of key terms: “prostate,” “biopsy,” “negative” and either “MRI” or “magnetic resonance.”  Each article was then evaluated for relevance and quality, in terms of reporting pathologic findings from biopsies performed in patients with at least one prior negative biopsy and who underwent MRI before the repeat biopsy. Articles were excluded if the MRI protocol did not include DWI or if it did not specifically discuss patients with a prior negative biopsy (i.e., biopsy naïve patients or patients on active surveillance),²⁴ if the previous negative biopsy was performed with MRI guidance, or if the repeat biopsy also was performed using contrast-enhanced ultrasound or ultrasound elastography. Included articles typically described the characteristics of patients, method for performing the targeting of MRI lesions, rates of detection of all cancer and of CS cancer on the post-MRI biopsy including the relative impact of MRI-targeted vs. systematic cores on CS cancer detection, association between MRI suspicion score (based on a variety of methods pre-dating PI-RADS V2) and ancillary laboratory biomarkers, and follow-up after a negative targeted biopsy or deferral of targeted biopsy. This white paper does not address the role of MRI in primary biopsy or in active surveillance.

Results

Literature Results and Summary Statement on the Detection of Clinically Significant Cancer at Repeat Biopsy using MRI Targeting

Numerous studies report the CDR of CS cancer on repeat biopsy using MRI targeting (Table 1). Variation likely represents differing criteria for CS cancer, patient selection for MRI and MRI-targeted biopsy, quality of the imaging, and the targeting methodology. The CDR of CS cancer on MRI-targeted biopsy in the re-biopsy setting ranges from 11-54%, although from 16-40% when restricting inclusion to studies that define CS cancer as having a Gleason score ≥ 7(Table 1). Additionally, the data indicate the potential to increase CS cancer detection on repeat biopsy when comparing MRI-targeted biopsies to standard systematic sampling alone. 

Table 1

Literature results on patient selection for MRI after a negative biopsy

Obtaining an MRI following a negative biopsy generally indicates a persistent clinical suspicion for prostate cancer, most commonly based on a persistently elevated or rising PSA or abnormal DRE. The PSA cutoff to indicate persistent suspicion has varied across studies. A PSA threshold of 4.0 ng/mL has been most commonly used, ^{28, 29, 31, 32, 34, 37-42} typically 4 to 10 ng/mL, and these generally indicate a utility for MRI before a repeat biopsy.^43-45 The utility of MRI for lower PSA values has not been established. An elevated PSA velocity or rise in PSA above prior values has also been evaluated as an indication for MRI in the negative biopsy setting.^{27, 28, 35, 46}

Prior studies have also stratified the CDR of a repeat biopsy with MRI-targeting by the number of prior negative biopsies. When not incorporating pre-biopsy MRI or MRI-targeting, the cancer detection rate of repeat biopsy decreases with an increasing number of prior negative biopsies. For example, Roehl et al. reported a cancer detection rate of 17%, 14%, 11%, 9%, and 7% on the second through sixth biopsy,⁴⁷ while Keetch et al. reported a cancer detection rate of 19%, 8%, and 7% on the second through fourth biopsy.³ However, when using pre-biopsy MRI, many studies have reported similar rates of detection of any cancer or of CS cancer, regardless of the number of prior negative biopsies.^{25, 28, 30, 33, 35, 36, 40, 46, 48, 49} For instance, Sonn et al. reported no change in significant cancer detection rate (GS≥7 or CCL≥4 mm) between patients with 1, 2, 3, or ≥4 negative biopsies (range, 23%-29%).³⁰

Summary statement on patient selection for repeat MRI directed biopsies

The accumulated evidence suggests prostate MRI has value for detecting CS cancer in patients with a prior negative biopsy and a persistently elevated or rising PSA, irrespective of the number of prior negative standard biopsies.

Literature results on the method of MRI-targeted biopsy

Three major strategies exist for targeting MRI-defined lesions in the repeat biopsy setting.^{10, 50-52} The approach involving the least amount of advanced technology is “cognitive” targeting, which involves estimating the location of a lesion detected on MRI and mentally transferring the target to the TRUS image during TRUS-guided biopsy without any technologic guidance. This approach does not require any additional hardware or software investment and can be applied in any clinical practice in which pre-biopsy MRI is available. The obvious limitation is the lack of visual feedback regarding accuracy of targeting the suspected cancerous lesion on MRI. Accuracy of this method is highly dependent on the operator’s familiarity with prostate MRI and ability to accurately and consistently correlate MRI targets to real-time ultrasound images with reasonable fidelity. The reliability of this approach is of particular concern for lesions that are small, anterior, or in otherwise difficult-to-target locations. Nevertheless, good results with cognitive biopsy have appeared in the literature.^{44, 46, 53}

A second approach is to perform targeted biopsy while the patient is within the MRI gantry. With this technique, MR images can be obtained to confirm placement of the needle within the target. This approach offers the advantage of being the most direct targeting. However, the procedure is relatively time-consuming and labor-intensive, as well as potentially uncomfortable for the patient who is often in the prone position during the extended procedure time (45-60 minutes for multiple targets).

