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Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy
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Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy Mark N. Alshak BA , Neal Patel MD , Michael D. Gross BS , Daniel Margolis MD , Jim C. Hu MD MPH PII: DOI: Reference:
S0090-4295(19)30842-8 https://doi.org/10.1016/j.urology.2019.07.049 URL 21788
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Urology
Received date: Revised date: Accepted date:
1 May 2019 15 July 2019 22 July 2019
Please cite this article as: Mark N. Alshak BA , Neal Patel MD , Michael D. Gross BS , Daniel Margolis MD , Jim C. Hu MD MPH , Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy, Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.07.049
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1 Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy Mark N. Alshak BA1, Neal Patel MD2, Michael D. Gross BS2, Daniel Margolis MD3, Jim C. Hu MD MPH2 Authors: 1 Weill Cornell Medical College, New York, NY, USA 2 Department of Urology, Weill Cornell Medicine, New York, NY, USA 3 Department of Radiology, Weill Cornell Medicine, New York, NY, USA Mark Alshak, BA Neal Patel, MD Michael Gross, BS Daniel Margolis, MD Jim C. Hu MD MPH
Corresponding Author: Jim C. Hu, MD MPH Department of Urology Weill Cornell Medical Center 525 East 68th 23 Street, Starr 900 New York, NY, 10065 [email protected] 646-962-9600 Figures: 4 Word Count: 2775 Acknowledgements: The authors have no conflicts of interest.
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2 Objective: To elucidate the accuracy of MRI and MRI-ultrasound fusion guided targeted biopsy (TBx) on risk stratification in men who underwent subsequent radical prostatectomy (RP). Materials and Methods: A single-center, retrospective study was performed in men at risk for prostate cancer who (n=140) underwent TBx and RP between November 2012 and August 2018. Comparisons were made between patients clinically staged by preoperative MRI and TBx Gleason grade group (GGG) and stage after RP. Multivariable regression was performed to identify factors associated with MRI and TBx compared to RP grading, staging, and consistency with National Comprehensive Cancer Network (NCCN) risk stratification. Results: There was an increase in NCCN risk stratification in 47 men (33.6%) and a decrease in 17 men (12.1%) compared to the resected prostate. GGG upgrading and downgrading occurred in 35 (25.0%) and 31 men (22.1%), respectively. Upstaging occurred in 41 men (29.3%). In adjusted analysis for age, BMI, PSA Density (PSAD), median maximal diameter of the regions of interest, and PIRADS, men with PIRADS 4 were less likely to be upgraded (OR 0.26, 95% CI 0.08-0.81, p=0.020) than PIRADS 3. PSAD ≥ 0.15 ng/mL/cc was associated with upstaging (OR 3.92, 95% CI 1.60-9.62, p=0.003). Conclusion: Accurate risk stratification is critical for disease management, mandated by the increasing use of active surveillance, partial gland ablation, and androgen deprivation therapy with radiation therapy for men with unfavorable intermediate and high-risk prostate cancer. This study confirms the need for advances in imaging and biomarker to increase the accuracy of pretreatment staging.
3 Introduction Magnetic resonance imaging-ultrasound targeted fusion biopsy (TBx) improves the detection of clinically significant prostate cancer (Gleason grade group [GGG] 2 or higher), compared to conventional transrectal ultrasound-guided (TRUS) biopsy.1 Furthermore, TRUS biopsy underestimates GGG at radical prostatectomy (RP) in up to 50% of men, which has significant clinical implications for appropriate clinical management.2,3 The increased use of active surveillance4, partial gland ablation, and use of androgen deprivation therapy (ADT) in prostate cancer patients with GGG3 and higher with external beam radiotherapy (XRT), supports the need for accurate risk stratification to avoid under or over-treatment. Prior studies have demonstrated that up to 28% of men who meet criteria for active surveillance and subsequently undergo RP are upgraded,5 however, this was prior to the United States Preventative Task Force Recommendations against routine annual screening and the advent of widespread use of MRI and TBx. The diagnostic shifts in clinical practice have resulted in less prostate cancer screening and cancer stage shifts in prostate cancer presentation. This highlights the need to examine factors that influence the accuracy of contemporary risk stratification.
Beyond candidacy for active surveillance, accurate risk stratification can dramatically impact decisions regarding conventional prostate treatment modalities. The decision to administer concurrent ADT and the duration of ADT, as well as the choice to treat with XRT and the duration of treatment, is reliant on pre-treatment National Comprehensive Cancer Network (NCCN) risk stratification.6 Moreover, the decision to treat with focal
4 therapy versus RP is dependent on accurate pre-treatment risk stratification and the decision of active surveillance for GGG2 and GGG3 remains controversial. 7 Recent level one evidence demonstrating the superiority of combined TBx and TRUS for detecting clinically significant prostate cancer8 and the TBx rapid adoption was the impetus for this retrospective analysis design. This study identified significant parameters driving TBx and RP grade and stage discordance.
Methods
Study Population This HIPPA compliant study was approved by the Weill Cornell Medicine (WCM) Institutional Review Board. Data was collected on men who underwent TBx at our institution between November 2012 and August 2018 (n=847). All men from this cohort who underwent TBx and RP at our institution were identified (n=140). Cancer diagnosed patients underwent robotic-assisted laparoscopic prostatectomy and fellowship trained uro-pathologists analyzed specimens.
MRI Fusion Biopsy The protocol was Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) compliant. The MRIs obtained prior to the release of PI-RADSv2 were re-interpreted by DJAM, a uro-radiologist who has reviewed over 2,000 prostate MRIs, with over 300 being whole-mount pathology specimens. The retrospective reviewing radiologist was blinded to TBx and pathological results. Regions of interest (ROI) were scored according to current PI-RADSv2 guidelines.9 Clinical stage was determined by MRI;
5 abnormal DRE did not contribute to T3 disease. Extracapsular extension (ECE) was defined as capsular irregularity or gross ECE.10 Biopsies were performed using the Artemis (Eigen, Grass Valley, CA). After biopsy of ROI(s), a 12-core systematic biopsy was taken with either the Artemis computer-generated template or freehand using cognitive tracking based on surgeon preference.
Statistical Analysis The primary study outcome focused on differences between MRI and TBx vs. RP specimens in terms of grade, stage, and the change in NCCN risk groups. Multivariable logistic regression was performed to identify factors independently associated with grade and stage discordance. All p-values are two-sided with statistical significance evaluated ≤ 0.05 alpha level. Stata/SE (College Station, Texas) version 13.1 was used for all statistical analysis.
6 Results Demographics and Patient Characteristics Demographic and clinical characteristics are presented in Table 1. Median age was 65.6 (Interquartile range [IQR] 60.3-70.3) years, body mass index (BMI) 26.5 (IQR 25.130.3) kg/m2, and PSAD 0.17 (IQR 0.12-0.28) ng/mL/cc. The median maximal diameter of the ROI was 1.3 (IQR 1.0-1.8) cm. PI-RADS categorization breakdown for the cohort was PI-RADS 3: 22 (15.7%), PI-RADS 4: 74 (52.9%), and PI-RADS 5: 44 (31.4%).
