Shyam Natarajan

Value of Targeted Prostate Biopsy Using Magnetic Resonance–Ultrasound Fusion in Men with Prior Negative Biopsy and Elevated Prostate-specific Antigen

BACKGROUND Conventional biopsy fails to detect the presence of some prostate cancers (PCas). Men with a prior negative biopsy but persistently elevated prostate-specific antigen (PSA) pose a diagnostic dilemma, as some harbor elusive cancer. OBJECTIVE To determine whether use of magnetic resonance-ultrasound (MR-US) fusion biopsy results in improved detection of PCa compared to repeat conventional biopsy. DESIGN, SETTING, AND PARTICIPANTS In a consecutive-case series, 105 subjects with prior negative biopsy and elevated PSA values underwent multiparametric magnetic resonance imaging (MRI) and fusion biopsy in an outpatient setting. INTERVENTION Suspicious areas on multiparametric MRI were delineated and graded by a radiologist; MR-US fusion biopsy was performed by a urologist using the Artemis device; targeted and systematic biopsies were obtained regardless of MRI result. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Detection rates of all PCa and clinically significant PCa (Gleason ≥3+4 or Gleason 6 with maximal cancer core length ≥4 mm) were determined. The yield of targeted biopsy was compared to systematic biopsy. The ability of an MRI grading system to predict clinically significant cancer was investigated. Stepwise multivariate logistic regression analysis was performed to determine predictors of significant cancer on biopsy. RESULTS AND LIMITATIONS Fusion biopsy revealed PCa in 36 of 105 men (34%; 95% confidence interval [CI], 25-45). Seventy-two percent of men with PCa had clinically significant disease; 21 of 23 men (91%) with PCa on targeted biopsy had significant cancer compared to 15 of 28 (54%) with systematic biopsy. Degree of suspicion on MRI was the most powerful predictor of significant cancer on multivariate analysis. Twelve of 14 (86%) subjects with a highly suspicious MRI target were diagnosed with clinically significant cancer. CONCLUSIONS MR-US fusion biopsy provides improved detection of PCa in men with prior negative biopsies and elevated PSA values. Most cancers found were clinically significant.

Targeted Biopsy in the Detection of Prostate Cancer Using an Office Based Magnetic Resonance Ultrasound Fusion Device

PURPOSE Targeted biopsy of lesions identified on magnetic resonance imaging may enhance the detection of clinically relevant prostate cancers. We evaluated prostate cancer detection rates in 171 consecutive men using magnetic resonance ultrasound fusion prostate biopsy. MATERIALS AND METHODS Subjects underwent targeted biopsy for active surveillance (106) or persistently increased prostate specific antigen but negative prior conventional biopsy (65). Before biopsy, each man underwent multiparametric magnetic resonance imaging at 3.0 Tesla. Lesions on magnetic resonance imaging were outlined in 3 dimensions and assigned increasing cancer suspicion levels (image grade 1 to 5) by a uroradiologist. A biopsy tracking system was used to fuse the stored magnetic resonance imaging with real-time ultrasound, generating a 3-dimensional prostate model on the fly. Working from the 3-dimensional model, transrectal biopsy of target lesions and 12 systematic biopsies were performed with the patient under local anesthesia in the clinic. RESULTS A total of 171 subjects (median age 65 years) underwent targeted biopsy. At biopsy, median prostate specific antigen was 4.9 ng/ml and prostate volume was 48 cc. A targeted biopsy was 3 times more likely to identify cancer than a systematic biopsy (21% vs 7%). Prostate cancer was found in 53% of men, 38% of whom had Gleason grade 7 or greater cancer. Of the men with Gleason 7 or greater cancer 38% had disease detected only on targeted biopsies. Targeted biopsy findings correlated with level of suspicion on magnetic resonance imaging. Of 16 men 15 (94%) with an image grade 5 target (highest suspicion) had prostate cancer, including 7 with Gleason 7 or greater cancer. CONCLUSIONS Prostate lesions identified on magnetic resonance imaging can be accurately targeted using magnetic resonance ultrasound fusion biopsy by a urologist in clinic. Biopsy findings correlate with level of suspicion on magnetic resonance imaging.

