Standard and Targeted Biopsy During Follow-up for Active Surveillance

Literature reviews News and Views From the Literature Prostate Cancer The Comparison of Magnetic Resonance Image–Guided Targeted Biopsy Versus Standard Template Saturation Biopsy in the Detection of Prostate Cancer Reviewed by Meena Davuluri, MD, MPH,1 Stacy Loeb, MD2 Department of Urology, Upstate Medical Center, Syracuse, NY; Departments of Urology and Population Health, New York University School of Medicine, New York, NY [Rev Urol. 2015;17(2):110-111 doi: 10.3909/riu0670] 1 2 © 2015 MedReviews®, LLC P revious studies have shown that when compared with the standard transrectal ultrasound (TRUS) biopsy, magnetic resonance imaging (MRI)ultrasound (US) fusion has improved cancer detection, accuracy, and overall diagnostic power.1 However, fewer data are available on the relative performance of MRItargeted biopsy (MRI-TB) compared with transperineal saturation biopsy, a diagnostic methodology with more comprehensive sampling compared with standard TRUS. Transperineal Magnetic Resonance Image Targeted Prostate Biopsy Versus Transperineal Template Prostate Biopsy in the Detection of Clinically Significant Prostate Cancer Kasivisvanathan V, Dufour R, Moore CM, et al J Urol. 2013;189:860-866 This study assessed the detection rate of clinically significant and insignificant prostate cancer in 182 men undergoing transperineal MRI-TB with cognitive fusion, followed by a 20-sector transperineal template prostate biopsy (TPB). Clinically significant cancers were defined using the University College London (UCL) definition 2 (maximum core length  4 mm or a Gleason score  3 1 4). Overall, MRI-TB had greater sampling efficiency, with a higher proportion of the cores testing positive for cancer (38% vs 14%). There was no statistically significant difference in the detection of clinically significant cancers between the two diagnostic methods (57% for MRI-TB vs 62% for TPB; P 5 .174). However, fewer clinically insignificant cancers were detected with MRI-TB compared with TPB (9% vs 17%; P 5 .024). Further analysis revealed no statistically significant difference in the detection of clinically significant cancers between the techniques in biopsy-naive, prior 110 • Vol. 17 No. 2 • 2015 • Reviews in Urology 4004170006_RIU0670.indd 110 10/07/15 2:20 PM Prostate Cancer negative biopsy, and active surveillance (AS) subsets. However, among men with a prior negative biopsy there was a greater risk of detecting insignificant cancer with TPB than MRI-TB (22% vs 3%; P 5 .03). Although the authors used the UCL definition 2 to define clinically significant cancers for the primary analysis, they also evaluated other criteria including the UCL 1, Harnden, and Goto definitions. Overall, the results were similar with the exception that, when using the Goto definition, TPB had a much greater detection of clinically significant disease compared with MRI-TB. Limitations of the study include a heterogeneous population of men undergoing initial, repeat, or AS biopsies. Although subset analysis was performed within each group, the numbers were small. Another limitation is the lack of blinding of the radiologists to the clinical picture of the patient, including prostate-specific antigen (PSA) levels, previous biopsies, and digital rectal examination. Furthermore, multiple radiologists and urologists with differing years of experience read the MRI and performed the biopsies. However, this could also be viewed as a strength because it provided greater insight to real-world clinical effectiveness. Finally, the logistical and cost implications of using general or spinal anesthesia for transperineal MRI-TB in a US setting requires further study. Comparative Analysis of Transperineal Template Saturation Prostate Biopsy Versus Magnetic Resonance Imaging Targeted Biopsy With Magnetic Resonance Imaging-Ultrasound Fusion Guidance Radtke JP, Kuru TH, Boxler S, et al J Urol. 2015;193:87-94 This study compared the use of MRI-TB with TPB to detect clinically significant and insignificant prostate cancer in biopsy-naive patients and those with previous negative TRUS biopsy results. None of the patients had a history of prostate cancer diagnosis or treatment. All