Changes in NCCN risk stratification based on RP pathology Preoperative risk stratification based on NCCN guidelines was determined using MRI and TBx (Table 1). Low risk constituted 13 men (9.3%), favorable intermediate risk 19 men (13.5%), unfavorable intermediate risk 54 men (38.6%), and high risk 54 men (38.6%). Based on RP pathology, 47 men (33.6%) had an increase in NCCN risk stratification. 13 of 13 (100%) with low risk cancer had an increase in risk stratification (1 to high risk due to pathological stage and grade group change, 4 to favorable intermediate risk due to both pathological stage and grade group change, and 8 to favorable intermediate due to pathological stage). 5 of 19 (26.3%) with favorable intermediate risk cancer had an increase (2 to high risk due to pathological stage and 3 to unfavorable intermediate risk due to grade group). Lastly, 29 of 54 (53.7%) with unfavorable intermediate disease increased to high risk (24 due to pathological stage, 4 due to grade group, and 1 due to both pathological stage and grade group).
7 Based on RP pathology, 17 men (12.1%) had a decrease in NCCN risk stratification. 1 of 13 (7.7%) with intermediate favorable risk decreased to low risk based on grade group change. 2 of 54 (3.7%) with intermediate unfavorable risk decreased to intermediate favorable risk, 1 due to both pathological stage and grade group change and 1 due to grade group change. 14 of 54 (25.9%) with high risk had a decrease (1 to intermediate favorable risk due to grade group change, 1 to intermediate favorable risk due to both grade group change and pathological stage, 2 to intermediate unfavorable risk due to grade group change, and 10 to intermediate unfavorable risk due to pathological stage).
Grade and Stage Discordance At RP, 35 men (25.0%) were upgraded and 31 men (22.1%) were downgraded from TBx (Table 2). 9 of 17 men (52.9%) with GGG1 on TBx were upgraded (8 to GGG2 and 1 to GGG3). 10 of 60 men (16.7%) with GGG2 were upgraded to GGG3 and 10 (16.7%) downgraded to GGG1. 8 of 36 men (22.2%) with GGG3 were upgraded (7 to GGG4, 1 to GGG5) and 13 (36.1%) were downgraded (12 to GGG2 and 1 to GGG1). 8 of 16 (50.0%) with GGG4 were upgraded to GGG5 and 5 (31.3%) were downgraded (3 to GGG3 and 2 to GGG2). Lastly, 3 of 10 (30.0%) with GGG5 were downgraded (2 to GGG4 and 1 to GGG3). At RP, 41 men (29.3%) were upstaged, with 31 (76.5%) due to extracapsular extension or 10 (24.4%) due to seminal vesicle invasion that was not observed on preoperative MRI. Upstaging occurred from clinical T2 to 33 (80.5%) with T3a and 8 (19.5%) with T3b.
8 Associations with Upgrading, Upstaging, and Increase in NCCN Risk Stratification In adjusted analysis (Table 3), PI-RADS 4 vs. PI-RADS 3 lesion were associated with upgrading (odds ratio [OR] 0.26, 95% confidence interval [95% CI] 0.08-0.81, p=0.020). Increasing age (OR 1.05, 95% CI 0.98-1.11, p=0.154), increasing BMI (OR 1.01, 95% CI 0.90-1.12, p=0.923), PSAD ≥ 0.15 ng/mL/cc (OR 0.74, 95% CI 0.33-1.64, p=0.453), diameter of ROI (OR 0.71, 95% CI 0.33-1.53, p=0.379), and PI-RADS 5 (OR 0.56, 95% CI 0.14-2.14, p=0.391) were not associated with upgrading.
In adjusted analysis, PSAD ≥ 0.15 ng/mL/cc (OR 3.92, 95% CI 1.60-9.62, p=0.003) was associated with upstaging from preoperative MRI. However, increasing age (OR 1.04, 95% CI 0.98-1.10, p=0.216), increasing BMI (OR 1.04, 95% CI 0.93-1.16, p=0.510), increasing diameter of ROI (OR 1.16, 95% CI 0.59-2.29, p=0.669), and PI-RADS 4 (OR 0.68 95% 0.21-2.28, p=0.535) and PI-RADS 5 (OR 0.83 95% 0.20-3.35, p=0.789) were not associated with upstaging.
In adjusted analysis, age (OR 0.95, 95% CI 0.90-1.01, p=0.125), BMI (OR 1.06, 95% CI 0.94-1.20, p=0.316), PSAD ≥ 0.15 ng/mL/cc (OR 1.52, 95% CI 0.63-3.63, p=0.351), diameter of ROI (OR 1.28, 95% CI 0.57-2.88, p=0.548), PI-RADS 4 (OR 0.735, 95% CI 0.24-2.28, p=0.594), and PI-RADS 5 (OR 0.25, 95% CI 0.06-1.15, p=0.075) were not associated with increase in NCCN risk stratification.
9 Associations with Downgrading and Decrease in NCCN Risk Stratification In adjusted analysis (Table 3), age (OR 1.02, 95% CI 0.96-1.08, p=0.541), BMI (OR 1.02, 95% CI 0.91-1.15, p=0.734), PSAD ≥ 0.15 ng/mL/cc (OR 0.81, 95% CI 0.34-1.78, p=0.453), diameter of ROI (OR 1.91, 95% CI 0.94-3.92, p=0.076), PI-RADS 4 (OR 1.27, 95% CI 0.35-4.55, p=0.715), and PI-RADS 5 (OR 0.52, 95% CI 0.10-2.50, p=0.414) were not associated with downgrading.
In adjusted analysis, age (OR 0.98, 95% CI 0.90-1.06, p=0.589), BMI (OR 0.985, 95% CI 0.83-1.17, p=0.864), PSAD ≥ 0.15 ng/mL/cc (OR 0.90, 95% CI 0.28-2.92, p=0.857), diameter of ROI (OR 0.35, 95% CI 0.086-1.45, p=0.149) were not associated with decrease in NCCN risk stratification.
10 Discussion
Gleason grade group identified on prostate biopsy has important treatment and prognostic implications, as risk stratified treatment decisions such as active surveillance or focal therapy rely heavily on grade, tumor volume, and accurate NCCN risk stratification for selection.6,11,12 However, conventional prostate biopsy frequently undergrades cancer and incorrectly assigns NCCN risk stratification. A meta-analysis of approximately 15,000 men showed Gleason upgrading occurred in 30%-50% of those who underwent subsequent RP.3 Moreover, a single institutional study demonstrated that the addition of TBx as compared to TRUS resulted in higher NCCN risk groups in 38% of cases.13 In this study, we sought to evaluate TBx grade group and preoperative MRI staging compared to RP specimen pathology and evaluate the change in NCCN risk stratification.
