Daniel J. Margolis

Prostate Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Patients with a Prior Negative Biopsy: A Consensus Statement by AUA and SAR

PURPOSE After 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. MATERIALS AND METHODS As a collaborative initiative of the AUA (American Urological Association) and SAR (Society of Abdominal Radiology) Prostate Cancer Disease Focused Panel, an expert panel of urologists and radiologists conducted a literature review and formed consensus statements regarding the role of prostate magnetic resonance imaging and magnetic resonance imaging targeted biopsy in patients with a negative biopsy, which are summarized in this review. RESULTS The panel recognizes that many options exist for men with a previously negative biopsy. If a biopsy is recommended, prostate magnetic resonance imaging and subsequent magnetic resonance imaging targeted cores appear to facilitate the detection of clinically significant disease over standardized repeat biopsy. Thus, when high quality prostate magnetic resonance imaging is available, it should be strongly considered for any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is under evaluation for a possible repeat biopsy. The decision of whether to perform magnetic resonance imaging in this setting must also take into account the results of any other biomarkers and the cost of the examination, as well as the availability of high quality prostate magnetic resonance imaging interpretation. If magnetic resonance imaging is done, it should be performed, interpreted and reported in accordance with PI-RADS version 2 (v2) guidelines. Experience of the reporting radiologist and biopsy operator are required to achieve optimal results and practices integrating prostate magnetic resonance imaging into patient care are advised to implement quality assurance programs to monitor targeted biopsy results. CONCLUSIONS Patients receiving a PI-RADS assessment category of 3 to 5 warrant repeat biopsy with image guided targeting. While transrectal ultrasound guided magnetic resonance imaging fusion or in-bore magnetic resonance imaging targeting may be valuable for more reliable targeting, especially for lesions that are small or in difficult locations, in the absence of such targeting technologies cognitive (visual) targeting remains a reasonable approach in skilled hands. At least 2 targeted cores should be obtained from each magnetic resonance imaging defined target. Given the number of studies showing a proportion of missed clinically significant cancers by magnetic resonance imaging targeted cores, a case specific decision must be made whether to also perform concurrent systematic sampling. However, performing solely targeted biopsy should only be considered once quality assurance efforts have validated the performance of prostate magnetic resonance imaging interpretations with results consistent with the published literature. In patients with negative or low suspicion magnetic resonance imaging (PI-RADS assessment category of 1 or 2, respectively), other ancillary markers (ie PSA, PSAD, PSAV, PCA3, PHI, 4K) may be of value in identifying patients warranting repeat systematic biopsy, although further data are needed on this topic. If a repeat biopsy is deferred on the basis of magnetic resonance imaging findings, then continued clinical and laboratory followup is advised and consideration should be given to incorporating repeat magnetic resonance imaging in this diagnostic surveillance regimen.

MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography–guided biopsy for prostate‐cancer detection in men with a raised prostate‐specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography–guided biopsy. Men in the MRI‐targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10‐to‐12–core, transrectal ultrasonography–guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI‐targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI‐targeted biopsy group, as compared with 64 of 248 (26%) in the standard‐biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI‐targeted biopsy group than in the standard‐biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, ‐13 percentage points; 95% CI, ‐19 to ‐7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI‐targeted biopsy was superior to standard transrectal ultrasonography–guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027.)

Prostate cancer risk stratification with magnetic resonance imaging.

In recent years, multiparametric magnetic resonance imaging (mpMRI) has shown promise for prostate cancer (PCa) risk stratification. mpMRI, often followed by targeted biopsy, can be used to confirm low-grade disease before enrollment in active surveillance. In patients with intermediate or high-risk PCa, mpMRI can be used to inform surgical management. mpMRI has sensitivity of 44% to 87% for detection of clinically significant PCa and negative predictive value of 63% to 98% for exclusion of significant disease. In addition to tumor identification, mpMRI has also been shown to contribute significant incremental value to currently used clinical nomograms for predicting extraprostatic extension. In combination with conventional clinical criteria, accuracy of mpMRI for prediction of extraprostatic extension ranges from 92% to 94%, significantly higher than that achieved with clinical criteria alone. Supplemental sequences, such as diffusion-weighted imaging and dynamic contrast-enhanced imaging, allow quantitative evaluation of cancer-suspicious regions. Apparent diffusion coefficient appears to be an independent predictor of PCa aggressiveness. Addition of apparent diffusion coefficient to Epstein criteria may improve sensitivity for detection of significant PCa by as much as 16%. Limitations of mpMRI include variability in reporting, underestimation of PCa volume and failure to detect clinically significant disease in a small but significant number of cases.