Clinical application of a 3D ultrasound-guided prostate biopsy system

OBJECTIVES Prostate biopsy (Bx) has for 3 decades been performed in a systematic, but blind fashion using 2D ultrasound (US). Herein is described the initial clinical evaluation of a 3D Bx tracking and targeting device (Artemis; Eigen, Grass Valley, CA). Our main objective was to test accuracy of the new 3D method in men undergoing first and follow-up Bx to rule out prostate cancer (CaP). MATERIALS AND METHODS Patients in the study were men ages 35-87 years (66.1 ± 9.9), scheduled for Bx to rule out CaP, who entered into an IRB-approved protocol. A total of 218 subjects underwent conventional trans-rectal US (TRUS); the tracking system was then attached to the US probe; the prostate was scanned and a 3D reconstruction was created. All Bx sites were visualized in 3D and tracked electronically. In 11 men, a pilot study was conducted to test ability of the device to return a Bx to an original site. In 47 men, multi-parametric 3 Tesla MRI, incorporating T2-weighted images, dynamic contrast enhancement, and diffusion-weighted imaging, was performed in advance of the TRUS, allowing the stored MRI images to be fused with real-time US during biopsy. Lesions on MRI were delineated by a radiologist, assigned a grade of CaP suspicion, and fused into TRUS for biopsy targeting. RESULTS 3D Bx tracking was completed successfully in 180/218 patients, with a success rate approaching 95% among the last 50 men. Average time for Bx with the Artemis device was 15 minutes with an additional 5 minutes for MRI fusion and Bx targeting. In the tracking study, an ability to return to prior Bx sites (n=32) within 1.2 ± 1.1 mm SD was demonstrated and was independent of prostate volume or location of Bx site. In the MRI fusion study, when suspicious lesions were targeted, a 33% Bx-positivity rate was found compared with a 7% positivity rate for systematic, nontargeted Bx (19/57 cores vs. 9/124 cores, P=0.03). CONCLUSION Use of 3D tracking and image fusion has the potential to transform MRI into a clinical tool to aid biopsy and improve current methods for diagnosis and follow-up of CaP.

MRI–ultrasound fusion for guidance of targeted prostate biopsy

Purpose of reviewProstate cancer (CaP) may be detected on MRI. Fusion of MRI with ultrasound allows urologists to progress from blind, systematic biopsies to biopsies, which are mapped, targeted and tracked. We herein review the current status of prostate biopsy via MRI/ultrasound fusion. Recent findingsThree methods of fusing MRI for targeted biopsy have been recently described: MRI–ultrasound fusion, MRI–MRI fusion (‘in-bore’ biopsy) and cognitive fusion. Supportive data are emerging for the fusion devices, two of which received US Food and Drug Administration approval in the past 5 years: Artemis (Eigen, USA) and Urostation (Koelis, France). Working with the Artemis device in more than 600 individuals, we found that targeted biopsies are two to three times more sensitive for detection of CaP than nontargeted systematic biopsies; nearly 40% of men with Gleason score of at least 7 CaP are diagnosed only by targeted biopsy; nearly 100% of men with highly suspicious MRI lesions are diagnosed with CaP; ability to return to a prior biopsy site is highly accurate (within 1.2 ± 1.1 mm); and targeted and systematic biopsies are twice as accurate as systematic biopsies alone in predicting whole-organ disease. SummaryIn the future, MRI–ultrasound fusion for lesion targeting is likely to result in fewer and more accurate prostate biopsies than the present use of systematic biopsies with ultrasound guidance alone.

Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies.

The current study was conducted to evaluate the performance of magnetic resonance (MR)‐ultrasound‐guided fusion biopsy in diagnosing clinically significant prostate cancer (csCaP).

Targeted Prostate Biopsy to Select Men for Active Surveillance—Do the Epstein Criteria Still Apply?

