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Attachments:Magnetic Resonance Imaging-Ultrasound Fusion Targeted
Prostate Biopsy in a Consecutive Cohort of Men with No
Previous Biopsy: Reduction of Over Detection through
Improved Risk Stratification
Neil Mendhiratta, Andrew B. Rosenkrantz, Xiaosong Meng, James S. Wysock,
Michael Fenstermaker, Richard Huang, Fang-Ming Deng, Jonathan Melamed,*
Ming Zhou, William C. Huang, Herbert Lepor and Samir S. Taneja
From the School of Medicine (NM, MF) and Departments of Radiology (ABR, SST), Surgery (XM), Urology (RH, WCH, HL, SST) and
Pathology (FMD, JM, MZ), New York University Langone Medical Center, New York and Department of Urology, New York Hospital
Queens (JSW), Flushing, New York
Purpose: MRF-TB (magnetic resonance imaging-ultrasound fusion targeted
prostate biopsy) may improve the detection of prostate cancer in men presenting
for prostate biopsy. We report clinical outcomes of 12-core systematic biopsy and
MRF-TB in men who presented for primary biopsy and further describe
pathological characteristics of cancers detected by systematic biopsy and not by
MRF-TB.
Materials and Methods: Clinical outcomes of 435 consecutive men who underwent
prebiopsy multiparametric magnetic resonance imaging followed by MRFTB
and systematic biopsy at our institution between June 2012 and March 2015
were captured in an institutional review board approved database. Clinical
characteristics, biopsy results and magnetic resonance imaging suspicion scores
were queried from the database.
Results: Prostate cancer was detected in 200 of 370 men (54.1%) with a mean
SD age of 64 8.5 years and mean SEM prostate specific antigen 6.8
0.3 ng/ml who met study inclusion criteria. The cancer detection rate of systematic
biopsy and MRF-TB was 47.3% and 43.5%, respectively (p 0.104).
MRF-TB detected more Gleason score 7 or greater cancers than systematic biopsy
(114 of 128 or 89.1% vs 95 of 128 or 74.2%, p 0.008). Of 39 cancers detected
by systematic biopsy but not by MRF-TB 32 (82.1%) demonstrated Gleason
6 disease, and 24 (61.5%) and 32 (82.1%) were clinically insignificant by Epstein
criteria and a UCSF CAPRA (University of California-San Francisco-Cancer of
the Prostate Risk Assessment) score of 2 or less, respectively.
Conclusions: In men presenting for primary prostate biopsy MRF-TB detects
more high grade cancers than systematic biopsy. Most cancers detected by systematic
biopsy and not by MRF-TB are at clinically low risk. Prebiopsy magnetic
resonance imaging followed by MRF-TB decreases the detection of low risk
cancers while significantly improving the detection and risk stratification of high
grade disease.
Key Words: prostatic neoplasms, magnetic resonance imaging,
ultrasonography, biopsy, diagnostic imaging
Abbreviations
and Acronyms
CDR cancer detection rate
GS Gleason score
mpMRI multiparametric MRI
MRGB MRI guided targeted
biopsy
MRI magnetic resonance
imaging
mSS maximum MRI suspicion
score
PCa prostate cancer
PSA prostate specific antigen
SB systematic biopsy
US ultrasound
Accepted for publication June 7, 2015.
Study received institutional review board
approval.
* Financial interest and/or other relationship
with the Department of Defense.
Correspondence: Division of Urologic
Oncology, Department of Urology, New York
University Langone Medical Center, 150 East
32nd St., Suite 200, New York, New York 10016
(telephone: 646-825-6321; FAX: 646-825-6399;
e-mail: [email protected]).
Editors Note: This article is the
of 5 published in this issue for
which category 1 CME credits
can be earned. Instructions for
obtaining credits are given with
the questions on pages and
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Dochead: Adult Urology FLA 5.4.0 DTD JURO12718_proof 14 September 2015 10:44 am EO: JU-15-801
0022-5347/15/1946-0001/0
THE JOURNAL OF UROLOGY
2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2015.06.078
Vol. 194, 1-6, December 2015
Printed in U.S.A. www.jurology.com j 1
PROSTATE cancer is the most common cancer diagnosed
in men in the United States and the second
most common cause of cancer death.1 Traditional
US guided prostate biopsy has been shown to have
limited sensitivity for detecting PCa.2,3 Consequently
an initial biopsy negative for PCa often does
not reliably indicate absent disease.4 Additionally in