Focal Laser Ablation of Prostate Cancer: Feasibility of Magnetic Resonance Imaging-Ultrasound Fusion for Guidance

Purpose: Focal laser ablation is a potential treatment in some men with prostate cancer. Currently focal laser ablation is performed by radiologists in a magnetic resonance imaging unit (in bore). We evaluated the safety and feasibility of performing focal laser ablation in a urology clinic (out of bore) using magnetic resonance imaging‐ultrasound fusion for guidance. Materials and Methods: A total of 11 men with intermediate risk prostate cancer were enrolled in this prospective, institutional review board approved pilot study. Magnetic resonance imaging‐ultrasound fusion was used to guide laser fibers transrectally into regions of interest harboring intermediate risk prostate cancer. Thermal probes were inserted for real‐time monitoring of intraprostatic temperatures during laser activation. Multiparametric magnetic resonance imaging (3 Tesla) was done immediately after treatment and at 6 months along with comprehensive fusion biopsy. Results: Ten of 11 patients were successfully treated while under local anesthesia. Mean procedure time was 95 minutes (range 71 to 105). Posttreatment magnetic resonance imaging revealed a confined zone of nonperfusion in all 10 men. Mean zone volume was 4.3 cc (range 2.1 to 6.0). No CTCAE grade 3 or greater adverse events developed and no changes were observed in urinary or sexual function. At 6 months magnetic resonance imaging‐ultrasound fusion biopsy of the treatment site showed no cancer in 3 patients, microfocal Gleason 3 + 3 in another 3 and persistent intermediate risk prostate cancer in 4. Conclusions: Focal laser ablation of prostate cancer appears safe and feasible with the patient under local anesthesia in a urology clinic using magnetic resonance imaging‐ultrasound fusion for guidance and thermal probes for monitoring. Further development is necessary to refine out of bore focal laser ablation and additional studies are needed to determine appropriate treatment margins and oncologic efficacy.

Commentary regarding a recent collaborative consensus statement addressing prostate MRI and MRI-targeted biopsy in patients with a prior negative prostate biopsy

consensus statement addressing prostate MRI and MRI-targeted biopsy in patients with a prior negative prostate biopsy Sadhna Verma, Andrew B. Rosenkrantz, Peter Choyke, Steven C. Eberhardt, Scott E. Eggener, Krishnanath Gaitonde, Masoom A. Haider, Daniel J. Margolis, Leonard S. Marks, Peter Pinto, Geoffrey A. Sonn, Samir S. Taneja Department of Radiology, College of Medicine, University of Cincinnati, 234 Goodman Street, PO Box 670761, Cincinnati OH 45267-0761, USA Department of Radiology, NYU Langone Medical Center, New York, USA Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, USA Department of Radiology, University of New Mexico, Albuquerque, USA Department of Urology, University of Chicago Medicine, Chicago, USA Department of Urology, College of Medicine, University of Cincinnati, Cincinnati, USA Department of Medical Imaging, Sunnybrook Health Sciences Center, University of Toronto, Toronto, USA Department of Radiology, Weill Cornell Medicine, Cornell University, Ithaca, USA Department of Urology, David Geffen School of Medicine, UCLA, Los Angeles, USA Urologic Oncology Branch, National Cancer Institute & NIH Clinical Center, National Institutes of Health, Bethesda, USA Department of Urology, Stanford University School of Medicine, Stanford, USA Department of Urologic Oncology, NYU Langone Medical Center, New York, USA

Focal Therapy Eligibility Determined by Magnetic Resonance Imaging/Ultrasound Fusion Biopsy

