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EUROPEAN UROLOGY 68 (2015) 8–19
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Platinum Priority – Collaborative Review – Prostate Cancer
Editorial by Stacy Loeb on pp. 20–21 of this issue
Detection of Clinically Significant Prostate Cancer Using Magnetic
Resonance Imaging–Ultrasound Fusion Targeted Biopsy:
A Systematic Review
Massimo Valerio a,b,c,*,y, Ian Donaldson a,b,y, Mark Emberton a,b, Behfar Ehdaie d,
Boris A. Hadaschik e, Leonard S. Marks f, Pierre Mozer g,h, Ardeshir R. Rastinehad i,
Hashim U. Ahmed a,b
a
Division of Surgery and Interventional Science, University College London, London, UK; b Department of Urology, University College London Hospitals NHS
Foundation Trust, London, UK; c Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; d Urology Service, Sidney Kimmel
Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;
e
Department of Urology, University Hospital
Heidelberg, Heidelberg, Germany; f Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA;
g
Department of Urology, Pitié-
h
Salpétrière Academic Hospital, Pierre et Marie Curie University, Paris, France; Institut des Systèmes Intelligents et de Robotique, l’Université Pierre et Marie
Curie, Paris, France; i Arthur Smith Institute for Urology and Departments of Radiology and Interventional Radiology, Hofstra North Shore-Jewish School of
Medicine, New Hyde Park, NY, USA
Article info
Abstract
Article history:
Accepted October 16, 2014
Context: The current standard for diagnosing prostate cancer in men at risk relies on a
transrectal ultrasound–guided biopsy test that is blind to the location of the cancer. To
increase the accuracy of this diagnostic pathway, a software-based magnetic resonance
imaging–ultrasound (MRI-US) fusion targeted biopsy approach has been proposed.
Objective: Our main objective was to compare the detection rate of clinically significant
prostate cancer with software-based MRI-US fusion targeted biopsy against standard
biopsy. The two strategies were also compared in terms of detection of all cancers,
sampling utility and efficiency, and rate of serious adverse events. The outcomes of
different targeted approaches were also compared.
Evidence acquisition: We performed a systematic review of PubMed/Medline, Embase
(via Ovid), and Cochrane Review databases in December 2013 following the Preferred
Reported Items for Systematic reviews and Meta-analysis statement. The risk of bias was
evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool.
Evidence synthesis: Fourteen papers reporting the outcomes of 15 studies (n = 2293;
range: 13–582) were included. We found that MRI-US fusion targeted biopsies detect
more clinically significant cancers (median: 33.3% vs 23.6%; range: 13.2–50% vs 4.8–
52%) using fewer cores (median: 9.2 vs 37.1) compared with standard biopsy techniques,
respectively. Some studies showed a lower detection rate of all cancer (median: 50.5% vs
43.4%; range: 23.7–82.1% vs 14.3–59%). MRI-US fusion targeted biopsy was able to
detect some clinically significant cancers that would have been missed by using only
standard biopsy (median: 9.1%; range: 5–16.2%). It was not possible to determine which
of the two biopsy approaches led most to serious adverse events because standard and
targeted biopsies were performed in the same session. Software-based MRI-US fusion
targeted biopsy detected more clinically significant disease than visual targeted biopsy
in the only study reporting on this outcome (20.3% vs 15.1%).
Keywords:
Image-guided biopsy
Image processing
computer assisted
Magnetic resonance imaging
Prostate neoplasms
Software
Targeted biopsy
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y
Contributed equally.
* Corresponding author. Division of Surgery and Interventional Science, University College London,
London, UK, W1P 7NN. Tel. +44 20 3447 9194; Fax: +44 20 3447 9303.
E-mail address: [email protected] (M. Valerio).
http://dx.doi.org/10.1016/j.eururo.2014.10.026
0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 68 (2015) 8–19
9
Conclusions: Software-based MRI-US fusion targeted biopsy seems to detect more
clinically significant cancers deploying fewer cores than standard biopsy. Because there
was significant study heterogeneity in patient inclusion, definition of significant cancer,
and the protocol used to conduct the standard biopsy, these findings need to be
confirmed by further large multicentre validating studies.
Patient summary: We compared the ability of standard biopsy to diagnose prostate
cancer against a novel approach using software to overlay the images from magnetic
resonance imaging and ultrasound to guide biopsies towards the suspicious areas of
the prostate. We found consistent findings showing the superiority of this novel
targeted approach, although further high-quality evidence is needed to change current
practice.
# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Recent level 1 evidence has shown that men with
intermediate- and high-risk prostate cancer (PCa) benefit
from immediate radical therapy [1,2]. Therefore accurate
attribution of cancer risk is critical. Inaccurate risk
attribution can lead to both overtreatment and its consequent detrimental impact on quality of life for men with
true low-risk cancer as well as undertreatment and the
potential for missing the window of curability for those men
with clinically significant disease.
The current standard for diagnosing PCa in men at risk
relies on a transrectal ultrasound (TRUS)-guided biopsy
test that is blind to the location of cancer. The test uses a
random deployment of 10–12 needles to sample the
prostate. If cancer is detected, a correct risk attribution is
possible in approximately 50% [3,4]. To increase the
accuracy of this diagnostic pathway, some experts
advocate an increase in the number of cores using the
same transrectal approach (saturation biopsies) [5];
others advocate transperineal template mapping biopsy
(sampling the prostate every 5 mm) [6]. More recently, it
was proposed that targeted biopsies to suspicious
lesion(s) detected by multiparametric magnetic resonance imaging (mpMRI) may increase the diagnostic
accuracy of TRUS biopsy [7]. A systematic review of the
literature recently showed that image-guided targeted
biopsy may detect the same number of men with
clinically significant disease using fewer cores compared
with standard biopsy [8].