A third approach is real-time MRI/ultrasound fusion guided prostate biopsy. With this method, a planning session is performed in advance of the biopsy procedure in which the boundaries of the prostate and the location of the target(s) are outlined on the MR images using vendor-specific segmentation software and needle tracking methods. The 3D prostate and target map are loaded into the fusion biopsy system before the biopsy. At the time of biopsy, the MRI data is fused to the TRUS imaging data using a combination of rigid and elastic registration to align the MRI and TRUS prostate segmentations. Once this is accomplished, movement of the TRUS is linked to a corresponding movement of the MRI so the biopsy can be performed under TRUS but using MRI guidance. This is achieved by either electromagnetic positioning devices on the TRUS probe, an articulated semi-automated robotic arm that tracks the motion of the ultrasound probe relative to the MRI, or a 3D ultrasound probe allowing real-time elastic registration with retrospective lesion targeting.  Studies suggest reasonable registration accuracy of fusion algorithms with a registration error of approximately 3 mm.^54-56 MRI-US fusion biopsy offers a number of advantages. Those who perform TRUS biopsy are already familiar with the principle elements of the procedure. The procedure duration is only ~5-10 minutes longer than routine TRUS biopsy, and can be incorporated into the existing clinical workflow. In addition, obtaining concurrent systematic cores, if desired, can be readily performed in the same session. A potential disadvantage of this method is theoretically reduced targeting accuracy compared with direct in-bore MRI guidance due to lack of real-time MRI feedback regarding needle localization.

There are numerous studies showing utility for the detection of CS cancer using all three approaches: cognitive targeting,^{44, 46, 53} in-bore targeting,^{26, 27, 29, 31} and fusion targeting.^{24, 28, 30, 57, 58} However, there is a paucity of data directly comparing any two methods within the same cohort of patients having a prior negative biopsy. In one study, Wysock et al reported that among 34 patients with a prior negative biopsy, Gleason score ≥7 cancer was identified in 20.6% of patients by fusion biopsy, compared with 14.7% of patients by cognitive biopsy (non-significant difference, but underpowered study).⁴⁵ Arsov et al. randomized patients with a prior negative biopsy to undergo either in-bore MRI-targeted biopsy or combined standard systematic and fusion-targeted biopsy. They identified no significant difference in the detection of any cancer or of CS cancer between the two groups.²⁶ Finally, Puech et al. reported no significant difference in cancer detection or grading between cognitive and fusion targeted cores in the same patient sample, although their cohort combined biopsy-naïve and prior negative biopsy patients.⁵⁹

Summary statement on the method of MRI directed biopsies

While use of advanced technology, such as a fusion system or in-bore biopsy system, may be helpful, the superiority of any specific approach has not been established. One approach may be to apply different methods of MRI targeting depending on characteristics of the lesion, for example using an in-bore or fusion system for lesions that are small or in a difficult-to-access region (i.e., the anterior or apical prostate), while using cognitive targeting for other lesions. While fusion and in-bore biopsy systems may have value in incrementally improving biopsy yield, they are expensive, and existing literature supports cognitive targeting as a sound approach for facilitating detection of CS cancer when advanced technologies are not available and operators are skilled with image guided procedures.

Additional considerations regarding conduct of MRI-targeted biopsy

During MRI-targeted biopsy, the large majority of studies report at least two cores from each MRI target.^{24, 26-29, 31, 32, 35, 36, 41, 43-45, 49, 53, 57, 60-63} Nonetheless, some studies report obtaining a larger number of cores (i.e, 4-6 cores) per lesion.^{24, 62} The number of cores may be increased for larger regions of interest.^{30, 49, 64} There is a paucity of data assessing the impact of a larger number of cores on cancer yield. Obtaining at least two cores from each target, with a larger number of cores at the discretion of the operator based on the lesion’s size and location, as well as confidence in targeting accuracy, appears logical.

