EURURO-7324; No. of Pages 11

Platinum Priority – Prostatic DiseaseEditorial by XXX on pp. x-y of this issue

Diagnostic Performance of Magnetic Resonance Imaging for the

Detection of Bone Metastasis in Prostate Cancer: A Systematic

Review and Meta-analysis

Sungmin Woo a,1, Chong Hyun Suh b,c,1, Sang Youn Kim a,*, Jeong Yeon Cho a,d, Seung Hyup Kim a,d

a Department of Radiology, Seoul National University College of Medicine, Seoul, Korea; b Department of Radiology and Research Institute of Radiology,

University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; c Department of Radiology, Namwon Medical Center, Jeollabuk-do,

Republic of Korea; d Institute of Radiation Medicine and Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Korea

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X

ava i lable at www.sc iencedirect .com

journa l homepage: www.europea nurology.com

Article info

Article history:

Accepted March 28, 2017

Associate Editor:

Giacomo Novara

Keywords:

Magnetic resonance imaging

Prostate cancer

Bone metastasis

Systematic review

Meta-analysis

Abstract

Context: Magnetic resonance imaging (MRI) has been tested for detecting bone metas-tasis and has shown promising results. Yet, consensus has not been reached regardingwhether it can replace the role of bone scintigraphy in this clinical setting or not.Objective: To review the diagnostic performance of contemporary (�1.5 T) MRI for thedetection of bone metastasis in patients with prostate cancer.Evidence acquisition: MEDLINE and EMBASE were searched up to January 22, 2017. Weincluded studies that used MRI using �1.5-T scanners for the detection of bonemetastasis in patients with prostate cancer, using histopathology or best value com-parator as the reference standard. Two independent reviewers assessed the methodo-logical quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Per-patient sensitivity and specificity of included studies were calculated, and pooled andplotted in a hierarchical summary receiver operating characteristic plot. Meta-regres-sion and sensitivity analyses were performed.Evidence synthesis: Ten studies (1031 patients) were included. Pooled sensitivity was0.96 (95% confidence interval [CI] 0.87–0.99) with a specificity of 0.98 (95% CI 0.93–0.99). At meta-regression analysis, only the number of imaging planes (�2 vs 1) was asignificant factor affecting heterogeneity (p < 0.01). Sensitivity analyses showed thatspecificity estimates were comparable and consistently high across all subgroups, butsensitivity estimates demonstrated some differences. Studies using two or more planes(n = 4) had the highest sensitivity (0.99 [95% CI 0.98–1.00]).Conclusions: Contemporary MRI shows excellent sensitivity and specificity for detec-tion of bone metastasis in patients with prostate cancer. Using two or more imagingplanes may further improve sensitivity. However, caution is needed in applying ourresults due to the heterogeneity among the included studies.Patient summary: We reviewed studies using contemporary magnetic resonance im-aging (MRI) for the detection of bone metastasis in prostate cancer patients. MRI showsexcellent diagnostic performance in finding patients with bone metastasis.

soc

ute. De0-74v@e

# 2017 European As

1 These authors contrib* Corresponding authorro, Jongno-gu, Seoul 11E-mail address: iwishlu

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

http://dx.doi.org/10.1016/j.eururo.2017.03.0420302-2838/# 2017 European Association of Urology. Published by Elsevier

iation of Urology. Published by Elsevier B.V. All rights reserved.

d equally.partment of Radiology, Seoul National University Hospital, 101 Daehak-4, Korea. Tel. +82 2 2072 4897; Fax: +82 2 743 6385.mpas.com (S.Y. Kim).

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

B.V. All rights reserved.

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X2

EURURO-7324; No. of Pages 11

1. Introduction

Determining the presence of bone metastasis is important

in the management of prostate cancer. It not only represents

the most common site of initial metastases, but also is a

major cause of morbidity and mortality in patients with

prostate cancer. Therefore, it is crucial to accurately detect

bone metastasis in order to plan the most optimal

management for patients with prostate cancer [1]. Current-

ly, Tc 99m bone scintigraphy (BS) is recommended by

guidelines as the initial work-up modality for bone

metastasis despite its poor accuracy, because it is widely

available compared with more advance modalities [2]. How-

ever, magnetic resonance imaging (MRI) has continuously

been tested for the purpose of detecting bone metastasis

during the past 3 decades and has shown promising results

[3]. Recent studies have shown that axial skeleton MRI,

whole-body MRI, and even routine prostate MRI are

excellent in determining bone metastasis in patients with

prostate cancer [4–6]. Yet, consensus has not been reached

regarding whether it can replace the role of BS in this

clinical setting or not.

