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Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis
EUO-259; No. of Pages 11 E U RO P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
available at www.sciencedirect.com journal homepage: euoncology.europeanurology.com
Prostate Cancer
Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis Shokhi Goel a, Jonathan E. Shoag a, Michael D. Gross a, Bashir Al Hussein Al Awamlh a, Brian Robinson a, Francesca Khani a, Becky Baltich Nelson b, Daniel J. Margolis a, Jim C. Hu a,* a
Weill Cornell Medical College, New York, NY, USA; b Samuel J. Wood Library & C.V. Starr Biomedical Information Center, Weill Cornell Medicine, New York,
NY, USA
Article info
Abstract
Article history: Received 29 June 2019Accepted August 1, 2019
Context: Multiparametric magnetic resonance imaging (mpMRI)-targeted transrectal prostate biopsy (TBx) may better predict pathology at radical prostatectomy than systematic transrectal prostate biopsy (SBx). Objective: To assess concordance between biopsy and radical prostatectomy pathology in men undergoing a TBx as compared with those undergoing an SBx. Evidence acquisition: Four electronic databases (Ovid MEDLINE, Ovid EMBASE, the Cochrane Library [Wiley], and EBSCHOHost) were searched from inception until July 2018. Studies were included if they were published after 2012, conducted both SBx and TBx, and compared the biopsy results with final pathology after radical prostatectomy for 50 patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized. Bias was appraised using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Evidence synthesis: Our search yielded 10 studies including 1215 men. However, our inclusion criteria applied only to a proportion of men included in these studies. The median age was 65 yr and the median prostate-specific antigen level was 7.2 ng/ml. In the eight studies examining upgrading at prostatectomy, pathology from SBx was significantly more likely to be upgraded relative to TBx (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.48–4.14, p = 0.001). We found no significant difference in downgrading (OR 1.13, 95% CI 0.48–2.67, p = 0.783) between TBx and SBx. For both biopsy-naïve men and men with a prior negative biopsy, results from SBx were more likely to be upgraded than TBx at prostatectomy (OR 1.6 [95% CI 1.02–2.27, p < 0.001] and OR 4.23 [95% CI 1.68–8.48, p = 0.003], respectively). Conclusions: Pathologic upgrading at prostatectomy was less likely with mpMRItargeted biopsy versus systematic biopsy alone, without concurrent increase in
Associate Editor: Gianluca Giannarini Keywords: Meta-analysis Prostate Imaging Reporting and Data System Magnetic resonance imaging– targeted Biopsy Prostate cancer Systematic review
* Corresponding author: Department of Urology, Weill Cornell Medical Center, 525 East 68th Street, Starr 900, New York, NY 10065, USA. Tel. +1-646-962-9600, Fax: +1-646-962-0715. E-mail address: [email protected] (J.C. Hu).
https://doi.org/10.1016/j.euo.2019.08.001 2588-9311/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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downgrading. This increased accuracy should improve confidence in management decisions based on MRI-targeted biopsy pathology. Patient summary: We reviewed the ability of multiparametric magnetic resonance imaging –targeted biopsy to predict cancer grade at radical prostatectomy. We found that targeted biopsy provides more accurate assessment of Gleason score at prostatectomy than systematic biopsy. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Introduction The diagnosis of prostate cancer lags behind other solid malignancies, as it remains the only cancer that is diagnosed mainly by systematic organ sampling rather than visual or image guidance. Prostatectomy specimens are upgraded in up to 36% of patients with low-grade disease and downgraded in up to 56% of those with high-grade disease [1]. Systematic transrectal ultrasound (TRUS)-guided (SBx) 10–12 core biopsy is frequently used to diagnose prostate cancer [2]. Unfortunately, SBx has relatively low sensitivity for high-grade cancer detection, with 25–30% of men with low-risk disease being upgraded at confirmatory biopsy or radical prostatectomy (RP) [3]. Increasing the number of cores sampled has not been shown to provide more accurate grading, and anterior tumors and large prostates are particularly difficult to sample accurately [4–8]. Increasingly, fusion of data from multiparametric magnetic resonance imaging (mpMRI) with real-time ultrasound has been used to target MRI-visible lesions in patients suspected to have prostate cancer. Between 2009 and 2015, there has been a 20-fold increase in the proportion of men undergoing MRI prior to biopsy, with almost 20% of men with a prior negative biopsy having MRI performed [9,10]. Targeted transrectal prostate biopsy (TBx) has been suggested to be more cost effective and even results in higher quality-adjusted life years of 7.21 (vs SBx 7.19) [11]. The adoption of MRI has been facilitated by data demonstrating the preferential detection of high-grade (Gleason score [GS] 3 + 4) cancer on MRI-targeted biopsy as compared with systematic biopsy alone [8,12]. For instance, the PROMIS trial found the use of mpMRI as a triage test before the initial prostate biopsy could reduce unnecessary biopsies by 25% and improve detection of clinically significant prostate cancer (csPCa) [12]. Furthermore, recent level 1 evidence from the PRECISION trial indicates that MRI-ultrasound (US) fusion biopsy better detects clinically significant, grade group 2 and higher prostate cancer when compared with the standard TRUS biopsy [13]. However, whether this is resultant from the detection of more aggressive cancers or simply represents selective sampling of higher-grade areas within an otherwise low-grade cancer is unknown (Fig. 1). TBx may result in less upgrading by detecting a higher percentage of cancer involvement per biopsy core [14–16]; conversely, selective sampling of higher-grade areas may result in pathologic downgrading at RP [17].
The use of high-grade cancer detection as a surrogate for oncologic efficacy in the context of targeted biopsy is unproven, as the relationship between biopsy grade and oncologic outcomes is from patients undergoing systematic biopsy—which detects cancers preferentially based on their size—or RP [18–20]. MRI detects otherwise occult cancers and can upgrade patients following a biopsy containing low-grade cancer only, who could otherwise be observed or be eligible for less aggressive therapy rather than proceeding to radical treatment. Further, treatment decisions such as the use of androgen deprivation therapy prior to radiation or selection of patients for focal therapy are heavily reliant on accurate biopsy Gleason grading [17]. Targeted biopsy platforms have proliferated and are now considered a stage 4 technology (long-term study) by the idea, development, exploration, assessment, and long-term study (IDEAL) criteria [21]. To date, systematic reviews and meta-analyses examining the interplay between targeted and systematic biopsies have not compared biopsy results with the prediction of final pathology after RP [16,22,23]. The Gleason grading system has been proved to be the most important determinant of tumor aggressiveness, disease outcome, and mortality from prostate cancer [24]. Nevertheless, the GS assigned at biopsy is often discrepant from the score determined at RP, with RP pathology considered the gold standard. For these reasons, we performed a systematic review and meta-analysis to elucidate the impact of TBx and SBx on RP grade group concordance. Evidence acquisition Search strategy
This study was registered with PROSPERO, the international prospective register of systematic reviews (registration number: CRD42018107091), and followed the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [25]. A comprehensive literature search was conducted by a medical librarian on June 9, 2018 using the following bibliographic databases from inception: Ovid MEDLINE (InProcess & Other Non-Indexed Citations and Ovid MEDLINE, 1946–present), Ovid EMBASE (1974–present), and the Cochrane Library (Wiley). No language or article-type restrictions were included in the search, but results were limited to those published in 2012 or later, as this was when the major prostate MRI grading scheme, Prostate Imaging
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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Fig. 1 – Illustration of Gleason 3 + 4 prostate cancer and the potential impact of sampling variation on biopsy Gleason score. CO = concordant; DG = downgraded; UG = upgraded.