The mpMRI involves combining T2-weighted images
with diffusion-weighted images (DWIs) and dynamic
contrast enhancement (DCE) [9,10]. A number of studies
showed that mpMRI has high sensitivity and specificity
[11–14]. Because the mpMRI and the biopsy are
performed on different days with the latter commonly
carried out using a transrectal ultrasound probe, a
number of devices that use image-fusion software have
been developed to overlay the mpMRI suspicious area
onto the ultrasound (US) images at the time of biopsy.
We conducted a systematic review of published studies
using MRI-TRUS image fusion targeted prostate biopsies to
assess the accuracy of detection for clinically significant PCa
compared with standard biopsies.
2.
Evidence acquisition
2.1.
Search strategy and selection criteria
The protocol of this study was registered before commencement in the Prospective Register of Systematic Review
(PROSPERO number CRD42013006734) [15]. It was
designed and carried out according to the Preferred
Reported Items for Systematic Reviews and Meta-analysis
guidelines [16]. Study designs considered for inclusion were
randomised controlled trials (RCTs), paired cohort and
retrospective direct comparative studies assessing the
detection of PCa in a clinical setting by MRI-TRUS image
fusion targeted biopsies compared with the local standard
of care.
The PubMed/Medline, Embase (via Ovid), and Cochrane
Review databases were searched from inception to December 10, 2013, limited to the English language and human
studies. We used the following search terms in all
databases: (‘‘MR’’ or ‘‘MRI’’ or ‘‘magnetic resonance imaging’’ or ‘‘transrectal’’ or ‘‘TRUS’’) AND (‘‘fusion’’ or ‘‘registration’’ or ‘‘targeted’’ or ‘‘target’’ or ‘‘computer’’ or ‘‘software’’)
AND (‘‘prostate’’ or ‘‘prostate neoplasm’’ or ‘‘prostate
cancer’’). Complete eligibility assessment was performed
independently by two investigators (M.V. and I.D.). After a
first screening based on study title, all papers were assessed
based on full text and excluded with reasons when
appropriate. Reference lists of included papers and latest
review articles were also hand-searched. Conference
abstracts reporting on original series were not included
in the final quantitative analysis, but main results were still
reported for completeness in a separate table. The two
investigators independently extracted data for each selected study using a standardised data extraction sheet defined
a priori by the study team. Disagreement between the two
reviewers was resolved by consensus once full data
extraction was complete. Corresponding authors of included original studies were contacted when data were not
available. In case of no reply, uncertain outcomes were not
reported. Duplicate reports from the same cohort were
excluded unless the study populations seemed only
partially overlapping (!50% increase in patient numbers
compared with the first report). Where this occurred, it was
made explicit in the summary tables.
10
EUROPEAN UROLOGY 68 (2015) 8–19
The primary outcome was the detection rate of clinically
significant disease by MRI-TRUS image fusion targeted
biopsy compared with the standard biopsy technique. The
definition used to determine clinical significance was the
one used by individual studies. Secondary outcomes were
detection rate of all cancer, sampling efficiency and utility,
and serious adverse event rate. We calculated sampling
efficiency as the median number of cores to diagnose one
man with clinically significant cancer. Utility was defined as
the number of men with clinically significant disease
detected by one sampling strategy but missed by the other
strategy.
The data extraction form was designed according to recent
Standards of Reporting for MRI-targeted Biopsy Studies
(START) of the prostate [17]. The following information was
extracted from each study: design, population (sample size,
prior biopsy or treatment, age, prostate-specific antigen,
prostate volume, number of mpMRI visible lesions per
patient), mpMRI characteristics and interpretation, type of
anaesthesia, standard biopsy (number of cores, sampling
route, blinding), MRI-TRUS image fusion targeted biopsy
procedure (software used, sampling route, time flow, number
of cores per lesion), separate histologic outcomes for
standard biopsy against targeted (detection rate of clinically
significant disease, detection rate of all cancer, biopsy
efficiency, utility of one biopsy approach compared with
the other), and serious adverse events (classification used,
number, and type). When the studies included a comparison
between two targeted approaches, of which at least one was
software based, the histologic outcomes mentioned earlier
were also extracted for the alternative targeted strategy, and
the direct comparison was displayed in a separate table.
2.2.
Risk of bias in individual studies
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 [18]. In case of
disagreement, the senior author (H.U.A.) was consulted
and arbitrated. The QUADAS-2 tool includes four domains—
patient selection, index test, reference test, and time flow—
that are all assessed in terms of risk of bias, and the first three
in terms of applicability. The signalling questions used to
score each domain were derived from the QUADAS-2 tool
statement and are displayed in Supplementary Table 1.
2.3.
Statistical analysis
Continuous variables are given using median, interquartile
range (IQR), and overall range; the mean with standard
deviation was used when the former was not available.
Categorical variables are given using frequencies and
percentages. All analyses were performed using SPSS
v.20.0 (IBM Corp., Armonk, NY, USA).
3.
Evidence synthesis
3.1.
Risk of bias
Fourteen original papers were included in the final analysis
(Fig. 1; Tables 1–3) [19–32]. Seven additional studies were
presented only at congresses and are reported for completeness in Supplementary Table 2 [33–39].
Most studies had a low risk of bias and low applicability
concerns with respect to patient selection (Figs. 2 and 3).