PURPOSE Established in 1994, the Epstein histological criteria (Gleason score 6 or less, 2 or fewer cores positive and 50% or less of any core) have been widely used to select men for active surveillance. However, with the advent of targeted biopsy, which may be more accurate than conventional biopsy, we reevaluated the likelihood of reclassification upon confirmatory rebiopsy using multiparametric magnetic resonance imaging-ultrasound fusion. MATERIALS AND METHODS We identified 113 men enrolled in active surveillance at our institution who met Epstein criteria and subsequently underwent confirmatory targeted biopsy via multiparametric magnetic resonance imaging-ultrasound fusion. Median patient age was 64 years, median prostate specific antigen was 4.2 ng/ml and median prostate volume was 46.8 cc. Targets or regions of interest on multiparametric magnetic resonance imaging-ultrasound fusion were graded by suspicion level and biopsied at 3 mm intervals along the longest axis (median 10.5 mm). Also, 12 systematic cores were obtained during confirmatory rebiopsy. Our reporting is consistent with START (Standards of Reporting for MRI-targeted Biopsy Studies) criteria. RESULTS Confirmatory fusion biopsy resulted in reclassification in 41 men (36%), including 26 (23%) due to Gleason grade 6 or greater and 15 (13%) due to high volume Gleason 6 disease. When stratified by suspicion on multiparametric magnetic resonance imaging-ultrasound fusion, the likelihood of reclassification was 24% to 29% for target grade 0 to 3, 45% for grade 4 and 100% for grade 5 (p=0.001). Men with grade 4 and 5 vs lower grade targets were greater than 3 times more likely to be reclassified (OR 3.2, 95% CI 1.4-7.1, p=0.006). CONCLUSIONS Upon confirmatory rebiopsy using multiparametric magnetic resonance imaging-ultrasound fusion men with high suspicion targets on imaging were reclassified 45% to 100% of the time. Criteria for active surveillance should be reevaluated when multiparametric magnetic resonance imaging-ultrasound fusion guided prostate biopsy is used.

The Role of Magnetic Resonance Imaging in Delineating Clinically Significant Prostate Cancer

OBJECTIVE To determine whether multiparametric magnetic resonance imaging might improve the identification of patients with higher risk disease at diagnosis and thereby reduce the incidence of undergrading or understaging. METHODS We retrospectively reviewed the clinical records of 115 patients who underwent multiparametric magnetic resonance imaging before radical prostatectomy. We used Epsteins criteria of insignificant disease with and without a magnetic resonance imaging (MRI) parameter (apparent diffusion coefficient) to calculate sensitivity, specificity, as well as negative and positive predictive values [NPV and PPV] across varying definitions of clinically significant cancer based on Gleason grade and tumor volume (0.2 mL, 0.5 mL, and 1.3 mL) on whole-mount prostate specimens. Logistic regression analysis was performed to determine the incremental benefit of MRI in delineating significant cancer. RESULTS The majority had a prostate-specific antigen from 4.1-10.0 (67%), normal rectal examinations (90%), biopsy Gleason score ≤ 6 (68%), and ≤ 2 cores positive (55%). Of the 58 patients pathologically staged with Gleason 7 or pT3 disease at prostatectomy, Epsteins criteria alone missed 12 patients (sensitivity of 79% and NPV of 68%). Addition of apparent diffusion coefficient improved the sensitivity and NPV for predicting significant disease at prostatectomy to 93% and 84%, respectively. MRI improved detection of large Gleason 6 (≥ 1.3 mL, P = .006) or Gleason ≥ 7 lesions of any size (P <.001). CONCLUSION Integration of MRI with existing clinical staging criteria helps identify patients with significant cancer. Clinicians should consider utilizing MRI in the decision-making process.

Magnetic Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds to Correlate Images with Whole Mount Pathology

Purpose: We evaluated the accuracy of magnetic resonance imaging in determining the size and shape of localized prostate cancer. Materials and Methods: The subjects were 114 men who underwent multiparametric magnetic resonance imaging before radical prostatectomy with patient specific mold processing of the specimen from 2013 to 2015. T2‐weighted images were used to contour the prostate capsule and cancer suspicious regions of interest. The contours were used to design and print 3‐dimensional custom molds, which permitted alignment of excised prostates with magnetic resonance imaging scans. Tumors were reconstructed in 3 dimensions from digitized whole mount sections. Tumors were then matched with regions of interest and the relative geometries were compared. Results: Of the 222 tumors evident on whole mount sections 118 had been identified on magnetic resonance imaging. For the 118 regions of interest mean volume was 0.8 cc and the longest 3‐dimensional diameter was 17 mm. However, for matched pathological tumors, of which most were Gleason score 3 + 4 or greater, mean volume was 2.5 cc and the longest 3‐dimensional diameter was 28 mm. The median tumor had a 13.5 mm maximal extent beyond the magnetic resonance imaging contour and 80% of cancer volume from matched tumors was outside region of interest boundaries. Size estimation was most accurate in the axial plane and least accurate along the base‐apex axis. Conclusions: Magnetic resonance imaging consistently underestimates the size and extent of prostate tumors. Prostate cancer foci had an average diameter 11 mm longer and a volume 3 times greater than T2‐weighted magnetic resonance imaging segmentations. These results may have important implications for the assessment and treatment of prostate cancer.