Reporting and Data System (PI-RADS), was released. The full Ovid MEDLINE search strategy is available in Supplementary Table 1. Study criteria
The 2061 results produced from the database searches were imported into Covidence (Veritas Health Innovation, Melbourne, Australia), a systematic review screening tool, and deduplicated. The remaining 1623 citations were screened by title and abstract against predetermined inclusion and exclusion criteria by two independent reviewers, with discrepancies resolved by consensus. To be eligible, articles had to meet the following inclusion criteria: (1) original studies with an experimental or semiexperimental design, (2) peer-reviewed studies, (3) studies in the field of urologic oncology, and (4) studies that compare transrectal biopsy outcomes with RP pathology. Exclusion criteria included: (1) reviews and meta-analyses, (2) studies for which only an abstract could be retrieved, (3) studies in a language other than English, (4) studies comparing systematic biopsies with transperineal biopsies instead of a transrectal approach, and (5) studies with N < 50 sample size examined at RP. Seventy articles were selected for full-text review. Both reference and relevant article lists for these articles were gathered and deduplicated, producing 832 additional citations for review, one of which was selected for further screening. From the full-text review, 10 articles met the inclusion criteria for this study. See Fig. 2 for the PRISMA
flow diagram outlining the study selection process. The two investigators independently extracted data for each selected study using a standardized data extraction sheet defined a priori by the study team. Disagreement between two reviewers was resolved by consensus once full data extraction was complete. Risk of bias assessment
Risk of bias in each study was assessed independently by the two investigators using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [26]. The QUADAS-2 tool includes four domains—patient selection, index test, reference test, and time flow—which are all assessed in terms of risk of bias and the first three in terms of applicability. The questions used to score each domain were derived from the QUADAS-2 tool statement and are displayed in Supplementary Table 2. Statistical analysis
The meta-analysis was performed using the random-effect model, and analysis was performed to assess whether pathologic upgrading/downgrading was influenced by the biopsy type. Further meta-analyses were carried out on patients with different prior biopsy statuses. Forest plots provide the summary data for each study, as well as the calculated odds ratios (ORs) and 95% confidence intervals (CIs) for upgrading of systematic versus targeted biopsies at RP. Statistical significance of each study and meta-analyses
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
Study
Design
Study population
MR characteristics and interpretation
Time from
Anesthesia
Comparator
MR-TRUS fusion targeted biopsy
MR to prostatectomy (mo) Sample
Prior
size
biopsy
Age (yr)
PSA
Prostate
(nm/ml)
volume
Strength of Endorectal magnetic
Paired cohort 52
Median 69, IQR (64–72)
(6.1–15.2)
IQR (30.6–60.4)
Prior negative
Median 64, IQR
Median 13.0,
Median 49, IQR
study
biopsy
(58–67)
IQR (9.5–20)
(36–69)
Paired cohort 208
Biopsy naïve
Median 62, IQR
Median 7.1, IQR
Median 38, IQR
(10)
(8.0)
(19)
study Boesen et al [33] Paired cohort 64
Median 8.6, IQR
Median 40.2,
Blinded
Software
Sampling
Targeted biopsy
Mean no. of
No. of
No. of
test
to MR
used
route
performed first
lesions per
cores per
targeted cores
results
3
N
PI-RADS
NR
Local
TRUS 1
3
N
PI-RADS
NR
Local
TRUS
patient
Y
DynaTRIM/
Y
Real-time
2 cores
lesion
per pt
Transrectal
Y
NR
NR
Mean 5.7
Transrectal
N
1.72
1–2
NR
Transrectal
Y
NR
2
Median 2, IQR
Urostation
10 cores
virtual sonography or none
Calio et al [27]
study
3
Y
NIH
NR
Local
suspicion
TRUS 1
Y
UroNav
2 cores
(2)
score Hambrock
Retrospective 96
Prior negative
Mean 66, range
Median 12,
Median 41,
et al [30]
cohort
biopsy
(51–74)
range (3–40)
range (12–79)
Le et al [34]
Paired cohort 54
Mixed (30%
Mean 62, IQR
Median 6.2, IQR
Mean 41, IQR
study
biopsy naïve,
(57–66)
(5.0–10.9)
(30–50)
NR
NR
NR
3
Y
15-point
NR
Local
scale 3
N
PI-RADS
TRUS
NA
10 cores Mean 2.7,
Local
IQR (1.7–3.2)
TRUS
None (in
Transrectal
NA
NR
1–3
Median 3,
Transrectal
Y
1.87
1/3mm
Mean 5.9, IQR
bore) N
Artemis
range (1–5)
12 cores
(4–8)
28% prior negative biopsy, 43% active surveillance) Kasivisvanathan
RCT
57
Biopsy naïve
1.5/3
Some
PI-RADS v2
NR
Multiple
et al [13] Patel et al [31]
NA
Multiple
cores Retrospective 201
Biopsy naïve
Median 66,
Median 8.1, 95%
Median 44, 95%
range (41–78)
CI (6.4–9.8)
CI (37–52)
Median 65,
Median 6.0,
Median 38.4,
biopsy
range (44–80)
range (1.0–48.0)
range (19–149)
Paired cohort 170
Mixed (26%
Mean 60.2, SD
Median 6.8, IQR
Median 39, IQR
study
prior negative
(7.3)
(4.4–10.7)
(30–48)
cohort Porpiglia et al
Retrospective 246
Prior negative
[32]
cohort
Siddiqui et al [28]
3
N
PI-RADS
NR
NR
1.5
Y
PI-RADS
NR
Local
Paired cohort 65 study
NR
TRUS TRUS 18–20
N NA
None
Transrectal and
(cognitive)
transperineal
BioJet
Transrectal and
cores 3
Y
Low,
NR
Local
TRUS
Transrectal and
NA
NR
NR NR
Median 4,
NA
NR
4–6
NR
Y
3.1, SD (1.3)
NR
Mean 6.2, SD
Y
Median 1,
range (1–6)
range (1–3)
transperineal Y
UroNav
Transrectal
12 cores
moderate, h
NR
transperineal
12 cores
(2.5)
igh
biopsy) Zhao et al [36]
TRUS 10–12
NR
NR
NR
3
N
NR
NR
NR
TRUS
NR
NR
NR
NR
NR
NR
4–10
12 cores
CI = confidence interval; IQR – interquartile range; MR = magnetic resonance; N = no; NA – not available; NIH = National Institute of Health; NR = not reported; PI-RADS = Prostate Imaging and Reporting and Data System; PSA = prostate-specific antigen; pt = patient; RCT = randomized controlled trial; SD = standard deviation; TRUS = transrectal ultrasound; Y = yes.