When performing MRI-targeted biopsy, approaches to pain control as well as the prevention and management of bleeding and infectious complications are similar to those for systematic biopsy.⁶⁵ It is advised that systematic and MRI-targeted cores be separately labeled for purposes of pathologic analysis and reporting given that current accepted clinical nomograms are derived from data based on standard systematic biopsy results.⁶⁶ In addition, the interpreting pathologist should routinely report the presence of inflammation, HGPIN, and ASAP within targeted cores, as the presence of a correlative histologic abnormality may provide assurance that the MRI-defined region-of-interest was accurately targeted when benign.⁴⁵

Literature results and summary statement on the Need for Concurrent Systematic Sampling when Performing MRI Targeting

The high sensitivity of MRI-targeted cores for CS cancer raises the question of whether systematic cores are also warranted at the time of an MRI-targeted repeat biopsy. Numerous investigations indicate the presence of occasional CS cancers that are missed by targeted biopsy (Table 2).  While the frequency is variable, the data suggests a modest fraction (0-23%) of CS cancers detected by systematic biopsies are missed by targeted biopsy. The quality of MRI acquisition and interpretation as well as the targeting technique itself likely impact the detection of CS cancer. Nonetheless, even with optimized conditions and expertise, a 5-10% false negative rate for CS lesions can be present. In addition, while the CDR of targeted biopsy for CS cancer is similar regardless of the number of prior negative biopsies, the likelihood of CS cancer being detected solely by systematic cores can be expected to depend on the number of prior negative systematic biopsy sessions. Nonetheless, as there is a small but variable occurrence of missed CS cancer on MRI targeted biopsy, we advise that a case-specific decision must be made regarding whether to also perform concurrent systematic sampling at the time of targeted biopsy in order to maximize CS cancer detection. Deferral of concurrent systematic biopsy should not be considered until performing quality assurance and demonstrating the results of MRI-targeted biopsy within the local practice.

Table 2

Literature on Deferral of Repeat Biopsy Based on MRI Findings

MRI performed before a repeat biopsy may be used for more than simply identifying biopsy targets but also in providing the level of suspicion for clinically significant cancers on repeat biopsy. Numerous studies have reported outcomes of MRI-targeted biopsies in men with a prior negative biopsy stratified by the level of suspicion on MRI. While PI-RADS V2 employs a 5-point scale for stratifying level of suspicion, various other similar multi-point schemes have previously been used. Numerous studies have demonstrated suspicion scores correlate strongly with the likelihood of CS cancer. For example, Kauffman et al. reported the presence of cancer on in-bore biopsy in all 155 patients with a PI-RADS score of 4, yet in 5 of 15 patients with a PI-RADS of 3;³² Meng et al. reported detection of GS≥7 tumor in 5-6% of patients with an MRI suspicion score of 2-3, 25% with a score of 4, and 83% with a score of 5;²⁴ Portalez et al. reported a CDR of 3%, 11%, 38%, 63%, and 83% for MRI suspicion score of 1-5, respectively;⁵⁸ Sonn et al. identified the MRI suspicion score to be the strongest predictor of CS cancer, with 86% of patients having PI-RADS 5 being found to have CS cancer,³⁰ compared with only 2% from PI-RADS 2-3 lesions; and Salami et al. reported a CDR of 83% in patients with a PI-RADS of 4-5.²⁸

If a threshold MRI suspicion score can be identified that has sufficient sensitivity for CS cancer, then it may be possible that patients with a normal MRI, or an MRI suspicion score below this threshold, may not require a repeat targeted biopsy. Past studies have investigated CDR in repeat systematic biopsies performed in the absence of suspicious lesions on MRI (Table 3), as well as the NPV of various PI-RADS categories with respect to concurrently performed systematic biopsy (Table 4). While suggesting a generally low frequency of missed cancer on MRI, such studies likely underestimate the true frequency of cancers missed on MRI given the lack of a reference standard such as radical prostatectomy, saturation or template biopsy, or long-term clinical follow-up.

Table 3. CDR in setting of ‘normal’ MRI

Table 4

Available evidence is inconclusive regarding outcomes when a repeat biopsy is deferred on the basis of MRI findings. Abdi et al. reported 24 patients with no suspicious lesion on MRI and in whom repeat biopsy was deferred and no patient had a change in PSA or DRE findings or was diagnosed with prostate cancer at a median follow-up of 16.7 months.²⁷ In addition, Arsov et al. reported 30 patients in whom repeat biopsy was deferred after a normal MRI and none had a significant PSA increase or was diagnosed with cancer at a median follow-up of approximately 1 year.³⁷ Nonetheless, such studies are significantly limited given the inability to exclude significant cancer based on short-term PSA and clinical follow-up, and as noted, the literature suggests a rate of CS cancer on non-targeted biopsy in 0-23% of men with a negative MRI. Thus, a negative MRI cannot be viewed in clinical practice as an indicator of the absence of CS cancer.

Summary statement on role of immediate re-biopsy after MRI

The available data suggest repeat biopsy in patients with persistent clinical suspicion for prostate cancer is justified in the setting of an MRI with a PI-RADS 4 or 5 lesion (a highly suspicious lesion) and that deferral of repeat biopsy may be considered in the setting of a negative (PI-RADS 1) or low-suspicion (PI-RADS 2) MRI. However, we believe there is insufficient data to support routinely deferring biopsy of lesions receiving a PI-RADS assessment category of 3, for which CS cancer rates following targeted biopsy have been highly variable. Additionally, the available data indicates 5-15% of CS cancers remain undetected on MRI. Therefore, CS cancer can never be entirely excluded on the basis of a negative MRI and continued clinical follow-up is warranted whenever repeat biopsy is deferred on the basis of a normal or low-suspicion MRI.

