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MR imaging
in the localization of
prostate cancer
(recurrence) and guiding interventions
Derya Yakar
Stellingen bij het proefschrift
MR imaging in localizing Prostate Cancer (recurrence)
and guiding interventions
1.
Op basis van de literatuur, lijkt MP-MRI de beste beschikbare beeldvormende
techniek op dit moment in het lokaliseren, het stadiëren, het bepalen van
agressiviteit, en het volume van prostaatkanker (dit proefschrift).
2.
Op basis van de literatuur, is het aanbevolen om voor de lokalisatie van
prostaatkanker een MP-MRI te verrichten bestaande uit ten minste T2-w, DCEMRI, en DWI (dit proefschrift).
3.
Het gebruik van een ERC in 3D MRSI in het lokaliseren van prostaatkanker op
3T geeft slechts in geringe mate een verbetering in vergelijking met het niet
gebruiken van een ERC (dit proefschrift).
4.
DCE-MRI gerichte MRGB bij patiënten met een biochemisch recidief na
radiotherapie van prostaatkanker is een haalbare techniek (dit proefschrift).
5.
Volgens de literatuur zijn detectiepercentages van MRGB van de prostaat bij
patiënten met een voorgeschiedenis van eerdere negatieve TRUSGB sessies
hoger dan herhaalde TRUSGB sessies (dit proefschrift).
6.
Het is mogelijk om transrectale prostaatbiopsie uit te voeren met 3T MRI
begeleiding en met behulp van een op afstand bestuurbare MR-compatibele
robot als hulpmiddel (dit proefschrift).
7.
Transperineale MR-geleide focale cryo-ablatie van prostaatkankerrecidief na
radiotherapie is uitvoerbaar en veilig (dit proefschrift).
8.
I was working on the proof of one of my poems all the morning, and took out a
comma. In the afternoon I put it back again (Oscar Wilde).
9.
It’s possible that I understand better what’s going on, or it’s equally possible that I
just think I do (Russ Cox).
10. The time you enjoy wasting is not wasted time (Bertrand Russell).
Derya Yakar
Lent, Augustus 2012
MR imaging in localizing
prostate cancer (recurrence) and
guiding interventions
Derya Yakar
© Derya Yakar, Lent, The Netherlands, August 2012
ISBN: 978-94-6191-426-2
Cover Design and layout: Nick Domhof, Derya Yakar
Printed by Ipskamp Drukkers Nijmegen
The research presented in this thesis was supported by the department of Radiology
of the Radboud University Medical Centre Nijmegen. Publication of this thesis was
financially supported by Radboud University Medical Centre Nijmegen, Invivo
International, Guerbet Nederland B.V., and Toshiba Medical Systems Nederland.
MR imaging in localizing
prostate cancer (recurrence) and
guiding interventions
Proefschrift
ter verkrijging van de graad van doctor
aan de Radboud Universiteit Nijmegen
op gezag van de rector magnificus prof. mr. S.C.J.J. Kortmann,
volgens besluit van het college van decanen
in het openbaar te verdedigen op dinsdag 4 december 2012
om 15.30 uur precies
door
Derya Yakar
geboren op 25 april 1981
te Nijmegen
Promotiecommissie
Promotor: Prof. dr. J.O. Barentsz
Copromotoren:
Dr. J.J. Fütterer
Dr. T.W. Scheenen
Manuscriptcommissie: Prof. dr. W.R. Gerritsen (voorzitter)
Prof. dr. M.A.A.J. van den Bosch, UMC Utrecht
Dr. J.P. Sedelaar
Paranimfen:Ilke Öner
Laura van Groenendael
The man who has no imagination has no wings.
- Muhammad Ali
Table of contents
Chapter 1
Introduction
11
General background, thesis aim and outline.
Chapter 2
The predictive value of MRI in the localization, staging, volume
23
estimation, assessment of aggressiveness, and guidance of
radiotherapy and biopsies in prostate cancer.
Yakar D, Debats OA, Bomers JG, Schouten MG, Vos PC, van Lin E, Fütterer JJ,
Barentsz JO.
J Magn Reson Imaging. 2012;35:20-31.
Chapter 3
Initial Results of 3-dimensional 1H-MR Spectroscopic Imaging
49
in the Localization of Prostate Cancer at 3 Tesla: Should we
use an Endorectal Coil?
Yakar D, Heijmink SW, Hulsbergen-van de Kaa CA, Huisman H, Barentsz JO,
Fütterer JJ, Scheenen TW.