[(Fig._1)TD$IG]
(PubMed, Embase, Cochrane Database)
(n = 5366)
g
I
Re
Screening
(n = 4094)
Records screened
(n = 4094)
Eligibility
Re
Records assessed for eligibility
(n = 121)
Records exc
(n = 3973)
Records excluded with reasons (n = 103):
Duplicates data set (n = 35)
Did not meet criteria (n = 49)
Technical report and preclinical (n = 13)
Re
(n = 1)
Comments (n = 5)
Included
er reference searching (n = 3)
Table 1–3: Full papers included (n = 14)
Supplementary Table 2: Conference reports (n = 7)
Fig. 1 – Preferred reporting items for systematic review and meta-analysis flowchart.
Table 1 – Design, study population, magnetic resonance, and biopsy procedures of the 15 studies included*
Study population
Study
Design
Sample
Prior biopsy
Age, yr
MR characteristics and Interpretation
PSA, ng/ml
Prostate volume,
Strength
ml
of magnetic
size
Sequences
Endorectal Interpreted by
coil
Score used
consensus
Comparator
Threshold
Time from
for targeted
field, T
Anaesthesia
MR-TRUS fusion targeted biopsy
Standard
Blinded to
Software
Sampling
test
MR results
used
Route
MR to
Targeted
Mean no.
No. of cores
biopsy
of lesions
per lesion
performed per patient
biopsy, d)
first
Mozer et al [19] Paired cohort study
152
Biopsy naive
Median (IQR):
Median (IQR):
Median (IQR):
63.7 (59.3–67.5)
6 (4–10)
38.5 (30–55)
1.5
Mean " SD:
Mean " SD:
Mean " SD:
1.5
Mean " SD:
Mean " SD:
Mean " SD:
1.5
Previous negative
Median (IQR):
Median (IQR):
Median (IQR):
3
biopsy
65 (59–70)
7.5 (5–11.2)
58 (39–82)
T2W, DWI, DCE
N
N
Likert
!2
30; 15–51;
Local
TRUS 12 cores
Y
Urostation
Transrectal
N
1
Median
Local
TRUS 10–12 cores
NR
Virtual
Transrectal
NR
NR
Median
median; IQR)
(range):
2 (2–3)
Delongchamps
Paired cohort study
131
Biopsy naive
et al [20],
64.6 " 6.7
first study
Delongchamps
Paired cohort study
133
Biopsy naive
et al [20],
64.5 " 7.9
second study
Sonn et al [21]
y
Paired cohort study
105
8.3 " 4.1
9 " 3.9
T2W, DWI, DCE
Y
Y
55.7 " 35.1
Benign,
Intermediate NR
intermediate,
Navigator
(range):
malignant
T2W, DWI, DCE
Y
Y
58.3 " 28.6
Benign,
4 (3–8)
Intermediate NR
Local
TRUS 10–12 cores
NR
Urostation
Transrectal
NR
NR
intermediate,
(range):
malignant
T2W, DWI, DCE
N
N
5-point scale
3 (2–5)
!2
7–21
Local
TRUS
N
Artemis
Transrectal
Y
1.3
12 Artemis
129
Miyagawa
Paired cohort study
85
et al [23]
Previous negative
Mean (range):
Mean (range):
Mean (range):
biopsy
64.7 (47–79)
9.6 (2.7–40)
51.1 (12–192)
Previous negative
Median (range):
Median (range): Median (range):
biopsy
69 (56–84)
9.9 (4–34.2)
4.2 (1–9)
1.5
T2W, DWI, DCE
Y
N
PI-RADS
NR
NR
Local
TRUS 12 cores
N
Urostation
Transrectal
Y
NR
NR
1.5
T2W, DWI, DCE
N
N
NR
NR
NR
Spinal
TRUS and
NR
Real-time
Transperineal
Y
1.2
Mean: 1.9
Transrectal
N
1.25
2
37.2 (18–141)
transperineal
Virtual
combined for
Sonography
10–11 cores
Puech et al [24] Paired cohort study
95
Mixed (68% biopsy
Median (range):
naive; 32% previous
65 (49–76)
10.05 " 8.8
Mixed (54% biopsy
Median (range):
Median (range): Median (range):
naive; 27% previous
65 (56.3–71)
5.1 (3.5–7.3)
46 (31–62.5)
Mixed (51% biopsy
Median (range):
Mean (range):
Mean (range):
naive; 49% previous
65.3 (42–82)
9.85 (0.5–104)
48.7 (9–108)
negative biopsy)
Wysock
Paired cohort study
125
et al [25]
Mean " SD:
Mean " SD:
1.5
T2W, DWI, DCE
N
N
Likert
52 " 24
3
T2W, DWI, DCE
N
N
T2W, DWI, DCE,
N
Y
!3
Mean (range):
Local
TRUS 12 cores
Y
7.3 (0–251)
5-point scale
!2
NR
Not suspicious,
Questionable NR
Virtual
Navigator
Local
TRUS 12 cores
Y
Artemis
Transrectal
Y
1.4
2
General
Ginsburg
N
BiopSee
Transperineal
Y
NR
Median
negative biopsy; 19%
on active
surveillance
Kuru et al [26]
Paired cohort study
347
3
spectroscopy
negative biopsy)
questionable,
transperineal
highly suspicious
24 cores biopsy
(range):
4 (2–6)
(range: 12–36)
Mouraviev
Paired cohort study
13
et al [27]
Mixed (46% biopsy
NR
NR
NR
3
T2W, DWI, DCE
Y
N
4-point scale
NR
2–3 wk
naive; 31% previous
with and without
(average with
negative biopsy; 23%
spectroscopy
no other
NR
TRUS 10–12 cores
NR
Virtual
Transrectal
NR
NR
2–4
Navigator
precision)
on active
surveillance)
Fiard et al [28]
Paired cohort study
30
Mixed (43% biopsy
Median (range):