Purpose: We assessed focal therapy eligibility in men who underwent multiparametric magnetic resonance imaging and targeted biopsy with correlation to whole mount histology after radical prostatectomy. Materials and Methods: Subjects were selected from among the 454 men in whom targeted biopsy proven prostate cancer was derived from regions of interest on multiparametric magnetic resonance imaging from 2010 to 2016. Focal therapy eligibility was limited to a maximum Gleason score of 4 + 3 in regions of interest with or without other foci of low risk prostate cancer (Gleason score 3 + 3 and less than 4 mm). Men who did not meet NCCN® intermediate risk criteria were classified as ineligible for focal therapy. Of the 454 men 64 underwent radical prostatectomy and biopsy findings were compared to final pathology findings. Results: Of the 454 men with a biopsy proven region of interest 175 (38.5%) were eligible for focal therapy. Fusion biopsy, which combined targeted and template biopsy, had 80.0% sensitivity (12 of 15 cases), 73.5% specificity (36 of 49) and 75.0% accuracy (48 of 64) for focal therapy eligibility. Targeted cores alone yielded 73.3% sensitivity (11 of 15 cases), 47.9% specificity (23 of 48) and 54.7% accuracy (35 of 64). Gleason score and extension across the midline differed in 4 and 9, respectively, of the 13 cases that showed discordant biopsy and whole mount histology. Conclusions: Using intermediate risk eligibility criteria more than a third of men with a targeted biopsy proven lesion identified on multiparametric magnetic resonance imaging would have been eligible for focal therapy. Eligibility determined by fusion biopsy was concordant with whole mount histology in 75% of cases. Improved selection criteria are needed to reliably determine focal therapy eligibility.

Value of Tracking Biopsy in Men Undergoing Active Surveillance of Prostate Cancer

Purpose We compared the upgrading rate obtained by resampling precise spots of prostate cancer (tracking biopsy) vs conventional systematic resampling during followup of men on active surveillance. Materials and Methods From 2009 to 2017 in 352 men prostate cancer was Gleason 3 + 3 in 268 and Gleason 3 + 4 in 84 at initial magnetic resonance imaging‐ultrasound fusion biopsy. These men subsequently underwent a second fusion biopsy. At the first biopsy session all men underwent 12‐core systematic biopsies and, when magnetic resonance imaging visible lesions were present, targeted biopsies. All cancerous sites were recorded electronically. During active surveillance at a second fusion biopsy session 6 to 18 months later tracking and systematic nontracking samples were obtained. The primary outcome measure was an increase in Gleason score (upgrading) at followup sampling, which was stratified by biopsy method. Results Overall 91 of the 352 men (25.9%) experienced upgrading at the second biopsy during a median 11‐month interval. The upgrade rate in the Gleason 3 + 3 and 3 + 4 groups was 26.9% and 22.6%, respectively. The mean number of cores taken at second biopsy was 12.2 ± 3.3 in men with upgrading and 12.4 ± 4.1 in those who remained stable (p not significant). Men with grade 0 to 4 magnetic resonance imaging targets were all upgraded at approximately the same rate of 20% to 30% (p not significant). However, 58.8% of the men with grade 5 magnetic resonance imaging targets were upgraded. Of the 91 upgrades 48 (53%) were detected only by tracking. Conclusions The tracking function of magnetic resonance imaging‐ultrasound fusion biopsy warrants further study. When specific sites are resampled in men undergoing active surveillance of prostate cancer, upgrading is detected more often than by nontracking biopsy.

MR Spectroscopic Imaging of Peripheral Zone in Prostate Cancer Using a 3T MRI Scanner: Endorectal versus External Phased Array Coils

Magnetic resonance spectroscopic imaging (MRSI) detects alterations in major prostate metabolites, such as citrate (Cit), creatine (Cr), and choline (Ch). We evaluated the sensitivity and accuracy of three-dimensional MRSI of prostate using an endorectal compared to an external phased array “receive” coil on a 3T MRI scanner. Eighteen patients with prostate cancer (PCa) who underwent endorectal MR imaging and proton (1H) MRSI were included in this study. Immediately after the endorectal MRSI scan, the PCa patients were scanned with the external phased array coil. The endorectal coil-detected metabolite ratio [(Ch+Cr)/Cit] was significantly higher in cancer locations (1.667 ± 0.663) compared to non-cancer locations (0.978 ± 0.420) (P < 0.001). Similarly, for the external phased array, the ratio was significantly higher in cancer locations (1.070 ± 0.525) compared to non-cancer locations (0.521 ± 0.310) (P < 0.001). The sensitivity and accuracy of cancer detection were 81% and 78% using the endorectal ‘receive’ coil, and 69% and 75%, respectively using the external phased array ‘receive’ coil.