E U R O P E A N U R O L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
Biopsy naïve
Standard
used
field (T)
(ml) Arsov et al [35]
coil
Score
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Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
Table 1 – Summary data for studies included for review.
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Fig. 2 – Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) diagram. RP = radical prostatectomy.
was set at p < 0.05. The forest plots also provide the weight given to each individual study, overall effect measure (Z), and heterogeneity among studies. The degree of variability across the studies was summarized using the I2 measure, which represents the percentage of total variation across studies that can be attributed to heterogeneity instead of chance (Supplementary Fig. 1). Studies with no events in either group were excluded from the meta-analysis. Evidence synthesis Study designs
Overall, 10 studies were included in this analysis, involving a total of 1215 men with a median age of 65 yr and median prostate-specific antigen (PSA) level of 7.2 ng/ml (see Fig. 2 and Table 1). These studies consisted of six paired cohort studies, three retrospective cohort studies, and one randomized controlled trial. Of the studies that reported
prior biopsy status, four were conducted in biopsy-naïve men, three studies were conducted in men with a prior negative TRUS biopsy, and two studies examined a mixed cohort. One study did not report biopsy status. No studies included men with radiorecurrent disease or a previous prostate cancer diagnosis. Of the studies, 40% included concurrent SBx and TBx, whereas 60% performed the biopsies in separate, but matched, cohorts. In the TBx group, correlation with RP was evaluated by comparing the overlap between the MRI region of interest and the RP specimen even when SBx was performed concurrently. The standard comparator was a 10- to 12-core TRUS biopsy in eight studies, a systematic mapping biopsy in one study, and a 12–20-core TRUS biopsy in one study. All mpMRI scans were performed on either a 1.5- or a 3-T scanner, and all men received T2-weighted scans with diffusion-weighted imaging and dynamic contrast enhancement. Three studies utilized an endorectal coil [13,27,28], and five out of the 10 studies used the PI-RADS v1 five-point scale. One
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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Fig. 3 – Forest plot of upgrading, downgrading, and concordance with radical prostatectomy for analyses that compared TBx with SBx. An odds ratio of >1 indicates relative chance of upgrading for TBx versus SBx. CI = confidence interval; M H = Mantel–Haenszel; MRI = magnetic resonance imaging; SBx = systematic TRUS biopsy; TBx = MRI-targeted biopsy; TRUS = transrectal ultrasound.
study used PI-RADS v2, whereas Calio et al [27] used the National Institute of Health suspicion score, and Siddiqui et al [28] utilized a low, moderate, or high score based on previously described criteria [29]. The final study, utilized a tumor probability 15-point scale for image classification [30]. The median time between biopsy and RP was 5 weeks. Pathologic upgrading
Targeted biopsy was upgraded 23.3% of the time, whereas systematic biopsy had an upgrade rate of 42.7% at RP. The odds of GS upgrading at RP after SBx compared with TBx were 1.75 (95% CI 1.03–2.47, p = 0.001; Fig. 2A). For biopsynaïve men, the odds of upgrading after SBx as opposed to TBx were 2.47 (95% CI 1.48–4.14, p < 0.001), while the odds of upgrading in men with a prior negative biopsy or unknown prior biopsy status were 4.23 (95% CI 1.68–8.48, p = 0.003) or 1.6 (95% 1.04–2.25, p = 0.085), respectively (Fig. 3 and 4). Within these studies, there was acceptable heterogeneity with I2 = 0–65% (Supplementary Fig. 1). Pathologic downgrading
A subset of studies reported their rates of pathologic downgrading at RP. On meta-analysis, the odds of GS downgrading after SBx compared with TBx were 1.13 (95% CI 0.48–2.67, p = 0.783; Fig. 3).
Risk of bias using QUADAS-2
Overall, the 10 studies included in this analysis had a low risk of bias and low applicability concerns (Fig. 5 and Supplementary Table 3). Of the five studies that had a high risk of bias in the patient selection category, four conducted TBx and SBx on separate patient cohorts [13,30–32]. Nevertheless, the cohorts were matched in terms of age, PSA, prostate volume, and pathologic stage at biopsy. In two studies, the high risk of selection bias was due to the inclusion of patients with a prior negative biopsy [32,33]. Four studies in the index test domain had a high or unclear risk of bias and applicability concerns [13,31,32,34]. Three of these studies conducted both transperineal and transrectal MRI-targeted biopsies [13,31,32], without delineating the difference among the two methods in tumor concordance, upgrading, or downgrading at RP. The high risk of bias in the index domain in one study [31] was due to inconsistent sampling, as biopsy cores taken during the targeted biopsy differed based on operator discretion. Le et al’s [34] study was biased due to substitution of a mapping biopsy for the systematic biopsy arm. Most studies had minimal risk of bias or applicability concerns in the reference standard. Porpiglia et al [32], however, had significant bias in this domain because 12–20 systematic cores were biopsied instead of the traditional 10–12 cores.
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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Fig. 4 – (A) Forest plot of upgrading based on prior biopsy status (ie, biopsy naïve, prior negative biopsy, and mixed cohort). An odds ratio of >1 indicates relative chance of upgrading at RP for TBx versus SBx. (B) Percentage of upgrading at RP based on prior biopsy status for TBx versus SBx. CI = confidence interval; MRI = magnetic resonance imaging; RP = radical prostatectomy; SBx = systematic TRUS biopsy; TBx = MRI-targeted biopsy; TRUS = transrectal ultrasound.
Unfortunately, many studies did not give individual cross-tabulations of TBx and SBx biopsy scores and their correspondence with RP grading. Others did not present data about downgrading at RP. We attempted to individually contact the study authors in these cases. Sometimes, targeted biopsy outcomes were partially or entirely pooled with standard biopsy outcomes, also limiting their inclusion in meta-analysis. These inconsistencies were not measured
using the QUADAS-2 tool but were instead incorporated into the result figures and tables provided. Summary of key findings
Our systematic review and meta-analysis show that TBx is associated with significantly less pathologic upgrading at the time of RP as compared with SBx alone, with 23.3% of TBx being upgraded versus 42.7% upgrading in SBx (OR 2.47,
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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Fig. 5 – Summary of risk of bias assessment of all papers included using the Quality Assessment for Diagnostic Studies-2 tool.