light of the increasing number of prostate biopsies
performed due to increased PSA5 the rate of over
detection of clinically low risk disease varies from
2% to 67% of cancer diagnoses,6 leading to unnecessary
morbidity associated with over treatment
and decreased quality of life.7,8
Current evidence demonstrates improved
sensitivity for detecting high grade PCa using
mpMRI followed by MRI targeted biopsy than
with standard 12-core systematic biopsy.9e12 We
compared the outcomes of targeted prostate biopsy
performed with automated MRI-US fusion and
12-core SB done with a computerized template in
the population of men with increased PSA and no
history of prostate biopsy. In light of recent
evidence suggesting that MRI targeted biopsy
selectively identifies high grade cancer compared
to SB13 we further characterized cancers that were
missed or mischaracterized as low grade by
MRF-TB alone.
MATERIALS AND METHODS
Study Design and Population
Between June 2012 and March 2015, 625 consecutive men
with no prior biopsy who presented to our institution for
prostate biopsy were offered prebiopsy mpMRI. No abnormality
was identified in 88 (14.1%) of these men. Of
the remaining 537 men 435 (81.0%) proceeded combined
MRF-TB and SB. Clinical data mSS and biopsy results
were recorded in an institutional review board approved
F1 database (fig. 1). Some men were excluded from analysis,
including 15 who underwent MRI with a nonstandard
prostate MRI protocol and 50 in whom the prebiopsy
mpMRI was not read according to standardized trial
reporting criteria.
Multiparametric MRI
mpMRI was performed using a 3 Tesla whole body system
and a pelvic phased array coil. It included multiplanar
turbo-spin echo T2-weighted images, axial single shot
echo-planar imaging diffusion-weighted imaging with
b-values of 50 and 1,000 seconds per mm2
, and dynamic
contrast enhanced imaging MRI after intravenous
administration of gadolinium chelate. Before biopsy MRI
studies were reviewed by a single fellowship trained
radiologist with 5 to 6 years of experience with prostate
MRI at the time of this study to identify suspicious foci in
the prostate. The probability of tumor was scored on a
5-point Likert scale, including mSS 2dlow probability,
3dequivocal, 4dhigh probability and 5dvery high probability
as previously reported.10,14,15 Studies with no
identified suspicious region received a score of 1 and were
not candidates for MRI targeted biopsy.
MRI-US Fusion Targeted Biopsy
MRF-TB was done with the Artemis ProFuse coregistration
system for mpMRI segmentation, coregistration
of MRI to US images and 3-dimensional
biopsy planning as described in our previous study.10
Briefly lesion boundaries were identified by the radiologist
on T2-weighted images and transferred to the Artemis
system for guidance during the biopsy procedure. Computer
assisted co-registration of segmented MRI and US images
of the prostate was performed by manual rigid translation
followed by automated elastic deformation.With the patient
in the left lateral decubitus position transrectal biopsies
were obtained beginning with 4 biopsy cores targeted to
each suspicious lesion identified on MRI and followed by
12-core computerized template biopsy with core locations
designated by the Artemis generated template. Procedures
were done using the Pro Focus or Noblus (Hitachi Aloka
Medical America, Wallingford, Connecticut) US system,
an end fire probe, a reusable biopsy gun, 18 gauge needles
and local anesthesia with 1% lidocaine infiltration.
For each patient all systematic and targeted biopsies
were performed by the same 1 of 4 faculty physicians with
expertise in prostate biopsy. All biopsy cores were
analyzed by specialized genitourinary pathologists at the
same single institution.
Data Analysis and Statistics
Biopsy results were compared using the highest GS obtained
by each technique. Determination of high grade
cancer was based on GS 7 or greater. Clinically insignifi-
cant cancer was assessed using Epstein criteria16 and a
UCSF CAPRA score of 2 or less.17 Other comparative data
points included the number of biopsy cores demonstrating
cancer, cancer core length per core and the percent of
Gleason pattern 4 disease.
Figure 1. Patient enrollment
2 MAGNETIC RESONANCE IMAGING-ULTRASOUND FUSION TARGETED PROSTATE BIOPSY
