MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis

Article (PDF Available)inNew England Journal of Medicine 378(19) · May 2018with 624 Reads
DOI: 10.1056/nejmoa1801993
Cite this publication
Abstract
Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography–guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography–guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12–core, transrectal ultrasonography–guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, −13 percentage points; 95% CI, −19 to −7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography–guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027.)
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1
The authors’ full names, academic de-
grees, and af filiations are lis ted in the Ap-
pendix. Address reprint requests to Dr.
Kasivisvanathan at the Division of Sur-
gery and Interventional Science, UCL, 3rd
Fl., Charles Bell House, 43-45 Foley St.,
London W1W 7T S, United Kingdom, or at
veeru . kasi@ ucl . ac . uk.
* A complete list of members of the
PRECISION Study Group is provided in
the Supplementary Appendix, available
at NEJM.org.
This article was published on March 19,
2018, at NEJM.org.
DOI: 10.1056/NEJMoa1801993
Copyright © 2018 Massachusetts Medical Society.
BAC KGRO UND
Multiparametric magnetic resonance imaging (MRI), with or without targeted bi-
opsy, is an alternative to standard transrectal ultrasonography–guided biopsy for
prostate-cancer detection in men with a raised prostate-specific antigen level who have
not undergone biopsy. However, comparative evidence is limited.
METHODS
In a multicenter, randomized, noninferiority trial, we assigned men with a clinical
suspicion of prostate cancer who had not undergone biopsy previously to undergo
MRI, with or without targeted biopsy, or standard transrectal ultrasonography–
guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy
(without standard biopsy cores) if the MRI was suggestive of prostate cancer; men
whose MRI results were not suggestive of prostate cancer were not offered biopsy.
Standard biopsy was a 10-to-12–core, transrectal ultrasonography–guided biopsy.
The primary outcome was the proportion of men who received a diagnosis of clini-
cally significant cancer. Secondary outcomes included the proportion of men who
received a diagnosis of clinically insignif icant cancer.
RE SULT S
A total of 500 men underwent randomization. In the MRI-targeted biopsy group,
71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer,
so they did not undergo biopsy. Clinically significant cancer was detected in 95 men
(38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the
standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence
interval [CI], 4 to 20; P = 0.005). MRI, with or without targeted biopsy, was nonin-
ferior to standard biopsy, and the 95% conf idence interval indicated the superior-
ity of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy
group than in the standard-biopsy group received a diagnosis of clinically insignifi-
cant cancer (adjusted difference, −13 percentage points; 95% CI, −19 to −7; P<0.001).
CONCLUSIONS
The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was
superior to standard transrectal ultrasonography–guided biopsy in men at clinical
risk for prostate cancer who had not undergone biopsy previously. (Funded by the
National Institute for Health Research and the European Association of Urology Re-
search Foundation; PRECISION ClinicalTrials.gov number, NCT02380027.)
ABS TR AC T
MRI-Targeted or Standard Biopsy
for Prostate-Cancer Diagnosis
V. Kasivisvanathan, A.S. Rannikko, M. Borghi, V. Panebianco, L.A. Mynderse,
M.H. Vaarala, A. Briganti, L. Budäus, G. Hellawell, R.G. Hindley, M.J. Roobol,
S. Eggener, M. Ghei, A. Villers, F. Bladou, G.M. Villeirs, J. Virdi, S. Boxler, G. Robert,
P.B. Singh, W. Venderink, B.A. Hadaschik, A. Ruffion, J.C. Hu, D. Margolis,
S. Crouzet, L. Klotz, S.S. Taneja, P. Pinto, I. Gill, C. Allen, F. Giganti, A. Freeman,
S. Morris, S. Punwani, N.R. Williams, C. Brew-Graves, J. Deeks, Y. Takwoingi,
M. Emberton, and C.M. Moore, for the PRECISION Study Group Collaborators*
Origina l A rt icl e
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M
en with a clinical suspicion of
prostate cancer on the basis of an ele-
vated prostate-specific antigen (PSA)
level or an abnormal digital rectal examination
are typically offered a standard transrectal ultra-
sonography–guided biopsy of the prostate during
which 10 to 12 cores are obtained. This approach
is associated with the underdetection of higher-
grade (clinically significant) prostate cancers and
the overdetection of low-grade (clinically insig-
nificant) cancers.
1
Despite randomized trials
showing that men with clinically insignificant
cancer do not benef it from treatment,
2,3
its iden-
tif ication still results in the overtreatment of
some men. Some men will receive radical treat-
ment that has side effects,
4,5
and others will
undergo active surveillance with repeated as-
sessment over time that has costs for patients
and health care systems.
6,7
An alternative diagnostic pathway in men
with a clinical suspicion of prostate cancer in-
volves multiparametric magnetic resonance im-
aging (MRI). With better standardization of the
conduct and reporting of multiparametric MRI,
the abilit y to detect clinically signif icant cancer
and to rule it out has improved over the past
decade.
1,8,9
Multiparametric MRI could be used
as a triage test to avoid a biopsy if the results
were negative,
1
whereas positive results could be
used for targeting abnormal areas in the pros-
tate during biopsy.
10,11
In single-center studies, the approach of ob-
taining MRI-targeted biopsy cores alone, with-
out performing standard biopsies, has shown
similar or higher rates of detection of clinically
significant cancer
12-1 5
and lower rates of detection
of clinically insignificant cancer
15
than standard
biopsy. We compared MRI-targeted biopsy with
standard transrectal ultrasonography–guided bi-
opsy in a pragmatic, multicenter, randomized trial.
The PRECISION (Prostate Evaluation for Clini-
cally Important Disease: Sampling Using Image
Guidance or Not?) trial aimed to evaluate pro-
spectively whether multiparametric MRI, with
targeted biopsy in the presence of an abnormal
lesion, was noninferior to standard transrectal
ultrasonography–guided biopsy in the detection
of clinically significant prostate cancer in men
with a clinical suspicion of prostate cancer who
had not undergone biopsy of the prostate previ-
ously.
Methods
Trial Design
We conducted this multicenter, randomized,
noninferiority trial at 25 centers in 11 countries
(Table S1 in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org).
Men who provided written informed consent
were randomly assigned in a 1:1 ratio to either
the MRI-targeted biopsy group or the standard-
biopsy group (Fig. S1 in the Supplementary Ap-
pendix). The assignment sequence used computer-
generated, randomly permuted blocks of unequal
size, stratified according to center. Group as-
signments were revealed by the Web-based sys-
tem once a participant had been assessed as eli-
gible and had provided written informed consent.
The full trial protocol, available at NEJM.org,
has been published previously
16
and was ap-
proved by the ethics review board at each par-
ticipating institution. The trial was monitored by
an independent trial steering committee and
data and safety monitoring committee. The trial
was designed by the Standards of Reporting for
MRI-Targeted Biopsy Studies (START) working
group,
10
and final decisions were made by the
first author and the last two authors. Data were
gathered by the trial team members who are
listed in Section S1 in the Supplementary Ap-
pendix. One author analyzed the data, and the
analysis was independently verif ied by another
author. The authors assume responsibility for
the accuracy and completeness of the data and
analyses and for the adherence of the trial to the
protocol. The first draft of the manuscript was
written by the first author.
No commercial entity was involved in the
trial. The trial was funded by the National Insti-
tute for Health Research and the European As-
sociation of Urology Research Foundation, with
trial governance from Universit y College London.
The funders had no role in the protocol develop-
ment, data analysis or interpretation, or manu-
script preparation.
Partic ipants
Participants were recruited in outpatient clinics
and were eligible for enrollment if they had not
undergone biopsy of the prostate previously and
had been referred with a clinical suspicion of
prostate cancer on the basis of an elevated PSA
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MRI-Targeted Biopsy for Prostate-Cancer Diagnosis
level, an abnormal digital rectal examination, or
both (Table S2 in the Supplementary Appendix).