men had 3T multiparametric MRI (mpMRI), which were read by experienced uroradiologists and graded with the Prostate Imaging-Reporting and Data System (PI-RADS) for standardization. MRI-TRUS fusion was performed using the BiopSee platform (rigid software registration). A median of 24 cores were sampled for the TPB and 4 cores for MRI-TB. In this analysis, clinically significant was defined as any Gleason score  7. Of the included 254 patients, 150 (51%) were found to have to prostate cancer and 86 (57%) of these were clinically significant. Of the clinically significant cancers, 12.8% were found by TPB alone and missed by MRI-TB; however, 20.9% of cases were found by MRI-TB alone and missed by TPB. The authors then stratified biopsy results by the PI-RADS score. In the overall cohort, PI-RADS scores of 3, 4, and 5 were associated with 2.2, 4.6, and 8.2fold respective greater risk of prostate cancer detection compared with having no suspicious lesions on MRI. Using a PI-RADS score . 2 as the threshold for biopsy would result in greater sensitivity for significant cancer detection but lower specificity than using a higher cutoff. Overall, 17 significant prostate cancers were detected in patients with PI-RADS scores of 1 or 2, all of whom were undergoing initial biopsy. In this series, no clinically significant cancers were missed by MRI-TB in the repeat biopsy setting. Based on these results, the authors recommended a combined approach of targeted and systematic biopsies for the initial biopsy, whereas MRI-TB alone may be sufficient in the repeat biopsy setting. Unlike the previous study, in this study a single expert radiologist reviewed all images, software-based registration was performed, and different criteria were used to define clinically significant disease. Similar to the previous study, the radiologist who reviewed the MRIs was not blinded to the clinical data; though this may reflect clinical practice, it may still influence the findings. Together, these studies provide consistent data that MRI-TB improves the detection of clinically significant prostate cancer compared with TPB. Further study is needed to determine the most cost-effective way to use these new diagnostic modalities in different settings. Currently, prospective trials are underway to further evaluate these biopsy strategies. Dr. Loeb is supported by the Laura and Isaac Perlmutter Cancer Center at NYU, the Louis Feil Charitable Lead Trust, and the National Institutes of Health under Award Number K07CA178258. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Reference 1. Siddiqui MM, Rais-Bahrami S, Truong H, et al. Magnetic resonance imaging/ultrasoundfusion biopsy significantly upgrades prostate cancer versus systematic 12-core transrectal ultrasound biopsy. Eur Urol. 2013;64:713-719. Vol. 17 No. 2 • 2015 • Reviews in Urology • 111 4004170006_RIU0670.indd 111 02/07/15 4:57 PM Prostate Cancer continued Standard and Targeted Biopsy During Follow-up for Active Surveillance Brian Weiss, MD,1 Stacy Loeb, MD2 1 Department of Urology, New York University School of Medicine, New York, NY; 2Departments of Urology and Population Health, New York University School of Medicine, New York, NY [Rev Urol. 2015;17(2):112-113 doi: 10.3909/riu0670a] © 2015 MedReviews®, LLC Many patients diagnosed with prostate cancer have low-risk disease that is unlikely to harm them during their lifetimes. Active surveillance (AS) has emerged as a crucial treatment option for patients with favorable-risk prostate cancer. Although its use continues to expand globally, there remains a lack of consensus on the optimal follow-up strategy.1 Many studies have evaluated predictors of progression during AS in an effort to provide insight into the appropriate timing of repeat prostate biopsy.2 Some AS programs incorporate a confirmatory biopsy because early reclassification often represents sampling error from the initial biopsy.3 A relatively new addition to AS is the use of MRI-targeted biopsy (MRI-TB). Predictors of Pathologic Progression on Biopsy Among Men on Active Surveillance for Localized Prostate Cancer: The Value of the Pattern of Surveillance Biopsies Cary KC, Cowan JE, Sanford M, et al Eur Urol. 2014;66:337-342 This retrospective study examined the patterns of repeat biopsy findings among 465 men from the AS program at the University of California, San Francisco, from 1996 to 2011. Although the strict inclusion criteria for this protocol are a prostate-specific antigen (PSA)  10 ng/mL, clinical stage T1-2, Gleason grade 6, , 33% positive cores, and , 50% tumor in any core, the study also included 31 patients with Gleason  7 disease and 41 with PSA . 