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Dochead: Adult Urology FLA 5.4.0 DTD JURO12718_proof 14 September 2015 10:44 am EO: JU-15-801
All analysis was done in SPSS, version 21.0.
Categoric variable comparisons were performed with the
chi-square test and continuous variables were evaluated
with the Student t-test. Comparison of cancer detection
rates between techniques was assessed by the McNemar
test.
RESULTS
A total of 370 men met study inclusion criteria.
T1 Table 1 lists additional patient characteristics.
Overall Cancer Detection
PCa was identified in 200 men (54.1%). The CDR of
SB and MRF-TB was 47.3% and 43.5%, respectively
(p 0.104). GS 7 or greater cancer was detected
T2 in 128 men (34.6%). Table 2 lists the CDRs of GS
6 and 7 or greater disease for each biopsy technique.
MRF-TB detected more GS 7 or greater cancers
than SB (114 of 128 or 89.1% vs 95 of 128 or 74.2%,
p 0.008). MRF-TB contributed to a 35% increase
in GS 7 or greater PCa detection compared to SB
while SB contributed to an 11% increase in GS 7 or
greater PCa detection compared to MRF-TB. Eight
of the 14 GS 7 or greater cancers (57%) detected by
SB that were missed or graded as GS 6 by MRF-TB
demonstrated minimal pattern 4 (GS 3 4) disease
in only 1 SB core. MRF-TB diagnosed more GS 7 or
greater disease using fewer cores per prostate than
T3 SB (table 3).
Detection of Clinically Low Risk Disease
While SB detected more cancers than MRF-TB,
32 of 39 cancers (82.1%) detected by SB but not by
MRF-TB were GS 6 while 24 of 39 (61.5%) and 32
of 39 (82.1%) were clinically insignificant by Epstein
criteria16 and a UCSF CAPRA score of 2 or less,17
respectively. In contrast 8 of 25 cancers (32.0%)
detected by MRF-TB but not by SB showed
GS 6 cancer, and only 3 (12.0%) and 6 of 25
(24.0%) were clinically insignificant by Epstein16
and UCSF CAPRA17 criteria, respectively.
Consequently compared to cancers detected only by
MRF-TB a higher proportion detected only by SB
were GS 6 (p
fig. 2).16,17 Table 4 lists descriptive features of T4
discordant SB and MRF-TB results. Ultimately
SB contributed to the detection of 32 additional
GS 6 cancers while detecting only 4 with GS 7 or
greater (4 3), or GS 7 (3 4) in more than 1 core
missed by MRF-TB.
MRI Suspicion Score and PCa Detection
Table 5 lists CDRs by mSS. Of 149 men with mSS 4 T5
or greater 98 (85.2%) were found to have PCa. In
this subgroup of 149 men 102 (68.5%) were found to
have GS 7 or greater cancer. MRF-TB did not detect
7 of these 102 cancers (6.9%) and SB did not detect
28 (27.5%) (p SD age 64.6 8.5
Mean SEM PSA (ng/ml) 6.8 0.3
Median cc MRI prostate vol (IQR) 46 (36e62)
No. MRI abnormalities (%):
1 232 (62.7)
2 118 (31.9)
3 18 (4.9)
4 2 (0.5)
No. mSS (%):
2 108 (29.2)
3 113 (30.5)
4 77 (20.8)
5 72 (19.5)
Table 2. Comparative outcomes of MRF-TB and SB
SB
No. MRF-TB (%)
Gleason 7 or Greater Gleason 6 No Ca Total No.
GS 7 or greater 81 (21.9) 7 (1.9) 7 (1.9) 95 (25.7)*
GS 6 16 (4.3) 32 (8.6) 32 (8.6) 80 (21.6)
No Ca 17 (4.6) 8 (2.2) 170 (46.0) 195 (52.7)
Totals 114 (30.8)* 47 (12.7) 209 (56.5) 370 (100)
* p 0.008.
p JURO12718_proof 14 September 2015 10:44 am EO: JU-15-801
While cancer detection remains of paramount
importance, there is a growing desire to decrease
the detection of indolent, potentially nonlethal
cancers.18 Various biomarkers and imaging techniques
are available that aim to discriminate men
with regard to the risk of high grade cancer but the
optimal implementation of these tools in clinical
practice remains unclear.19,20 Recent evidence has
supported prebiopsy MRI to improve the detection
of high risk cancer in men who present for a first
prostate biopsy.21 In our cohort of men without
previous biopsy prebiopsy mpMRI followed by MRFTB
provided overall better detection of high grade
cancer than SB while limiting the detection of cancer
with low risk features.
Mozer et al reported the outcomes of comparing
MRF-TB with extended 12-core systematic biopsy
in men with no previous biopsies.22 In a cohort
of 152 men overall CDR was lower for MRF-TB
than for SB (54% vs 57%) as we noted in our
study. There was almost no difference in the
detection of GS 7 or greater cancers between the 2
techniques in their biopsy results (21.7% vs
22.4%). However, when categorized as clinically
significant disease (at least 1 core with GS 3
or greater 4 or 6 with a maximum cancer