Literature results on follow-up after negative MRI directed biopsies.

A number of studies have reported results from continued follow-up evaluation following a benign MRI-targeted biopsy in the repeat biopsy setting. Kauffman et al. reported no patient with a negative in-bore biopsy was diagnosed with prostate cancer after a median follow-up of 27 months (range, 23-60 months).³² In a separate study, Kauffman et al. reported at median 33 months of follow-up (range, 18-53 months), no patient with a negative in-bore biopsy was diagnosed with prostate cancer.³¹ In contrast, a number of studies indicate CS cancer cannot be completely excluded based on a negative targeted biopsy. For example, Vourganti et al. reported that among 10 patients with a negative fusion biopsy who subsequently underwent an additional fusion biopsy, three were positive for cancer, one of which was high grade.³⁶ In all three of these patients, the cancer was only identified on fusion cores, and none were originally low-suspicion MRI lesions.³⁶ In addition, Kuru et al. reported that among 25 patients who underwent an additional biopsy at a median of 12 months following an initial negative targeted biopsy in the repeat biopsy setting, three were diagnosed with cancer, two of which had a primary Gleason pattern of 4.⁴⁹ Moreover, Engehausen et al. reported that 10 of 57 patients with a negative in-bore biopsy were diagnosed with cancer within three years.⁶⁸

Summary statement on follow-up after negative MRI directed biopsies.

Continued clinical follow-up and consideration of repeat biopsy remain warranted following a negative MRI-targeted biopsy. Such follow-up can be performed through a combination of serial PSA measurements, DRE evaluations, and possibly repeat MRI examinations. For an MRI lesion with very high suspicion (i.e., PI-RADS assessment category of 5) that is negative on targeted biopsy, an earlier repeat targeted biopsy should be considered.³⁶

Literature on the role of ancillary markers in MRI-targeted biopsies

A number of studies have evaluated whether ancillary laboratory data may be used in selecting whether MRI-based lesions warrant biopsy in the prior negative biopsy setting. For instance, Kauffman et al. reported PCA3 score was not helpful in predicting repeat biopsy results in the overall cohort, although it was helpful in patients with a PI-RADS score of 3.³² In this subset, all patients with a positive in-bore biopsy had a PCA3 score over 35, and in 6 of 10 patients with a negative biopsy, the PCA3 score was less than 35.³² When combining a threshold PI-RAD score of 3 and a threshold PCA3 score of 35, the measures achieved a NPV of 100% and PPV of 84.6%,³² however caution should be exercised when applying this data due to the small size of the study. Also, Hoeks et al. reported significantly more cancers were identified on in-bore biopsy in patients with a PSAD over, rather than below, 0.15 (52% vs. 24%, respectively).³⁴ Additional investigators have attempted to create multivariable models combining MRI findings and other laboratory data in predicting repeat biopsy results. MRI findings have consistently been retained as a significant independent factor in such models (Table 5).

Table 5. Key factors identified in multivariate analyses of MRI and laboratory biomarkers 

Summary statement on the role of ancillary markers in MRI-targeted biopsies

Non-imaging markers (i.e., PSA-based measures as well as PCA3) are likely useful in further selecting patients with a negative or low-suspicion MRI (PI-RADS score of 1 or 2, respectively) that may deserve a systematic biopsy despite the MRI results. However, targeted biopsy remains warranted for intermediate or high suspicion MRI lesions despite results from these ancillary markers given the consistently observed strong independent effect of the MRI suspicion score on cancer detection in multivariate models. Further investigation is warranted to identify which of these markers best complements MRI findings in the repeat biopsy setting.