Therefore, we performed a systematic review and meta-

analysis to evaluate the diagnostic performance of contem-

porary MRI for the detection of bone metastasis in patients

with prostate cancer.

2. Evidence acquisition

The present meta-analysis was written according to the

Preferred Reporting Items for Systematic Reviews and

Meta-Analyses guidelines. The research question for the

purpose of this meta-analysis was formulated based on

the following Patient Index test Comparator Outcomes

Study design (PICOS) criteria [7]: What is the diagnostic

performance of contemporary MRI (magnetic field

strength �1.5 T) for the detection of bone metastasis in

patients with prostate cancer, as compared with histo-

pathological results or best value comparator (BVC; a

combination of imaging/clinical/biological studies and at

least 6 mo of follow-up)?

2.1. Literature search

A computerized search of MEDLINE and EMBASE databases

up to January 22, 2017 was performed to identify studies

that were relevant to our research question. The search

query combined synonyms for prostate cancer, MRI, bone,

and diagnostic accuracy as follows: ([‘‘prostat* cancer’’] OR

[‘‘prostat* carcinoma’’] OR [‘‘prostat* neoplasm’’] OR [‘‘pro-

stat* tumor’’]) AND ([bone] OR [skeletal]) AND ([‘‘magnetic

resonance imaging’’] OR [‘‘MR imaging’’] OR [MRI] OR [MR])

AND ([detection] OR [detectability] OR [positivity] OR

[sensitivity] OR [specificity] OR [diagnosis] OR [diagnostic]

OR [accuracy] OR [performance]). Bibliographies of identi-

fied articles were screened to identify additional relevant

studies. The search was limited to studies on ‘‘humans’’

using the ‘‘English’’ language.

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

2.2. Study selection

2.2.1. Inclusion criteria

We included studies that met the following PICOS criteria

(10): (1) patients diagnosed with prostate cancer, (2) MRI

used as the index test for detection of bone metastasis, (3)

histopathology or BVC as the reference standard for

comparison, (4) sufficient information to reconstruct

2 � 2 contingency tables regarding sensitivity and specific-

ity, and (5) publication type of original articles.

2.2.2. Exclusion criteria

The exclusion criteria were as follows: (1) study population

of <10 patients; (2) study population comprising patients

with tumors other than prostate cancer (however, studies

were included if the diagnostic performance was separately

provided for each type of tumor); (3) review articles,

guidelines, consensus statements, letters, editorials, and

conference abstracts; (4) MRI with a magnetic field strength

of <1.5 T; (5) MRI used for the detection of bone metastasis

in prostate tumor, but focusing on topics rather than on

diagnostic accuracy; (6) overlapping patient population;

and (7) insufficient data for the reconstruction of

2 � 2 tables. In case of an overlapping study population,

the study with the largest study population was included.

Authors of the studies were contacted for provision of

further information when 2 � 2 tables could not be

reconstructed.

The literature search and study selection process was

independently performed by two reviewers (S.W. and

C.H.S., with 4 yr of experience in performing systematic

reviews and meta-analyses) with consultation from a third

reviewer (S.Y.K.) for reaching a consensus when disagree-

ment was present.

2.3. Data extraction and quality assessment

The following data were extracted from the selected studies

using a standardized form: (1) patient characteristics—

number of patients, number of patients with bone

metastasis, clinical setting (newly diagnosed vs treated

and risk stratification of bone metastasis according to

clinical criteria), median age and range of patients, prostate-

specific antigen (PSA) level, PSA doubling time, Gleason

score (based on biopsy and radical prostatectomy [RP]

specimens in primary and treated prostate cancer, respec-

tively), and clinical T stage (pathological T stage in post-RP

patients); (2) study characteristics—origin of study

(authors, institution, and duration of patient recruitment),

publication year, study design (prospective vs retrospective,

multicenter vs single center, and consecutive vs noncon-

secutive enrollment), reference standard, interval between

MRI and reference standard, blinding to reference standard,

and characteristics of readers (number and experience);

and (3) MRI characteristics—magnet field strength; scanner

model and manufacturer; coverage of MRI (whole body,

axial skeleton or pelvis [as included in routine prostate

multiparametric MRI]); type of MRI sequences used among

diffusion-weighted imaging (DWI), contrast-enhanced (CE)

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X 3

EURURO-7324; No. of Pages 11

MRI, T1-weighted imaging (T1WI), T2-weighted imaging

(T2WI), or short tau inversion recovery (STIR), and their

corresponding technical parameters; and criteria for bone

metastasis.