Participants were required to have a PSA level of
20 ng per milliliter or less, to have results on
digital rectal examination that did not suggest
extracapsular disease, and to be suitable candi-
dates for biopsy of the prostate and for MRI.
MRI and MRI-Targeted Biopsy
Multiparametric MRI was performed with the
use of a 1.5-T or 3.0-T scanner with a pelvic
phased-array coil, with or without an endorectal
coil (Table S3 in the Supplementary Appendix).
T
2
-weighted, dif fusion-weighted, and dynamic
contrast-enhanced sequences were acquired ac-
cording to minimum standards that have been
set by consensus guidelines.
8
Areas on the mul-
tiparametric MRI that were suggestive of pros-
tate cancer were categorized by a local radiolo-
gist according to the Prostate Imaging–Reporting
and Data System, version 2 (PI-RADS v2),
9
on a
scale from 1 to 5, with higher numbers indicat-
ing a greater likelihood of clinically significant
cancer. Table S4 in the Supplementary Appendix
provides details regarding the experience of the
clinicians who took part in the trial.
Men who had a positive result on the multi-
parametric MRI — that is, in whom an area with
a score of 3 (equivocal regarding the likelihood
of prostate cancer), 4 (likely to be prostate can-
cer), or 5 (highly likely to be prostate cancer)
was identif ied — underwent MRI-targeted bi-
opsy with the use of real-time ultrasonographic
guidance. A maximum of three areas that were
suggestive of prostate cancer were permitted to
be chosen for targeted biopsy, with a maximum
of 4 biopsy cores obtained per area, resulting in
a maximum of 12 biopsy cores obtained per
participant. MRI-targeted biopsy registration (i.e.,
matching of the image of the target on MRI with
the real-time image of the prostate during bi-
opsy) could be performed by means of visual
registration or software-assisted registration
(also known as MRI–ultrasonographic fusion)
10
and could be carried out through the transrectal
or transperineal route, according to local exper-
tise (Table S5 in the Supplementary Appendix).
In the absence of abnormal areas on the multi-
parametric MRI (i.e., a negative result, with a
score of 1 or 2), the participant was not offered
a protocol biopsy.
Standard Tr ansrectal Ultr asonogr aphy–
Guided Biops y
Biopsy was carried out by experienced operators
who used a standard transrectal technique. A to-
tal of 10 to 12 biopsy cores were obtained from
the peripheral zone of the prostate at the base,
mid gland, and apex.
17
Participant-Reported Outcome Measures
Participant-reported questionnaires were used to
collect data about intervention-specific side effects
immediately and at 30 days after biopsy and after
MRI.
16,18
Health-related quality of life was as-
sessed with the use of the EuroQol–5 Dimension
Self-Report Questionnaire at baseline, 24 hours
after the intervention, and 30 days after the in-
tervention.
19 -21
Outc omes
The primary outcome was the proportion of men
with clinically significant cancer, defined as the
presence of a single biopsy core indicating dis-
ease of Gleason score 3+4 (Gleason sum of 7) or
greater (the Gleason score is composed of a pri-
mary [most predominant] grade plus a secondar y
[highest nonpredominant] grade; the range for a
primary or secondary grade is from 3 to 5, with
the Gleason sum ranging from 6 to 10, and with
higher scores indicating a more aggressive form
of prostate cancer). Secondary outcomes includ-
ed the proportion of men with clinically insig-
nif icant cancer (Gleason score 3+3), the propor-
tion of men in the MRI-targeted biopsy group
who did not undergo biopsy, and the proportion
of men with adverse events after the interven-
tion. All the secondary outcomes are listed in Table
S6 in the Supplementary Appendix. Outcomes were
reported according to the START guidelines,
10
which are the consensus criteria for reporting
studies of MRI-targeted prostate biopsies.
Follow-up
Participants were followed until the visit at which
their treatment decisions were made or until their
30-day postintervention questionnaires were
completed, whichever was later. Participants who
underwent further diagnostic tests as a result of
the outcome of the treatment-decision visit were
additionally followed until after the results of the
further investigation were made available and re-
corded. These participants included men who
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had negative test results in either the standard-
biopsy group or the MRI-targeted biopsy group
and underwent additional testing. Participants
who had negative test results in either group at
the end of the trial period returned to standard-
care monitoring at each center, which typically
involved surveillance of the PSA level. Partici-
pants who underwent radical prostatectomy on
the basis of their treatment decision were also
followed until the pathological testing results of
their radical prostatectomy were available. Par-
ticipants provided written informed consent for
long-term follow-up as part of future studies
involving additional contact from the trial center
and linkage to national databases.
Quality Control
Uroradiologists and pathologists at the coordi-
nating center, who were unaware of the results
of the original reports, reviewed 25% of the mul-
tiparametric MRIs and 15% of the original patho-
logical specimens. These MRIs and specimens
had been chosen at random from participants at
every site.
Statistical Analysis
Using a noninferiority margin of 5 percentage
points that was agreed on at an expert consen-
sus group meeting
10
and a one-sided alpha level
of 2.5%, we calculated that the randomization of
422 men would provide the trial with 90%
power to show the noninferiority of MRI, with
or without targeted biopsy, to standard biopsy,
assuming a detection rate of clinically signifi-
cant cancer of 40% in the group that underwent
MRI, with or without targeted biopsy, and 30%
in the standard-biopsy group. This sample size
was increased to 470 to allow for a 10% rate of
withdrawal and loss to follow-up. Detailed justi-
fication of the sample size is provided in the
protocol.
16
The statistical analysis plan was prespecified
and approved by the data and safety monitoring
committee before the analysis of any data. For
the primar y outcome, if the lower boundary of
the two-sided 95% confidence interval for the
difference in the rates of detection of clinically
signif icant cancer in the MRI-targeted biopsy
group relative to the standard-biopsy group was
greater than −5 percentage points, then MRI,
with or without targeted biopsy, would be
deemed to be noninferior. Furthermore, if the
lower boundary was greater than zero, superior-
ity would be claimed. The difference was esti-
mated with the use of a generalized linear mixed
model (with the use of an identity link function
with a binomial distribution) that included trial
center as a random effect.
All the participants who underwent random-
ization were included in the primary intention-
to-treat analysis. Analyses were repeated in the
modif ied intention-to-treat population and the
per-protocol population as sensitivity analyses
(Table S7A, S7B, and S7C in the Supplementary
Appendix). The modified intention-to-treat anal-
ysis excluded participants who did not complete
a diagnostic test strategy; this analysis was car-
ried out to prevent unequal withdrawal in the
two groups from contributing to a difference
between the groups. The per-protocol analysis
included only men who under went the randomly
assigned testing procedure as specified in the
protocol; this analysis was carried out because
this was a noninferiority trial, so a per-protocol
analysis would reduce the chance of biasing the
result toward the null. If, after participants had
undergone the trial test procedures, further tests
provided different information about the pres-
ence of cancer, no adjustment was made to the
analyses of the primary and secondary out-
comes. A post hoc Bonferroni correction was
used to adjust for three secondary outcomes
(proportion of men with clinically insignif icant
cancer, maximum cancer core length, and
health-related qualit y of life), with a two-sided P
value of less than 0.017 considered to indicate
statistical significance. The methods of analysis
of the other outcomes are described in Section
S2 in the Supplementary Appendix.
Resu lts
Trial Population
From February 2016 through August 2017, a to-
tal of 500 participants underwent randomization
at 23 of the 25 sites, with 252 participants being
assigned to the MRI-targeted biopsy group and
248 to the standard-biopsy group (Fig. 1, and
Table S1 in the Supplementary Appendix). The
characteristics of the participants at baseline
were similar in the t wo groups (Table 1).