10 ng/mL who did not meet the strict criteria but elected AS. Serial biopsy results during surveillance were classified as negative, positive without progression, or progression (increase in Gleason grade and/or biopsy volume beyond the prespecified cutoffs). All initial biopsies were  10 cores, confirmatory biopsies were recommended within 12 months of diagnostic biopsy, and further surveillance biopsies were then performed every 12 to 24 months based on previous biopsy history and imaging results. In the final 2 years of the study, MRI was also performed following the initial diagnosis. Of the confirmatory biopsies performed, 108 (23%) results were negative, 262 (56%) were positive with no progression, and 95 (20%) showed progression. Of the 108 patients with a negative confirmatory biopsy result, 81 underwent a third biopsy, of which 52 (64%) results were negative, 22 (27%) were positive without progression, and 7 (9%) met criteria for progression. By the fourth biopsy, progression was found in only one patient (3%) whose third biopsy result was negative, compared with four (31%) of those with a stably positive third biopsy result. Of the 262 patients with a positive confirmatory biopsy result without progression, 184 underwent a third biopsy. On this biopsy, 33 (18%) had negative results, 111 (60%) had positive results without progression, and 40 (22%) had progression. By the fourth biopsy, only two (9%) patients with a negative third biopsy result progressed, compared with 13 (22%) of those whose third biopsy result was positive without progression. On multivariable logistic regression of 242 men with three or more biopsies and  3 years of follow-up, PSA density (odds ratio [OR] 2.35; 95% confidence interval [CI], 1.31-4.22; P , .01) and negative confirmatory biopsy result (OR 0.28; 95% CI, 0.11-0.70; P , .01) were independently associated with the risk of progression. In a separate multivariable model of 131 patients with four or more biopsies and at least 4 years of follow-up, PSA density (OR 2.55; 95% CI, 1.14-5.72; P 5 .02) and negative confirmatory and third surveillance biopsy result (OR 0.15; 95% CI, 0.03-0.72; P 5 .02) were independently associated with the risk of progression. Limitations of this study include its retrospective design, as well as inclusion of some men who did not meet strict surveillance criteria. Nevertheless, a separate analysis was performed excluding these patients and had similar results. This study confirms numerous previous studies demonstrating the prognostic value of PSA density among men undergoing AS.4 This study also provides novel data on the importance of serial biopsy, possibly allowing for less intense follow-up of men with one or more negative surveillance biopsy results. Targeted Prostate Biopsy to Select Men for Active Surveillance: Do the Epstein Criteria Still Apply? Hu JC, Chang E, Natarajan S, et al J Urol. 2014;192:385-390 This retrospective study enrolled 113 men with prostate cancer from the University of California, Los Angeles 112 • Vol. 17 No. 2 • 2015 • Reviews in Urology 4004170006_RIU0670.indd 112 09/07/15 11:04 AM Prostate Cancer (UCLA) AS program from 2010 to 2013 who met Epstein histologic criteria for low-risk prostate cancer at initial diagnosis (Gleason score  6,  two positive cores and  50% core involvement). Patients underwent 3T multiparametric MRI (mpMRI) using a multichannel external phased array coil. Images were reviewed by an experienced uroradiologist who was blinded to the initial diagnostic biopsy results. Regions of interest were scored from 1 to 5 using the UCLA scoring system, with higher scores indicating more suspicious regions. Men with  grade 2 lesions underwent targeted biopsies (median of 4) with mpMRI-US fusion using the Artemis device (Eigen, Grass Valley, CA), in addition