core length o f4 mm or greater) vs clinically
insignificant disease, MRF-TB detected more significant
cancers than SB (43.4% vs 36.8%).
Delongchamps et al also reported outcomes of
prebiopsy MRI and targeted biopsy vs standard
transrectal biopsy in 391 men who presented for the
first biopsy.23 Of 264 men who underwent targeted
biopsy using rigid or elastic co-registration of MRI
and US images targeted biopsy demonstrated
higher GS 7 or greater cancer detection than standard
biopsy. In these 2 groups but not in the visual
co-registration group targeted biopsy also yielded
higher overall cancer detection than standard biopsy.
Pokorny et al reported the results of MRGB vs
standard transrectal biopsy in biopsy naive men.11
Of 142 men with abnormal mpMRI, defined as a
PI-RADS (Prostate Imaging Reporting and Data
System) score of 3 or greater, PCa was detected by
standard biopsy in 101 (71.1%) vs 99 (69.7%) by
MRGB. However, MRGB detected more high risk
cancer than standard biopsy (65.5% vs 52.1%).
When interpreting the published literature on
MRI targeted biopsy, critical concepts regarding the
value of targeted biopsy should be considered. Past
series have shown higher overall CDR than
ours,11,22,23 which may suggest differences in the
underlying prevalence and stage of disease among
tested cohorts. The relative added benefit of MRI
targeting likely varies with cancer prevalence as SB
is more likely to identify cancer in men with high
prevalence and more advanced stage of disease.
Additionally the definitions of clinical significance
currently reported are to some extent arbitrary with
inadequate correlation with eventual disease
outcome. In this regard reporting standards can
greatly influence the outcome of the study and
inflate the perceived impact of targeting. While to
our knowledge previously reported measures of
clinical significance have not been validated in the
setting of MRI targeted biopsy, we used several of
these definitions to better illustrate the significance
of disease.
To our knowledge this study represents the
largest reported cohort of biopsy naive men undergoing
MRI-US software fusion targeted and 12-core
systematic prostate biopsy. This analysis was
Table 4. Discordant results between MRF-TB and SB
Max GS Detected No. Pts
No. Max GS (%) No. Max SB Core Ca (%) No. mSS (%)
6 7 (3 4) 7 (4 3) 8 or Greater 10% or Less 10%e50% 50% or Greater 2 or 3 4 or 5
By SB vs MRF-TB: 46 32 (70) 8 (17) 5 (11) 1 (2) 19 (41) 18 (39) 9 (20) 30 (65) 16 (35)
7 or Greater vs 6 7 e 4 (57) 3 (43) 0 1 (14) 2 (29) 4 (57) 3 (43) 4 (57)
7 or Greater vs neg 7 e 4 (57) 2 (29) 1 (14) 2 (29) 4 (57) 1 (14) 3 (53) 4 (57)
6 vs neg 32 32 (100) ee e 16 (50) 12 (38) 4 (12) 24 (75) 8 (25)
By MRF-TB vs SB: 41 8 (20) 19 (46) 7 (17) 7 (17) 5 (12) 4 (10) 32 (78) 11 (27) 30 (73)
7 or Greater vs 6 16 e 12 (75) 3 (19) 1 (6) 0 3 (19) 13 (81) 1 (6) 15 (94)
7 or Greater vs neg 17 e 7 (41) 4 (24) 6 (35) 1 (6) 1 (6) 15 (88) 3 (18) 14 (82)
6 vs Neg 8 8 (100) ee e 4 (50) 0 4 (50) 7 (88) 1 (12)
Figure 2. PCa missed by MRF-TB and SB. Asterisk indicates
MRF-TB vs SB detection of GS 6 cancer p JURO12718_proof 14 September 2015 10:44 am EO: JU-15-801
intended to investigate differences between cancers
detected by traditional 12-core SB and by MRF-TB
using an MRI-US fusion platform in men with
mpMRI visualized lesions suspicious for PCa and
use the information derived to inform biopsy practice.
By yielding a lower rate of overall cancer
detection but a higher rate of GS 7 or greater cancer
detection compared to SB our outcomes of MRF-TB
reflect the trends reported in other MRI guided
prostate biopsy trials. They also demonstrate a
significant reduction in low risk PCa detection with
MRF-TB.
Because the problem of over detection of low
risk disease by traditional biopsy methods has
prompted an effort to selectively identify high risk
PCa, an approach is to consider the relative
contribution of SB to MRF-TB outcomes. A larger
proportion of PCa detected by MRF-TB was found
to be high grade compared to that detected by SB,
including 20% diagnosed as low grade by SB and
17 men in whom SB detected no cancer. Importantly
we noted that 62% to 82% of PCa detected
by SB and missed by MRF-TB in biopsy naive
men were likely to be clinically insignificant.
Conversely as few as 12% of PCas detected by
MRF-TB and not by SB were clinically insignifi-