The methodological quality of the included studies was

assessed using the Quality Assessment of Diagnostic

Accuracy Studies-2 (QUADAS-2) tool [8]. Data extraction

and quality assessment were performed independently by

two reviewers (S.W. and C.H.S.), and consensus was reached

via discussion with a third reviewer (S.Y.K.).

2.4. Data synthesis and analysis

The primary outcome of this meta-analysis was the per-

patient diagnostic performance of MRI for the detection of

bone metastasis in patients with prostate cancer. As a

secondary outcome, we aimed to assess the presence of

heterogeneity among the included studies and explore

potential causes.

Two by two tables were tabulated for the included

studies to calculate their sensitivity and specificity. If

diagnostic performance of several MRI sequences were

separately assessed, we selected the results using the most

advanced MRI sequence or most comprehensive MRI

protocol (ie, DWI + conventional sequences > DWI >

conventional sequences). When results from multiple

independent readers were given, the result with the highest

accuracy was used. Of note, although one study included in

our meta-analysis [9] assessed bone metastasis on a per-

lesion basis, it was analyzed as per-patient for the following

reasons: (1) this was the only study not providing per-

patient diagnostic performance and (2) the mean number of

lesions per patient in this study was 1.1 (26/24).

Summary estimates of sensitivity and specificity were

calculated using hierarchical logistic regression modeling

including bivariate and hierarchical summary receiver

operating characteristic (HSROC) modeling [10–12]. These

results were plotted using HSROC curves with 95%

confidence and prediction regions. Publication bias was

evaluated using visual analysis of the Deeks et al’s funnel

plot and calculating the p value using Deeks et al’s

asymmetry test [13].

Heterogeneity was determined using the following: (1)

Cochran’s Q test with p < 0.05 indicating the presence of

heterogeneity; (2) Higgins I2 test with the following criteria

for the interpretation of the degree of heterogeneity:

inconsistency index (I2) = 0–40%, heterogeneity might not

be important; 30–60%, moderate heterogeneity may be

present; 50–90%, substantial heterogeneity may be present;

and 75–100%, considerable heterogeneity [14]; and (3)

testing for the presence of a threshold effect (a positive

correlation between sensitivity and false positive rate)

among the selected studies.

Meta-regression analyses using several covariates were

performed to explore the cause of heterogeneity as follows:

(1) clinical setting (newly diagnosed vs treated), (2)

reference standard (BVC only vs inclusion of histopatholo-

gy), (3) magnet field strength (1.5 vs 3 T), (4) MRI coverage

(pelvis vs axial skeleton/whole body), (5) MRI sequence

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

(only conventional sequences vs DWI included), (6) number

of imaging planes (1 vs �2), and (7) minimum slice

thickness among sequences used (�4 vs >4 mm). In

addition, sensitivity analyses for the various settings

stratified to the covariates described above were performed.

The ‘‘midas’’ module in Stata 10.0 (StataCorp LP, College

Station, TX, USA) and ‘‘mada’’ package in R software version

3.2.1 (R Foundation for Statistical Computing, Vienna,

Austria) were used for statistical analyses, with

p < 0.05 indicating statistical significance.

3. Evidence synthesis

3.1. Literature search

The systematic literature search initially yielded 1689 arti-

cles. After removing 697 duplicates, screening of the

992 titles and abstracts yielded 46 potentially eligible

original articles. Full-text reviews were considered and

36 studies were excluded due to the following reasons: not

in the field of interest (n = 21), insufficient data to

reconstruct 2 � 2 tables (n = 9), <10 patients (n = 2), study

population shared with other studies (n = 3), and non-

English publication (n = 1). Ultimately, 10 studies including

1031 patients evaluating the diagnostic performance of MRI

for the detection of bone metastasis in patients with

prostate cancer were included in this meta-analysis [4–

6,9,15–20]. The study selection process is summarized in

Figure 1.