Our study has several important findings. First, although TBx and MRI have a clear role in improving the detection of clinically significant prostate cancer and accuracy of NCCN risk stratification in men with an elevated PSA,1,8,13 a significant number in our cohort had a higher grade group (25%) or stage (29.3%) at RP. Additionally, these discordances changed NCCN risk stratification. This is especially important in men opting for radiation therapy as the non-trivial decision to adding ADT is based on pretreatment NCCN risk stratification.14 The current NCCN guidelines also differentiate treatment options within intermediate risk strata, recommending active surveillance for lower volume, favorable risk, grade group 2 disease. In our study, however, 33.6% of
11 men had an increase in NCCN risk stratification on RP, even with the addition of standard systematic biopsy.
Second, our 22.1% rate of downgrading is high compared to published studies. The majority of downgrading was from grade group 3 to 2 (38.7%) and grade group 2 to 1 (32.3%) with the majority of percent 4 found on biopsy being <5% of total tumor volume. The rate of downgrading in TBx has not been well captured. Arora et al. reports in 99 men who underwent TBx a downgrade rate of 6.1%, 15 while Beksac et al. identified 18.5% downgrading in 104 TBx compared to 9.7% downgrading in TRUS biopsies. 16 Considering the rate of downgrading from TRUS prostate biopsy is 11%,17 it seems the rate of downgrading associated with TBx may be significantly higher than TRUS Bx. This downgrading may be due to overcalling Gleason pattern 4 on tangentially sectioned small glands of pattern 3 that mimic poorly formed glands or when a needle biopsy samples a tertiary higher-grade pattern.18 This may also show that MRI is more sensitive for pattern 4 and 5, such that targets are enriched for these patterns compared to the pattern 3 components which may predominate outside of the targeted regions. There were four cases where grade groups were downgraded by 2 levels from TBx to RP (one case from grade group 3 to 1, 2 cases of grade group 4 to 2, and 1 case of grade group 5 to 3). This could, in part, be not only due to artifact on biopsy but may also reflect that RP pathology is an imperfect characterization of the organ since slices are spaced 3-5mm apart and could miss cancer.
12 Third, PSAD was significantly associated with upstaging from MRI to RP. In our study, we show that PSAD greater than 0.15 ng/mL/cc is associated with higher risk of adverse pathological stage, not captured on MRI. Prior studies have shown that MRI has a high specificity for the detection ECE and SVI, however the sensitivity is much lower.19 In our series approximately 27% of MRIs did not have evidence of ECE or SVI, which was seen on RP pathology. Pathological stage carries important prognostic value and the ability to accurately determine the presence of ECE or SVI can be valuable in guiding treatment decisions for newly diagnosed prostate cancer. 20 This provides further evidence that the additional clinical characteristics in combination with MRI and TBx may be necessary for accurate pre-treatment staging, especially because MRI technique, which complies with PI-RADS v2, is optimized for target detection and not staging.
Le et al. similarly assessed whole mount pathology in patients undergoing RP after TBx at their institution. In 54 patients (40% of whom were previously on active surveillance), the investigators found 17% of men were upgraded and 2% downgraded. 21 Their downgrade rate differs significantly from our series. While the discordance rate was much higher in our cohort, it highlights variation that may be due to patient selection. Although TBx has the potential to decrease the discordance rate between biopsy and RP, the learning curve for training a center to become proficient in TBx is likely more prolonged than published opinion.22 Furthermore, Ozkan et al. looked at the interobserver variability in Gleason histological grading of prostate cancer and found there to be only a 51.7% concordance between two pathologists. 23 Considering multiple
13 pathologists may be involved, grade discordance may be due to this interobserver variability rather than true differences in Gleason score.
Another potential mechanism for grade discordance may be related to the heterogeneous nature of lesions seen on MRI. In men with a PI-RADS 5 lesion, 12/38 (31.6%) were upgraded. Of these 12 patients, 2 (16.7%) were from Gleason grade group 1 to 2. PI-RADS 5 lesions have a strong correlation with the presence of clinically significant disease,24 however they typically represent larger, heterogeneous lesions. 25 This may potentially lead to under sampling if the lesion is biopsied with two cores. In a study evaluating men who underwent TBx, Mesko et al. demonstrated that intratarget heterogeneity (defined as a difference of Gleason grade between 2 cores within a single target) was present in over half the MRI defined ROI. 26 Recently, it has been shown that in men with high risk ROI, performing a saturation biopsy of the ROI can decrease the rate and risk of Gleason grade upgrading at RP. 27 Thus, in men with heterogeneous ROI found on pre-biopsy MRI, more than 2 cores of the ROI should be considered to improve cancer assessment. Lastly, the detection of clinically significant cancer using MRI is limited by the amount of cancer present. 28 Given the multifocal nature of the disease, there is potential of small aggressive foci to go undetected by TBx, which are later detected at RP.29
These findings highlight the need for additional biomarkers to help improve pretreatment prostate cancer risk stratification. Supplementary Figure 1 provides an overview of the clinical variables relevant to the screening, risk stratification, and staging
14 of prostate cancer. Salamsi et al. recently showed that a higher 17-gene Oncotype DX Genomic prostate score is associated with finding adverse pathology in men undergoing RP.30 Thus, in men who are considering partial gland ablation, radiation therapy, or active surveillance, TBx in combination with biomarkers for favorable intermediate risk disease may aid risk stratification for treatment selection beyond exclusion of active surveillance.
Our study must be interpreted within the context of the study design. Larger, multicenter cohort studies are still necessary to fully evaluate TBx relative to conventional TRUS, particularly as there is greater time and effort involved with TBx, but similar current reimbursement from payers. Additionally, these patients represent a small cohort of the total number that present for TBx, so the prevalence of disease is skewed in this population. Moreover, differences in patient selection between series may significantly affect the rates of discordance between TBx and RP. The quick evolution of the diagnostic technology within this realm is reflective in our cohort as the early patients required their MRIs to be re-categorized due to the use of old standardized reporting systems. Lastly, our series included patients from several different urologists as opposed to single surgeon. There is a clear learning curve to TBx that needs to be better defined. As our center’s TBx volume increases, we expect an improvement in concordance. Conclusion Accurate Gleason grading and staging with prostate biopsy and MRI remains a challenge. A large portion of men undergoing TBx have grade discordance with RP
15 pathological assessment resulting in a change in NCCN risk stratification. These finding have important implications, as men not undergoing RP may not have a true assessment of their disease burden with biopsy alone. The improving utility of prostate biomarkers will hopefully bridge this gap in the future.