Median (range): Median (range):
naive; 57% previous
64 (61–67)
6.3 (5.2–8.8)
3
T2W, DWI, DCE
N
N
PI-RADS
None
46 (31–59)
negative biopsy)
Rastinehad
Paired cohort study
105
et al [29]
Median
General
(range): 24
or local
TRUS 12 cores
N
Urostation
Transrectal
N
1.25
2
TRUS 12 cores
Y
UroNav
Transrectal
Y
1.9
3.9 (mean)
EUROPEAN UROLOGY 68 (2015) 8–19
Paired cohort study
et al [22]
Median
(range):
guided cores
Portalez
Median
(8–70)
Mixed (33% biopsy
Mean (range):
Median (range): NR
naive; 67% previous
65.8 (42–87)
7.53 (0.6–62)
3
T2W, DWI, DCE
Y
N
Low, moderate,
None
NR
Local
high
negative biopsy)
Siddiqui
Paired cohort study
582
Mixed (55% previous
Paired cohort study
171
Mixed (38% previous
et al [30]
Sonn et al [31]
negative biopsy)
negative biopsy; 62%
Mean " SD:
Mean " SD:
Mean " SD:
3
T2W, DWI, DCE,
Median: 65;
Median: 4.9;
Median: 48;
3
T2W, DWI, DCE
range: NR
range: NR
range: NR
61.3 " 8.4
9.9 " 13.1
56.4 " 31.2
Y
Y
Low, moderate,
N
N
5-point scale
spectroscopy
None
Median: 39
Local
TRUS 12 cores
Y
UroNav
Transrectal
N
2.6 " 1.3
At least 2
!2
7–21 d
Local
TRUS 12
N
Artemis
Transrectal
Y
Mean
Median
Artemis
(range):
(range):
guided cores
1.6 (0–4)
2.2 (1–6)
1.4
At least 2
high
on active
surveillance)
Rud et al [32]
Comparative series
90
Mixed (12% biopsy
Median (range):
Median (range): Median (range):
naive; 69% rebiopsy;
64 (50–80)
7 (1–74)
28 (8–115)
1.5
T2W, DWI
N
N
Low, moderate,
None
NR
Local
TRUS 12 cores
NR
Urostation
Transrectal
Y
high
19% failure after
EBRT)
DCE = dynamic contrast enhanced; DWI = diffusion-weighted image; EBRT = external-beam radiation therapy; IQR = interquartile range; MR = magnetic resonance; N = no; NR = not reported; PSA = prostate-specific
antigen; SD = standard deviation; T2W = T2 weighted; TRUS = transrectal ultrasound; Y = yes.
*
Part of this cohort was already reported in another study included in this systematic review.
y
The studies are ordered according to prior biopsy status with biopsy-naive population first.
11
12
Table 2 – Primary and secondary outcomes of magnetic resonance-transrectal ultrasound fusion targeted biopsy versus standard biopsy
Histologic results
Study
Mozer et al [19]
Portalez et al [22]
Miyagawa
et al [23]
Puech et al [24]
Wysock et al [25]
Kuru et al [26]
Mouraviev
et al [27]
Fiard et al [28]
Cancer core
length !4 mm
or Gleason !3 + 4
Cancer core
length !5 mm
or Gleason !3 + 4
Cancer core
length !5 mm
or Gleason !3 + 4
Cancer core
length !4 mm
or Gleason !3 + 4
Gleason !3 + 4
NR
Detection
Detection rate Detection
rate clinically
clinically
rate any
significant
significant
cancer
disease SB, % disease TB, %
SB, %
Detection
rate any
cancer
TB, %
Efficiency of
Efficiency of TB Additional Additional
Standard
No. of serious No. of serious
SB in detecting in detecting one utility of
utility of classification
adverse
adverse events
one patient
patient with
SB vs TB, % TB vs SB, %
used
events SB, %
TB, %
with clinically
clinically
significant
significant
disease
disease
36.9
43.4
56.6
53.9
32.6
4.6
2.7
9.2
NR
NR
NR
NR
NR
45.8
82.1
NR
NR
1.5
9
NR
NR
NR
NR
NR
33.1
75.6.
NR
NR
1.5
9.8
NR
NR
NR
14.7
21.7
27.5
23.7
81.6
25.2
4.9
11.3
NR
NR
NR
NR
NR
NR
NR
20.9
40
43.4
52.9
33.1
NR
4.5
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR#
NR#
NR
NR
NR
Cancer core
length !3 mm
or Gleason !3 + 4
Gleason !3 + 4
NCCN criteria
52
NR#
59
NR#
23.2
NR#
NR
38*
23.2
41.1*
NR
50.4*
36
50.6*
31.2
47.9*
9.8
12.3*
NR
12.4*
NR
5.9*
NR
NR
Epstein criteria
NR
NR
NR
46.2
NR
NR
0
NR
NR
Total cancer
length !10 mm
or Gleason !3 + 4
Epstein criteria
33.3
50
43
55
NR
4
3.3
5
NR
NR
NR
32.4
44.8
48.6
50.5
37.1
8.7
3.8
16.2
NR
NR
NR
9.8
12.3
4.8
15.1
13.2
46.2
43.8
43.9
14.3
43.5
35.1
67.5
122.5
82.9
252
37.7
24.3
NR
1.2
7
0
6.5
7.3
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Rastinehad
et al [29]
Siddiqui et al [30] Gleason !4 + 3
Sonn et al [31]
Gleason !3 + 4
Rud et al [32]
Gleason !3 + 4
0
0
Complications were given as a
whole, with the two procedures
performed in the same session:
one surgical drainage of perineal
haematoma; three interventions
for haematuria
NR
NR
NR = not reported; SB = standard biopsy; TB = targeted biopsy.