3.2. Characteristics of included studies

The patient characteristics are described in Table 1. The size

of the study population ranged from 21 to 308 patients,

with the percentage of patients with bone metastasis

ranging from 6.8% to 71.4%. Four studies included only

patients with newly diagnosed prostate cancer, three

included only those with treated prostate cancer, and three

included a mixed population of newly diagnosed and

treated prostate cancer. The patients had a median age of

63–78 yr. Six studies were based on patients with a

clinically ‘‘high risk’’ of bone metastasis, two studies

included patients with any risk, and two studies were

unclear regarding this risk. The median PSA and Gleason

scores were 2.7–31 ng/ml and 7–9, respectively.

The study characteristics are summarized in Table 2. The

study design was prospective in six studies and retrospec-

tive in four. All but two studies were single-center studies.

Patient recruitment was consecutive in all but two studies

(nonconsecutive 1:3 matching for normal and metastasis in

one study and not explicit in another). Four studies used

either histopathology or BVC as the reference standard;

while the other six used only BVC. The imaging modalities

used in the included studies for BVC included BS, targeted x-

ray, computed tomography (CT), MRI, and positron emis-

sion tomography/CT. The interval between MRI and the

reference standard was not provided in three studies. MRI

was interpreted blinded to the reference standard in all but

one study, which was not explicit.

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

Fig. 1 – Flow diagram showing study selection process for meta-analysis. MRI = magnetic resonance imaging.

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X4

EURURO-7324; No. of Pages 11

The MRI characteristics are shown in Table 3. Six studies

used 3-T scanners, two used 1.5-T scanners, and two used

1.5- or 3-T scanners. Regarding coverage of MRI, four

studies used whole-body MRI, two assessed the axial

skeleton, and four covered only the pelvis using a routine

prostate MRI protocol. A combination of DWI and conven-

tional sequences (T1WI, T2WI, and/or STIR) was used in five

studies, only DWI in one study, and only conventional

sequences in four studies. The criteria for bone metastasis

were explicit in seven studies; however, three studies were

not clear on this issue as one study was not explicit

regarding the role of T1WI and STIR, another study did not

provide any criteria, and the other simply stated the use of a

five-point Likert scale.

3.3. Quality assessment

Overall, the quality of the studies was considered moderate,

with eight of the 10 studies satisfying at least four of the

seven QUADAS-2 domains (Fig. 2). Regarding the patient

selection domain, one study was considered to have a high

risk of bias due to a nonconsecutive case/control design

[19]. In addition, one study was considered to have an

unclear risk of bias, as it did not explicitly mention whether

patient enrollment was consecutive or not [9]. There was

high concern for applicability in one study, as it included

patients with no metastasis or oligometastasis (<5 metas-

tases) based on conventional imaging and excluding those

with polimetastasis [15]. Regarding the index test domain,

there was an unclear risk of bias in four studies, as it was

unclear whether MRI was evaluated blinded to the

reference standard in one study [9] and whether a

prespecified threshold was used in three studies

[15,16,19]. There was low concern for applicability in all

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

10 studies. Regarding the reference standard domain, all the

studies had an unclear risk of bias, as it was unclear whether

the derivation of the reference standard was blinded to MRI.

There was unclear concern for applicability in three studies,

as they did not explicitly mention whether MRI–reference

standard interval was at least 6 mo when BVC was used as

the reference standard [6,15,20]. Regarding the flow and

timing domain, three studies had a high risk of bias as

different reference standards were applied within the study

[4,6,16,19]. Two studies were considered to have an unclear

risk of bias as the MRI–reference standard interval was not

provided [15,20].

3.4. Diagnostic accuracy

The sensitivity and specificity of the 10 individual studies

were 72–100% and 70–100%, respectively. Although the

Cochran’s Q test suggested that heterogeneity was not

present (Q = 2.970, p = 0.113), the Higgins I2 statistics

demonstrated substantial heterogeneity with regard to

both sensitivity (I2 = 81.44%) and specificity (I2 = 85.85%).

No threshold effect was shown upon visualization of the

coupled forest plot of sensitivity and specificity (Fig. 3), with

a correlation coefficient between sensitivity and false

positive rate of –0.581 (95% confidence interval [CI] –

0.886 to 0.077).