Invest Radiol. 2011;46:301-306.
Chapter 4
Feasibility of 3T dynamic contrast-enhanced MR-guided
65
biopsy in localizing local recurrence of prostate cancer after
external beam radiation therapy.
Yakar D, Hambrock T, Huisman H, Hulsbergen-van de Kaa CA, van Lin E,
Vergunst H, Hoeks CM, van Oort IM, Witjes JA, Barentsz JO, Fütterer JJ.
Invest Radiol. 2010;45:121-125.
Chapter 5
MR-guided biopsy of the prostate, feasibility, technique and
81
clinical applications.
Yakar D, Hambrock T, Hoeks C, Barentsz JO, Fütterer JJ.
Top Magn Reson Imaging. 2008;19:291-295.
Chapter 6
Clinical Applications in Various Body Regions: MRI-Guided
Prostate Biopsies.
Yakar D, Fütterer JJ.
Book chapter: Interventional Magnetic Resonance Imaging. Springer-Verlag 2012.
95
Chapter 7
Feasibility in patients of a pneumatically actuated MR-
113
compatible robot for MR-guided prostate biopsy.
Yakar D, Schouten MG, Bosboom DG, Barentsz JO, Scheenen TW, Fütterer JJ.
Radiology. 2011;260:241-247.
Chapter 8
Feasibility of MR-guided focal cryo-ablation in recurrent
131
prostate cancer after radiotherapy.
Bomers JG, Yakar D, Sedelaar JPM, Vergunst H, Barentsz JO, de Lange F,
Fütterer JJ.
Accepted with revision; Radiology 2012.
Chapter 9
Summary and conclusions
147
Chapter 10
Samenvatting en conclusies
157
Appendices
Dankwoord
169
Curriculum Vitae
175
List of publications and presentations
179
List of abbreviations
3D
3 dimensional
3T
3 Tesla
ADC
apparent diffusion coefficient
AUCs
areas under the curve
CAD computer aided detection
CADx
computer aided diagnosis
C/C
choline-to-creatine
CC/C
choline-creatine-to-citrate
CSRs
cancer suspicious regions
CT
computed tomography
DCE
dynamic contrast-enhanced
DIL
dominant intra-prostatic lesion
DRE
digital rectal examination
DWI
diffusion weighted imaging
EBRT
external beam radiation therapy
ERC
endorectal coil
GRE
gradient echo
IFE
interactive front end
IMRT
intensity modulated radiation therapy
MR
magnetic resonance
MRGB
magnetic resonance imaging guided biopsy
MRI
magnetic resonance imaging
MP multi-parametric
MRSI
magnetic resonance spectroscopic imaging
NPV
negative predictive value
PCA
prostate cancer
PPV
positive predictive value
PSA
prostate specific antigen-level
ROC
receiver operating characteristic
ROIs
regions of interest
RP
radical prostatectomy
RT
radiation therapy
T2-wT2-weighted
TE
time to echo
TR
time to repeat
TRUS
transrectal ultrasound
TRUSGB
transrectal ultrasound guided biopsy
USPIO
ultra-small superparamagnetic particles of iron oxide
1
introduction
Introduction
Prostate cancer (PCa) is a significant health burden. In developed countries it
is the most commonly diagnosed form of male cancer. In terms of estimated
cancer deaths it is the third leading cause after lung and colorectal cancer
(1). As in all cancers, when diagnosed in an early stage a successful curative
management plan is attainable.
In the diagnosis of PCa parameters such as TNM stage, aggressiveness
(represented by the Gleason score), and volume estimation are essential to both
treatment choice as well as its success. Urologists base their every day decisionmaking on nomograms that have incorporated these parameters (2).
However, the generally used diagnostic methods, like digital rectal
transrectal ultrasound (TRUS)-guided biopsy, which are the input for these
nomograms, are imperfect. DRE misses a substantial proportion of significant
cancers and identifies predominantly tumours when they are large and in a
more advanced pathologic stage (3, 4). PSA is considered as the most useful
tumour marker for diagnosis, staging and monitoring of PCa. It correlates well
with advanced clinical and pathological stages in most cases, but due to low
overlap between different tumour stages (5). Also, other benign causes such
as benign prostatic hyperplasia and prostatitis can cause elevated PSA levels.