A total of 71 of 252 participants (28%) in the
MRI-targeted biopsy group had a result on mul-
tiparametric MRI that was not suggestive of
prostate cancer (PI-RADS v2 score, ≤2), and so
they did not undergo biopsy. Among the partici-
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MRI-Targeted Biopsy for Prostate-Cancer Diagnosis
pants with a positive result on multiparametric
MRI, 51 of 175 (29%) had a PI-RADS v2 score of
3, 70 (40%) had a score of 4, and 54 (31%) had
a score of 5 (Table S8 in the Supplementary Ap-
pendix). The remaining 6 men did not complete
the MRI assessment (Fig. 1). Among the partici-
pants who underwent biopsy, a median of 4 bi-
opsy cores were obtained in the MRI-targeted
biopsy group, as compared with a median of 12
cores in the standard-biopsy group (Table S9 in
the Supplementary Appendix).
Outc omes
Clinically significant cancer was detected in 95
men (38%) in the MRI-targeted biopsy group, as
compared with 64 (26%) in the standard-biopsy
group (adjusted difference, 12 percentage points;
95% confidence interval [CI], 4 to 20; P = 0.005)
(Table 2). The lower boundary of the 95% confi-
dence interval for the difference was greater
than −5 percentage points, so MRI, with or
without targeted biopsy, was deemed to be non-
inferior to standard transrect al ultrasonogra-
phy–guided biopsy in the detection of clinically
signif icant cancer. Furthermore, the 95% confi-
dence interval showed the superiority of MRI,
with or without targeted biopsy, over transrectal
ultrasonography–guided biopsy. The results
were consistent in the modified intention-to-
treat and per-protocol populations (Fig. 2).
Fewer participants received a diagnosis of
clinically insignificant cancer in the MRI-target-
ed biopsy group than in the standard-biopsy
group (23 men [9%] vs. 55 [22%]; adjusted dif-
ference, −13 percentage points; 95% CI, −19 to
−7; P<0.001). In men with cancer, the mean
maximum cancer core length was 7.8 mm in the
MRI-targeted biopsy group and 6.5 mm in the
standard-biopsy group (adjusted mean differ-
ence, 1.0 mm; 95% CI, 0.0 to 2.1; P = 0.053). In-
terpretations of the results for these secondary
outcomes were unchanged by post hoc Bonfer-
roni correction (see Section S3 in the Supple-
mentary Appendix).
A greater percentage of cores were positive
for cancer in the MRI-targeted biopsy group (422
of 967 cores [44%]) than in the standard-biop-
sy group (515 of 2788 [18%]). Among men with
a positive result on MRI, the percentage of men
with clinically significant cancer was highest
among participants with a PI-RADS v2 score of
5 (83%), followed by those with a score of 4
(60%) and those with a score of 3 (12%). Con-
Figure 1. Enrollment, Randomization, and Follow-up of the Participants.
Men who were randomly assigned to the magnetic resonance imaging
(MRI)–targeted biopsy group underwent MRI. If the MRI revealed results
that were suggestive of prostate cancer, the participant under went a target-
ed biopsy; men whose MRI results were not suggestive of prostate cancer
were not offered biopsy. Men who were assigned to the standard-biopsy
group underwent standard transrectal ultrasonography–guided biopsy.
PSA denotes prostate-specific antigen.
500 Underwent randomization
877 Participants were assessed
for eligibility
377 Were excluded before
randomization
148 Did not meet inclusion
criteria
193 Declined to participate
36 Had other reason
252 Were assigned to undergo MRI
with or without targeted biopsy
240 Underwent assigned intervention
12 Did not undergo assigned
intervention
1 Did not want further investi-
gation
6 Had abnormal MRI, but did
not undergo targeted biopsy
5 Could not undergo MRI
248 Were assigned to undergo standard
biopsy
228 Underwent assigned intervention
20 Did not undergo assigned
intervention
6 Preferred PSA surveillance
6 Did not want further investi-
gation
1 Was lost to follow-up (left
recruiting site)
1 Underwent transperineal
template biopsy
6 Underwent MRI
2 Had decision made by
clinician owing to medical
risk associated with imme-
diate standard biopsy
4 Preferred MRI
252 Were included in the intention-
to-treat analysis
245 Were included in the modified
intention-to-treat analysis
7 Did not complete diagnostic
test strategy
235 Were included in the per-protocol
analysis
17 Were excluded
12 Did not undergo assigned
intervention
2 Underwent MRI without the
use of contrast material
1 Did not undergo biopsy of
lesion found on MRI
1 Underwent standard biopsy
and targeted biopsy
1 Underwent transperineal
template biopsy and
targeted biopsy
248 Were included in the intention-
to-treat analysis
235 Were included in the modified
intention-to-treat analysis
13 Did not complete diagnostic
test strategy
227 Were included in the per-protocol
analysis
21 Were excluded
20 Did not undergo assigned
intervention
1 Had 15 standard-biopsy cores
obtained
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versely, the percentage of men without cancer
was highest among participants with a PI-RADS
v2 score of 3 (67%), followed by those with a
score of 4 (31%) and those with a score of 5 (6%)
(Fig. 3).
Quality of Life and Safety
Health-related quality of life at 24 hours and at 30
days after the intervention did not differ signif i-
cantly between the MRI-targeted biopsy group
and the standard-biopsy group. The intervention
was associated with similar results regarding im-
mediate postintervention discomfort and pain in
the two groups. The participant-reported compli-
cations at 30 days were less frequent in the MRI-
targeted biopsy group than in the standard-biopsy
group, including events of blood in the urine
(30% vs. 63%), blood in the semen (32% vs. 60%),
pain at the site of the procedure (13% vs. 23%),
rectal bleeding (14% vs. 22%), and erectile dys-
function (11% vs. 16%). These findings ref lected
the lower percentage of men undergoing biopsy
and fewer biopsy cores obtained in the MRI-tar-
geted biopsy group than in the standard-biopsy
group. A total of 2% of the men in the MRI-
targeted biopsy group and 2% in the standard-
biopsy group had serious adverse events. Details
regarding health-related quality-of-life scores,
participant-reported complications, and adverse
events are provided in Tables S10 through S12 in
the Supplementary Appendix.
Further Diagnostic Testing
After the discussion of the test results with each
participant, more men in the standard-biopsy
group (39 men [16%]) than in the MRI-targeted
biopsy group (7 [3%]) underwent further diag-
nostic tests. Of the 39 further diagnostic tests
that were performed in the standard-biopsy
group, 38 (in 15% of the participants in the
group) were diagnostic multiparametric MRIs
that were carried out in men with negative re-
sults on the transrectal ultrasonography–guided
biopsy. In the MRI-targeted biopsy group, only 3
participants (1%) with negative results on MRI
subsequently underwent standard transrectal ul-
trasonography–guided biopsy. More men who
underwent MRI-targeted biopsy (104 men [41%])
than men who underwent standard transrectal
ultrasonography–guided biopsy (74 [30%]) ad-
opted a strategy of monitoring of the PSA level,
although the percentage of men undergoing ac-
tive surveillance or radical treatment was similar
in the two groups.
Among the participants who underwent fur-
ther biopsy, clinically significant cancer was
detected in none of the 4 men in the MRI-target-
ed biopsy group and in 3 of 9 men (33%) in the
standard-biopsy group. Of the 71 men with
negative results on MRI and no biopsy, 3 (4%)
were discharged, 62 (87%) were referred for
monitoring of the PSA level, 3 (4%) underwent
further prostate biopsy (all had negative results),
1 (1%) underwent an additional multiparametric
MRI, and 2 (3%) had missing information. The
percentage of men whose Gleason score was
upgraded (i.e., found to be higher) after radical
prostatectomy was similar in the MRI-targeted
biopsy group (5 of 30 men [17%]) and the stan-
dard-biopsy group (4 of 27 [15%]). Details are
provided in Tables S13 through S15 in the Sup-
plementary Appendix.
Characteristic
MRI-Targeted Biopsy Group
(N = 252)
Standard-Biopsy Group
(N = 248)
Age — yr 64.4±7.5 64.5±8.0
PSA level — ng/ml
Median 6.75 6.50
Interquartile range 5.16–9.35 5.14–8.65
Family history of prostate cancer — no. (%) 48 (19) 40 (16)
Abnormal digital rectal examination — no. (%) 36 (14) 38 (15)
* Plus–minus values are means ±SD. Men who were randomly assigned to the MRI-targeted biopsy group underwent
MRI. If the MRI revealed results that were suggestive of prostate cancer, the participant underwent a targeted biopsy;
men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Men who were assigned to the
standard-biopsy group underwent standard transrectal ultrasonography–guided biopsy. The characteristics of the par-
ticipants at baseline were similar in the two groups. PSA denotes prostate-specific antigen.