For all 10 studies combined, the pooled sensitivity and

specificity were 0.96 (95% CI 0.87–0.99) and 0.98 (95% CI

0.93–0.99), respectively. In the HSROC curve, there was a

large difference between the 95% confidence and prediction

regions, additionally indicating that heterogeneity was

present between the studies (Fig. 4). The area under the

HSROC curve was 0.99 (95% CI 0.98–1.00). According to the

Deeks et al’s [13] funnel plot, the likelihood of publication

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

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E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X 5

EURURO-7324; No. of Pages 11

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

bias was low, with a p value of 0.23 for slope coefficient

(Fig. 5).

3.5. Exploration of heterogeneity

The results of meta-regression analyses are shown in

Table 4. Only the number of imaging planes used was shown

to be a significant factor affecting heterogeneity (p < 0.01).

Specifically, sensitivity was significantly higher when using

two or more imaging planes (0.99 [95% CI 0.98–1.00])

compared with when using only one plane (0.87 [95% CI

0.80–0.94], p < 0.01). Although specificity also showed

‘‘statistically’’ higher values when using two or more planes,

the difference was not considered meaningful: 0.99 (95% CI

0.98–1.00) versus 0.95 (95% CI 0.90–1.00; p = 0.01). Other-

wise, clinical setting, reference standard, magnet field

strength, MRI coverage, type of MRI sequences used, and

minimum slice thickness were not shown to be significant

factors affecting the heterogeneity.

The results of sensitivity analyses are shown in

Figure 6. The specificity estimates were comparable with

consistently high values across all subgroups (0.91–0.99). In

general, the sensitivity estimates were also comparable

across most subgroups with pooled sensitivity ranging from

0.93 to 1.00; however, a few subgroups showed slightly

lower pooled sensitivity. Specifically, studies that included

only patients with treated prostate cancer (0.89 [95% CI

0.74–1.00]), used both 1.5- or 3-T scanners (0.89 [95% CI

0.80–0.94]), and used only one imaging plane for analysis

(0.87 [95% CI 0.80–0.94]) tended to show lower sensitivity.

However, pooling the results for studies including patients

with any risk and those using both 1.5- or 3-T scanners were

considered unstable as only two studies were included in

these subgroups. In addition, when a sensitivity analysis

was performed using nine studies, excluding a single study

[15] that (1) was considered to have high concern for

applicability regarding patient selection and (2) showed

particularly inferior diagnostic performance in terms of

both sensitivity and specificity, the degree of heterogeneity

was substantially decreased (I2 = 57.14 and 75.64 for

sensitivity and specificity, respectively) with sensitivity of

0.97 (95% CI 0.89–0.99) and 0.98 (95% CI 0.95–0.99).

3.6. Discussion

In the current meta-analysis, we evaluated the diagnostic

accuracy of contemporary MRI (using scanners with a

magnetic field strength of 1.5 T or higher) for the detection of

bone metastasis in patients with prostate cancer. Our results

show that the pooled per-patient sensitivity and specificity

of the 10 included studies were 0.96 (95% CI 0.87–0.99) and

0.98 (95% CI 0.93–0.99), respectively. Based on this excellent

diagnostic performance of MRI for the detection of bone

metastasis, MRI could be used as one of the primary

modalities for triaging patients with newly diagnosed or

treated prostate cancer and to help decide on the most

optimal management. Although we did not directly compare

the performance between MRI and BS, which would be best

addressed by well-designed randomized controlled trials,

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

Table 2 – Study characteristics

First author Origin of study Study design Reference standard Blinding Reader characteristics

Publication

year

Duration

of patient

recruitment

Institution Prospective Multicenter Consecutive

enrollment

Methods Details of BVC MRI–reference

standard

interval

No. Consensus Experience

(yr)