Summary

Following an initial negative biopsy, there is an ongoing need for strategies to improve patient selection for repeat biopsy as well as the diagnostic yield from repeat biopsies. Many options exist for men with a previously negative biopsy. If a biopsy is recommended, prostate MRI and subsequent MRI-targeted cores appear to facilitate the detection of CS disease over standardized repeat biopsy. Thus, when high-quality prostate MRI is available, it should be strongly considered in any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is undergoing a repeat biopsy. The decision whether to perform MRI in this setting must also take into account results of any other biomarkers, the cost of the examination, as well as availability of high quality prostate MRI interpretation. If MRI is done, it should be performed, interpreted, and reported in accordance with PI-RADS V2 guidelines. Experience by the reporting radiologist and biopsy operator are required to achieve optimal results and practices integrating prostate MRI into patient management are advised to implement quality assurance programs to monitor targeted biopsy results. Patients receiving a PI-RADS assessment category of 3-5 warrant repeat biopsy with image guided targeting. While TRUS-MRI fusion or in-bore MRI-targeting may be valuable for more reliable targeting, especially for MRI lesions that are small or in difficult locations, in the absence of such targeting technologies, cognitive (visual) targeting remains a sound approach in skilled hands. At least two targeted cores should be obtained from each MRI-defined target. Given a number of studies showing a small fraction of missed CS cancers by MRI-targeted cores, a case-specific decision must be made whether to also perform concurrent systematic sampling. However, performing solely targeted biopsy should only should be considered once quality assurance efforts have validated the performance of prostate MRI interpretations with results consistent with the published literature. In patients with a negative or low-suspicion MRI (PI-RADS assessment category of 1 or 2, respectively), other ancillary (i.e., PSA, PSAD, PSAV, PCA3, PHI, 4K) may be of value to identify patients warranting repeat systematic biopsy, although further data is needed on this topic. If a repeat biopsy is deferred on the basis of the MRI findings, then continued clinical and laboratory follow-up is advised and consideration should be given to incorporating repeat MRI in this diagnostic surveillance regimen.