Table 1. Characteristics of the Participants at Baseline.*
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MRI-Targeted Biopsy for Prostate-Cancer Diagnosis
Outcome
MRI-Targeted Biopsy
Group
(N = 252)
Standard-Biopsy
Group
(N = 248) Difference† P Value
Biopsy outcome — no. (%) — —
No biopsy because of negative result on MRI 71 (28) 0
Benign tissue 52 (21) 98 (40)
Atypical small acinar proliferation 05 (2)
High-grade prostatic intraepithelial neoplasia 4 (2) 10 (4)
Gleason score
3+3 23 (9) 55 (22)
3+4 52 (21) 35 (14)
3+5 2 (1) 1 (<1)
4+3 18 (7) 19 (8)
4+4 13 (5) 6 (2)
4+5 7 (3) 2 (1)
5+5 3 (1) 1 (<1)
No biopsy‡ 4 (2) 3 (1)
Withdrawal from trial§ 3 (1) 13 (5)
Clinically significant cancer¶
Intention-to-treat analysis — no. (%) 95 (38) 64 (26) 12 (4 to 20) 0.005
Modified intention-to-treat analysis
— no./total no. (%)
95/245 (39) 64/235 (27) 12 (3 to 20) 0.007
Per-protocol analysis — no./total no. (%) 92/235 (39) 62/227 (27) 12 (3 to 20) 0.007
Clinically insignificant cancer — no. (%) 23 (9) 55 (22) −13 (−19 to −7) <0.001
Maximum cancer core length — mm 7.8±4.1 6.5±4.5 1.0 (0.0 to 2.1) 0.053
Core positive for cancer — no./total no. of cores (%) 422/967 (44) 515/2788 (18) — —
Men who did not undergo biopsy — no. (%)‖ 78 (31) 16 (6) — —
* Clinically significant cancer was defined as the presence of a single biopsy core indicating disease of Gleason score 3+4 (Gleason sum of 7)
or greater, and clinically insignificant cancer as a biopsy sample with a Gleason score of 3+3 (Gleason sum of 6). The Gleason score is
composed of a primary (most predominant) grade plus a secondary (highest nonpredominant) grade; the range for a primary or secondary
grade is from 3 to 5, with the Gleason sum ranging from 6 to 10, and with higher scores indicating a more aggressive form of prostate
cancer.
Differences between rates are shown in percentage points, and the difference in maximum cancer core length is shown in millimeters.
Differences in the percentages of men with clinically significant cancer detected and men with clinically insignificant cancer were calculated
with a generalized linear mixed model (with the use of an identity link function with a binomial distribution) that included trial center as a
random effect. The between-center variance estimates for the intention-to-treat analysis of the proportion of men with clinically significant
cancer was 0.002 and for the proportion of men with clinically insignificant cancer was 0; the 95% prediction intervals for the detection rates of
clinically significant and clinically insignificant cancer, incorporating between-center variation, were 14 to 39% and 17 to 28%, respectively, for
standard biopsy, and 26 to 51% and 4 to 11%, respectively, for MRI-targeted biopsy. The difference in the maximum cancer core length was
calculated with the use of a linear mixed model with trial center as a random effect. The between-center estimate of variance was 2.14; the
95% prediction interval for the maximum cancer core length, incorporating between-center variation, was 3.3 to 9.8 mm for standard biopsy
and 4.4 to 10.8 mm for MRI-targeted biopsy.
In four participants in the MRI-targeted biopsy group, MRI identified at least one area with a score on the Prostate Imaging–Reporting and
Data System, version 2, of 3 or greater (on a scale from 1 to 5, with higher numbers indicating a greater likelihood of clinically significant
cancers), but targeted biopsy was not performed. In the standard-biopsy group, three participants declined transrectal ultrasonography–
guided biopsy and underwent an MRI. The MRI revealed no areas that were suggestive of prostate cancer, and the participants did not
undergo biopsy.
§ These participants did not complete any diagnostic test.
The intention-to-treat analysis included all the participants who underwent randomization, the modified intention-to-treat analysis excluded
participants who did not complete a diagnostic test strategy, and the per-protocol analysis included only participants who underwent the
randomly assigned testing procedure as specified in the protocol.
Data include men who did not undergo biopsy because they withdrew before undergoing any diagnostic test or because they did not com-
plete the diagnostic strategy.
Table 2. Comparison of Cancer Detection between Groups.*
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Quality Control
Results of the quality-control review of multipa-
rametric MRI showed that the percentage of
cases that were scored with agreement for con-
cordant biopsy decision by the central radiology
team and the site radiologist was 78% (50 of 64
cases). The percentage of cases that were scored
with agreement on the Gleason score by the
central pathologists and the site pathologist was
88% (53 of 60 cases). Details are provided in
Table S16A, S16B, and S16C in the Supplemen-
tary Appendix.
Disc ussion
The ideal test for prostate cancer would be
minimally invasive, have few side effects, iden-
tify a high proportion of men who would benefit
from treatment, and minimize the identification
of men with clinically insignificant cancer in
order to prevent overtreatment. In men with a
clinical suspicion of prostate cancer who had not
undergone biopsy of the prostate previously, the
PRECISION trial showed that MRI, with or with-
out targeted biopsy, appeared to achieve these
goals better than the traditional standard of
care, transrectal ultrasonography–guided biop-
sy. MRI, with or without targeted biopsy, led to
fewer men undergoing biopsy, more clinically
signif icant cancers being identified, less overde-
tection of clinically insignificant cancer, and
fewer biopsy cores being obtained than did stan-
dard transrect al ultrasonography–guided biopsy.
Slightly more than one quarter of the men
avoided a biopsy altogether, and the 30-day
participant-reported side-effect profile appeared
to be more favorable in the MRI-targeted biopsy
group than in the standard-biopsy group. The
MRI-targeted biopsy approach was also well ad-
hered to by the participants and clinicians, with
only 7 of 252 men (3%) not completing the diag-
nostic test strategy (Fig. 1).
The results of single-center studies have been
mixed. Some studies have not shown the superi-
ority of an MRI-based pathway over transrectal
ultrasonography–guided biopsy, although these
comparisons were likely to have been underpow-
ered.
12,22
Other single-center studies have shown
advantages of an MRI-based diagnostic pathway
over transrectal ultrasonography–guided biop-
sy,
13,14 ,23
and a meta-analysis of published studies
had findings concordant with those of our tri-
al.
15
These single-center studies have limitations
in their lack of generalizability, and the majority
of the studies were small and nonrandomized.
The PRECISION trial was an international
trial, and key strengths included its size and
pragmatism.
24
We did not limit the performance
of MRI-targeted biopsy to highly experienced
operators, and most of the participating investi-
gators had modest experience with MRI-targeted
biopsy, particularly as compared with standard
Figure 2. Intention-to-Treat, Modified Intention-to-Treat, and Per-Protocol Analyses of the Primary Outcome
for the Detection of Clinically Significant Prostate Cancer.
Shown are the absolute differences between the MRI-targeted biopsy group and the standard-biopsy group in the
rates of detection of clinically significant cancer. The intention-to-treat analysis included all the participants who
underwent randomization, the modified intention-to-treat analysis excluded participants who did not complete a
diagnostic test strategy, and the per-protocol analysis included only participants who under went the randomly as-
signed testing procedure as specified in the protocol. If the lower boundary of the two-sided 95% confidence inter-
val for the difference (MRI-targeted biopsy group minus standard-biopsy group) was greater than −5 percentage
points (dashed line), then MRI, with or without targeted biopsy, would be deemed to be noninferior. If the lower
boundary was greater than zero (solid line), superiority would be claimed.