Conde-Moreno [15] 2016 10.2014–3.2015 Consorcio

Hospitalario

Provincial de

Castellon

Yes No Yes BVC All imaging studies (BS, CT, WB-

DW-MRI, choline-PET/CT) by a

multidisciplinary team

NR Yes NR NR NR

Kitajima [16] 2014 6.2009–4.2012 Mayo Clinic No No Yes BVC or

histopathology

Dedicated CT, MRI, or PET–CT

and follow-up after 6 mo

NR Yes 2 Independent 22/2

Lecouvet [4] 2007 NR a Cliniques

universitaires

Saint Luc

Yes No Yes BVC or

histopathology

CT correlation for equivocal MRI

findings or imaging (BS, MRI),

clinical, and biological follow-

up at 6 mo by specialists for

each modality

NR Yes 2 Consensus Senior MSK

radiologist/

senior resident

Lecouvet [5] 2012 3.2007–3.2010 Cliniques

universitaires

Saint Luc

Yes No Yes BVC All available imaging tests (BS/

TXR, WB-MRI) and clinical/

biological follow-up after 6 mo

by specialists for each modality

NR Yes 2 Independent Senior MSK

radiologist/

fellow

Mosavi [17] 2012 10.2009–3.2011 Uppsala

University

Hospital

Yes No Yes BVC BS, MRI (T1WI, STIR), and

follow-up using 18F-NaF PET/CT

and DWI

�7 mo Yes 2 Consensus 20

Pasoglou [18] 2015 2.2012–12.2012 Cliniques

universitaires

Saint Luc,

Centre

Hospitalier

Universitaire

Vaudois

Yes Yes Yes BVC Consensus session of all

available MRI by radiologists,

prospective clinical and

biological follow-up by uro-

oncologist, and imaging follow-

up at 6 mo

NR Yes NR NR NR

Piccardo [9] 2014 NR E.O. Galliera

Hospital, Azienda

Sanitaria dell’Alto

Adige

Yes Yes NR BVC Contrast-enhanced CT and

multiparametric MRI at 12 mo

follow-up, and response to

treatment, lab tests, other

imaging studies (x-ray, BS)

12–18 mo NR NR NR NR

Vargas [19] 2016 1.2000–6.2014 Memorial Sloan

Kettering

Cancer Center

No No No BVC or

histopathology

At least 1 yr or imaging/clinical

follow-up

>1 yr Yes 2 Independent 5/7

Venkitaraman [20] 2009 1.2001–10.2005 Royal Marsden

Hospital

No No Yes BVC MRI, BS, or other imaging (TXR,

CT) and follow-up studies (BS or

MRI) assessing treatment

response

NR Yes 1 NR

Woo [6] 2016 1.2013–12.2013 Seoul National

University Hospital

No No Yes BVC or

histopathology

Comprehensive review of initial

and follow-up BS, MRI, CT, TXR,

and PET, and clinical/laboratory

follow-up at a multidisciplinary

urological–oncological

conference

NR Yes 2 Independent 20/34

BS = bone scintigraphy; BVC = best value comparator; CT = computed tomography; DW = diffusion weighted; DWI = diffusion-weighted imaging; MRI = magnetic resonance imaging; MSK = musculoskeletal; NR = not

reported; PET = positron emission tomography; STIR = short tau inversion recovery; TXR = targeted x-ray; T1WI = T1-weighted imaging; WB = whole body.a Duration of patient recruitment not reported, but overlap with Lecouvet et al [5] (3.2007–3.2010) not possible.

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EURURO-7324; No. of Pages 11

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

we speculate that MRI is a more superior modality in terms

of the sensitivity and specificity for detecting bone

metastasis in patients with prostate cancer, given the

well-known limited diagnostic performance of BS in the

literature (ie, pooled sensitivity and specificity of 0.71 and

0.91, respectively) [21]. However, as our meta-analysis was

based on a per-patient basis and we did not assess the per-

lesion diagnostic performance of MRI, whether MRI can be

used to identify the metastatic burden or as a modality for

assessing global treatment response cannot be answered

from the results of our study.

There was significant heterogeneity among the includ-

ed studies. Based on meta-regression analysis, the only

statistically significant factor that may be attributable to

this heterogeneity was the number of imaging planes

used for the determination of bone metastasis. Specifi-

cally, studies that used two or more planes (0.99) showed

significantly greater sensitivity compared with those

using only one plane (0.87). Regarding MRI technology,

use of DWI or slice thickness (�4 or >4 mm) was not

shown to affect the heterogeneity. Regarding slice

thickness, the cutoff value of 4 mm was based on practical

guidelines and may not have been a significant factor as

all but two of the included studies had a minimum slice

thickness of 5 or less [17,20,22,23]. However, it is unclear

why the addition of DWI did not result in superior results

compared with using only conventional sequences of

T1WI, T2WI, or STIR. Of note, CE MRI was not separately

analyzed as a covariate in the current meta-analysis, as it

was used in only two studies, where it was not a

dominant sequence but rather one among several MRI

sequences included in their multiparametric prostate

MRI protocol [6,16]. Further studies may be needed to

verify the added value of DWI and CE MRI in determining

bone metastasis. Collectively, based on these results

with regard to technical aspects of MRI, guidelines

should recommend that at least two different planes be

used when assessing bone metastasis from prostate

cancer.