References
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16 12. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997; 277(18): 1445-51. 13. Mesko S, Marks L, Ragab O, et al. Targeted prostate biopsy Glaeson score heterogeneity and implications for risk stratification. Am J Clin Oncol. 2016; 41(5):297501. 14. Keane FK, Chen MH, Zhang D, et al. The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease. Cancer 2014; 120(12): 1787-93. 15. Arora H, Elshafei A, Nyame Y, et al. MP38-12. Propensity Score Analysis of Pathological Outcome at Radical Prostatectomy For Magnetic Resonance ImagingTransrectal Ultrasound Fusion Prostate Biopsy Versus Untargeted Extended Transrectal Ultrasound Guided Prostate Biopsy. The Journal of Urology 2017; 197(4), e488 - e489. 16. Beksac, AT, Cumarasamy S, Gupta A, et al. MRI Fusion Biopsy is Associated with a Higher Rate of Pathologic Downgrading at Radical Prostatectomy [abstract]. In: 18 th Annual Meeting of the Society of Urologic Oncology; 2017 Nov 20-Dec 1; Washington, DC. SUO. Poster nr 186. 17. The SEARCH Database Study Group, Freedland SJ, Kane CJ, et al. Upgrading and Downgrading of Prostate Needle Biopsies: Risk Factors and Clinical Implications. Urology. 2007; 69(3): 495-499. 18. Epstein JI, Feng Z, Trock BJ, et al. Upgrading and Downgrading of Prostate Cancer from Biopsy to Radical Prostatectomy: Incidence and Predictive Factors Using the Modified Gleason Grading System and Factoring in Tertiary Grades. European urology 2012; 61(5):1019-1024. 19. de Rooij M, Hamoen EH, Witjes JA, Barentsz JO, Rovers MM. Accuracy of Magnetic Resonance Imaging for Local Staging of Prostate Cancer: A Diagnostic Metaanalysis. Eur Urol 2016; 70(2): 233-45. 20. Eggener SE, Scardino PT, Walsh PC, et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185(3): 869-75. 21. Le JD, Stephenson S, Brugger M, et al. Magnetic resonance imaging-ultrasound fusion biopsy for prediction of final prostate pathology. J Urol 2014; 192(5): 1367-73. 22. Nassiri N, Natarajan S, Margolis DJ, Marks LS. Targeted Prostate Biopsy: Lessons Learned Midst the Evolution of a Disruptive Technology. Urology 2015; 86(3): 432-8. 23. Ozkan TA, Eruyar AT, Cebeci OO, et al. Interobserver variability in Gleason histological grading of prostate cancer, Scandinavian Journal of Urology 2016; 50(6), 420-424. 24. Cash H, Maxeiner A, Stephan C, 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 J Urol 2016; 34(4): 525-32. 25. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging Reporting and Data System: 2015, Version 2. Eur Urol 2016; 69(1): 16-40. 26. Mesko S, Marks L, Ragab O, et al. Targeted Prostate Biopsy Gleason Score Heterogeneity and Implications for Risk Stratification. Am J Clin Oncol 2016.
17 27. Brian P. Calio AS, Dordaneh Sugano , Sonia Gaur , Mahir Maruf ,, Amit L. Jain MJM, Peter L. Choyke , Bradford J. Wood , Peter A., Pinto BT. Risk of upgrading from prostate biopsy to radical prostatectomy pathology: Does Saturation Biopsy of Index Lesion during mpMRI-TRUS fusion biopsy help? Journal of Urology 2018; In press 28. Le JD, Tan N, Shkolyar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol 2015; 67(3): 569-76. 29. Filson CP, Natarajan S, Margolis DJ, et al. Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies. Cancer 2016; 122(6): 884-92. 30. Salmasi A, Said J, Shindel AW, et al. A 17-gene Genomic Prostate Score assay provides independent information on adverse pathology in the setting of combined mpMRI fusion-targeted and systematic prostate biopsy. J Urol 2018.
Supplementary Figure 1 Legend: PSA = prostate specific antigen; DRE = digital rectal exam; PHI = prostate health index; PI-RADS = prostate imaging reporting & data system; TRUS Bx = transrectal ultrasound guided prostate biopsy; MRI Tbx = Magnetic resonance imaging-ultrasound targeted fusion biopsy; PCA3 = prostate cancer antigen 3; PSMA = prostate specific membrane antigen
18 Table 1: Baseline characteristics of men undergoing TBx and RP
n=140 Clinical Characteristics Age, median (IQR) BMI, median (IQR) PSA, median (IQR) Prostate volume, median (IQR) PSAD, median (IQR) MRI Characteristics Maximal Diameter of ROI, median (IQR) PI-RADS
65.6 (60.3-70.3) years 26.5 (25.1-30.3) kg/m2 5.95 (4.6-10.1) ng/mL 36.7 (30.0-47.3) cc 0.17 (0.12-0.28) ng/mL/cc
1.3 (1.0-1.8) cm 3 4 5
22 (15.7%) 74 (52.9%) 44 (31.4%)
Low Favorable intermediate Unfavorable intermediate High
13 (9.3%) 19 (13.5%) 54 (38.6%) 54 (38.6%)
NCCN Risk Stratification
19 Table 2: Fusion biopsy Gleason grade group compared to radical prostatectomy Gleason grade group
TBx Gleason Grade Group 1 2 3 4 5
RP Gleason Grade Group 1 2 3 4 8 10 1
8 40 12 2
1 10 16 3 1
7 3 2
5
1 8 7
20 Table 3: Multivariable regression assessing independent clinical characteristics associated with Gleason grade upgrading, upstaging, increase in NCCN risk stratification, decrease in NCCN risk stratification, and downgrading at RP Upgrade
Age BMI PSAD* Diameter of Index Lesion PI-RADS** 4 5
Upstage OR
95% CI
0.98-1.11 0.90-1.12 0.33-1.64 0.33-1.53
pvalue 0.154 0.923 0.453 0.379
1.04 1.04 3.92 1.16
0.98-1.10 0.93-1.16 1.60-9.62 0.59-2.29
pvalue 0.216 0.510 0.003 0.669
0.08-0.81 0.14-2.14
0.020 0.391
0.68 0.83
0.21-2.28 0.20-3.35
0.535 0.789
OR
95% CI
1.05 1.01 0.74 0.71 0.26 0.56
Increase in NCCN risk stratification
Age BMI PSAD* Diameter of Index Lesion PI-RADS** 4 5
Decrease in NCCN risk stratification
OR
95% CI
p-value
OR
95% CI
p-value
0.95 1.06 1.52
0.90-1.01 0.94-1.20 0.63-3.63
0.125 0.316 0.351
0.98 0.96 0.90
0.90-1.06 0.83-1.17 0.28-2.92
0.589 0.864 0.857
1.28
0.57-2.88
0.548
0.35
0.086-1.45
0.149
0.76 0.25
0.24-2.28 0.06-1.15
0.594 0.075 Downgrade
Age BMI PSAD* Diameter of Index Lesion PI-RADS** 4 5 *PSAD: <0.15 referent ** PI-RADS 3 referent
OR
95% CI
1.02 1.02 0.81 1.91
0.96-1.08 0.91-1.15 0.34-1.87 0.94-3.92
pvalue 0.541 0.734 0.615 0.076
1.27 0.52
0.35-4.55 0.10-2.50
0.715 0.414
21
Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy Mark N. Alshak BA , Neal Patel MD , Michael D. Gross BS , Daniel Margolis MD , Jim C. Hu MD MPH PII: DOI: Reference:
S0090-4295(19)30842-8 https://doi.org/10.1016/j.urology.2019.07.049 URL 21788
To appear in:
Urology
Received date: Revised date: Accepted date:
1 May 2019 15 July 2019 22 July 2019
Please cite this article as: Mark N. Alshak BA , Neal Patel MD , Michael D. Gross BS , Daniel Margolis MD , Jim C. Hu MD MPH , Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy, Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.07.049
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1 Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy Mark N. Alshak BA1, Neal Patel MD2, Michael D. Gross BS2, Daniel Margolis MD3, Jim C. Hu MD MPH2 Authors: 1 Weill Cornell Medical College, New York, NY, USA 2 Department of Urology, Weill Cornell Medicine, New York, NY, USA 3 Department of Radiology, Weill Cornell Medicine, New York, NY, USA Mark Alshak, BA Neal Patel, MD Michael Gross, BS Daniel Margolis, MD Jim C. Hu MD MPH
Corresponding Author: Jim C. Hu, MD MPH Department of Urology Weill Cornell Medical Center 525 East 68th 23 Street, Starr 900 New York, NY, 10065 [email protected] 646-962-9600 Figures: 4 Word Count: 2775 Acknowledgements: The authors have no conflicts of interest.