−5 0 5 10 15 20 25
MRI with or without Targeted Biopsy
Better
Standard Biopsy
Better
Intention-to-treat analysis
Modified intention-to-treat analysis
Per-protocol analysis
Difference in Rate of Primary Outcome (95% CI)
percentage points Analysis
12 (3–20)
12 (4–20)
−10
12 (3–20)
Noninferiority
margin
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9
MRI-Targeted Biopsy for Prostate-Cancer Diagnosis
transrectal ultrasonography–guided biopsy. We
also allowed nonacademic centers outside the
original expert group to take part. In addition,
either 1.5-T or 3.0-T MRI machines were permit-
ted, and the use of an endorectal coil was per-
mitted but not required. Also, various techniques
of MRI-targeted biopsy, with visual registration
or software-assisted registration with either
transrectal or transperineal access routes, were
permitted. This approach is supported by a me-
ta-analysis of studies that showed a lack of supe-
riority of any one registration approach.
25
We
believed that the results would be more general-
izable if we permitted centers to use their local
expertise and resources than if we required that
they use a particular operating system or access
route that may not have been available to all
centers outside of the trial. We observed differ-
ences among centers in the detection of clini-
cally significant cancers. However, on average,
MRI with or without targeted biopsy was conclu-
sively superior to standard transrectal ultraso-
nography–guided biopsy.
Our trial has limitations. First, despite the
use of standardized reporting of MRI results,
9
the central quality-control review of multipara-
metric MRIs (Table S16A in the Supplementary
Appendix) showed moderate agreement (78%)
between the site and the central radiologist read-
ing, a finding that highlights that there is still
room for improvement in attaining consistency
in the reporting of the results of multiparamet-
ric MRI. Regardless, the degree of agreement
with central interpretation was similar to the
interrater agreement that has been seen in other
studies involving expert readers of multipara-
metric MRIs.
1,26
This finding highlights the need
for further research regarding improvements to
the standardization, reproducibility, and report-
ing of multiparametric MRIs.
Second, a small proportion of the pathologi-
cal test results were upgraded or downgraded on
central pathological review. However, the differ-
ences were not substantial bet ween groups, and
the agreement that was seen on central review
was consistent with that seen in the literature.
27
Third, there are concerns about the men with
negative results on multiparametric MRI who do
not undergo biopsy. It has been shown that
these men have a low risk of clinically signifi-
cant cancer,
1
but nonetheless, follow-up with
monitoring of the PSA level is routine, reason-
able, and safe. Participants provided consent for
long-term follow-up in national registries. More-
over, this trial showed that, among men with
negative results on initial tests, a far greater
proportion of the participants in the standard-
biopsy group underwent further diagnostic tests
than did those in the MRI-targeted biopsy
group, a finding that confirms that a negative
result on multiparametric MRI was more reas-
suring to the participants and clinicians than a
negative result on standard transrectal ultraso-
nography–guided biopsy.
Fourth, it is possible that clinically signif i-
cant cancers may have been missed by the
omission of standard biopsy cores in men in
the MRI-targeted biopsy group. Previous well-
designed studies have highlighted that the percent-
age of cases of clinically signif icant cancer that
are missed by MRI-targeted biopsy but detected
by standard transrectal ultrasonography–guided
Figure 3. Percentages of Men with Clinically Significant, Clinically Insignificant,
and No Cancer, Identified According to PI-RADS v2 Score.
For men randomly assigned to the MRI-targeted biopsy group, the areas of
the prostate were scored with the use of the Prostate Imaging–Reporting
and Data System, version 2 (PI-R ADS v2). Scores range from 1 to 5, with
higher numbers indicating a greater likelihood of clinically significant can-
cer; a score of 3 indicates equivocal results, 4 results that are likely to be
prostate cancer, and 5 results that are highly likely to be prostate cancer.
Men who had a score of 3 or higher under went MRI-targeted biopsy. Clini-
cally significant cancer was defined as the presence of a single biopsy core
indicating disease of Gleason score 3+4 (Gleason sum of 7) or greater, and
clinically insignif icant cancer as a biopsy sample with a Gleason score of
3+3 (Gleason sum of 6). The Gleason score is composed of a primary
(most predominant) grade plus a secondary (highest nonpredominant)
grade; the range for a primary or secondary grade is from 3 to 5, with the
Gleason sum ranging from 6 to 10, and with higher scores indicating a
more aggressive form of prostate cancer. Percentages may not total 100
because of rounding.
Participants, According to
Disease Status (%)
100
12
22
67
60
9
31
83
11
6
80
90
70
60
40
30
10
50
20
03
(N=51)
4
(N=70)
5
(N=54)
PI-RADS v2 Score
Clinically insignificant
cancer
No cancer
Clinically significant
cancer
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10
The
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biopsy is low, between 0% and 10%.
12,13,23,28
De-
spite more than one quarter of the men avoiding
a biopsy, this trial showed that when clinicians
limited themselves to the use of MRI-targeted
biopsies only, the rates of detection of clinically
signif icant cancer were higher than those seen
with the standard of care. Furthermore, because
systematic biopsy was avoided, clinically insig-
nificant cancer was detected in fewer men,
which may have a substantial benefit in reducing
the overtreatment of men with prostate cancer.
If both systematic biopsy and MRI-targeted bi-
opsy were carried out in the same man at the
same time, the performance of one test could be
inf luenced by the other, which would make it
difficult to evaluate the unbiased performance
of each test individually.
We acknowledge that the acquisition and re-
porting of MRI of the prostate are specialist
skills with a learning curve and that the radiolo-
gists involved in this trial were reporting a high
volume of MRIs per year (median, 300 MRIs per
year). We suggest that those who report MRIs of
the prostate report a high volume of scans under
the supervision of a radiologist who is experi-
enced in MRI of the prostate. We acknowledge
that a change in the standard of care for pros-
tate-cancer diagnosis would entail changes in
health care systems to accommodate appropriate
MRI capacity and to meet the training needs of
radiologists and urologists. From a health eco-
nomics perspective, the cost savings with MRI,
with or without targeted biopsy, over standard
transrectal ultrasonography–guided biopsy may
emerge from the earlier detection of clinically
significant cancers, fewer cases of insignificant
cancer diagnosed, and fewer repeat biopsies.
Reports from other studies and in different
contexts suggest that this pathway may be cost-
effective in the long term.
29-31
In conclusion, in men with a clinical suspi-
cion of prostate cancer, we found that a diagnos-
tic pathway including risk assessment with MRI
before biopsy and MRI-targeted biopsy in the
presence of a lesion suggestive of cancer was
superior to the diagnostic pathway of standard
transrectal ultrasonography–guided biopsy.
The views expressed in th is article are those of t he author s
and not necessarily those of the Nat ional Health Service, the
Nationa l Institute for Health Research (NIHR), the U.K. Depart-
ment of Healt h, or the European Association of Urolog y Re-
search Foundation (EAURF).
Supported by the NI HR through a doct oral fellowship award
(DRF-2014-07-146, to Dr. Kasivisvanat han) and by a grant
(2015001) from the EAURF. This article presents independent
research funded by the NIHR and EAURF. Dr. Deeks is a Unit ed
Kingdom N IHR Senior Invest igator Emeritus and has received
support from the NI HR Birm ingha m Biomedic al Rese arch Cen-
tre. Dr. Tak woingi is supported by the NI HR through a postdoc-
toral fellowship award (PDF-2017-10-059). Dr. Emberton is a
United Kingdom NIHR Senior Investig ator and receives research
support from UCL Hospita ls–UCL NI HR Biomedical Research
Centre.
Disclosure forms provided by t he authors are ava ilable w ith
the fu ll text of this art icle at NEJM.org.
We thank t he participants who volu nteered to ta ke part in this
trial and the trial teams that cared for them, t he investigators
for thei r contribution, t he UCL Surgical and Inter ventional Tri-
als Unit for coordination of t he trial, and the trial st eering com-
mittee and dat a and sa fety monitoring committee for oversight
of the trial.