References

1. Gore JL, Shariat SF, Miles BJ, Kadmon D, Jiang N, Wheeler TM, et al. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. The Journal of urology. 2001;165(5):1554-9.
2. Shinohara K, Nguyen H, Masic S. Management of an increasing prostate-specific antigen level after negative prostate biopsy. The Urologic clinics of North America. 2014;41(2):327-38.
3. Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. The Journal of urology. 1994;151(6):1571-4.
4. Bittner N, Merrick GS, Butler WM, Bennett A, Galbreath RW. Incidence and pathological features of prostate cancer detected on transperineal template guided mapping biopsy after negative transrectal ultrasound guided biopsy. The Journal of urology. 2013;190(2):509-14.
5. Crawford ED, Rove KO, Barqawi AB, Maroni PD, Werahera PN, Baer CA, et al. Clinical-pathologic correlation between transperineal mapping biopsies of the prostate and three-dimensional reconstruction of prostatectomy specimens. The Prostate. 2013;73(7):778-87.
6. Kirby R, Fitzpatrick JM. Optimising repeat prostate biopsy decisions and procedures. BJU international. 2012;109(12):1750-4.
7. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362(13):1192-202.
8. Hoeks CM, Barentsz JO, Hambrock T, Yakar D, Somford DM, Heijmink SW, et al. Prostate cancer: multiparametric MR imaging for detection, localization, and staging. Radiology. 2011;261(1):46-66.
9. Hamoen EH, de Rooij M, Witjes JA, Barentsz JO, Rovers MM. Use of the Prostate Imaging Reporting and Data System (PI-RADS) for Prostate Cancer Detection with Multiparametric Magnetic Resonance Imaging: A Diagnostic Meta-analysis. European urology. 2015;67(6):1112-21.
10. Marks L, Young S, Natarajan S. MRI-ultrasound fusion for guidance of targeted prostate biopsy. Current opinion in urology. 2013;23(1):43-50.
11. American Urological Association. White Paper: AUA/Optimal Techniques of Prostate Biopsy and Specimen Handling. [pdf]
12. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection. Version 2.2015. http://www.nccn.org/professionals/physician_gls/PDF/prostate_detection.pdf. Accessed on: December 14, 2015.
13. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. European urology. 2014;65(1):124-37.
14. Eberhardt SC, Carter S, Casalino DD, Merrick G, Frank SJ, Gottschalk AR, et al. ACR Appropriateness Criteria prostate cancer--pretreatment detection, staging, and surveillance. Journal of the American College of Radiology : JACR. 2013;10(2):83-92.
15. American College of Radiology. Prostate Imaging Reporting and Data System (PI-RADS). http://www.acr.org/Quality-Safety/Resources/PIRADS. Accessed on: September 12, 2015.
16. Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, Villeirs G, et al. ESUR prostate MR guidelines 2012. European radiology. 2012;22(4):746-57.
17. Muller BG, Shih JH, Sankineni S, Marko J, Rais-Bahrami S, George A, et al. Prostate Cancer: Interobserver Agreement and Accuracy with the Revised Prostate Imaging Reporting and Data System at Multiparametric MR Imaging. Radiology. 2015:142818.
18. Seltzer SE, Getty DJ, Tempany CM, Pickett RM, Schnall MD, McNeil BJ, et al. Staging prostate cancer with MR imaging: a combined radiologist-computer system. Radiology. 1997;202(1):219-26.
19. Futterer JJ, Heijmink SW, Scheenen TW, Jager GJ, Hulsbergen-Van de Kaa CA, Witjes JA, et al. Prostate cancer: local staging at 3-T endorectal MR imaging--early experience. Radiology. 2006;238(1):184-91.
20. Latchamsetty KC, Borden LS, Jr., Porter CR, Lacrampe M, Vaughan M, Lin E, et al. Experience improves staging accuracy of endorectal magnetic resonance imaging in prostate cancer: what is the learning curve? The Canadian journal of urology. 2007;14(1):3429-34.
21. American College of Radiology. Meetings/Courses: Prostate MR. http://www.acr.org/meetings-events/ec-prostate-mr. Accessed on: November 14, 2015.
22. Garcia-Reyes K, Passoni NM, Palmeri ML, Kauffman CR, Choudhury KR, Polascik TJ, et al. Detection of prostate cancer with multiparametric MRI (mpMRI): effect of dedicated reader education on accuracy and confidence of index and anterior cancer diagnosis. Abdominal imaging. 2015;40(1):134-42.
23. Akin O, Riedl CC, Ishill NM, Moskowitz CS, Zhang J, Hricak H. Interactive dedicated training curriculum improves accuracy in the interpretation of MR imaging of prostate cancer. European radiology. 2010;20(4):995-1002.
24. Meng X, Rosenkrantz AB, Mendhiratta N, Fenstermaker M, Huang R, Wysock JS, et al. Relationship Between Prebiopsy Multiparametric Magnetic Resonance Imaging (MRI), Biopsy Indication, and MRI-ultrasound Fusion-targeted Prostate Biopsy Outcomes. European urology. 2015.
25. Mendhiratta N, Meng X, Rosenkrantz AB, Wysock JS, Fenstermaker M, Huang R, et al. Pre-Biopsy MRI and MRI-Ultrasound Fusion-Targeted Prostate Biopsy in Men with Previous Negative Biopsies: Impact on Repeat Biopsy Strategies. Urology. 2015.
26. Arsov C, Rabenalt R, Blondin D, Quentin M, Hiester A, Godehardt E, et al. Prospective Randomized Trial Comparing Magnetic Resonance Imaging (MRI)-guided In-bore Biopsy to MRI-ultrasound Fusion and Transrectal Ultrasound-guided Prostate Biopsy in Patients with Prior Negative Biopsies. European urology. 2015.
27. Abdi H, Zargar H, Goldenberg SL, Walshe T, Pourmalek F, Eddy C, et al. Multiparametric magnetic resonance imaging-targeted biopsy for the detection of prostate cancer in patients with prior negative biopsy results. Urologic oncology. 2015;33(4):165 e1-7.