[email protected] [email protected] [email protected] [email protected] [email protected]
2 Objective: To elucidate the accuracy of MRI and MRI-ultrasound fusion guided targeted biopsy (TBx) on risk stratification in men who underwent subsequent radical prostatectomy (RP). Materials and Methods: A single-center, retrospective study was performed in men at risk for prostate cancer who (n=140) underwent TBx and RP between November 2012 and August 2018. Comparisons were made between patients clinically staged by preoperative MRI and TBx Gleason grade group (GGG) and stage after RP. Multivariable regression was performed to identify factors associated with MRI and TBx compared to RP grading, staging, and consistency with National Comprehensive Cancer Network (NCCN) risk stratification. Results: There was an increase in NCCN risk stratification in 47 men (33.6%) and a decrease in 17 men (12.1%) compared to the resected prostate. GGG upgrading and downgrading occurred in 35 (25.0%) and 31 men (22.1%), respectively. Upstaging occurred in 41 men (29.3%). In adjusted analysis for age, BMI, PSA Density (PSAD), median maximal diameter of the regions of interest, and PIRADS, men with PIRADS 4 were less likely to be upgraded (OR 0.26, 95% CI 0.08-0.81, p=0.020) than PIRADS 3. PSAD ≥ 0.15 ng/mL/cc was associated with upstaging (OR 3.92, 95% CI 1.60-9.62, p=0.003). Conclusion: Accurate risk stratification is critical for disease management, mandated by the increasing use of active surveillance, partial gland ablation, and androgen deprivation therapy with radiation therapy for men with unfavorable intermediate and high-risk prostate cancer. This study confirms the need for advances in imaging and biomarker to increase the accuracy of pretreatment staging.
3 Introduction Magnetic resonance imaging-ultrasound targeted fusion biopsy (TBx) improves the detection of clinically significant prostate cancer (Gleason grade group [GGG] 2 or higher), compared to conventional transrectal ultrasound-guided (TRUS) biopsy.1 Furthermore, TRUS biopsy underestimates GGG at radical prostatectomy (RP) in up to 50% of men, which has significant clinical implications for appropriate clinical management.2,3 The increased use of active surveillance4, partial gland ablation, and use of androgen deprivation therapy (ADT) in prostate cancer patients with GGG3 and higher with external beam radiotherapy (XRT), supports the need for accurate risk stratification to avoid under or over-treatment. Prior studies have demonstrated that up to 28% of men who meet criteria for active surveillance and subsequently undergo RP are upgraded,5 however, this was prior to the United States Preventative Task Force Recommendations against routine annual screening and the advent of widespread use of MRI and TBx. The diagnostic shifts in clinical practice have resulted in less prostate cancer screening and cancer stage shifts in prostate cancer presentation. This highlights the need to examine factors that influence the accuracy of contemporary risk stratification.
Beyond candidacy for active surveillance, accurate risk stratification can dramatically impact decisions regarding conventional prostate treatment modalities. The decision to administer concurrent ADT and the duration of ADT, as well as the choice to treat with XRT and the duration of treatment, is reliant on pre-treatment National Comprehensive Cancer Network (NCCN) risk stratification.6 Moreover, the decision to treat with focal
4 therapy versus RP is dependent on accurate pre-treatment risk stratification and the decision of active surveillance for GGG2 and GGG3 remains controversial. 7 Recent level one evidence demonstrating the superiority of combined TBx and TRUS for detecting clinically significant prostate cancer8 and the TBx rapid adoption was the impetus for this retrospective analysis design. This study identified significant parameters driving TBx and RP grade and stage discordance.
Methods
Study Population This HIPPA compliant study was approved by the Weill Cornell Medicine (WCM) Institutional Review Board. Data was collected on men who underwent TBx at our institution between November 2012 and August 2018 (n=847). All men from this cohort who underwent TBx and RP at our institution were identified (n=140). Cancer diagnosed patients underwent robotic-assisted laparoscopic prostatectomy and fellowship trained uro-pathologists analyzed specimens.
MRI Fusion Biopsy The protocol was Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) compliant. The MRIs obtained prior to the release of PI-RADSv2 were re-interpreted by DJAM, a uro-radiologist who has reviewed over 2,000 prostate MRIs, with over 300 being whole-mount pathology specimens. The retrospective reviewing radiologist was blinded to TBx and pathological results. Regions of interest (ROI) were scored according to current PI-RADSv2 guidelines.9 Clinical stage was determined by MRI;
5 abnormal DRE did not contribute to T3 disease. Extracapsular extension (ECE) was defined as capsular irregularity or gross ECE.10 Biopsies were performed using the Artemis (Eigen, Grass Valley, CA). After biopsy of ROI(s), a 12-core systematic biopsy was taken with either the Artemis computer-generated template or freehand using cognitive tracking based on surgeon preference.
Statistical Analysis The primary study outcome focused on differences between MRI and TBx vs. RP specimens in terms of grade, stage, and the change in NCCN risk groups. Multivariable logistic regression was performed to identify factors independently associated with grade and stage discordance. All p-values are two-sided with statistical significance evaluated ≤ 0.05 alpha level. Stata/SE (College Station, Texas) version 13.1 was used for all statistical analysis.
6 Results Demographics and Patient Characteristics Demographic and clinical characteristics are presented in Table 1. Median age was 65.6 (Interquartile range [IQR] 60.3-70.3) years, body mass index (BMI) 26.5 (IQR 25.130.3) kg/m2, and PSAD 0.17 (IQR 0.12-0.28) ng/mL/cc. The median maximal diameter of the ROI was 1.3 (IQR 1.0-1.8) cm. PI-RADS categorization breakdown for the cohort was PI-RADS 3: 22 (15.7%), PI-RADS 4: 74 (52.9%), and PI-RADS 5: 44 (31.4%).