95% CI 1.48–4.14, p = 0.001), with no significant increase in pathologic downgrading at RP (OR 1.13, CI 0.48–2.67, p = 0.783). There are a large number of biopsy studies reporting cancer detection on biopsy; however, we chose to limit our included studies to those with pathology at prostatectomy. This hampered the size of the cohorts incorporated. For example, while Siddiqui et al [28] reported on 1003 men undergoing a biopsy, only 170 (17%) had prostatectomy data included. Furthermore, centers employed different definitions of clinical significance, and only two studies (those of Arsov et al and Zhao et al) reported their data at the level of each possible GS (ie, 3 + 3, 3 + 4, 4 + 3, etc.). Both studies demonstrated reduced upgrading at RP for targeted biopsies as GS increased, although analyses in these subgroups only were not computed due to the small sample sizes. Further, the approach for conducting MRI-TRUS fusion targeted biopsy is not standardized, and we found significant variation in the threshold for biopsy, MRI scoring, and
the number of targeted biopsy cores sampled per region of interest. For example, 40% of studies did not use PI-RADS scoring. Therefore, a comparison of PI-RADS scoring and pathologic outcomes was not possible in this analysis (see Table 1). MRI-targeted biopsy is a relatively new technique, with studies demonstrating a significant learning curve, with accuracy improving after the 98th biopsy for a fixed robotic arm platform [35]. No studies accounted for the learning curve associated with TBx, or mentioned interobserver variability in interpreting mpMRI or pathology findings. Significant heterogeneity exists in outcomes of TRUS-guided prostate biopsies as well as MRI-targeted biopsies [36]; studies have shown that surgeon experience with TRUS-guided biopsy may affect MRI-TRUS detection rates as well [37,38]. Since targeted and systematic biopsies were performed during the same session, it is also difficult to assign adverse effects to one approach versus another. It is generally hypothesized that the risks of bleeding, infection, and urinary retention increase with additional cores sampled.
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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Studies have shown that MRI-targeted biopsies typically contain a higher percentage of cancer per core due to preferential sampling of the tumor [23,39]. In our analysis, two studies reported different definitions of clinically significant cancer at biopsy [28,33]. For instance, Boesen et al [33] delineated csPCa as GS > 6 with the maximum core length >50% on biopsy and GS > 6 on RP. In contrast, Siddiqui et al [28] defined csPCa in terms of START consortium risk category (low, intermediate, and high risk) with anything with GS = 3 + 4 with >50% of cores positive for cancer on biopsy and GS = 3 + 4 in <20% of the total prostate on final RP pathology. A consistent definition of clinically significant disease and/or standardized reporting of pathology results in future studies would facilitate consistency in comparing outcomes. Considerable disparity also exists in the literature regarding MRI-targeted biopsy’s ability to better detect RP pathology in biopsy-naïve men and men with a prior negative biopsy. While not directly related to our primary outcome, Sonn et al [41] showed that the utility of TBx to detect cancer is best in the prior negative biopsy group, although the FUTURE trial discovered no difference in TBx’s ability to detect aggressive prostate cancer [42]. In the three studies examining men with a prior negative biopsy, our analysis found a significant difference in upgrading rates at RP for patients with a prior negative biopsy undergoing a TBx, with the odds of upgrading after SBx compared with TBx being 4.23 (95% CI 1.68–8.48, p = 0.003). For the biopsynaïve population, two recent randomized trials found no differences in clinically significant cancer detection between TBx and SBx. Nevertheless, our analysis, which instead compared biopsy results with final RP pathology, indicated the potential of MRI-targeted biopsies to reduce upgrading rates in the biopsy-naïve population. For biopsynaïve men, the odds of upgrading at SBx as opposed to that at TBx were 2.47 (95% CI 1.48–4.14, p < 0.001). Given that our analysis was able to include only three studies in this analysis due to study design limitations, both of these populations warrant further subgroup analysis when considering the merits of MRI-guided biopsies. Limitations
Our study must be interpreted in the context of our metaanalysis design. First, there was variability in both study design and reporting among our included studies. Metaanalyses are inherently subject to publication bias, and therefore, small-study effects, as negative results are unlikely to be incorporated or published. Our quantitative analysis consisted of 10 studies, but due to variation in reporting schemas within these studies, only a proportion of men from each study that met our criteria were included for each analysis (see the section on risk of bias). Moreover, there was significant variation in study design. Four studies conducted TBx and SBx concurrently, whereas TBx and SBx were conducted in different cohorts in the other studies. Nevertheless, the cohorts were matched in terms of PSA, prostate volume, and pathologic stage. The differences in MRI assessment also contribute to significant variation in outcomes.
9
In an effort to address heterogeneity due to variation in biopsy technique, we excluded transperineally guided MRItargeted biopsies. Further, patients with negative MRI or MRI TBx were not included, so these results do not apply to these men. Few articles delineated whether upgrading was observed in the region of interest or from a systematic biopsy. Additionally, while this study contributes to the understanding of pathologic risk as it relates to targeted biopsy, it is certainly not complete, and inter- and intratumoral heterogeneity may still be unaccounted for [43,44]. Given the significant learning curve of conducting MRIUS fusion biopsies, large-scale, prospective research is needed to determine targeted biopsy’s impact in the clinic. Conclusions MRI-targeted prostate biopsy results in less pathologic upgrading, and equivalent downgrading, as compared with systematic biopsy at prostatectomy. This improved risk stratification has broad implications, and suggests that targeted biopsy can better select patients for active surveillance, focal therapy, and androgen deprivation therapy in combination with radiotherapy, than systematic biopsy alone. Nevertheless, robust prospective studies are needed to confirm these results. Author contributions: Shokhi Goel had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shoag, Hu. Acquisition of data: Goel, Gross, Baltich. Analysis and interpretation of data: Goel, Gross. Drafting of the manuscript: Goel. Critical revision of the manuscript for important intellectual content: Khani, Robinson, Shoag, Hu. Daniel J. Margolis, Bashir Al Hussein Al Awamlh Statistical analysis: Goel. Obtaining funding: Hu. Administrative, technical, or material support: Shoag, Hu. Supervision: Shoag, Hu. Other: None.
Financial disclosures: Shokhi Goel certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: The Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust supported this research Also supported by the Damon Runyon Physician Scientist Training Award.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. euo.2019.08.001.