Appendix
The authors’ full names and academic degrees are as follows: Veeru Kasivisvanathan, M.R.C.S., Antti S. Rannikko, Ph.D., Marcelo
Borghi, M.D., Valeria Panebianco, M.D., Lance A. Mynderse, M.D., Markku H. Vaarala, Ph.D., Alberto Briganti, Ph.D., Lars Budäus,
M.D., Giles Hellawell, F.R.C.S.(Urol.), Richard G. Hindley, F.R.C.S.(Urol.), Monique J. Roobol, Ph.D., Scott Eggener, M.D., Maneesh
Ghei, F.R.C.S.(Urol.), Arnauld Villers, M.D., Franck Bladou, M.D., Geert M. Villeirs, Ph.D., Jaspal Virdi, F.R.C.S.(Urol.), Silvan Boxler,
M.D., Grégoire Robert, Ph.D., Paras B. Singh, F.R.C.S.(Urol.), Wulphert Venderink, M.D., Boris A. Hadaschik, M.D., Alain Ruffion,
Ph.D., Jim C. Hu, M.D., Daniel Margolis, M.D., Sébastien Crouzet, Ph.D., Laurence Klotz, M.D., Samir S. Taneja, M.D., Peter Pinto,
M.D., Inderbir Gill, M.D., Clare Allen, F.R.C.R., Francesco Giganti, M.D., Alex Freeman, F.R.C.Path., Stephen Morris, Ph.D., Shonit
Punwani, F.R.C.R., Norman R. Williams, Ph.D., Chris Brew-Graves, M.Sc., Jonathan Deeks, Ph.D., Yemisi Takwoingi, Ph.D., Mark
Emberton, F.R.C.S.(Urol.), and Caroline M. Moore, F.R.C.S.(Urol.).
The authors’ affiliations are as follows: University College London (UCL) and UCL Hospitals NHS Foundation Trust (V.K., C.A., F.G.,
A.F., S.M., S.P., M.E., C.M.M.), London North West Healthcare NHS Trust (G.H.), Whittington Health NHS Trust (M.G.), Royal Free
London NHS Foundation Trust (P.B.S.), and UCL Surgical and Interventional Trials Unit (N.R.W., C.B.-G.), London, Hampshire Hos-
pitals NHS Foundation Trust, Basingstoke (R.G.H.), Princess Alexandra Hospital NHS Trust, Harlow (J.V.), and the Institute of Applied
Health Research and the NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham (J.D., Y.T.) — all in
the United Kingdom; Helsinki University and Helsinki University Hospital, Helsinki (A.S.R.), and Medical Research Center Oulu, Uni-
versity of Oulu and Oulu University Hospital, Oulu (M.H.V.) — all in Finland; Centro de Urología, Buenos Aires (M.B.); Sapienza
University, Rome (V.P.), and IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan (A.B.) — all in Italy; Mayo
Clinic, Rochester, MN (L.A.M.); Martini Klinik, Hamburg (L.B.), University Hospital Essen, Essen (B.A.H.), and University Hospital
Heidelberg, Heidelberg (B.A.H.) — all in Germany; Erasmus University Medical Center, Rotterdam (M.J.R.), and Radboud University
Medical Center, Nijmegen (W.V.) — both in the Netherlands; University of Chicago, Chicago (S.E.); Université de Lille and Centre
Hospitalier Universitaire Lille, Lille (A.V.), Université de Bordeaux and Bordeaux Pellegrin University Hospital, Bordeaux (G.R.), and
Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud (A.R.), and Hospices Civils de Lyon of the Hôpital Edouard Herriot (S.C.), Lyon
— all in France; Jewish General Hospital, Montreal (F.B.), and Sunnybrook Health Sciences Centre, Toronto (L.K.) — both in Canada;
The New England Journal of Medicine
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MRI-Targeted Biopsy for Prostate-Cancer Diagnosis
Ghent University Hospital, Ghent, Belgium (G.M.V.); University Hospital Bern, Bern, Switzerland (S.B.); Weill Cornell Medicine, New
York–Presbyterian Hospital (J.C.H., D.M.), and New York University Langone Medical Center (S.S.T.), New York; National Institutes of
Health, Bethesda, MD (P.P.); and the University of Southern California Institute of Urology, Keck School of Medicine, Los Angeles (I.G.).
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  • Article
    Full-text available
    To overcome the limitations regarding two dimensional (2D) greyscale (GS) transrectal ultrasound (TRUS)-guided biopsy in prostate cancer (PCa) detection and tissue packaging in biopsy processing, there is an ongoing focus on new imaging and pathology techniques. A three-dimensional (3D) model of the prostate with biopsy needle guidance can be generate by the Navigo™ workstation (UC-care, Israel). The SmartBX™ system (UC-care, Israel) provides a prostate biopsy core preembedding method. The aim of this study was to compare cancer detection rates between the 3D TRUS-guidance and preembedding method with conventional 2D GS TRUS-guidance among patients undergoing prostate biopsies. We retrospectively analyzed the records of all patients who underwent prostate biopsies for PCa detection at our institution from 2007 to 2016. The cohort was divided into a 2D GS TRUS-guidance cohort (from 2007 to 2013, n = 1149) and a 3D GS TRUS-guidance with preembedding cohort (from 2013 to 2016, n = 469). Effect of 3D GS TRUS-guidance with preembedding on detection rate of PCa and clinically significant PCa (Gleason score ≥ 7 or > 2 biopsy cores with a Gleason score 6) was compared to 2D GS TRUS-guidance using regression models. Detection rate of PCa and clinically significant PCa was 39.0 and 24.9% in the 3D GS TRUS cohort compared to 33.5 and 19.0% in the 2D GS TRUS cohort, respectively. On multivariate regression analysis the use of 3D GS TRUS-guidance with preembedding was associated with a significant increase in detection rate of PCa (aOR = 1.33; 95% CI: 1.03–1.72) and clinically significant PCa (aOR = 1.47; 95% CI: 1.09–1.98). Our results suggest that 3D GS TRUS-guidance with biopsy core preembedding improves PCa and clinically significant PCa detection compared to 2D GS TRUS-guidance. Additional studies are needed to justify the application of these systems in clinical practice.
  • Article
    The use of multiparametric magnetic resonance imaging (mpMRI) in prostate cancer (PCa) diagnosis is rapidly evolving to try to overcome the limitations of the current diagnostic pathway using systematic transrectal ultrasound-guided biopsies (TRUSbx) for all men with clinical suspicion of PCa. Prostate mpMRI allows for high quality lesion detection and characterization and has been shown to improve detection of significant PCa with a more accurate Gleason score grading. Suspicious lesions can be stratified by suspicion and sampled by selective MRI-guided targeted biopsies (TBx) for improved diagnostic accuracy. Several TBx methods have been established and include MRI/TRUS image fusion biopsies (cognitive or software-assisted) and in-bore biopsies, but none have yet proven superior in clinical practice. However, while MRI in-bore biopsy is not routinely used due to its costs and limited availability, MRI/TRUS image fusion is rapidly embraced as it allows skilled urologists to perform TBx in an outpatient clinic. Furthermore, it gives the operator the advantage of adding TBx to the systematic standard biopsy scheme, which is the currently recommended approach. With the anticipated increased future use of prebiopsy mpMRI, a more widespread implementation of MRI/TRUS image fusion platforms is concurrently expected in clinical practice. Therefore, the objective of this review is to assess the current status, challenges and future perspectives of prostate MRI/TRUS image fusion biopsies.