Changes in NCCN risk stratification based on RP pathology Preoperative risk stratification based on NCCN guidelines was determined using MRI and TBx (Table 1). Low risk constituted 13 men (9.3%), favorable intermediate risk 19 men (13.5%), unfavorable intermediate risk 54 men (38.6%), and high risk 54 men (38.6%). Based on RP pathology, 47 men (33.6%) had an increase in NCCN risk stratification. 13 of 13 (100%) with low risk cancer had an increase in risk stratification (1 to high risk due to pathological stage and grade group change, 4 to favorable intermediate risk due to both pathological stage and grade group change, and 8 to favorable intermediate due to pathological stage). 5 of 19 (26.3%) with favorable intermediate risk cancer had an increase (2 to high risk due to pathological stage and 3 to unfavorable intermediate risk due to grade group). Lastly, 29 of 54 (53.7%) with unfavorable intermediate disease increased to high risk (24 due to pathological stage, 4 due to grade group, and 1 due to both pathological stage and grade group).
7 Based on RP pathology, 17 men (12.1%) had a decrease in NCCN risk stratification. 1 of 13 (7.7%) with intermediate favorable risk decreased to low risk based on grade group change. 2 of 54 (3.7%) with intermediate unfavorable risk decreased to intermediate favorable risk, 1 due to both pathological stage and grade group change and 1 due to grade group change. 14 of 54 (25.9%) with high risk had a decrease (1 to intermediate favorable risk due to grade group change, 1 to intermediate favorable risk due to both grade group change and pathological stage, 2 to intermediate unfavorable risk due to grade group change, and 10 to intermediate unfavorable risk due to pathological stage).
Grade and Stage Discordance At RP, 35 men (25.0%) were upgraded and 31 men (22.1%) were downgraded from TBx (Table 2). 9 of 17 men (52.9%) with GGG1 on TBx were upgraded (8 to GGG2 and 1 to GGG3). 10 of 60 men (16.7%) with GGG2 were upgraded to GGG3 and 10 (16.7%) downgraded to GGG1. 8 of 36 men (22.2%) with GGG3 were upgraded (7 to GGG4, 1 to GGG5) and 13 (36.1%) were downgraded (12 to GGG2 and 1 to GGG1). 8 of 16 (50.0%) with GGG4 were upgraded to GGG5 and 5 (31.3%) were downgraded (3 to GGG3 and 2 to GGG2). Lastly, 3 of 10 (30.0%) with GGG5 were downgraded (2 to GGG4 and 1 to GGG3). At RP, 41 men (29.3%) were upstaged, with 31 (76.5%) due to extracapsular extension or 10 (24.4%) due to seminal vesicle invasion that was not observed on preoperative MRI. Upstaging occurred from clinical T2 to 33 (80.5%) with T3a and 8 (19.5%) with T3b.
8 Associations with Upgrading, Upstaging, and Increase in NCCN Risk Stratification In adjusted analysis (Table 3), PI-RADS 4 vs. PI-RADS 3 lesion were associated with upgrading (odds ratio [OR] 0.26, 95% confidence interval [95% CI] 0.08-0.81, p=0.020). Increasing age (OR 1.05, 95% CI 0.98-1.11, p=0.154), increasing BMI (OR 1.01, 95% CI 0.90-1.12, p=0.923), PSAD ≥ 0.15 ng/mL/cc (OR 0.74, 95% CI 0.33-1.64, p=0.453), diameter of ROI (OR 0.71, 95% CI 0.33-1.53, p=0.379), and PI-RADS 5 (OR 0.56, 95% CI 0.14-2.14, p=0.391) were not associated with upgrading.
In adjusted analysis, PSAD ≥ 0.15 ng/mL/cc (OR 3.92, 95% CI 1.60-9.62, p=0.003) was associated with upstaging from preoperative MRI. However, increasing age (OR 1.04, 95% CI 0.98-1.10, p=0.216), increasing BMI (OR 1.04, 95% CI 0.93-1.16, p=0.510), increasing diameter of ROI (OR 1.16, 95% CI 0.59-2.29, p=0.669), and PI-RADS 4 (OR 0.68 95% 0.21-2.28, p=0.535) and PI-RADS 5 (OR 0.83 95% 0.20-3.35, p=0.789) were not associated with upstaging.
In adjusted analysis, age (OR 0.95, 95% CI 0.90-1.01, p=0.125), BMI (OR 1.06, 95% CI 0.94-1.20, p=0.316), PSAD ≥ 0.15 ng/mL/cc (OR 1.52, 95% CI 0.63-3.63, p=0.351), diameter of ROI (OR 1.28, 95% CI 0.57-2.88, p=0.548), PI-RADS 4 (OR 0.735, 95% CI 0.24-2.28, p=0.594), and PI-RADS 5 (OR 0.25, 95% CI 0.06-1.15, p=0.075) were not associated with increase in NCCN risk stratification.
9 Associations with Downgrading and Decrease in NCCN Risk Stratification In adjusted analysis (Table 3), age (OR 1.02, 95% CI 0.96-1.08, p=0.541), BMI (OR 1.02, 95% CI 0.91-1.15, p=0.734), PSAD ≥ 0.15 ng/mL/cc (OR 0.81, 95% CI 0.34-1.78, p=0.453), diameter of ROI (OR 1.91, 95% CI 0.94-3.92, p=0.076), PI-RADS 4 (OR 1.27, 95% CI 0.35-4.55, p=0.715), and PI-RADS 5 (OR 0.52, 95% CI 0.10-2.50, p=0.414) were not associated with downgrading.
In adjusted analysis, age (OR 0.98, 95% CI 0.90-1.06, p=0.589), BMI (OR 0.985, 95% CI 0.83-1.17, p=0.864), PSAD ≥ 0.15 ng/mL/cc (OR 0.90, 95% CI 0.28-2.92, p=0.857), diameter of ROI (OR 0.35, 95% CI 0.086-1.45, p=0.149) were not associated with decrease in NCCN risk stratification.
10 Discussion
Gleason grade group identified on prostate biopsy has important treatment and prognostic implications, as risk stratified treatment decisions such as active surveillance or focal therapy rely heavily on grade, tumor volume, and accurate NCCN risk stratification for selection.6,11,12 However, conventional prostate biopsy frequently undergrades cancer and incorrectly assigns NCCN risk stratification. A meta-analysis of approximately 15,000 men showed Gleason upgrading occurred in 30%-50% of those who underwent subsequent RP.3 Moreover, a single institutional study demonstrated that the addition of TBx as compared to TRUS resulted in higher NCCN risk groups in 38% of cases.13 In this study, we sought to evaluate TBx grade group and preoperative MRI staging compared to RP specimen pathology and evaluate the change in NCCN risk stratification.