In this study, when the TB approach had already sampled one area, this area was excluded by the SB approach. In addition, the local histopathology analysis process did not allow us to distinguish discordance in
grade between the two biopsy approaches (pooled analysis).
#
In this study, the targeted approach, including visual and magnetic resonance–transrectal ultrasound fusion biopsy, is given as a whole; therefore it was not possible to distinguish the outcomes of software biopsy
alone.
*
EUROPEAN UROLOGY 68 (2015) 8–19
Delongchamps
et al [20],
first study
Delongchamps
et al [20],
second study
Sonn et al [21] *
Definition for
clinically
significant
disease
Adverse events
NR = not reported.
In this study, the targeted approach, including visual and magnetic resonance–transrectal ultrasound fusion biopsy, is given as an whole; therefore it was not possible to distinguish the outcomes of each targeted
approach.
Per target
1: Artemis
2: Cognitive fusion
Kuru
et al [25]
#
0
7.6
13.2
9.8
32
20.3
15.1
26.7
NR#
NR#
NR#
NR#
53
1: Virtual Navigator
2: Cognitive fusion
Puech
et al [24]
Per target
First cognitive,
then software
registration
First software
registration,
then cognitive
NR#
NR#
47
Additional
utility of
strategy 2 vs
strategy 1, %
Additional
utility of
strategy 1 vs
strategy 2, %
Efficiency of strategy
2 in detecting one
patient with
clinically
significant cancer
Efficiency of
strategy 1 in
detecting one
patient with
clinically
significant
cancer
Detection rate
any cancer
strategy 2, %
Detection rate
any cancer
strategy 1, %
Detection rate
clinically
significant
strategy 2, %
Detection rate
clinically
significant
strategy 1, %
Targeted
biopsy first
Statistical
analysis
used in
the study
Targeted
strategies
used
Study
Histologic results
Table 3 – Head-to-head comparison between two targeted biopsy approaches, one using an magnetic resonance–transrectal ultrasound fusion platform and the other a cognitive fusion
EUROPEAN UROLOGY 68 (2015) 8–19
13
However, two studies were scored as potentially biased.
One had a small sample size (n = 13) and significant
patient heterogeneity [27]; the other had significant
limitations, such as a retrospective design and patient
heterogeneity [32].
In four studies the index test domain demonstrated a
high risk of bias and applicability concern. In two studies
this was due to an unclear interpretation of sampling results
that was not clarified despite contacting the study authors
[27,32]. In another study, the index test was correctly
described and conducted, but the histologic outcomes of the
image fusion targeted biopsies were partially pooled with
the standard biopsy outcomes. Consequently, the comparative interpretation of results was not possible [26]. Finally,
another study pooled together the results of both MRI-TRUS
fusion biopsies and visual registration biopsy. Visual
registration involves the biopsy operator making a judgement about where to deploy the needle by looking at the
mpMRI on a separate screen [24].
None of the studies used an adequate reference test with
13 using the current standard of TRUS biopsy. One study
used a more accurate test, namely transperineal biopsy
using a limited sampling template protocol (not every 5 mm
as often done for template mapping biopsies) [40], but there
were concerns about incorporation bias. Systematic transperineal template cores were not taken from areas that
were previously sampled using MRI-TRUS image fusion
targeted biopsies [26]. As a result, the detection rate of
clinically significant disease was given as a whole and thus
comparison between the two could not be made.
In terms of flow and timing, one study was at high risk of
bias because there was no adequate description and not all
patients underwent the reference test [32]; two other
papers did not describe flow and timing [20,27].
3.2.
Description of devices
In the studies included in this review, we identified eight
image fusion platforms currently being used clinically to
perform MRI-TRUS targeted biopsies (Supplementary
Table 3). MRI-TRUS image fusion is most simply described
as a way to align a preprocedure MRI to an intraprocedure
US to accurately direct the biopsy needle to a US region of
interest defined by mpMRI. Multiple devices available to do
this can broadly be classified by the (1) fusion process as
either rigid or nonrigid; (2) the mode of acquisition of the
prostate US, either automatic or manual; and (3) the biopsy
approach, either transrectal or transperineal.
Rigid fusion uses a direct overlay of the mpMRI onto the
US images at the time of biopsy (Fig. 4). It does not take into
account changes in shape and position of the prostate at the
time of biopsy or try to compensate for this. Nonrigid fusion
aims to compensate for prostate deformation at the time of
biopsy. This occurs due to different positions in which the
mpMRI and US are performed (supine vs left lateral or
lithotomy), and the presence and movement of an
endorectal US probe that causes changes in prostate shape.
The nonrigid fusion process can be achieved with elastic
registration of the prostate US and MRI surfaces [41] or by
14
EUROPEAN UROLOGY 68 (2015) 8–19
[(Fig._2)TD$IG]
Reference
19
20
1,2
21
22
23
24
25
26
27
28
29
30
31
32
+ = Low
Risk of bias
Applicability concerns
Pa!ent
selec!on
Index test
Reference
standard
Flow and
!ming
Pa!ent
selec!on
Index test
Reference
standard
+
+
+
+
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
+
+
+
-
-
+
?
+
+
+
+
+
+
?
+
+
+
+
-
+
+
+
+
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
+
+
+
-
-
? = Unclear
- = High
Fig. 2 – Independent risk of bias assessment per study using the Quality Assessment for Diagnostic Studies-2 tool. One paper reported two studies with
identical design but using a different magnetic resonance-transrectal ultrasound fusion platform [20].