cant. Even among GS 7 or greater PCas detected
by SB that were missed or graded as GS 6 by MRFTB
most lesions demonstrated a minimal Gleason
pattern 4 component, suggesting that these men
represent the lower end of the spectrum of intermediate
risk. Had all men in this study undergone
MRF-TB alone, the detection of up to 32 clinically
insignificant cancers would have been avoided and
only 4 cancers with GS 7 or greater (4 3) or GS 7
(3 4) in more than 1 core would have been
missed among 370 men.
Additionally by considering the relative
contribution of SB in men stratified by mSS it may
be possible to further optimize the balance between
high grade PCa detection and avoidance of
low risk disease. Of 32 clinically insignificant
cancers detected by SB and missed by MRF-TB 22
(68.8%) were detected in men with mSS less than
4. Only 3 GS 7 or greater cancers were detected by
SB alone in this subgroup of 221 men. Therefore,
prebiopsy MRI followed by targeted biopsy and
avoidance of systematic biopsy in select men,
especially those with mSS 2 or 3, may provide the
greatest potential to limit the detection of low risk
cancer while maximizing the detection of high
grade disease.
This study benefited from institutional experience
with prostate MRI, the fact that all mpMRIs
were interpreted and scored by a single experienced
radiologist and the standardized biopsy approach
performed by a few experienced operators. Limitations
of our study include the potential for selection
bias, given its retrospective nature and the referral
pattern of our practice. We believe that the consecutive
nature of our cohort to an extent minimizes
the possibility of bias as men were largely referred
based on community screening practices. Additionally
our conclusions regarding disease risk are
based purely on biopsy and were not validated by
prostatectomy. Due to current practices of selectively
offering prostatectomy to patients at higher
risk such a study may not be feasible. Disease risk
in our study was defined based on risk stratification
methods derived from systematic biopsy. As such
they may not be valid in the setting of MRF-TB.
Despite this we believe they offer the best known
means to assess risk in the biopsy setting. Finally
because outcomes of biopsy in men with normal
MRI were not included in this analysis, the impact
of avoiding biopsy in those men could not be
measured in our study. However, based on our early
experience suggesting a high negative predictive
value of normal MRI24 we believe that the likelihood
of missing significant disease in this population
is low.
Despite the inherent limitations of our analysis
we strongly believe that the outcomes of this study
support the practice of prebiopsy MRI followed by
selective targeted biopsy as a tool to maximize the
identification of high grade cancer and limit the
detection of indolent disease in the group of men
with abnormal MRI.
CONCLUSIONS
In men with increased PSA who present for initial
prostate biopsy prebiopsy mpMRI followed by
MRF-TB in those with suspicious MRI limits over
detection of clinically insignificant PCa while
providing greater detection of clinically significant
PCa than SB alone. The majority of PCas detected
by SB but missed by MRF-TB represent clinically
insignificant disease based on several definitions.
mpMRI provides added ability to predict the risk of
GS 7 or greater cancer with a negative predictive
value of 89% for detecting GS 7 or greater disease
Table 5. Cancer detection rate by mSS
mSS (approach) No. Pts
No. Max GS (%)
7 or Greater 6 No. Neg (%)
4 or 5: 149 102 (68.5) 25 (16.8) 22 (14.8)
MRF-TB 95 (63.8)* 20 (13.4) 34 (22.8)
SB 74 (49.7)* 38 (25.5) 37 (24.8)
2 or 3: 221 26 (11.8) 47 (21.3) 148 (67.0)
MRF-TB 19 (8.6) 27 (12.2) 175 (79.2)
SB 21 (9.5) 42 (19.0) 158 (71.5)
*MRF-TB vs SB p JURO12718_proof 14 September 2015 10:44 am EO: JU-15-801
in men with a maximum mSS of 2/3 and a positive
predictive value of 69% in men with a maximum
mSS of 4/5. Prebiopsy mpMRI is an effective tool
for further risk stratification in men with clinical
suspicion of prostate cancer and no previous
biopsy.
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Predictive value of negative 3T multiparametric
prostate MRI on 12 core biopsy results. J Urol,
suppl., 2014; 191: e754, abstract MP67-14. Research Article Review