Multiple Regions of Interest on Multiparametric Magnetic Resonance Imaging are Not Associated with Increased Detection of Clinically Significant Prostate Cancer on Fusion Biopsy

Purpose: We sought to determine the association between multiple regions of interest on prebiopsy magnetic resonance imaging and the detection of clinically significant prostate cancer in men undergoing magnetic resonance imaging‐ultrasound fusion biopsy. Materials and Methods: We performed a retrospective, single institution analysis of men who underwent fusion biopsy. Men with prior positive biopsies, magnetic resonance imaging performed elsewhere and/or magnetic resonance imaging prior to release of the PI‐RADS™ (Prostate Imaging Reporting and Data System) version 2 were excluded from study, resulting in 381 participants. Modeled independent variables included patient age, number of regions of interest with a PI‐RADS categorization of 3 or greater, body mass index, prostate specific antigen, prostate volume and PI‐RADS categorization. Multivariable logistic regression was performed to determine factors associated with finding clinically significant prostate cancer (Gleason 7 or greater) on biopsy. Results: Median age was 67.2 years (IQR (61.6–73.0) and median prostate specific antigen was 6.6 ng/ml (5.0–10.0). Adjusted analysis demonstrated that age (OR 1.10, 95% CI 1.06–1.15, p ≤0.001), body mass index (OR 1.08, 95% CI 1.01–1.16, p = 0.038) and prostate specific antigen (OR 1.06, 95% CI 1.01–1.10, p = 0.015) were associated with detection of clinically significant prostate cancer. PI‐RADS categories 4 (OR 4.62, 95% CI 2.23–9.33) and 5 (OR 6.75, 95% CI 2.72–16.71, each p <0.001) were associated with greater odds of clinically significant prostate cancer. Multiple regions of interest were not associated with the detection of clinically significant prostate cancer (OR 1.05, 95% CI 0.60–1.84, p = 0.857). Conclusions: Multiple regions of interest do not portend a greater likelihood of finding clinically significant prostate cancer. Physicians should recognize that multiple regions of interest should not influence the decision to perform fusion biopsy. Our findings may ease patient anxiety concerning these findings.

A Multireader Exploratory Evaluation of Individual Pulse Sequence Cancer Detection on Prostate Multiparametric Magnetic Resonance Imaging (MRI)

RATIONALE AND OBJECTIVES To determine independent contribution of each prostate multiparametric magnetic resonance imaging (mpMRI) sequence to cancer detection when read in isolation. MATERIALS AND METHODS Prostate mpMRI at 3-Tesla with endorectal coil from 45 patients (n = 30 prostatectomy cases, n = 15 controls with negative magnetic resonance imaging [MRI] or biopsy) were retrospectively interpreted. Sequences (T2-weighted [T2W] MRI, diffusion-weighted imaging [DWI], and dynamic contrast-enhanced [DCE] MRI; N = 135) were separately distributed to three radiologists at different institutions. Readers evaluated each sequence blinded to other mpMRI sequences. Findings were correlated to whole-mount pathology. Cancer detection sensitivity, positive predictive value for whole prostate (WP), transition zone, and peripheral zone were evaluated per sequence by reader, with reader concordance measured by index of specific agreement. Cancer detection rates (CDRs) were calculated for combinations of independently read sequences. RESULTS 44 patients were evaluable (cases median prostate-specific antigen 6.83 [ range 1.95-51.13] ng/mL, age 62 [45-71] years; controls prostate-specific antigen 6.85 [2.4-10.87] ng/mL, age 65.5 [47-71] years). Readers had highest sensitivity on DWI (59%) vs T2W MRI (48%) and DCE (23%) in WP. DWI-only positivity (DWI+/T2W-/DCE-) achieved highest CDR in WP (38%), compared to T2W-only (CDR 24%) and DCE-only (CDR 8%). DWI+/T2W+/DCE- achieved CDR 80%, an added benefit of 56.4% from T2W-only and of 42% from DWI-only (P < .0001). All three sequences interpreted independently positive gave highest CDR of 90%. Reader agreement was moderate (index of specific agreement: T2W = 54%, DWI = 58%, DCE = 33%). CONCLUSIONS When prostate mpMRI sequences are interpreted independently by multiple observers, DWI achieves highest sensitivity and CDR in transition zone and peripheral zone. T2W and DCE MRI both add value to detection; mpMRI achieves highest detection sensitivity when all three mpMRI sequences are positive.