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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available at www.sciencedirect.com journal homepage: euoncology.europeanurology.com
Prostate Cancer
Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis Shokhi Goel a, Jonathan E. Shoag a, Michael D. Gross a, Bashir Al Hussein Al Awamlh a, Brian Robinson a, Francesca Khani a, Becky Baltich Nelson b, Daniel J. Margolis a, Jim C. Hu a,* a
Weill Cornell Medical College, New York, NY, USA; b Samuel J. Wood Library & C.V. Starr Biomedical Information Center, Weill Cornell Medicine, New York,
NY, USA
Article info
Abstract
Article history: Received 29 June 2019Accepted August 1, 2019
Context: Multiparametric magnetic resonance imaging (mpMRI)-targeted transrectal prostate biopsy (TBx) may better predict pathology at radical prostatectomy than systematic transrectal prostate biopsy (SBx). Objective: To assess concordance between biopsy and radical prostatectomy pathology in men undergoing a TBx as compared with those undergoing an SBx. Evidence acquisition: Four electronic databases (Ovid MEDLINE, Ovid EMBASE, the Cochrane Library [Wiley], and EBSCHOHost) were searched from inception until July 2018. Studies were included if they were published after 2012, conducted both SBx and TBx, and compared the biopsy results with final pathology after radical prostatectomy for 50 patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized. Bias was appraised using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Evidence synthesis: Our search yielded 10 studies including 1215 men. However, our inclusion criteria applied only to a proportion of men included in these studies. The median age was 65 yr and the median prostate-specific antigen level was 7.2 ng/ml. In the eight studies examining upgrading at prostatectomy, pathology from SBx was significantly more likely to be upgraded relative to TBx (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.48–4.14, p = 0.001). We found no significant difference in downgrading (OR 1.13, 95% CI 0.48–2.67, p = 0.783) between TBx and SBx. For both biopsy-naïve men and men with a prior negative biopsy, results from SBx were more likely to be upgraded than TBx at prostatectomy (OR 1.6 [95% CI 1.02–2.27, p < 0.001] and OR 4.23 [95% CI 1.68–8.48, p = 0.003], respectively). Conclusions: Pathologic upgrading at prostatectomy was less likely with mpMRItargeted biopsy versus systematic biopsy alone, without concurrent increase in
Associate Editor: Gianluca Giannarini Keywords: Meta-analysis Prostate Imaging Reporting and Data System Magnetic resonance imaging– targeted Biopsy Prostate cancer Systematic review
* Corresponding author: Department of Urology, Weill Cornell Medical Center, 525 East 68th Street, Starr 900, New York, NY 10065, USA. Tel. +1-646-962-9600, Fax: +1-646-962-0715. E-mail address: [email protected] (J.C. Hu).
https://doi.org/10.1016/j.euo.2019.08.001 2588-9311/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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downgrading. This increased accuracy should improve confidence in management decisions based on MRI-targeted biopsy pathology. Patient summary: We reviewed the ability of multiparametric magnetic resonance imaging –targeted biopsy to predict cancer grade at radical prostatectomy. We found that targeted biopsy provides more accurate assessment of Gleason score at prostatectomy than systematic biopsy. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Introduction The diagnosis of prostate cancer lags behind other solid malignancies, as it remains the only cancer that is diagnosed mainly by systematic organ sampling rather than visual or image guidance. Prostatectomy specimens are upgraded in up to 36% of patients with low-grade disease and downgraded in up to 56% of those with high-grade disease [1]. Systematic transrectal ultrasound (TRUS)-guided (SBx) 10–12 core biopsy is frequently used to diagnose prostate cancer [2]. Unfortunately, SBx has relatively low sensitivity for high-grade cancer detection, with 25–30% of men with low-risk disease being upgraded at confirmatory biopsy or radical prostatectomy (RP) [3]. Increasing the number of cores sampled has not been shown to provide more accurate grading, and anterior tumors and large prostates are particularly difficult to sample accurately [4–8]. Increasingly, fusion of data from multiparametric magnetic resonance imaging (mpMRI) with real-time ultrasound has been used to target MRI-visible lesions in patients suspected to have prostate cancer. Between 2009 and 2015, there has been a 20-fold increase in the proportion of men undergoing MRI prior to biopsy, with almost 20% of men with a prior negative biopsy having MRI performed [9,10]. Targeted transrectal prostate biopsy (TBx) has been suggested to be more cost effective and even results in higher quality-adjusted life years of 7.21 (vs SBx 7.19) [11]. The adoption of MRI has been facilitated by data demonstrating the preferential detection of high-grade (Gleason score [GS] 3 + 4) cancer on MRI-targeted biopsy as compared with systematic biopsy alone [8,12]. For instance, the PROMIS trial found the use of mpMRI as a triage test before the initial prostate biopsy could reduce unnecessary biopsies by 25% and improve detection of clinically significant prostate cancer (csPCa) [12]. Furthermore, recent level 1 evidence from the PRECISION trial indicates that MRI-ultrasound (US) fusion biopsy better detects clinically significant, grade group 2 and higher prostate cancer when compared with the standard TRUS biopsy [13]. However, whether this is resultant from the detection of more aggressive cancers or simply represents selective sampling of higher-grade areas within an otherwise low-grade cancer is unknown (Fig. 1). TBx may result in less upgrading by detecting a higher percentage of cancer involvement per biopsy core [14–16]; conversely, selective sampling of higher-grade areas may result in pathologic downgrading at RP [17].
The use of high-grade cancer detection as a surrogate for oncologic efficacy in the context of targeted biopsy is unproven, as the relationship between biopsy grade and oncologic outcomes is from patients undergoing systematic biopsy—which detects cancers preferentially based on their size—or RP [18–20]. MRI detects otherwise occult cancers and can upgrade patients following a biopsy containing low-grade cancer only, who could otherwise be observed or be eligible for less aggressive therapy rather than proceeding to radical treatment. Further, treatment decisions such as the use of androgen deprivation therapy prior to radiation or selection of patients for focal therapy are heavily reliant on accurate biopsy Gleason grading [17]. Targeted biopsy platforms have proliferated and are now considered a stage 4 technology (long-term study) by the idea, development, exploration, assessment, and long-term study (IDEAL) criteria [21]. To date, systematic reviews and meta-analyses examining the interplay between targeted and systematic biopsies have not compared biopsy results with the prediction of final pathology after RP [16,22,23]. The Gleason grading system has been proved to be the most important determinant of tumor aggressiveness, disease outcome, and mortality from prostate cancer [24]. Nevertheless, the GS assigned at biopsy is often discrepant from the score determined at RP, with RP pathology considered the gold standard. For these reasons, we performed a systematic review and meta-analysis to elucidate the impact of TBx and SBx on RP grade group concordance. Evidence acquisition Search strategy
This study was registered with PROSPERO, the international prospective register of systematic reviews (registration number: CRD42018107091), and followed the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [25]. A comprehensive literature search was conducted by a medical librarian on June 9, 2018 using the following bibliographic databases from inception: Ovid MEDLINE (InProcess & Other Non-Indexed Citations and Ovid MEDLINE, 1946–present), Ovid EMBASE (1974–present), and the Cochrane Library (Wiley). No language or article-type restrictions were included in the search, but results were limited to those published in 2012 or later, as this was when the major prostate MRI grading scheme, Prostate Imaging
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
EUO-259; No. of Pages 11 E U R O P E A N U RO L O GY O N C O L O GY X X X ( 2 019 ) X X X – X X X
3
Fig. 1 – Illustration of Gleason 3 + 4 prostate cancer and the potential impact of sampling variation on biopsy Gleason score. CO = concordant; DG = downgraded; UG = upgraded.