  • Article
    Introduction The goal of radical prostatectomy is to eradicate oncological disease while achieving the best possible functional outcomes. In this regard, nerve sparing offers a greater chance of recovering potency after surgery. Accurately locating prostate cancer foci is instrumental for identifying good candidates for this approach whilst maintaining safe oncological margins. In addition to this, the length of membranous urethra is an independent predictor of time to, and extent of, continence recovery. The introduction of Mp-MRI allows visualising malignant tissue within the prostate gland, which could lead to image-directed surgery planning as with other solid-organ cancers such as kidney, pancreas, breast or testes. Methods A narrative review of the available literature was performed. Results Mp-MRI demonstrated moderate sensitivity and high specificity to detect extra-capsular extension, seminal vesicle involvement or T3 stage. Measurements of membranous urethral length have shown to be useful in predicting probability of achieving continence after surgery. Furthermore, image-guided surgery has shown to be accurate to determine surgical planes to safely preserve neurovascular bundles. Conclusion The use of Mp-MRI for pre-surgical planning introduces a new scenario where the previously homogeneous radical prostatectomy can be tailored to suit patient and tumour features. This has the potential to improve functional outcomes whilst not compromising on surgical margins. Moreover, the introduction of Mp-MRI increases the ability to predict functional outcomes after surgery and allows for a more accurate local staging. This in turn provides more information to both patients and clinicians in the decision-making process regarding treatment.
  • Article
    Prostate cancer risk prediction models and multiparametric magnetic resonance imaging (mpMRI) are used for individualised pre-biopsy risk assessment. However, biparametric MRI (bpMRI) has emerged as a simpler, more rapid MRI approach (fewer scan sequences, no intravenous contrast-media) to reduce costs and facilitate a more widespread clinical implementation. It is unknown how bpMRI and risk models perform conjointly. Therefore, the objective was to develop a predictive model for significant prostate cancer (sPCa) in biopsy-naive men based on bpMRI findings and clinical parameters. Eight hundred and seventy-six biopsy-naive men with clinical suspicion of prostate cancer (prostate-specific antigen, <50 ng/mL; tumour stage
  • Article
    Basingstoke was a participating centre in the MRC funded PROMIS trial between 2013 and 2015 recruiting 130 patients. In response to a perceived change in prostate biopsy histological grading following the introduction of pre-biopsy magnetic resonance imaging at our centre, we decided to undertake a retrospective analysis of prostate histology before and after participation in the study.
  • Article
    The accurate identification and stratified treatment of clinically significant early-stage prostate cancer have been ongoing concerns since the outcomes of large international prostate cancer screening trials were reported. The controversy surrounding clinical and cost benefits of prostate cancer screening has highlighted the lack of strategies for discriminating high-risk disease (that requires early treatment) from low-risk disease (that could be managed using watchful waiting or active surveillance). Advances in molecular subtyping and multiomics nanotechnology-based prostate cancer risk delineation can enable refinement of prostate cancer molecular taxonomy into clinically meaningful and treatable subtypes. Furthermore, the presence of intertumoural and intratumoural heterogeneity in prostate cancer warrants the development of novel nanodiagnostic technologies to identify clinically significant prostate cancer in a rapid, cost-effective and accurate manner. Circulating and urinary next-generation prostate cancer biomarkers for disease molecular subtyping and the newest complementary nanodiagnostic platforms for enhanced biomarker detection are promising tools for precision prostate cancer management. However, challenges in merging both aspects and clinical translation still need to be overcome.
  • Article
    Full-text available
    Introduction The classical pathway for the diagnosis of prostate cancer is transrectal ultrasound-guided (TRUS) biopsy of the prostate initiated on the basis of a raised prostate-specific antigen (PSA). An alternative pathway is to perform multi-parametricMRI (MPMRI) to localise cancer and to use this information to influence the decision for, and conduct of, a subsequent biopsy, known as an MPMRI-targeted biopsy. An MPMRI pathway has been shown to detect a similar or greater amount of clinically significant cancer as TRUS biopsy but has several advantages, including the potential to biopsy fewer men with fewer cores. Methods This is a pragmatic, international, multicentre, parallel group randomised study in which men are allocated in a 1:1 ratio to an MPMRI or TRUS biopsy pathway. This study will assess whether an MPMRI-targeted biopsy approach is non-inferior to a standard TRUS biopsy approach in the diagnosis of clinically significant cancer. Men in the MRI arm will undergo targeted biopsy of suspicious areas only and no biopsy will be carried out if the MRI is non-suspicious. Men in the TRUS biopsy will undergo a standard 10–12-core TRUS biopsy. The main inclusion criteria are a serum PSA ≤20 ng/mL, a digital rectal examination finding of T2 or less and no prior prostate biopsy. The primary outcome is the proportion of men with clinically significant cancer detected. A sample size of at least 470 patients is required. Key secondary outcomes include the proportion of clinically insignificant cancer detected. Ethics and dissemination Ethical approval was obtained from the National Research Ethics Committee East Midlands, Leicester (15/EM/0188). Results of this study will be disseminated through national and international papers. The participants and relevant patient support groups will be informed about the results of the study. Registration details NCT02380027; Pre-results
  • Article
    Background: The current recommendation of using transrectal ultrasound-guided biopsy (TRUSB) to diagnose prostate cancer misses clinically significant (CS) cancers. More sensitive biopsies (eg, template prostate mapping biopsy [TPMB]) are too resource intensive for routine use, and there is little evidence on multiparametric magnetic resonance imaging (MPMRI). Objective: To identify the most effective and cost-effective way of using these tests to detect CS prostate cancer. Design, setting, and participants: Cost-effectiveness modelling of health outcomes and costs of men referred to secondary care with a suspicion of prostate cancer prior to any biopsy in the UK National Health Service using information from the diagnostic Prostate MR Imaging Study (PROMIS). Intervention: Combinations of MPMRI, TRUSB, and TPMB, using different definitions and diagnostic cut-offs for CS cancer. Outcome measurements and statistical analysis: Strategies that detect the most CS cancers given testing costs, and incremental cost-effectiveness ratios (ICERs) in quality-adjusted life years (QALYs) given long-term costs. Results and limitations: The use of MPMRI first and then up to two MRI-targeted TRUSBs detects more CS cancers per pound spent than a strategy using TRUSB first (sensitivity = 0.95 [95% confidence interval {CI} 0.92-0.98] vs 0.91 [95% CI 0.86-0.94]) and is cost effective (ICER = £7,076 [€8350/QALY gained]). The limitations stem from the evidence base in the accuracy of MRI-targeted biopsy and the long-term outcomes of men with CS prostate cancer. Conclusions: An MPMRI-first strategy is effective and cost effective for the diagnosis of CS prostate cancer. These findings are sensitive to the test costs, sensitivity of MRI-targeted TRUSB, and long-term outcomes of men with cancer, which warrant more empirical research. This analysis can inform the development of clinical guidelines. Patient summary: We found that, under certain assumptions, the use of multiparametric magnetic resonance imaging first and then up to two transrectal ultrasound-guided biopsy is better than the current clinical standard and is good value for money.
  • Article
    Background We previously found no significant differences in mortality between men who underwent surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long-term mortality. Methods From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation. We extended follow-up through August 2014 for our primary outcome, all-cause mortality, and the main secondary outcome, prostate-cancer mortality. We describe disease progression, treatments received, and patient-reported outcomes through January 2010 (original follow-up). Results During 19.5 years of follow-up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], −1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) assigned to observation (absolute difference in risk, 4.0 percentage points; 95% CI, −0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associated with lower all-cause mortality than observation among men with intermediate-risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 25.6) but not among those with low-risk disease (absolute difference, 0.7 percentage points; 95% CI, −10.5 to 11.8) or high-risk disease (absolute difference, 2.3 percentage points; 95% CI, −11.5 to 16.1) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate-specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease-related or treatment-related limitations in activities of daily living were greater with surgery than with observation through 2 years. Conclusions After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veterans Affairs and others; PIVOT ClinicalTrials.gov number, NCT00007644.)