Our study has several important findings. First, although TBx and MRI have a clear role in improving the detection of clinically significant prostate cancer and accuracy of NCCN risk stratification in men with an elevated PSA,1,8,13 a significant number in our cohort had a higher grade group (25%) or stage (29.3%) at RP. Additionally, these discordances changed NCCN risk stratification. This is especially important in men opting for radiation therapy as the non-trivial decision to adding ADT is based on pretreatment NCCN risk stratification.14 The current NCCN guidelines also differentiate treatment options within intermediate risk strata, recommending active surveillance for lower volume, favorable risk, grade group 2 disease. In our study, however, 33.6% of
11 men had an increase in NCCN risk stratification on RP, even with the addition of standard systematic biopsy.
Second, our 22.1% rate of downgrading is high compared to published studies. The majority of downgrading was from grade group 3 to 2 (38.7%) and grade group 2 to 1 (32.3%) with the majority of percent 4 found on biopsy being <5% of total tumor volume. The rate of downgrading in TBx has not been well captured. Arora et al. reports in 99 men who underwent TBx a downgrade rate of 6.1%, 15 while Beksac et al. identified 18.5% downgrading in 104 TBx compared to 9.7% downgrading in TRUS biopsies. 16 Considering the rate of downgrading from TRUS prostate biopsy is 11%,17 it seems the rate of downgrading associated with TBx may be significantly higher than TRUS Bx. This downgrading may be due to overcalling Gleason pattern 4 on tangentially sectioned small glands of pattern 3 that mimic poorly formed glands or when a needle biopsy samples a tertiary higher-grade pattern.18 This may also show that MRI is more sensitive for pattern 4 and 5, such that targets are enriched for these patterns compared to the pattern 3 components which may predominate outside of the targeted regions. There were four cases where grade groups were downgraded by 2 levels from TBx to RP (one case from grade group 3 to 1, 2 cases of grade group 4 to 2, and 1 case of grade group 5 to 3). This could, in part, be not only due to artifact on biopsy but may also reflect that RP pathology is an imperfect characterization of the organ since slices are spaced 3-5mm apart and could miss cancer.
12 Third, PSAD was significantly associated with upstaging from MRI to RP. In our study, we show that PSAD greater than 0.15 ng/mL/cc is associated with higher risk of adverse pathological stage, not captured on MRI. Prior studies have shown that MRI has a high specificity for the detection ECE and SVI, however the sensitivity is much lower.19 In our series approximately 27% of MRIs did not have evidence of ECE or SVI, which was seen on RP pathology. Pathological stage carries important prognostic value and the ability to accurately determine the presence of ECE or SVI can be valuable in guiding treatment decisions for newly diagnosed prostate cancer. 20 This provides further evidence that the additional clinical characteristics in combination with MRI and TBx may be necessary for accurate pre-treatment staging, especially because MRI technique, which complies with PI-RADS v2, is optimized for target detection and not staging.
Le et al. similarly assessed whole mount pathology in patients undergoing RP after TBx at their institution. In 54 patients (40% of whom were previously on active surveillance), the investigators found 17% of men were upgraded and 2% downgraded. 21 Their downgrade rate differs significantly from our series. While the discordance rate was much higher in our cohort, it highlights variation that may be due to patient selection. Although TBx has the potential to decrease the discordance rate between biopsy and RP, the learning curve for training a center to become proficient in TBx is likely more prolonged than published opinion.22 Furthermore, Ozkan et al. looked at the interobserver variability in Gleason histological grading of prostate cancer and found there to be only a 51.7% concordance between two pathologists. 23 Considering multiple
13 pathologists may be involved, grade discordance may be due to this interobserver variability rather than true differences in Gleason score.
Another potential mechanism for grade discordance may be related to the heterogeneous nature of lesions seen on MRI. In men with a PI-RADS 5 lesion, 12/38 (31.6%) were upgraded. Of these 12 patients, 2 (16.7%) were from Gleason grade group 1 to 2. PI-RADS 5 lesions have a strong correlation with the presence of clinically significant disease,24 however they typically represent larger, heterogeneous lesions. 25 This may potentially lead to under sampling if the lesion is biopsied with two cores. In a study evaluating men who underwent TBx, Mesko et al. demonstrated that intratarget heterogeneity (defined as a difference of Gleason grade between 2 cores within a single target) was present in over half the MRI defined ROI. 26 Recently, it has been shown that in men with high risk ROI, performing a saturation biopsy of the ROI can decrease the rate and risk of Gleason grade upgrading at RP. 27 Thus, in men with heterogeneous ROI found on pre-biopsy MRI, more than 2 cores of the ROI should be considered to improve cancer assessment. Lastly, the detection of clinically significant cancer using MRI is limited by the amount of cancer present. 28 Given the multifocal nature of the disease, there is potential of small aggressive foci to go undetected by TBx, which are later detected at RP.29
These findings highlight the need for additional biomarkers to help improve pretreatment prostate cancer risk stratification. Supplementary Figure 1 provides an overview of the clinical variables relevant to the screening, risk stratification, and staging
14 of prostate cancer. Salamsi et al. recently showed that a higher 17-gene Oncotype DX Genomic prostate score is associated with finding adverse pathology in men undergoing RP.30 Thus, in men who are considering partial gland ablation, radiation therapy, or active surveillance, TBx in combination with biomarkers for favorable intermediate risk disease may aid risk stratification for treatment selection beyond exclusion of active surveillance.
Our study must be interpreted within the context of the study design. Larger, multicenter cohort studies are still necessary to fully evaluate TBx relative to conventional TRUS, particularly as there is greater time and effort involved with TBx, but similar current reimbursement from payers. Additionally, these patients represent a small cohort of the total number that present for TBx, so the prevalence of disease is skewed in this population. Moreover, differences in patient selection between series may significantly affect the rates of discordance between TBx and RP. The quick evolution of the diagnostic technology within this realm is reflective in our cohort as the early patients required their MRIs to be re-categorized due to the use of old standardized reporting systems. Lastly, our series included patients from several different urologists as opposed to single surgeon. There is a clear learning curve to TBx that needs to be better defined. As our center’s TBx volume increases, we expect an improvement in concordance. Conclusion Accurate Gleason grading and staging with prostate biopsy and MRI remains a challenge. A large portion of men undergoing TBx have grade discordance with RP
15 pathological assessment resulting in a change in NCCN risk stratification. These finding have important implications, as men not undergoing RP may not have a true assessment of their disease burden with biopsy alone. The improving utility of prostate biomarkers will hopefully bridge this gap in the future.