[(Fig._3)TD$IG]
QUADAS-2 Domain
Flow and !ming
Reference standard
Index test
Pa!ents selec!on
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
90%
100%
QUADAS-2 Domain
Propor!on of students with low, high, or unclear
risk of bias
Reference standard
Index test
Pa!ents selec!on
0%
10%
20%
30%
40%
50%
60%
70%
80%
Propor!on of students with low, high, or unclear
concerns regarding applicability
Fig. 3 – Summary of risk of bias assessment of all papers included using the Quality Assessment of Diagnostic Accuracy Studies-2 tool.
EUROPEAN UROLOGY 68 (2015) 8–19
15
[(Fig._4)TD$IG]
Fig. 4 – Description of the process of magnetic resonance (MR) to ultrasound image fusion. (a) The T2-weighted anatomic sequence is contoured
(in red) to visualise the prostate. (b) Intraoperatively, the margins of the prostate are visualised by the surgeon and need to be contoured (in white)
when using nonrigid registration. (c) Finally, in rigid fusion systems the surgeon overlaps manually the contouring of the prostate on the MR over the
contour of the prostate on the ultrasound. In nonrigid fusion systems, the software tries to compensate for the difference in prostate contouring that
is clearly seen as the area not aligned in this image.
statistical motion modelling of how the prostate should
deform using physical constraints [42].
3.3.
Study designs
One paper reported two studies [20]; therefore 15 studies
were included overall. Fourteen used a paired cohort design
(Table 1). A total of 2293 men were included with a sample
size ranging from 13 to 582. Three studies were conducted
in biopsy-naive men, three in men with a previous negative
TRUS biopsy, eight studies reported on a mixed cohort who
were either biopsy naive or had undergone a previous
prostate biopsy, and one also included men with radiorecurrent disease (Table 1).
All mpMRI scans were performed on either a 1.5- or 3-T
scanner. As a minimum, all men had T2-weighted scans and
DWI. Fourteen of the 15 studies also performed DCE, three
studies used MR spectroscopy (in addition to T2 weighting,
diffusion, and dynamic contrast), and six studies required
the addition of an endorectal coil. The mpMRIs were
reported on a scale of suspicion, but the increments used
differed between studies. For instance, the Likert scale is
very similar to breast mammography reporting in which
1 confers the lowest radiologic suspicion for cancer and
5 means the radiologist is very confident that a lesion is
cancer. Others used a 3- or 4- point scale, and a number
reported mpMRI using the Prostate Imaging-Reporting and
Data System that has a 5-point scale for each type of MRI
sequence and then uses the aggregate total as the headline
score (out of 15 or 20). The standard comparator was a
10- to 12-core TRUS biopsy in 14 studies, either as a
standard protocol or following a preplanned map, although
one study used transperineal template biopsies. In the MRTRUS targeted biopsies, the median number of cores
deployed per target was between 2 and 4.2.
3.4.
Primary outcome
The median detection of clinically significant disease was
23.6% (range: 4.8–52%) for standard biopsy and 33.3%
(range: 13.2–50%) for MRI-TRUS image fusion targeted
biopsy (Table 2). Across all studies in which both rates were
reported, the use of MRI-TRUS fusion allowed the detection
of greater numbers of clinically significant cancers compared with standard biopsy. The absolute difference in
detection rate between the two approaches was a median of
6.8% (range: 0.9–41.4%) and always in favour of the
approach based on MR-TRUS software.
Substantial discrepancy was found in the definition of
clinically significant disease. Only one study did not report
the criteria for defining this outcome, and there was no
clarification provided by the authors when approached
[23]. In all the remaining studies, the presence of Gleason
pattern 4 was considered clinically significant disease. In
eight studies, maximum cancer core length was also
considered, although the threshold above which clinically
significant disease was defined ranged from 3 mm to
10 mm.
3.5.
Secondary outcomes
3.5.1.
Detection of any cancer
The median detection rate of any cancer was 43.4% (range:
14.3–59%) and 50.5% (range: 23.7–82.1%) in the standard
biopsy strategy versus MRI-TRUS image fusion biopsy,
respectively. The absolute difference in overall detection of
PCa between the two approaches was a median +6.9% in
favour of the MRI-TRUS image fusion targeted biopsy
approach (range: #8.8% to +53.2%). In four studies, standard
biopsies detected more clinically insignificant disease than
the software-based approach.
3.5.2.
Efficiency
In all series, an image fusion approach was more efficient in
detecting clinically significant disease. The median number
of cores needed to detect one man with clinically significant
cancer was 37.1 (interquartile range [IQR]: 32.6–82.8;
range: 23.2–252) and 9.2 (IQR: 4.6–24.8; range: 4–37.7) for
standard and MRI-TRUS image fusion targeted biopsy,
respectively. The median difference in number of cores
required across the series was 32.1 cores (IQR: 28.3–57;
range: 21.4–84.8) in favour of the targeted approach. In
other words, to detect the same number of clinically
significant cancers with standard biopsy, approximately
16
EUROPEAN UROLOGY 68 (2015) 8–19
four times the number of cores would be needed compared
with an image fusion targeted approach.
3.5.3.
Utility
Utility in our study was defined as the number of clinically
significant cancers detected by one sampling strategy but
missed by the other strategy. Considering absolute differences, MRI-TRUS image fusion biopsies detected a median
of 9.1% additional clinically significant cancers (range:
5–16.2%) that were missed by standard biopsy alone. In
contrast, standard biopsies detected a median of 2.1%
(range: 0–12.4%) additional clinically significant cancers
that were missed by MRI-TRUS fusion biopsies. However, if
the study using transperineal mapping biopsies is removed
so the standard biopsy is only a TRUS biopsy approach, the
range stood at 0–7%.