Shortcomings of gray scale TRUS-guided prostate biopsy are an inherently low
sensitivity for detection of PCa (6), a high false-negative biopsy rate and over- or
underestimating of the true Gleason score (2, 7). More rigorous biopsy schemes
such as three dimensional (3D) template-guided transperineal saturation biopsies
-up to 80 cores- have shown to augment cancer detection rates to some degree
(8-10). Nevertheless, such drastic biopsy methods have many drawbacks like
patient discomfort, complication rates, the need of anaesthetics, and intensive
pathologic processing. Other biopsy methods such as magnetic resonance
guided biopsy (MRGB) has also been the subject of various research articles. The
purpose of chapter 5 and 6 is to give an overview on the literature concerning
MRGB.
In summary, PSA, DRE, and TRUS guided biopsy do not have the ability to
correctly localize, stage, determine volume, and aggressiveness of PCa. In the
15
Introduction
specificity it cannot accurately stage an individual patient, as there is large
Chapter 1
examination (DRE), prostate specific antigen (PSA)-level, and gray scale
new era of more precise therapy forms such as intensity modulated radiation
therapy (IMRT) and focal ablative therapies (e.g. cryosurgery, high-intensityfocused ultrasound, laser therapy, and radiofrequency ablation), this information
is of utmost importance.
The ideal PCa assessment tool should be able to gather this information in a
non-invasive way. This information can then serve therapy choice, and guidance
of interventions and treatments.
Magnetic resonance (MR) imaging in the assessment of PCa has been used
for multiple indications, e.g. detection of PCa in patients with elevated/rising
PSA level and multiple prior negative TRUS-guided biopsy sessions, localization,
detection of recurrent disease, staging local as well as distant disease, and
guiding biopsies (11). The purpose of chapter 2 is to give an extensive overview
on the potential role of multi-parametric (MP) MR imaging in focal therapy with
respect to patient selection and directing (robot guided) biopsies and IMRT. A
part of this introduction is based on the aforementioned review in chapter 2.
16
Localization of PCa
Localizing PCa is important in clinical situations in patients with a rising PSA and previous
negative biopsies. Imaging can serve in such situations for guiding biopsies. Also,
localizing PCa is important in determining the cancer’s distance to the neurovascular
bundle, the prostate capsule, and other adjacent organs. This information influences
therapy choice. In localizing PCa with MR imaging, studies report on the incremental
value of MP-MR imaging, such as dynamic contrast-enhanced (DCE-MRI), diffusion
weighted imaging (DWI), and MR spectroscopic imaging (MRSI) (12-17), as opposed
to anatomical T2-weighted (T2-w) imaging only. Areas under the curve of 0.90 when
T2-w, DCE-MRI and MRSI were combined in localizing PCa have been reported (14).
It is therefore recommended to perform MP-MR imaging consisting of at least T2-w,
and 2 functional MR imaging techniques such as DCE-MRI, and DWI/ MRSI. However,
the lack of consensus in imaging protocols (e.g. with/without endorectal coil, field
strengths, b-values, post-processing methods) makes defining definite guidelines
troublesome. A first step was taken by the European Society of Urogenital Radiology
group, which resulted in a guideline with minimal and optimal imaging acquisition
protocols (18). The purpose of chapter 3 is to compare the diagnostic performance
of 3 Tesla (3T), 3-dimensional 3D MRSI in the localization of PCa with and without the
use of an endorectal coil (ERC).
Recurrent PCa after radiotherapy and MR-guided prostate biopsy
The majority of patients with PCa is either treated with radical prostatectomy
or radiotherapy. Approximately 30% will experience biochemical recurrent
disease (19). Currently, PSA elevation after RT is the best indicator of biologically
active tumour (20, 21). Whenever such an elevation of PSA has taken place,
the main objective is to find out whether the increase in PSA is due to local or
distant recurrent disease. Imaging is required, as further detailed information
about the site of recurrence is needed. Detecting local recurrent disease in the
prostate after radiotherapy is difficult with conventional imaging techniques. The
prostate will be characterized by a diffuse low signal on T2-w MR images (22,
23). For this reason, T2-w MR imaging is less helpful in localizing recurrence of
PCa. Gadolinium-based contrast agents are of added value. Studies evaluating
between 73%-85% (24, 25). The incremental value of DWI and MRSI in localizing
PCa after RT has also shown to be useful (26, 27).
Recurrent cancer suspicious regions (CSRs) seen on MP-MRI can be targeted
for biopsy. This can be done by either performing a TRUS-guided biopsy, a TRUS-MR
fusion guided biopsy, or an MRGB. No studies have been performed comparing
these different biopsy methods. MRGB has shown to improve the cancer detection
(28-30). No studies have investigated MRGB in patients with a biochemical
recurrence after radiotherapy. The purpose of chapter 4 is to assess the feasibility
of the combination of diagnostic 3T MR imaging and MRGB in the localization of
local recurrence of PCa after external beam radiation therapy (EBRT).