Reporting and Data System (PI-RADS), was released. The full Ovid MEDLINE search strategy is available in Supplementary Table 1. Study criteria
The 2061 results produced from the database searches were imported into Covidence (Veritas Health Innovation, Melbourne, Australia), a systematic review screening tool, and deduplicated. The remaining 1623 citations were screened by title and abstract against predetermined inclusion and exclusion criteria by two independent reviewers, with discrepancies resolved by consensus. To be eligible, articles had to meet the following inclusion criteria: (1) original studies with an experimental or semiexperimental design, (2) peer-reviewed studies, (3) studies in the field of urologic oncology, and (4) studies that compare transrectal biopsy outcomes with RP pathology. Exclusion criteria included: (1) reviews and meta-analyses, (2) studies for which only an abstract could be retrieved, (3) studies in a language other than English, (4) studies comparing systematic biopsies with transperineal biopsies instead of a transrectal approach, and (5) studies with N < 50 sample size examined at RP. Seventy articles were selected for full-text review. Both reference and relevant article lists for these articles were gathered and deduplicated, producing 832 additional citations for review, one of which was selected for further screening. From the full-text review, 10 articles met the inclusion criteria for this study. See Fig. 2 for the PRISMA
flow diagram outlining the study selection process. The two investigators independently extracted data for each selected study using a standardized data extraction sheet defined a priori by the study team. Disagreement between two reviewers was resolved by consensus once full data extraction was complete. Risk of bias assessment
Risk of bias in each study was assessed independently by the two investigators using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [26]. The QUADAS-2 tool includes four domains—patient selection, index test, reference test, and time flow—which are all assessed in terms of risk of bias and the first three in terms of applicability. The questions used to score each domain were derived from the QUADAS-2 tool statement and are displayed in Supplementary Table 2. Statistical analysis
The meta-analysis was performed using the random-effect model, and analysis was performed to assess whether pathologic upgrading/downgrading was influenced by the biopsy type. Further meta-analyses were carried out on patients with different prior biopsy statuses. Forest plots provide the summary data for each study, as well as the calculated odds ratios (ORs) and 95% confidence intervals (CIs) for upgrading of systematic versus targeted biopsies at RP. Statistical significance of each study and meta-analyses
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
Study
Design
Study population
MR characteristics and interpretation
Time from
Anesthesia
Comparator
MR-TRUS fusion targeted biopsy
MR to prostatectomy (mo) Sample
Prior
size
biopsy
Age (yr)
PSA
Prostate
(nm/ml)
volume
Strength of Endorectal magnetic
Paired cohort 52
Median 69, IQR (64–72)
(6.1–15.2)
IQR (30.6–60.4)
Prior negative
Median 64, IQR
Median 13.0,
Median 49, IQR
study
biopsy
(58–67)
IQR (9.5–20)
(36–69)
Paired cohort 208
Biopsy naïve
Median 62, IQR
Median 7.1, IQR
Median 38, IQR
(10)
(8.0)
(19)
study Boesen et al [33] Paired cohort 64
Median 8.6, IQR
Median 40.2,
Blinded
Software
Sampling
Targeted biopsy
Mean no. of
No. of
No. of
test
to MR
used
route
performed first
lesions per
cores per
targeted cores
results
3
N
PI-RADS
NR
Local
TRUS 1
3
N
PI-RADS
NR
Local
TRUS
patient
Y
DynaTRIM/
Y
Real-time
2 cores
lesion
per pt
Transrectal
Y
NR
NR
Mean 5.7
Transrectal
N
1.72
1–2
NR
Transrectal
Y
NR
2
Median 2, IQR
Urostation
10 cores
virtual sonography or none
Calio et al [27]
study
3
Y
NIH
NR
Local
suspicion
TRUS 1
Y
UroNav
2 cores
(2)
score Hambrock
Retrospective 96
Prior negative
Mean 66, range
Median 12,
Median 41,
et al [30]
cohort
biopsy
(51–74)
range (3–40)
range (12–79)
Le et al [34]
Paired cohort 54
Mixed (30%
Mean 62, IQR
Median 6.2, IQR
Mean 41, IQR
study
biopsy naïve,
(57–66)
(5.0–10.9)
(30–50)
NR
NR
NR
3
Y
15-point
NR
Local
scale 3
N
PI-RADS
TRUS
NA
10 cores Mean 2.7,
Local
IQR (1.7–3.2)
TRUS
None (in
Transrectal
NA
NR
1–3
Median 3,
Transrectal
Y
1.87
1/3mm
Mean 5.9, IQR
bore) N
Artemis
range (1–5)
12 cores
(4–8)
28% prior negative biopsy, 43% active surveillance) Kasivisvanathan
RCT
57
Biopsy naïve
1.5/3
Some
PI-RADS v2
NR
Multiple
et al [13] Patel et al [31]
NA
Multiple
cores Retrospective 201
Biopsy naïve
Median 66,
Median 8.1, 95%
Median 44, 95%
range (41–78)
CI (6.4–9.8)
CI (37–52)
Median 65,
Median 6.0,
Median 38.4,
biopsy
range (44–80)
range (1.0–48.0)
range (19–149)
Paired cohort 170
Mixed (26%
Mean 60.2, SD
Median 6.8, IQR
Median 39, IQR
study
prior negative
(7.3)
(4.4–10.7)
(30–48)
cohort Porpiglia et al
Retrospective 246
Prior negative
[32]
cohort
Siddiqui et al [28]
3
N
PI-RADS
NR
NR
1.5
Y
PI-RADS
NR
Local
Paired cohort 65 study
NR
TRUS TRUS 18–20
N NA
None
Transrectal and
(cognitive)
transperineal
BioJet
Transrectal and
cores 3
Y
Low,
NR
Local
TRUS
Transrectal and
NA
NR
NR NR
Median 4,
NA
NR
4–6
NR
Y
3.1, SD (1.3)
NR
Mean 6.2, SD
Y
Median 1,
range (1–6)
range (1–3)
transperineal Y
UroNav
Transrectal
12 cores
moderate, h
NR
transperineal
12 cores
(2.5)
igh
biopsy) Zhao et al [36]
TRUS 10–12
NR
NR
NR
3
N
NR
NR
NR
TRUS
NR
NR
NR
NR
NR
NR
4–10
12 cores
CI = confidence interval; IQR – interquartile range; MR = magnetic resonance; N = no; NA – not available; NIH = National Institute of Health; NR = not reported; PI-RADS = Prostate Imaging and Reporting and Data System; PSA = prostate-specific antigen; pt = patient; RCT = randomized controlled trial; SD = standard deviation; TRUS = transrectal ultrasound; Y = yes.