to systematic 12-core prostate biopsy. The primary outcome of this study was reclassification beyond Epstein histologic criteria,5 with patients grouped into mpMRI grade 0-3, 4, and 5 categories. Confirmatory biopsy was performed a median of 10 months (interquartile range 6-19) after prostate cancer diagnosis, with no relationship observed between interbiopsy interval and likelihood of reclassification. The results of confirmatory biopsy were negative in 38 (33.6%), whereas 35 (31.0%) still fulfilled the Epstein criteria and 26 (23%) were reclassified due to upgrading to a Gleason score  7, and 15 (13.3%) were reclassified by volume. Overall, 80.5% of men had an MRI-detectable target lesion, and the likelihood of reclassification increased in men with higher suspicion scores. Specifically, reclassification occurred in 27.0% of men with grade 0-3 lesions, 46.9% with grade 4 lesions, and 100% with grade 5 lesions. Men with mpMRI grade 4-5 lesions had significantly more reclassification than those with grade 2-3 lesions (OR 3.2; 95% CI, 1.4-7.1; P 5 .006). Of note, men with grade 2-3 lesions had a similar risk of reclassification (27%-29%) compared with those with no targets. Finally, in 90 men who underwent both systematic and targeted biopsy, overall concordance for insignificant (Gleason 313 5 6) versus significant prostate cancer (Gleason 314  7) was 50%. Significant cancer was detected in 3 men (3%) on targeted biopsy who had no cancer detected on systematic biopsy, and in 10 (11%) men on systematic biopsy with a negative targeted biopsy result. Limitations of this study include its retrospective design and lack of standardization for the initial prostate biopsy, potentially inflating the number of men with reclassification at rebiopsy due to insufficient initial sampling. Also, this study did not compare confirmatory biopsy with radical prostatectomy specimens, which are the gold standard for pathology. Overall, however, this study demonstrates how targeted biopsy is an important advancement in technology that can further help to appropriately stratify patients for AS. Nevertheless, the fact that systematic biopsy detected significant cancer in 11% of patients without disease on targeted biopsy suggests that we are not yet ready to abandon systematic biopsy in this population. In summary, the use of AS is expanding for men with low-risk prostate cancer. Men with a negative confirmatory biopsy result are at significantly lower risk of subsequent reclassification, whereas those with a Grade 4-5 lesion on MRI are at significantly greater risk. These studies highlight novel strategies to improve risk stratification in this population which may ultimately reduce patient anxiety and help to define the optimal intensity of follow-up during AS. Dr. Loeb is supported by the Laura and Isaac Perlmutter Cancer Center at NYU, the Louis Feil Charitable Lead Trust, and the National Institutes of Health under Award Number K07CA178258. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. References 1. 2. 3. 4. 5. Ganz PA, Barry JM, Burke W, et al. National Institutes of Health State-of-the-Science Conference: role of active surveillance in the management of men with localized prostate cancer. Ann Intern Med. 2012;156:591-595. Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol. 2015;67:619-626. Berglund RK, Masterson TA, Vora KC, et al. Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. J Urol. 2008;180:1964-1967. Tseng KS, Landis P, Epstein JI, et al. Risk stratification of men choosing surveillance for low risk prostate cancer. J Urol. 2010;183:1779-1785. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994;271:368-374. MRI/Ultrasound Fusion Biopsy Versus Standard 12-Core Biopsy Brian Weiss, MD,1 Stacy Loeb, MD2 Department of Urology, New York University School of Medicine, New York, NY; 2Departments of Urology and Population Health, New York University School of Medicine, New York, NY [Rev Urol. 2015;17(2):113-115 doi: 10.3909/riu0670b] 1 © 2015 MedReviews®, LLC Prostate biopsy effectively samples , 1% of the prostate and many men undergo multiple repeat biopsies during their lifetimes.1 Recently, numerous studies have examined the use of multiparametric MRI (mpMRI) of the