28. Salami SS, Ben-Levi E, Yaskiv O, Ryniker L, Turkbey B, Kavoussi LR, et al. In patients with a previous negative prostate biopsy and a suspicious lesion on magnetic resonance imaging, is a 12-core biopsy still necessary in addition to a targeted biopsy? BJU international. 2015;115(4):562-70.
29. Hambrock T, Somford DM, Hoeks C, Bouwense SA, Huisman H, Yakar D, et al. Magnetic resonance imaging guided prostate biopsy in men with repeat negative biopsies and increased prostate specific antigen. The Journal of urology. 2010;183(2):520-7.
30. Sonn GA, Chang E, Natarajan S, Margolis DJ, Macairan M, Lieu P, et al. Value of targeted prostate biopsy using magnetic resonance-ultrasound fusion in men with prior negative biopsy and elevated prostate-specific antigen. European urology. 2014;65(4):809-15.
31. Kaufmann S, Kruck S, Kramer U, Gatidis S, Stenzl A, Roethke M, et al. Direct comparison of targeted MRI-guided biopsy with systematic transrectal ultrasound-guided biopsy in patients with previous negative prostate biopsies. Urologia internationalis. 2015;94(3):319-25.
32. Kaufmann S, Bedke J, Gatidis S, Hennenlotter J, Kramer U, Notohamiprodjo M, et al. Prostate cancer gene 3 (PCA3) is of additional predictive value in patients with PI-RADS grade III (intermediate) lesions in the MR-guided re-biopsy setting for prostate cancer. World journal of urology. 2015.
33. Durmus T, Reichelt U, Huppertz A, Hamm B, Beyersdorff D, Franiel T. MRI-guided biopsy of the prostate: correlation between the cancer detection rate and the number of previous negative TRUS biopsies. Diagnostic and interventional radiology. 2013;19(5):411-7.
34. Hoeks CM, Schouten MG, Bomers JG, Hoogendoorn SP, Hulsbergen-van de Kaa CA, Hambrock T, et al. Three-Tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. European urology. 2012;62(5):902-9.
35. Roethke M, Anastasiadis AG, Lichy M, Werner M, Wagner P, Kruck S, et al. MRI-guided prostate biopsy detects clinically significant cancer: analysis of a cohort of 100 patients after previous negative TRUS biopsy. World journal of urology. 2012;30(2):213-8.
36. Vourganti S, Rastinehad A, Yerram NK, Nix J, Volkin D, Hoang A, et al. Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. The Journal of urology. 2012;188(6):2152-7.
37. Arsov C, Quentin M, Rabenalt R, Antoch G, Albers P, Blondin D. Repeat transrectal ultrasound biopsies with additional targeted cores according to results of functional prostate MRI detects high-risk prostate cancer in patients with previous negative biopsy and increased PSA - a pilot study. Anticancer research. 2012;32(3):1087-92.
38. Franiel T, Stephan C, Erbersdobler A, Dietz E, Maxeiner A, Hell N, et al. Areas suspicious for prostate cancer: MR-guided biopsy in patients with at least one transrectal US-guided biopsy with a negative finding--multiparametric MR imaging for detection and biopsy planning. Radiology. 2011;259(1):162-72.
39. Hambrock T, Futterer JJ, Huisman HJ, Hulsbergen-vandeKaa C, van Basten JP, van Oort I, et al. Thirty-two-channel coil 3T magnetic resonance-guided biopsies of prostate tumor suspicious regions identified on multimodality 3T magnetic resonance imaging: technique and feasibility. Investigative radiology. 2008;43(10):686-94.
40. Schouten MG, Hoeks CM, Bomers JG, Hulsbergen-van de Kaa CA, Witjes JA, Thompson LC, et al. Location of Prostate Cancers Determined by Multiparametric and MRI-Guided Biopsy in Patients With Elevated Prostate-Specific Antigen Level and at Least One Negative Transrectal Ultrasound-Guided Biopsy. AJR American journal of roentgenology. 2015;205(1):57-63.
41. Sciarra A, Panebianco V, Cattarino S, Busetto GM, De Berardinis E, Ciccariello M, et al. Multiparametric magnetic resonance imaging of the prostate can improve the predictive value of the urinary prostate cancer antigen 3 test in patients with elevated prostate-specific antigen levels and a previous negative biopsy. BJU international. 2012;110(11):1661-5.
42. Zamecnik P, Schouten MG, Krafft AJ, Maier F, Schlemmer HP, Barentsz JO, et al. Automated real-time needle-guide tracking for fast 3-T MR-guided transrectal prostate biopsy: a feasibility study. Radiology. 2014;273(3):879-86.
43. Busetto GM, De Berardinis E, Sciarra A, Panebianco V, Giovannone R, Rosato S, et al. Prostate cancer gene 3 and multiparametric magnetic resonance can reduce unnecessary biopsies: decision curve analysis to evaluate predictive models. Urology. 2013;82(6):1355-60.
44. Pepe P, Garufi A, Priolo G, Pennisi M. Can 3-Tesla pelvic phased-array multiparametric MRI avoid unnecessary repeat prostate biopsy in patients with PSA < 10 ng/mL? Clinical genitourinary cancer. 2015;13(1):e27-30.
45. Wysock JS, Rosenkrantz AB, Huang WC, Stifelman MD, Lepor H, Deng FM, et al. A prospective, blinded comparison of magnetic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of MR-targeted prostate biopsy: the PROFUS trial. European urology. 2014;66(2):343-51.
46. Lee SH, Chung MS, Kim JH, Oh YT, Rha KH, Chung BH. Magnetic resonance imaging targeted biopsy in men with previously negative prostate biopsy results. Journal of endourology / Endourological Society. 2012;26(7):787-91.