References
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16 12. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997; 277(18): 1445-51. 13. Mesko S, Marks L, Ragab O, et al. Targeted prostate biopsy Glaeson score heterogeneity and implications for risk stratification. Am J Clin Oncol. 2016; 41(5):297501. 14. Keane FK, Chen MH, Zhang D, et al. The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease. Cancer 2014; 120(12): 1787-93. 15. Arora H, Elshafei A, Nyame Y, et al. MP38-12. Propensity Score Analysis of Pathological Outcome at Radical Prostatectomy For Magnetic Resonance ImagingTransrectal Ultrasound Fusion Prostate Biopsy Versus Untargeted Extended Transrectal Ultrasound Guided Prostate Biopsy. The Journal of Urology 2017; 197(4), e488 - e489. 16. Beksac, AT, Cumarasamy S, Gupta A, et al. MRI Fusion Biopsy is Associated with a Higher Rate of Pathologic Downgrading at Radical Prostatectomy [abstract]. In: 18 th Annual Meeting of the Society of Urologic Oncology; 2017 Nov 20-Dec 1; Washington, DC. SUO. Poster nr 186. 17. The SEARCH Database Study Group, Freedland SJ, Kane CJ, et al. Upgrading and Downgrading of Prostate Needle Biopsies: Risk Factors and Clinical Implications. Urology. 2007; 69(3): 495-499. 18. Epstein JI, Feng Z, Trock BJ, et al. Upgrading and Downgrading of Prostate Cancer from Biopsy to Radical Prostatectomy: Incidence and Predictive Factors Using the Modified Gleason Grading System and Factoring in Tertiary Grades. European urology 2012; 61(5):1019-1024. 19. de Rooij M, Hamoen EH, Witjes JA, Barentsz JO, Rovers MM. Accuracy of Magnetic Resonance Imaging for Local Staging of Prostate Cancer: A Diagnostic Metaanalysis. Eur Urol 2016; 70(2): 233-45. 20. Eggener SE, Scardino PT, Walsh PC, et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol 2011; 185(3): 869-75. 21. Le JD, Stephenson S, Brugger M, et al. Magnetic resonance imaging-ultrasound fusion biopsy for prediction of final prostate pathology. J Urol 2014; 192(5): 1367-73. 22. Nassiri N, Natarajan S, Margolis DJ, Marks LS. Targeted Prostate Biopsy: Lessons Learned Midst the Evolution of a Disruptive Technology. Urology 2015; 86(3): 432-8. 23. Ozkan TA, Eruyar AT, Cebeci OO, et al. Interobserver variability in Gleason histological grading of prostate cancer, Scandinavian Journal of Urology 2016; 50(6), 420-424. 24. Cash H, Maxeiner A, Stephan C, 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 J Urol 2016; 34(4): 525-32. 25. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging Reporting and Data System: 2015, Version 2. Eur Urol 2016; 69(1): 16-40. 26. Mesko S, Marks L, Ragab O, et al. Targeted Prostate Biopsy Gleason Score Heterogeneity and Implications for Risk Stratification. Am J Clin Oncol 2016.
17 27. Brian P. Calio AS, Dordaneh Sugano , Sonia Gaur , Mahir Maruf ,, Amit L. Jain MJM, Peter L. Choyke , Bradford J. Wood , Peter A., Pinto BT. Risk of upgrading from prostate biopsy to radical prostatectomy pathology: Does Saturation Biopsy of Index Lesion during mpMRI-TRUS fusion biopsy help? Journal of Urology 2018; In press 28. Le JD, Tan N, Shkolyar E, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol 2015; 67(3): 569-76. 29. Filson CP, Natarajan S, Margolis DJ, et al. Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies. Cancer 2016; 122(6): 884-92. 30. Salmasi A, Said J, Shindel AW, et al. A 17-gene Genomic Prostate Score assay provides independent information on adverse pathology in the setting of combined mpMRI fusion-targeted and systematic prostate biopsy. J Urol 2018.
Supplementary Figure 1 Legend: PSA = prostate specific antigen; DRE = digital rectal exam; PHI = prostate health index; PI-RADS = prostate imaging reporting & data system; TRUS Bx = transrectal ultrasound guided prostate biopsy; MRI Tbx = Magnetic resonance imaging-ultrasound targeted fusion biopsy; PCA3 = prostate cancer antigen 3; PSMA = prostate specific membrane antigen
18 Table 1: Baseline characteristics of men undergoing TBx and RP
n=140 Clinical Characteristics Age, median (IQR) BMI, median (IQR) PSA, median (IQR) Prostate volume, median (IQR) PSAD, median (IQR) MRI Characteristics Maximal Diameter of ROI, median (IQR) PI-RADS
65.6 (60.3-70.3) years 26.5 (25.1-30.3) kg/m2 5.95 (4.6-10.1) ng/mL 36.7 (30.0-47.3) cc 0.17 (0.12-0.28) ng/mL/cc
1.3 (1.0-1.8) cm 3 4 5
22 (15.7%) 74 (52.9%) 44 (31.4%)
Low Favorable intermediate Unfavorable intermediate High
13 (9.3%) 19 (13.5%) 54 (38.6%) 54 (38.6%)
NCCN Risk Stratification
19 Table 2: Fusion biopsy Gleason grade group compared to radical prostatectomy Gleason grade group
TBx Gleason Grade Group 1 2 3 4 5
RP Gleason Grade Group 1 2 3 4 8 10 1
8 40 12 2
1 10 16 3 1
7 3 2
5
1 8 7
20 Table 3: Multivariable regression assessing independent clinical characteristics associated with Gleason grade upgrading, upstaging, increase in NCCN risk stratification, decrease in NCCN risk stratification, and downgrading at RP Upgrade
Age BMI PSAD* Diameter of Index Lesion PI-RADS** 4 5
Upstage OR
95% CI
0.98-1.11 0.90-1.12 0.33-1.64 0.33-1.53
pvalue 0.154 0.923 0.453 0.379
1.04 1.04 3.92 1.16
0.98-1.10 0.93-1.16 1.60-9.62 0.59-2.29
pvalue 0.216 0.510 0.003 0.669
0.08-0.81 0.14-2.14
0.020 0.391
0.68 0.83
0.21-2.28 0.20-3.35
0.535 0.789
OR
95% CI
1.05 1.01 0.74 0.71 0.26 0.56
Increase in NCCN risk stratification
Age BMI PSAD* Diameter of Index Lesion PI-RADS** 4 5
Decrease in NCCN risk stratification
OR
95% CI
p-value
OR
95% CI
p-value
0.95 1.06 1.52
0.90-1.01 0.94-1.20 0.63-3.63
0.125 0.316 0.351
0.98 0.96 0.90
0.90-1.06 0.83-1.17 0.28-2.92
0.589 0.864 0.857
1.28
0.57-2.88
0.548
0.35
0.086-1.45
0.149
0.76 0.25
0.24-2.28 0.06-1.15
0.594 0.075 Downgrade
Age BMI PSAD* Diameter of Index Lesion PI-RADS** 4 5 *PSAD: <0.15 referent ** PI-RADS 3 referent
OR
95% CI
1.02 1.02 0.81 1.91
0.96-1.08 0.91-1.15 0.34-1.87 0.94-3.92
pvalue 0.541 0.734 0.615 0.076
1.27 0.52
0.35-4.55 0.10-2.50
0.715 0.414
21