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Biopsy naïve
Standard
used
field (T)
(ml) Arsov et al [35]
coil
Score
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Table 1 – Summary data for studies included for review.
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Fig. 2 – Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) diagram. RP = radical prostatectomy.
was set at p < 0.05. The forest plots also provide the weight given to each individual study, overall effect measure (Z), and heterogeneity among studies. The degree of variability across the studies was summarized using the I2 measure, which represents the percentage of total variation across studies that can be attributed to heterogeneity instead of chance (Supplementary Fig. 1). Studies with no events in either group were excluded from the meta-analysis. Evidence synthesis Study designs
Overall, 10 studies were included in this analysis, involving a total of 1215 men with a median age of 65 yr and median prostate-specific antigen (PSA) level of 7.2 ng/ml (see Fig. 2 and Table 1). These studies consisted of six paired cohort studies, three retrospective cohort studies, and one randomized controlled trial. Of the studies that reported
prior biopsy status, four were conducted in biopsy-naïve men, three studies were conducted in men with a prior negative TRUS biopsy, and two studies examined a mixed cohort. One study did not report biopsy status. No studies included men with radiorecurrent disease or a previous prostate cancer diagnosis. Of the studies, 40% included concurrent SBx and TBx, whereas 60% performed the biopsies in separate, but matched, cohorts. In the TBx group, correlation with RP was evaluated by comparing the overlap between the MRI region of interest and the RP specimen even when SBx was performed concurrently. The standard comparator was a 10- to 12-core TRUS biopsy in eight studies, a systematic mapping biopsy in one study, and a 12–20-core TRUS biopsy in one study. All mpMRI scans were performed on either a 1.5- or a 3-T scanner, and all men received T2-weighted scans with diffusion-weighted imaging and dynamic contrast enhancement. Three studies utilized an endorectal coil [13,27,28], and five out of the 10 studies used the PI-RADS v1 five-point scale. One
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Fig. 3 – Forest plot of upgrading, downgrading, and concordance with radical prostatectomy for analyses that compared TBx with SBx. An odds ratio of >1 indicates relative chance of upgrading for TBx versus SBx. CI = confidence interval; M H = Mantel–Haenszel; MRI = magnetic resonance imaging; SBx = systematic TRUS biopsy; TBx = MRI-targeted biopsy; TRUS = transrectal ultrasound.
study used PI-RADS v2, whereas Calio et al [27] used the National Institute of Health suspicion score, and Siddiqui et al [28] utilized a low, moderate, or high score based on previously described criteria [29]. The final study, utilized a tumor probability 15-point scale for image classification [30]. The median time between biopsy and RP was 5 weeks. Pathologic upgrading
Targeted biopsy was upgraded 23.3% of the time, whereas systematic biopsy had an upgrade rate of 42.7% at RP. The odds of GS upgrading at RP after SBx compared with TBx were 1.75 (95% CI 1.03–2.47, p = 0.001; Fig. 2A). For biopsynaïve men, the odds of upgrading after SBx as opposed to TBx were 2.47 (95% CI 1.48–4.14, p < 0.001), while the odds of upgrading in men with a prior negative biopsy or unknown prior biopsy status were 4.23 (95% CI 1.68–8.48, p = 0.003) or 1.6 (95% 1.04–2.25, p = 0.085), respectively (Fig. 3 and 4). Within these studies, there was acceptable heterogeneity with I2 = 0–65% (Supplementary Fig. 1). Pathologic downgrading
A subset of studies reported their rates of pathologic downgrading at RP. On meta-analysis, the odds of GS downgrading after SBx compared with TBx were 1.13 (95% CI 0.48–2.67, p = 0.783; Fig. 3).
Risk of bias using QUADAS-2
Overall, the 10 studies included in this analysis had a low risk of bias and low applicability concerns (Fig. 5 and Supplementary Table 3). Of the five studies that had a high risk of bias in the patient selection category, four conducted TBx and SBx on separate patient cohorts [13,30–32]. Nevertheless, the cohorts were matched in terms of age, PSA, prostate volume, and pathologic stage at biopsy. In two studies, the high risk of selection bias was due to the inclusion of patients with a prior negative biopsy [32,33]. Four studies in the index test domain had a high or unclear risk of bias and applicability concerns [13,31,32,34]. Three of these studies conducted both transperineal and transrectal MRI-targeted biopsies [13,31,32], without delineating the difference among the two methods in tumor concordance, upgrading, or downgrading at RP. The high risk of bias in the index domain in one study [31] was due to inconsistent sampling, as biopsy cores taken during the targeted biopsy differed based on operator discretion. Le et al’s [34] study was biased due to substitution of a mapping biopsy for the systematic biopsy arm. Most studies had minimal risk of bias or applicability concerns in the reference standard. Porpiglia et al [32], however, had significant bias in this domain because 12–20 systematic cores were biopsied instead of the traditional 10–12 cores.
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Fig. 4 – (A) Forest plot of upgrading based on prior biopsy status (ie, biopsy naïve, prior negative biopsy, and mixed cohort). An odds ratio of >1 indicates relative chance of upgrading at RP for TBx versus SBx. (B) Percentage of upgrading at RP based on prior biopsy status for TBx versus SBx. CI = confidence interval; MRI = magnetic resonance imaging; RP = radical prostatectomy; SBx = systematic TRUS biopsy; TBx = MRI-targeted biopsy; TRUS = transrectal ultrasound.
Unfortunately, many studies did not give individual cross-tabulations of TBx and SBx biopsy scores and their correspondence with RP grading. Others did not present data about downgrading at RP. We attempted to individually contact the study authors in these cases. Sometimes, targeted biopsy outcomes were partially or entirely pooled with standard biopsy outcomes, also limiting their inclusion in meta-analysis. These inconsistencies were not measured
using the QUADAS-2 tool but were instead incorporated into the result figures and tables provided. Summary of key findings
Our systematic review and meta-analysis show that TBx is associated with significantly less pathologic upgrading at the time of RP as compared with SBx alone, with 23.3% of TBx being upgraded versus 42.7% upgrading in SBx (OR 2.47,
Please cite this article in press as: Goel S, et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol (2019), https://doi.org/10.1016/j.euo.2019.08.001
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Fig. 5 – Summary of risk of bias assessment of all papers included using the Quality Assessment for Diagnostic Studies-2 tool.