47. Roehl KA, Antenor JA, Catalona WJ. Serial biopsy results in prostate cancer screening study. The Journal of urology. 2002;167(6):2435-9.
48. Cash H, Maxeiner A, Stephan C, Fischer T, Durmus T, Holzmann J, et al. The detection of significant prostate cancer is correlated with the Prostate Imaging Reporting and Data System (PI-RADS) in MRI/transrectal ultrasound fusion biopsy. World journal of urology. 2015.
49. Kuru TH, Roethke MC, Seidenader J, Simpfendorfer T, Boxler S, Alammar K, et al. Critical evaluation of magnetic resonance imaging targeted, transrectal ultrasound guided transperineal fusion biopsy for detection of prostate cancer. The Journal of urology. 2013;190(4):1380-6.
50. Puech P, Ouzzane A, Gaillard V, Betrouni N, Renard B, Villers A, et al. Multiparametric MRI-targeted TRUS prostate biopsies using visual registration. BioMed research international. 2014;2014:819360.
51. Logan JK, Rais-Bahrami S, Turkbey B, Gomella A, Amalou H, Choyke PL, et al. Current status of magnetic resonance imaging (MRI) and ultrasonography fusion software platforms for guidance of prostate biopsies. BJU international. 2014;114(5):641-52.
52. Nassiri N, Natarajan S, Margolis DJ, Marks LS. Targeted Prostate Biopsy: Lessons Learned Midst the Evolution of a Disruptive Technology. Urology. 2015.
53. Park BK, Lee HM, Kim CK, Choi HY, Park JW. Lesion localization in patients with a previous negative transrectal ultrasound biopsy and persistently elevated prostate specific antigen level using diffusion-weighted imaging at three Tesla before rebiopsy. Investigative radiology. 2008;43(11):789-93.
54. Martin PR, Cool DW, Romagnoli C, Fenster A, Ward AD. Magnetic resonance imaging-targeted, 3D transrectal ultrasound-guided fusion biopsy for prostate cancer: Quantifying the impact of needle delivery error on diagnosis. Medical physics. 2014;41(7):073504.
55. Xu S, Kruecker J, Turkbey B, Glossop N, Singh AK, Choyke P, et al. Real-time MRI-TRUS fusion for guidance of targeted prostate biopsies. Comput Aided Surg. 2008;13(5):255-64.
56. Natarajan S, Marks LS, Margolis DJ, Huang J, Macairan ML, Lieu P, et al. Clinical application of a 3D ultrasound-guided prostate biopsy system. Urologic oncology. 2011;29(3):334-42.
57. Borkowetz A, Platzek I, Toma M, Laniado M, Baretton G, Froehner M, et al. Comparison of systematic transrectal biopsy to transperineal magnetic resonance imaging/ultrasound-fusion biopsy for the diagnosis of prostate cancer. BJU international. 2014.
58. Portalez D, Mozer P, Cornud F, Renard-Penna R, Misrai V, Thoulouzan M, et al. Validation of the European Society of Urogenital Radiology scoring system for prostate cancer diagnosis on multiparametric magnetic resonance imaging in a cohort of repeat biopsy patients. European urology. 2012;62(6):986-96.
59. Puech P, Rouviere O, Renard-Penna R, Villers A, Devos P, Colombel M, et al. Prostate cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy--prospective multicenter study. Radiology. 2013;268(2):461-9.
60. Brock M, Loppenberg B, Roghmann F, Pelzer A, Dickmann M, Becker W, et al. Impact of real-time elastography on magnetic resonance imaging/ultrasound fusion guided biopsy in patients with prior negative prostate biopsies. The Journal of urology. 2015;193(4):1191-7.
61. Grey AD, Chana MS, Popert R, Wolfe K, Liyanage SH, Acher PL. Diagnostic accuracy of magnetic resonance imaging (MRI) prostate imaging reporting and data system (PI-RADS) scoring in a transperineal prostate biopsy setting. BJU international. 2015;115(5):728-35.
62. Kuru TH, Saeb-Parsy K, Cantiani A, Frey J, Lombardo R, Serrao E, et al. Evolution of repeat prostate biopsy strategies incorporating transperineal and MRI-TRUS fusion techniques. World journal of urology. 2014;32(4):945-50.
63. Pepe P, Garufi A, Priolo G, Dibenedetto G, Salemi M, Pennisi M, et al. Accuracy of 3 Tesla pelvic phased-array multiparametric MRI in diagnosing prostate cancer at repeat biopsy. Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica / Associazione ricerche in urologia. 2014;86(4):336-9.
64. Sonn GA, Natarajan S, Margolis DJ, MacAiran M, Lieu P, Huang J, et al. Targeted biopsy in the detection of prostate cancer using an office based magnetic resonance ultrasound fusion device. The Journal of urology. 2013;189(1):86-91.
65. Bjurlin MA, Carter HB, Schellhammer P, Cookson MS, Gomella LG, Troyer D, et al. Optimization of initial prostate biopsy in clinical practice: sampling, labeling and specimen processing. The Journal of urology. 2013;189(6):2039-46.
66. Shariat SF, Karakiewicz PI, Margulis V, Kattan MW. Inventory of prostate cancer predictive tools. Current opinion in urology. 2008;18(3):279-96.
67. Filson CP, Natarajan S, Margolis DJ, Huang J, Lieu P, Dorey FJ, et al. Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies. Cancer. 2016 Mar 15;122(6):884-92. PubMed PMID: 26749141. Pubmed Central PMCID: PMC4777653.
68. Tewes S, Hueper K, Hartung D, Imkamp F, Herrmann TR, Weidemann J, et al. Targeted MRI/TRUS fusion-guided biopsy in men with previous prostate biopsies using a novel registration software and multiparametric MRI PI-RADS scores: first results. World journal of urology. 2015.
69. Engehausen DG, Engelhard K, Schwab SA, Uder M, Wach S, Wullich B, et al. Magnetic resonance image-guided biopsies with a high detection rate of prostate cancer. TheScientificWorldJournal. 2012;2012:975971.