The current study highlights that regardless of the

coverage of MRI—that is, whether it covered only the pelvis

in routine prostate MRI, or whether a dedicated axial

skeleton or whole-body MRI was utilized—there was

consistently high per-patient sensitivity (0.94, 0.95, and

0.97, respectively) and specificity (0.99, 0.94, and 0.97,

respectively). This is substantiated by the literature in that

although the use of axial skeleton or whole-body MRI may

allow identification of a greater number of metastatic bone

lesions, the probability of missing a patient with metastasis

is negligible due to the fact that isolated peripheral

metastasis is highly uncommon as prostate cancer primari-

ly metastasizes to the lower spine and pelvis before

spreading throughout the whole body [4,6,24]. The decision

to simply use routine prostate MRI, or perform additional

axial skeleton or whole-body MRI should be based on

further studies assessing cost effectiveness, where the latter

two would be more effective in terms of per-lesion

detection, but would increase cost in terms of MRI

acquisition time and medical costs.

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

Fig. 2 – Grouped bar charts showing risk of bias (left) and concerns for applicability (right) of 10 included studies using QUADAS-2. QUADAS-2 = QualityAssessment of Diagnostic Accuracy Studies-2.

Fig. 3 – Coupled forest plots of pooled sensitivity and specificity. Numbers are pooled estimates with 95% CIs in parentheses. Correspondingheterogeneity statistics are provided at bottom right corners. Horizontal lines indicate 95% CIs. CI = confidence interval.

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X8

EURURO-7324; No. of Pages 11

Please cite this article in press as: Woo S, et al. Diagnostic Performance of Magnetic Resonance Imaging for the Detection of BoneMetastasis in Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.03.042

Fig. 4 – Hierarchical summary receiver operating characteristic curve ofthe diagnostic performance of MRI for detection of bone metastasis inpatients with prostate cancer. AUC = area under the curve;MRI = magnetic resonance imaging; SENS = sensitivity; SPEC = specificity;SROC = summary receiver operating characteristic.

Fig. 5 – Deeks et al’s [13] funnel plot for per-patient analysis. A p valueof 0.23 suggests that the likelihood of publication bias islow. ESS = effective sample size.

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X 9

EURURO-7324; No. of Pages 11

The clinical setting (newly diagnosed or treated prostate

cancer) is a major factor when determining bone metastasis

in prostate cancer patients. Although not significant at meta-

regression analysis, sensitivity analysis showed that studies

including only treated prostate cancer patients showed a

tendency for lower sensitivity compared with those includ-

ing only patients with newly diagnosed prostate cancer

(0.89 vs 0.93). We speculate that in patients who have

already received systemic treatment (ie, androgen depriva-

tion therapy), the imaging characteristics of metastatic bone

lesions may have changed compared with the original (or

pretreatment) appearance, thereby hindering accurate

detection [25,26]. This may not be applicable for patients

treated with local therapy such as RP; however, we were

Table 4 – Results of meta-regression analysis of MRI for the detection

Covariates Subgroup

Clinical setting Newly diagnosed

Treated

Reference standard BVC only

BVC or histopathology

Magnetic field strength 3 T used

1.5 T only

MRI coverage Pelvis

Axial skeleton or whole body

MRI sequence DWI used

Conventional sequences only

Number of imaging planes �2

1

Minimum slice thickness �4 mm

>4 mm

BVC = best value comparator; CI = confidence interval; DWI = diffusion-weighted

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

unable to perform separate analyses according to the type of

treatment as the included studies did not provide separate

diagnostic performance values. Another aspect of clinical

setting is the risk stratification for possibility of bone

metastasis. Guidelines recommend that screening for bone

metastasis be performed in high-risk patients [2]. Based on

sensitivity analysis, the pooled sensitivity and specificity

were comparable in studies including only high-risk patients

(0.95 and 0.93, respectively), in studies on patients with any

risk (0.91 and 0.99, respectively), and for all 10 studies

(0.96 and 0.98, respectively). However, one study included

only patients with no or less than five metastatic bone

lesions based on conventional imaging, and reported

distinctively inferior diagnostic performance compared with

the other nine studies (sensitivity of 0.72 and specificity of

0.70). This study was considered to have high concern for

applicability as in real-life clinical practice; metastatic

screening would not be employed for patients with low or

of bone metastasis in patients with prostate cancer

Meta-analytic summary estimates

Sensitivity(95% CI)