95% CI 1.48–4.14, p = 0.001), with no significant increase in pathologic downgrading at RP (OR 1.13, CI 0.48–2.67, p = 0.783). There are a large number of biopsy studies reporting cancer detection on biopsy; however, we chose to limit our included studies to those with pathology at prostatectomy. This hampered the size of the cohorts incorporated. For example, while Siddiqui et al [28] reported on 1003 men undergoing a biopsy, only 170 (17%) had prostatectomy data included. Furthermore, centers employed different definitions of clinical significance, and only two studies (those of Arsov et al and Zhao et al) reported their data at the level of each possible GS (ie, 3 + 3, 3 + 4, 4 + 3, etc.). Both studies demonstrated reduced upgrading at RP for targeted biopsies as GS increased, although analyses in these subgroups only were not computed due to the small sample sizes. Further, the approach for conducting MRI-TRUS fusion targeted biopsy is not standardized, and we found significant variation in the threshold for biopsy, MRI scoring, and
the number of targeted biopsy cores sampled per region of interest. For example, 40% of studies did not use PI-RADS scoring. Therefore, a comparison of PI-RADS scoring and pathologic outcomes was not possible in this analysis (see Table 1). MRI-targeted biopsy is a relatively new technique, with studies demonstrating a significant learning curve, with accuracy improving after the 98th biopsy for a fixed robotic arm platform [35]. No studies accounted for the learning curve associated with TBx, or mentioned interobserver variability in interpreting mpMRI or pathology findings. Significant heterogeneity exists in outcomes of TRUS-guided prostate biopsies as well as MRI-targeted biopsies [36]; studies have shown that surgeon experience with TRUS-guided biopsy may affect MRI-TRUS detection rates as well [37,38]. Since targeted and systematic biopsies were performed during the same session, it is also difficult to assign adverse effects to one approach versus another. It is generally hypothesized that the risks of bleeding, infection, and urinary retention increase with additional cores sampled.
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Studies have shown that MRI-targeted biopsies typically contain a higher percentage of cancer per core due to preferential sampling of the tumor [23,39]. In our analysis, two studies reported different definitions of clinically significant cancer at biopsy [28,33]. For instance, Boesen et al [33] delineated csPCa as GS > 6 with the maximum core length >50% on biopsy and GS > 6 on RP. In contrast, Siddiqui et al [28] defined csPCa in terms of START consortium risk category (low, intermediate, and high risk) with anything with GS = 3 + 4 with >50% of cores positive for cancer on biopsy and GS = 3 + 4 in <20% of the total prostate on final RP pathology. A consistent definition of clinically significant disease and/or standardized reporting of pathology results in future studies would facilitate consistency in comparing outcomes. Considerable disparity also exists in the literature regarding MRI-targeted biopsy’s ability to better detect RP pathology in biopsy-naïve men and men with a prior negative biopsy. While not directly related to our primary outcome, Sonn et al [41] showed that the utility of TBx to detect cancer is best in the prior negative biopsy group, although the FUTURE trial discovered no difference in TBx’s ability to detect aggressive prostate cancer [42]. In the three studies examining men with a prior negative biopsy, our analysis found a significant difference in upgrading rates at RP for patients with a prior negative biopsy undergoing a TBx, with the odds of upgrading after SBx compared with TBx being 4.23 (95% CI 1.68–8.48, p = 0.003). For the biopsynaïve population, two recent randomized trials found no differences in clinically significant cancer detection between TBx and SBx. Nevertheless, our analysis, which instead compared biopsy results with final RP pathology, indicated the potential of MRI-targeted biopsies to reduce upgrading rates in the biopsy-naïve population. For biopsynaïve men, the odds of upgrading at SBx as opposed to that at TBx were 2.47 (95% CI 1.48–4.14, p < 0.001). Given that our analysis was able to include only three studies in this analysis due to study design limitations, both of these populations warrant further subgroup analysis when considering the merits of MRI-guided biopsies. Limitations
Our study must be interpreted in the context of our metaanalysis design. First, there was variability in both study design and reporting among our included studies. Metaanalyses are inherently subject to publication bias, and therefore, small-study effects, as negative results are unlikely to be incorporated or published. Our quantitative analysis consisted of 10 studies, but due to variation in reporting schemas within these studies, only a proportion of men from each study that met our criteria were included for each analysis (see the section on risk of bias). Moreover, there was significant variation in study design. Four studies conducted TBx and SBx concurrently, whereas TBx and SBx were conducted in different cohorts in the other studies. Nevertheless, the cohorts were matched in terms of PSA, prostate volume, and pathologic stage. The differences in MRI assessment also contribute to significant variation in outcomes.
9
In an effort to address heterogeneity due to variation in biopsy technique, we excluded transperineally guided MRItargeted biopsies. Further, patients with negative MRI or MRI TBx were not included, so these results do not apply to these men. Few articles delineated whether upgrading was observed in the region of interest or from a systematic biopsy. Additionally, while this study contributes to the understanding of pathologic risk as it relates to targeted biopsy, it is certainly not complete, and inter- and intratumoral heterogeneity may still be unaccounted for [43,44]. Given the significant learning curve of conducting MRIUS fusion biopsies, large-scale, prospective research is needed to determine targeted biopsy’s impact in the clinic. Conclusions MRI-targeted prostate biopsy results in less pathologic upgrading, and equivalent downgrading, as compared with systematic biopsy at prostatectomy. This improved risk stratification has broad implications, and suggests that targeted biopsy can better select patients for active surveillance, focal therapy, and androgen deprivation therapy in combination with radiotherapy, than systematic biopsy alone. Nevertheless, robust prospective studies are needed to confirm these results. Author contributions: Shokhi Goel had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shoag, Hu. Acquisition of data: Goel, Gross, Baltich. Analysis and interpretation of data: Goel, Gross. Drafting of the manuscript: Goel. Critical revision of the manuscript for important intellectual content: Khani, Robinson, Shoag, Hu. Daniel J. Margolis, Bashir Al Hussein Al Awamlh Statistical analysis: Goel. Obtaining funding: Hu. Administrative, technical, or material support: Shoag, Hu. Supervision: Shoag, Hu. Other: None.
Financial disclosures: Shokhi Goel certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: The Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust supported this research Also supported by the Damon Runyon Physician Scientist Training Award.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. euo.2019.08.001.
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