  • Article
    Purpose of review: To review the role of prebiopsy multiparametric MRI in biopsy-naïve men for the detection of clinically significant prostate cancer. Recent findings: Recent level 1 evidence shows that multiparametric MRI has high sensitivity and negative predictive value for the detection of clinically significant prostate cancer in biopsy-naïve men. Concurrent developments include important work in the standardization of MRI reporting. The low specificity and positive predictive value of MRI means that biopsy is still necessary following MRI. MRI-targeted prostate biopsy has emerged as an alternative diagnostic test to transrectal ultrasound guided prostate biopsy, though its exact role in biopsy-naïve men and the optimal technique remain to be defined. Summary: There is the potential for MRI to be used as a triage test to allow a proportion of men to avoid biopsy and remain on prostate-specific antigen surveillance. MRI-suspicious areas can be sampled more intensively using MRI-targeted biopsy that can be carried out in a variety of ways. Future work should focus on the cost-effectiveness of introducing a prebiopsy MRI pathway in biopsy-naïve men and addressing the training needs for such a change. VIDEO ABSTRACT: http://links.lww.com/COU/A11.
  • Article
    Full-text available
    Importance Patients diagnosed with localized prostate cancer have to decide among treatment strategies that may differ in their likelihood of adverse effects. Objective To compare quality of life (QOL) after radical prostatectomy, external beam radiotherapy, and brachytherapy vs active surveillance. Design, Setting, and Participants Population-based prospective cohort of 1141 men (57% participation among eligible men) with newly diagnosed prostate cancer were enrolled from January 2011 through June 2013 in collaboration with the North Carolina Central Cancer Registry. Median time from diagnosis to enrollment was 5 weeks, and all men were enrolled with written informed consent prior to treatment. Final follow-up date for current analysis was September 9, 2015. Exposures Treatment with radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance. Main Outcomes and Measures Quality of life using the validated instrument Prostate Cancer Symptom Indices was assessed at baseline (pretreatment) and 3, 12, and 24 months after treatment. The instrument contains 4 domains—sexual dysfunction, urinary obstruction and irritation, urinary incontinence, and bowel problems—each scored from 0 (no dysfunction) to 100 (maximum dysfunction). Propensity-weighted mean domain scores were compared between each treatment group vs active surveillance at each time point. Results Of 1141 enrolled men, 314 pursued active surveillance (27.5%), 469 radical prostatectomy (41.1%), 249 external beam radiotherapy (21.8%), and 109 brachytherapy (9.6%). After propensity weighting, median age was 66 to 67 years across groups, and 77% to 80% of participants were white. Across groups, propensity-weighted mean baseline scores were 41.8 to 46.4 for sexual dysfunction, 20.8 to 22.8 for urinary obstruction and irritation, 9.7 to 10.5 for urinary incontinence, and 5.7 to 6.1 for bowel problems. Compared with active surveillance, mean sexual dysfunction scores worsened by 3 months for patients who received radical prostatectomy (36.2 [95% CI, 30.4-42.0]), external beam radiotherapy (13.9 [95% CI, 6.7-21.2]), and brachytherapy (17.1 [95% CI, 7.8-26.6]). Compared with active surveillance at 3 months, worsened urinary incontinence was associated with radical prostatectomy (33.6 [95% CI, 27.8-39.2]); acute worsening of urinary obstruction and irritation with external beam radiotherapy (11.7 [95% CI, 8.7-14.8]) and brachytherapy (20.5 [95% CI, 15.1-25.9]); and worsened bowel symptoms with external beam radiotherapy (4.9 [95% CI, 2.4-7.4]). By 24 months, mean scores between treatment groups vs active surveillance were not significantly different in most domains. Conclusions and Relevance In this cohort of men with localized prostate cancer, each treatment strategy was associated with distinct patterns of adverse effects over 2 years. These findings can be used to promote treatment decisions that incorporate individual preferences.
  • Article
    Background The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. Methods We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. Results There were 17 prostate-cancer–specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). Conclusions At a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)
  • Article
    Background: An approach based on multiparametric magnetic resonance imaging (mpMRI) might increase the detection rate (DR) of clinically significant prostate cancer (csPCa). Objective: To compare an mpMRI-based pathway with the standard approach for the detection of prostate cancer (PCa) and csPCa. Design, setting, and participants: Between November 2014 and April 2016, 212 biopsy-naïve patients with suspected PCa (prostate specific antigen level ≤15 ng/ml and negative digital rectal examination results) were included in this randomized clinical trial. Patients were randomized into a prebiopsy mpMRI group (arm A, n=107) or a standard biopsy (SB) group (arm B, n=105). Intervention: In arm A, patients with mpMRI evidence of lesions suspected for PCa underwent mpMRI/transrectal ultrasound fusion software-guided targeted biopsy (TB) (n=81). The remaining patients in arm A (n=26) with negative mpMRI results and patients in arm B underwent 12-core SB. Outcomes measurements and statistical analysis: The primary end point was comparison of the DR of PCa and csPCa between the two arms of the study; the secondary end point was comparison of the DR between TB and SB. Results and limitations: The overall DRs were higher in arm A versus arm B for PCa (50.5% vs 29.5%, respectively; p=0.002) and csPCa (43.9% vs 18.1%, respectively; p<0.001). Concerning the biopsy approach, that is, TB in arm A, SB in arm A, and SB in arm B, the overall DRs were significantly different for PCa (60.5% vs 19.2% vs 29.5%, respectively; p<0.001) and for csPCa (56.8% vs 3.8% vs 18.1%, respectively; p<0.001). The reproducibility of the study could have been affected by the single-center nature. Conclusions: A diagnostic pathway based on mpMRI had a higher DR than the standard pathway in both PCa and csPCa. Patient summary: In this randomized trial, a pathway for the diagnosis of prostate cancer based on multiparametric magnetic resonance imaging (mpMRI) was compared with the standard pathway based on random biopsy. The mpMRI-based pathway had better performance than the standard pathway.
  • Article
    Introduction: Transrectal ultrasound-guided biopsy (TRUSGB) is the recommended approach to diagnose prostate cancer (PCa). Overdiagnosis and sampling errors represent major limitations. Magnetic resonance imaging (MRI)-targeted biopsy (MRTB) detects higher proportion of significant PCa and reduces diagnosis of insignificant PCa. Costs prevent MRTB from becoming the new standard in PCa diagnosis. The present study aimed at assessing whether added costs of MRI outweigh benefits of MRTB in a cost-utility model. Materials and methods: A Markov model was developed to estimate quality-adjusted life-year gained (QALY) and costs for 2 strategies (the standard 12-core TRUSGB strategy and the MRTB strategy) over 5, 10, 15, and 20 years. MRI was used as triage test in biopsy-naive men with clinical suspicion of PCa. The model takes into account probability of men harboring PCa, diagnostic accuracy of both procedures, and probability of being assigned to various treatment options. Direct medical costs based on health care system perspective were included. Results: Following standard TRUSGB pathway, calculated cumulative effects at 5, 10, 15, and 20 years were 4.25, 7.17, 9.03, and 10.09 QALY, respectively. Cumulative effects in MRTB pathway were 4.29, 7.26, 9.17, and 10.26 QALY, correspondingly. Costs related to TRUSGB strategy were $8,027, $11,406, $14,883, and $17,587 at 5, 10, 15, and 20 years, respectively, as compared with $7,231, $10,450, $13,267, and $15,400 for the MRTB strategy. At 5, 10, 15, and 20 years, MRTB was the established dominant strategy. Conclusions: Incorporation of MRI and MRTB in PCa diagnosis and management represents a cost-effective measure at 5, 10, 15, and 20 years after initial diagnosis.
  • Article
    The Prostate Imaging - Reporting and Data System Version 2 (PI-RADS™ v2) is the product of an international collaboration of the American College of Radiology (ACR), European Society of Uroradiology (ESUR), and AdMetech Foundation. It is designed to promote global standardization and diminish variation in the acquisition, interpretation, and reporting of prostate multiparametric magnetic resonance imaging (mpMRI) examination, and it is based on the best available evidence and expert consensus opinion. It establishes minimum acceptable technical parameters for prostate mpMRI, simplifies and standardizes terminology and content of reports, and provides assessment categories that summarize levels of suspicion or risk of clinically significant prostate cancer that can be used to assist selection of patients for biopsies and management. It is intended to be used in routine clinical practice and also to facilitate data collection and outcome monitoring for research.