prostate as a standalone technology as well as targeted biopsies using MRI-US fusion.2 This review summarizes two studies demonstrating the potential that targeted biopsies hold in limiting the diagnosis of insignificant disease while still detecting significant cancer. Vol. 17 No. 2 • 2015 • Reviews in Urology • 113 4004170006_RIU0670.indd 113 02/07/15 4:57 PM Prostate Cancer continued Magnetic Resonance Imaging/ Ultrasound-Fusion Biopsy Significantly Upgrades Prostate Cancer Versus Systematic 12-core Transrectal Ultrasound Biopsy Siddiqui MM, Rais-Bahrami S, Truong H, et al Eur Urol. 2013;64:713-719 There are several ways to perform MRI-guided prostate biopsies, which include direct MRI-guided biopsy, MRI-US fusion, and cognitive coregistration. The current study was designed to assess whether MRI-US fusion results in a more accurate biopsy than standard 12-core transrectal ultrasound (TRUS) biopsy. From 2007 to 2012, 582 patients (including 89 patients on AS and 320 with prior negative biopsy results) were enrolled in a prospective trial at the National Institutes of Health. All men underwent 3T mpMRI prior to prostate biopsy, which were reviewed by two experienced genitourinary radiologists. All participants then underwent a standard 12-core TRUS-guided biopsy (blinded to the MRI results), with the addition of at least two additional cores using MRI-US fusion for each lesion identified on MRI. The mean number of targeted biopsies per patient was 5.7 versus 12 cores with standard biopsy. Positive biopsy results were classified as clinically significant, high grade (Gleason  4 1 3), or clinically insignificant, lowgrade disease (Gleason  3 1 4). Among men with prostate cancer detected on 12-core prostate biopsy, performing the targeted biopsies resulted in Gleason upgrading in 81 (32%) cases. Targeted biopsies resulted in 43 (22%) additional cases of Gleason  3 1 4 prostate cancer and 38 (67%) additional cases of clinically significant prostate cancer. Conversely, compared with targeted biopsy, 12-core biopsy resulted in Gleason score upgrading in 67 (26%) cases. Adding 12-core biopsy to the targeted biopsy resulted in 60 (36%) additional cases of Gleason  3 1 4 prostate cancer and 7 (8%) additional cases of clinically significant prostate cancer. Overall, 17 patients with high-grade disease would have been labeled as cancer free based on standard 12-core biopsy results alone. On multivariable analysis, significant predictors of Gleason score upgrading on targeted prostate biopsy were smaller prostate volume (odds ratio [OR] 0.84; 95% confidence interval [CI], 0.74-0.93; P 5 .005), higher PSA level (OR 1.03; 95% CI, 1.01-1.05; P 5 .004), more lesions on MRI (OR 1.4; 95% CI, 1.2-1.8; P 5 .0005), and higher MRI suspicion score (OR 1.7; 95% CI, 1.02-3.0; P 5 .04). A limitation of the study is that the two biopsy modalities were compared with each other, unlike other studies using template mapping biopsy or radical prostatectomy specimens as the gold standard. In addition, the study population was heterogeneous and a substantial proportion had previous negative prostate biopsy results. Consequently, more data are needed to evaluate the incremental value of this technique among biopsy-naive patients. Finally, men with no visible lesions on MRI were excluded from the study, and all targeting was done using a fusion platform so the generalizability of these results to alternate techniques, such as cognitive fusion, is unknown. Nonetheless, this study adds to increasing evidence that suspicious lesions on multiparametric MRI increase the risk of high-grade disease, and that fusion biopsy can enhance its detection. Comparison of MR/Ultrasound FusionGuided Biopsy With Ultrasound-Guided Biopsy for the Diagnosis of Prostate Cancer Siddiqui MM, Rais-Bahrami S, Turkbey B, et al JAMA. 2015;313:390-397 This article is an extension of the aforementioned study by Siddiqui and colleagues (Eur Urol. 2013;64:713-719). The goal of this study was to assess targeted versus standard biopsy, and the two approaches combined, for the diagnosis of intermediate- to high-risk prostate cancer. Using the previously described imaging and prostate biopsy protocol, 1215 men were prospectively evaluated for study