Targeted Biopsy to Detect Gleason Score Upgrading during Active Surveillance for Men with Low versus Intermediate Risk Prostate Cancer

Purpose: We sought to determine the rate of upgrading to Gleason score 4 + 3 or greater using targeted biopsy for diagnosis and monitoring in men undergoing active surveillance of prostate cancer. Materials and Methods: Study subjects comprised all 259 men, including 196 with Gleason score 3 + 3 and 63 with Gleason score 3 + 4, who were diagnosed by magnetic resonance imaging/ultrasound fusion guided biopsy from 2009 to 2015 and underwent subsequent fusion biopsy for as long as 4 years of active surveillance. The primary end point was the discovery of Gleason score 4 + 3 or greater prostate cancer. Followup biopsies included targeting of positive sites, which were tracked in an Artemis™ device. Kaplan‐Meier curves were generated to determine upgrading rates, stratified by initial Gleason score and prostate specific antigen density. Results: Based on a Cox proportional hazard model, men with Gleason score 3 + 4 were 4.65 times more likely to have upgrading than men with an initial Gleason score of 3 + 3 at 3 years (p <0.01). By the third surveillance year 63% of men with Gleason score 3 + 4 had been upgraded compared with 18.0% who started with Gleason score 3 + 3 (p <0.01). Of all 33 upgrades 32 (97%) occurred at a magnetic resonance imaging visible or a tracked site of tumor, rather than at a previously negative systematic site. Independent predictors of upgrading were Gleason score 3 + 4, prostate specific antigen density 0.15 ng/ml/cm3 or greater and a grade 5 lesion on magnetic resonance imaging. The incidence rate ratio of upgrading (Gleason score 3 + 4 vs 3 + 3) was 4.25 per year of patient followup (p <0.01). Conclusions: During active surveillance of prostate cancer, targeting of tracked tumor foci by magnetic resonance imaging/ultrasound fusion biopsy allows for heightened detection of Gleason score 4 + 3 or greater cancers. Baseline variables directly related to important upgrading that warrant increased vigilance include Gleason score 3 + 4, prostate specific antigen density 0.15 ng/ml/cm3 or greater and grade 5 lesions on magnetic resonance imaging.

Initial experience with electronic tracking of specific tumor sites in men undergoing active surveillance of prostate cancer

OBJECTIVES Targeted biopsy, using magnetic resonance (MR)-ultrasound (US) fusion, may allow tracking of specific cancer sites in the prostate. We aimed to evaluate the initial use of the technique to follow tumor sites in men on active surveillance of prostate cancer. METHODS AND MATERIALS A total of 53 men with prostate cancer (all T1c category) underwent rebiopsy of 74 positive biopsy sites, which were tracked and targeted using the Artemis MR-US fusion device (Eigen, Grass Valley, CA) from March 2010 through January 2013. The initial biopsy included 12 cores from a standard template (mapped by software) and directed biopsies from regions of interest seen on MR imaging (MRI). In the repeat biopsy, samples were taken from sites containing cancer at the initial biopsy. Outcomes of interest at second MR-US biopsy included (a) presence of any cancer and (b) presence of clinically significant cancer. RESULTS All cancers on initial biopsy had either Gleason score 3+3 = 6 (n = 63) or 3+4 = 7 (n = 11). At initial biopsy, 23 cancers were within an MRI target, and 51 were found on systematic biopsy. Cancer detection rate on repeat biopsy (29/74, 39%) was independent of Gleason score on initial biopsy (P = not significant) but directly related to initial cancer core length (P<0.02). Repeat sampling of cancerous sites within MRI targets was more likely to show cancer than resampling of tumorous systematic sites (61% vs. 29%, P = 0.005). When initial cancer core length was≥4 mm within an MRI target, more than 80% (5/6) of follow-up tracking biopsies were positive. An increase of Gleason score was uncommon (9/74, 12%). CONCLUSIONS Monitoring of specific prostate cancer-containing sites may be achieved in some men using an electronic tracking system. The chances of finding tumor on repeat specific-site sampling was directly related to the length of tumor in the initial biopsy core and presence of tumor within an MRI target; upgrading of Gleason score was uncommon. Further research is required to evaluate the potential utility of site-specific biopsy tracking for patients with prostate cancer on active surveillance.