Specificity(95% CI)

p

0.97 (0.93–1.00) 0.96 (0.91–1.00) 0.10

0.93 (0.83–1.00) 0.99 (0.97–1.00)

0.96 (0.87–1.00) 0.98 (0.95–1.00) 0.86

0.95 (0.88–1.00) 0.98 (0.95–1.00)

0.95 (0.87–1.00) 0.99 (0.98–1.00) 0.08

0.96 (0.91–1.00) 0.95 (0.89–1.00)

0.94 (0.86–1.00) 0.99 (0.97–1.00) 0.34

0.97 (0.92–1.00) 0.96 (0.91–1.00)

0.96 (0.89–1.00) 0.99 (0.96–1.00) 0.68

0.95 (0.89–1.00) 0.96 (0.90–1.00)

0.99 (0.98–1.00) 0.99 (0.98–1.00) <0.01

0.87 (0.80–0.94) 0.95 (0.90–1.00)

0.96 (0.88–1.00) 0.99 (0.98–1.00) 0.18

0.96 (0.90–1.00) 0.96 (0.91–1.00)

imaging; MRI = magnetic resonance imaging.

ance of Magnetic Resonance Imaging for the Detection of Boneeta-analysis. Eur Urol (2017), http://dx.doi.org/10.1016/

Fig. 6 – Forest plots of sensitivity analyses showing pooled sensitivity and specificity estimates and corresponding 95% CIs for various subgroups.BVC = best value comparator; CI = confidence interval; DWI = diffusion-weighted imaging; ST = slice thickness. a Risk of bone metastasis based onclinical criteria (Gleason grade, clinical T stage, prostate-specific antigen, or prostate-specific antigen doubling time). b Unstable pooled estimates (<3studies). c Excluding study by Conde-Moreno et al [15].

E U R O P E A N U R O L O G Y X X X ( 2 0 1 7 ) X X X – X X X10

EURURO-7324; No. of Pages 11

intermediate risk of bone metastasis only. Therefore, we

performed sensitivity analysis excluding this single study,

and yielded consistent diagnostic performance with a

substantially lower degree of heterogeneity: sensitivity

and specificity of 0.97 (95% CI 0.89–0.99) and 0.98 (95% CI

0.95–0.99), respectively; I2 = 57.4 and 75.64, respectively.

One of the major limitations of our meta-analysis is that all

included studies used BVC or predominantly BVC as the

reference standard. As BVC is based on a combination of

clinical, laboratory, imaging, and follow-up studies, this

inherently imposes a significant risk for differential verifica-

tion biases among all included patients. However, it is unlikely

that any further study will solely use biopsy or surgery to

obtain histopathological results for the reference standard

when determining bone metastasis, as this would not be

feasible in clinical practice and would be ethically unjustifi-

able. Another limitation of this meta-analysis is that we were

unable to assess the per-lesion diagnostic performance of

MRI, as only two studies provided such information. Future

studies may be needed to elucidate the per-lesion sensitivity

and specificity of MRI for the detection of bone metastasis in

patients with prostate cancer. Furthermore, caution is needed

in applying our results to routine clinical practice, as there was

substantial heterogeneity among the included studies and we

used the results with the highest accuracy when diagnostic

performance from multiple independent readers were

provided in the included studies.

4. Conclusions

MRI shows excellent sensitivity and specificity for the

detection of bone metastasis in patients with prostate

cancer. Studies using two or more planes for assessment

Please cite this article in press as: Woo S, et al. Diagnostic PerformMetastasis in Prostate Cancer: A Systematic Review and Mj.eururo.2017.03.042

showed the highest sensitivity and specificity, while

diagnostic performance was consistently high across

multiple subgroups.

Author contributions: Sang Youn Kim 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: Woo, Suh, S.Y. Kim.

Acquisition of data: Woo, Suh, S.Y. Kim.

Analysis and interpretation of data: Woo, Suh, S.Y. Kim.

Drafting of the manuscript: Woo.

Critical revision of the manuscript for important intellectual content: Suh,

S.Y. Kim, Cho, S.H. Kim.

Statistical analysis: Suh.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: S.Y. Kim, Cho, S.H. Kim.

Other: None.

Financial disclosures: Sang Youn Kim 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, consultan-

cies, 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: None.

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