inclusion with 3T mpMRI. After excluding 181 men with no lesions on MRI and 31 with prior treatment for prostate cancer, the analysis ultimately included 1003 men who all underwent both targeted and standard prostate biopsy. Biopsy results were classified as low-risk (Gleason 6, or Gleason 3 1 4 with , 50% cancerous involvement of any core and , 33% of standard biopsy cores positive for cancer). Intermediate-risk disease was defined as higher-volume Gleason 3 1 4 disease, and any Gleason  4 1 3 was considered high risk. Overall, 690 (69%) patients demonstrated concordance between the two biopsy strategies for the presence of low- or high-risk cancer. Although a similar absolute number of cancers were diagnosed by targeted biopsy (461) and standard biopsy (469), targeted biopsy alone diagnosed 30% more high-risk disease compared with standard biopsy (P , .001). Meanwhile, targeted biopsy 114 • Vol. 17 No. 2 • 2015 • Reviews in Urology 4004170006_RIU0670.indd 114 02/07/15 4:57 PM Prostate Cancer alone detected 17% fewer low-risk cancers than standard biopsy (P 5 .002). Combining targeted and standard biopsy led to the diagnosis of 103 (22%) additional cases, but the vast majority (83%) were Gleason 6 or low-volume Gleason 3 1 4, and only 5% were classified as high-risk. The authors estimated that 200 men would need to undergo standard biopsy in addition to targeted biopsy to find one case of high-risk prostate cancer. Meanwhile, 17 extra low-risk cancers would be detected per each additional high-risk cancer diagnosed. Subset analysis was performed in 170 patients who underwent radical prostatectomy to compare biopsy results with whole-gland pathology. This subset included 17 men whose cancer was detected on standard biopsy alone and 20 men whose cancer was found only in the targeted biopsy. Intermediate- to high-risk cancer was found at prostatectomy in 3 (18%) versus 12 (60%) of these men, respectively. Overall, the sensitivity of targetedonly biopsy was 77% compared with 53% for standard biopsy when compared with final prostatectomy pathology. Specificity was similar for both techniques (68% vs 66%). On receiver operating characteristic analysis, targeted biopsy outperformed both standard biopsy (area under the operating curve [AUC] 0.73 vs 0.59; P 5 .005) and the combined technique (AUC 0.73 vs 0.67; P 5 .04). Finally, the authors performed a subgroup analysis of 196 biopsy-naive patients who had similar targeted biopsy risk distribution compared with the repeat biopsy group (P 5 .52). The risk distribution at standard biopsy was higher for biopsy-naive patients, and was not significantly different from targeted biopsy. The addition of standard biopsy to targeted biopsy led to upgrading to intermediate risk in 11 (5.6%) and to high risk in 7 (3.6%) patients. A significant limitation of this study is that the majority of patients had previous biopsies, so additional validation is necessary in a larger population of men without prior biopsy. Similar to their earlier study, patients with no visible lesions on MRI were excluded from the study, so it is not possible to compare the results of biopsy for these patients. Overall, improvements in prostate cancer detection protocols are needed to decrease the detection of clinically insignificant disease while maximizing early detection of potentially life-threatening disease. These studies highlight how targeted fusion biopsies can help reduce the detection of clinically insignificant disease while increasing the efficiency of detection of high-risk prostate cancer. Dr. Loeb is supported by the Laura and Isaac Perlmutter Cancer Center at NYU, the Louis Feil Charitable Lead Trust, and the National Institutes of Health under Award Number K07CA178258. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. References 1. 2. Welch HG, Fisher ES, Gottlieb DJ, Barry MJ. Detection of prostate cancer via biopsy in the Medicare-SEER population during the PSA era. J Natl Cancer Inst. 2007;99:1395-1400. de Rooij M, Hamoen EH, Fütterer JJ, et al. Accuracy of multiparametric MRI for prostate cancer detection: a meta-analysis. AJR Am J Roentgenol. 2014;202:343-351. Vol. 17 No. 2 • 2015 • Reviews in Urology • 115 4004170006_RIU0670.indd 115 02/07/15 4:57 PM