3.5.4.
Adverse events
Only two studies reported adverse events, but in none was a
standard classification system used. One study stated that
no adverse events occurred [25]. In another, four serious
adverse events occurred, although it was not possible to
distinguish which of the two approaches led to the adverse
event because standard and targeted biopsies were performed in the same session under general anaesthesia [26].
3.6.
Comparison of different magnetic resonance imaging-
transrectal ultrasound image fusion targeted approaches
Two studies evaluated the outcomes of MRI-TRUS image
fusion biopsies versus visual registration targeted biopsy
(Table 3). One study did not report sufficient information to
determine the primary outcome measure and a number of
the secondary outcome measures. In the only outcome
reported, namely detection of any cancer, MRI-TRUS image
fusion biopsies had a higher rate (53% vs 47%; no p value
given) [24]. The other study evaluated the two targeting
approaches in 125 men presenting with a total of
172 targets. In a per target analysis, MRI-TRUS image
software biopsies detected more clinically significant
cancers (20.3% vs 15.1%; p = 0.05) and more cancer overall
(32% vs 26.7%; p = 0.14). It also had better efficiency
compared with visual registration requiring 9.8 rather than
13.2 cores to detect one man with clinically significant
cancer [25]. There was no additional utility in using visual
registration targeting, whereas the image fusion approach
detected 7.6% additional clinically significant cancers that
would have been missed by the visual registration
approach. However, the study was underpowered to show
the demonstrated absolute difference in detection rate of
approximately 5% because it was powered a priori to
demonstrate a 15% difference in detection rate.
3.7.
Discussion
Our systematic review shows that MRI-TRUS image fusion
targeted biopsies detect more clinically significant cancers
using fewer cores compared with standard biopsy techniques. Most studies also showed a higher detection of
clinically insignificant cancer, although four studies demonstrated a lower detection rate of clinically insignificant
cancer by MRI-TRUS image fusion biopsies.
Our systematic review had some limitations. First, the
definition of clinically significant disease varied between
studies. This corresponds to the current uncertainty of
identifying the determinants of cancer progression on
biopsy. Although Gleason grade is an accepted prognostic
indicator [43], it has been difficult to define the volume of
cancer that is significant due to the current inaccuracies of
the diagnostic pathway. Surrogate markers of cancer
volume using cancer core length and number of positive
biopsies are currently used [44]. The exact threshold for
these is not clear. Historically, investigators have used
lesion volume of 0.2 ml [45] or 0.5 ml [46] to define the
threshold, although more recently, it was suggested that a
pure Gleason 6 lesion could be 1.3 ml before defining it as
clinically significant [47].
Second, it was not possible to determine the overall
accuracy of a MRI-TRUS image fusion approach because an
accurate reference test was not used. Therefore, although an
image fusion approach for targeting seems to be superior to
a standard TRUS biopsy, the residual diagnostic error of
such an approach is not known. The UK Prostate Imaging
Compared to Transperineal Ultrasound Guided Biopsy for
Significant Prostate Cancer Risk Evaluation (PICTURE) study
will evaluate this [48].
Third, most studies included a heterogeneous population. For instance, in men with previous negative findings
or in men with low-risk disease on standard biopsy,
applying another test may introduce selection bias.
Although we agree this is possible, we would argue that
given the consistency of the results across the studies,
heterogeneity increases external validity and suggests
wide application of MRI-TRUS image fusion in the
spectrum of men looking for precise risk attribution.
Particularly, the value of the fusion approach was
consistently demonstrated in studies including only
biopsy-naive men.
Fourth, the procedure of MR-TRUS fusion targeted biopsy
is not standardised. There was significant variability across
the studies in terms of MR characteristics and interpretation, threshold for biopsy, targeted biopsy conduct, and
number of cores per target. Although this is to be expected
during the development phase of a new interventional
procedure, standardisation of the technique will allow
better comparison between different software and against
standard tests. Finally, only one study compared an image
fusion approach to visual registration; further comparative
research is needed in this area [48].
Despite these limitations, we believe our review has
significant implications. First, when high-quality mpMRI is
available, an image fusion approach might be offered in
addition to standard sampling. This seems to allow better
risk stratification with additional limited sampling and
could therefore help improve decision making for men
diagnosed with PCa. Second, despite the wide differences in
software characteristics that indicate a possible difference
in accuracy, this systematic review shows that the
EUROPEAN UROLOGY 68 (2015) 8–19
outcomes are similar. Therefore the choice for one unit
should be guided by factors such as cost, usability, interface,
and flexibility of use. Third, this systematic review should
guide future research. A more robust assessment of the
diagnostic accuracy of image fusion targeted biopsy
compared with an accurate reference test and at the same
time with the current standard of practice, namely TRUS
biopsy, is needed. This will require paired cohort studies or
RCTs that have sufficiently large sample sizes with
homogeneous populations to detect the differences we
have reported here. These comparative studies need to be
multicentre to ascertain validity and reproducibility.
Equally, additional evidence is needed to compare visual
registration with an image fusion because there are cost
implications if new capital has to be purchased. Some of
these trials are already under way, and the results will be
available in the next few years [48].