Be sure to use this format with your answers inserted between each question and to answer all of the questions completely.

Article citation:

1. Introduction
a. Briefly describe the topic and goals of the research

b. Is the past research summarized in a way that conveys the need for the current study? Summarize the most pertinent past research.

c. What additional information was the present experiment supposed to add to the field?

d. State the studys hypothesis or hypotheses. If there is no explicitly stated hypothesis, what is the research question or the intention of the study?

e. How will the current study change or add to our understanding of the area being investigated?

f. Are there any gaps in the logic of the development of the hypotheses and research questions? If so, what?

2. Methods
a. Who were the participants? Were the inclusionary and exclusionary criteria on which they were selected appropriate and adequate?

b. What experimental groups were included in the study and did they adequately test the research question?

c. What was the setting of the study?

d. Identify the type of design used and summarize the design.

e. List all of the variables. Indicate how they were operationally defined.
i. If correlational, indicate which variables were to be associated with one another

ii. If experimental, indicate which variables were independent and dependent

iii. If not a or b, indicate which variables were investigated

f. Were the research participants randomly assigned to conditions?

g. Did the study have the necessary control or comparison groups to eliminate the influence of confounding extraneous variables?

h. Were there any attempts to control for biases that may arise from experimenter expectancies or research participant perceptions?

i. Did the operationalization of the independent and dependent variables seem to have captured the construct being investigated and the construct being measured?

3. Confounds and Ethical Issues
a. Indicate whether or not there were any biases present in the selection of participants. If so, how could they have been avoided?

b. Indicate whether or not there were any biases present during the running of the study (consider experimental bias, participant bias etc).

c. Consider the guidelines of the American Psychological Association. Were the participants at any risk? If so, what safeguards did the researcher institute into the study?

d. Did the exp

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