The last aspect to consider is whether we are ready to
change practice based on this review. There are a number of
barriers to recommend immediate change. MRI-TRUS
image fusion targeted biopsy needs to be considered a
‘‘complex procedure’’ [49], in which the final outcome
depends on a chain of events from image acquisition, image
interpretation by experts in the field, software accuracy,
and finally biopsy operator ability, skill, and expertise. Each
of these steps is important for the following one to be
successful and therefore for the final outcome. This means
that before recommending wide adoption, these elements
need to be available on site, quality assured, and quality
controlled so as not to affect the ultimate outcomes. MRITRUS image fusion might overcome the barriers inherent
when using visual registration targeted biopsies because a
high degree of expertise is required in specialist centres for
the latter. With more than 1 million biopsies of the prostate
performed every year in the United States and another
estimated million in Europe, it will not be possible to
centralise these biopsies in specialist centres. Therefore
specific training in tertiary centres, courses at international
and national meetings, and structured mentorship
should be set up. These quality and training issues
have been dealt with by programmes in breast cancer
screening with mammography or breast MRI in high-risk
groups [50].
Another significant issue are the cost and time implications. An image fusion approach combines the cost of the
mpMRI plus the software/device. Although at face value,
this seems more costly than a standard approach, the
implications of potentially increased diagnostic accuracy
and the downstream implications on follow-up and
treatment should be taken into account. Early evidence
shows that a targeted biopsy approach using MRI-TRUS
fusion might be cost effective [51,52]. Time issues also need
to be considered because MRI-TRUS fusion biopsies require
additional time for contouring the lesions before the
procedure and for image fusion and synchronisation.
Although this added time might be problematic in terms
of efficiencies in working, the added diagnostic value
conferred by this targeted strategy might offset such
additional resource implications.
4.
17
Conclusions
Our systematic review shows that mpMRI-to-US image
fusion targeted prostate biopsies detect more clinically
significant cancers using fewer cores compared with
standard biopsy techniques. Some studies confirmed a
lower detection rate of clinically insignificant cancer using
mpMRI to target the biopsies. Before this approach is
incorporated into standard practice across all centres,
consideration must be given to the need for the required
expertise and skills and the current impediments to wider
dissemination. If our findings were confirmed by large
multicentre validating studies and also shown to be cost
effective, MRI-TRUS image fusion targeted biopsies should
be incorporated into the standard diagnostic pathway.
Author contributions: Massimo Valerio 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: Valerio, Ahmed.
Acquisition of data: Valerio, Donaldson.
Analysis and interpretation of data: Valerio, Donaldson, Emberton, Ehdaie,
Hadaschik, Marks, Mozer, Rastinehad, Ahmed.
Drafting of the manuscript: Valerio, Donaldson, Ahmed.
Critical revision of the manuscript for important intellectual content:
Emberton, Ehdaie, Hadaschik, Marks, Mozer, Rastinehad, Ahmed.
Statistical analysis: Valerio, Donaldson, Ahmed.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Emberton, Ehdaie, Hadaschik, Marks, Mozer, Rastinehad,
Ahmed.
Other (specify): None.
Financial disclosures: Massimo Valerio 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: Massimo
Valerio has received funding for conference attendance from Geoscan
Medical. Boris A. Hadaschik has received research funding from Medcom
and UroMed and is a paid consultant to Dendreon, Janssen, and Teva. He
has also received funding for conference attendance from Bayer and
Astellas. Pierre Mozer has been involved in the patent of the Urostation
(Koelis) system. Mark Emberton and Hashim U. Ahmed receive funding
from USHIFU, GSK, AngioDynamics, and Advanced Medical Diagnostics
for clinical trials. Mark Emberton is a paid consultant to AngioDynamics,
Steba Biotech, and SonaCare Medical (previously called USHIFU). Both
have previously received consultancy payments from Oncura/GE
Healthcare and Steba Biotech. None of these sources had any input
regarding this paper. The SICPA Foundation supports the ongoing
fellowship and PhD programme of Valerio Massimo. Ian Donaldson
receives funding from the Wellcome Trust and Department of Health.
Behfar Hadaschik receives funding from the German Research Foundation, German Cancer Aid, and the European Foundation for Urology.
Mark Emberton and Hashim U. Ahmed would like to acknowledge
funding from the Medical Research Council (UK), the Pelican Cancer
Foundation charity, Prostate Cancer UK, St. Peters Trust charity, Prostate
Cancer Research Centre, the Wellcome Trust, National Institute of Health
Research-Health Technology Assessment programme, and the US
National Institute of Health-National Cancer Institute. Mark Emberton
receives funding in part from the UK National Institute of Health
Research UCLH/UCL Comprehensive Biomedical Research Centre.
18
EUROPEAN UROLOGY 68 (2015) 8–19
Leonard S. Marks was supported in his work at UCLA by Award Number
[15] PROSPERO international prospective register of systematic reviews.
R01CA158627 from the National Cancer Institute. The content is solely
University of York Centre for Review s and Dissemination Web site.
the responsibility of the authors and does not necessarily represent the
http://www.crd.york.ac.uk/PROSPERO/display_record.
official views of the National Cancer Institute or the National Institutes of
asp?ID=CRD42013006734#.U7sRNLHaq8Q.
[16] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items
Health.
Funding/Support and role of the sponsor: None.
for systematic reviews and meta-analyses: the PRISMA statement.
BMJ 2009;339:b2535.
[17] Moore CM, Kasivisvanathan V, Eggener S, et al. Standards of reporting for MRI-targeted biopsy studies (START) of the prostate: recommendations from an International Working Group. Eur Urol
Appendix A. Supplementary data
2013;64:544–52.
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
eururo.2014.10.026.
[18] Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised
tool for the quality assessment of diagnostic accuracy studies. Ann
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[19] Mozer P, Rouprêt M, Le Cossec C, et al. First round of targeted
biopsies with magnetic resonance imaging/ultrasound-fusion
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