MR-compatible robot for transrectal prostate biopsy
So far, the only commercially available MR-guided prostate biopsy device is a
manually adjustable standard for needle guide positioning (30, 31). The radiologist
has to adjust the needle guide into the direction of the region of interest by
hand, based on MR images (31). Consequently, the patient has to be moved
in and out of the scanner bore each time to adjust the direction of the needle
guide. It is conceivable that during these time consuming manoeuvres, there is
abundance of time for movement of the patient as well as movement of the
prostate, possibly leading to less accuracy. Furthermore, one can imagine that
this procedure is unpleasant for the patient. For these reasons an MR-compatible
17
Introduction
rate in subjects with an elevated PSA and repetitive negative TRUS-guided biopsies
Chapter 1
DCE-MRI after radiotherapy report sensitivities between 70%-74% and specificities
robot for transrectal prostate biopsy has been developed and investigated.
The purpose of chapter 7 is to assess the feasibility of a remote controlled,
pneumatically actuated, MR-compatible, robotic device as an aid to perform
transrectal biopsy in the prostate with real-time 3T MR imaging guidance.
Focal MR-guided cryo-ablation of PCa recurrence after radiotherapy
After radiotherapy recurrence, salvage prostatectomy is a treatment option.
However, high rates of incontinence (0-67%) or rectal injury (0–8%) (32, 33)
have led to the search for other salvage treatment options. For this reason,
ablative techniques such as cryo-ablation, high intensity focused ultrasound,
and photodynamic therapy have been developed. Cryo-ablation, performed
under TRUS guidance is an established treatment option for both men with newly
diagnosed as well as recurrent PCa (34). Nevertheless, in the new era of focal
therapies MR image guidance may be a more suited imaging method. MP-MR
imaging enables an accurate localization of the recurrent cancer as well as image
guidance during the treatment itself. This way the recurrent cancer is treated and
18
non-cancerous prostate tissue and nearby critical structures are kept away at a
safe distance, potentially leading to less treatment related complications. The
purpose of chapter 8 is to assess the feasibility of MR guided focal cryoablation
at 1.5T in patients with locally recurrent PCa after initial radiotherapy.
Aim and Outline of this thesis
The aim of Chapter 2 is to provide an overview on the potential role of MP-MR
imaging in focal therapy with respect to patient selection and directing (robot
guided) biopsies and IMRT. It discusses the role of MP-MRI in the localization,
staging, volume estimation, assessment of aggressiveness, and guidance of
radiotherapy and biopsies in PCa.
The aim of Chapter 3 is to compare the diagnostic performance of 3T, 3D MRSI in
the localization of PCa with and without the use of an ERC. This is investigated in
18 patients, using histopathology as the standard of reference. Omitting the use
of an ERC could save time, costs, and patient discomfort.
The aim of Chapter 4 is to assess the feasibility of the combination of diagnostic 3T
MR imaging and MRGB in the localization of local recurrence of PCa after EBRT. This
is evaluated in 24 patients. All patients underwent a diagnostic 3T MR examination
of the prostate consisting of T2-w and DCE-MRI. Gadolinium-based MR imaging
techniques can be useful in not only localizing local recurrence after radiotherapy
but probably also in guiding MRGB.
The aim of Chapter 5 and 6 is to provide a review concerning MRGB of the
prostate. An overview of the literature, technical details, and future developments
is discussed.
The aim of Chapter 7 is to assess the feasibility of a remote controlled, pneumatically
in the prostate with real-time 3T MR imaging guidance. This is evaluated in 10
patients.
The aim of Chapter 8 is to assess the feasibility of MR guided focal cryo-ablation
at 1.5T in patients with locally recurrent PCa after initial radiotherapy. This is
investigated in 10 patients. All patients are followed up with MP-MRI to monitor
are recorded carefully.
In Chapter 9 the general results are summarized and discussed. Chapter 10
provides a Dutch translation of these findings.
19
Introduction
treatment induced changes and PSA measuring. Also treatment complications
Chapter 1
actuated, MR-compatible, robotic device as an aid to perform transrectal biopsy
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Roethke M, Anastasiadis AG, Lichy M, et al. MRI-guided prostate biopsy detects clinically
significant cancer: analysis of a cohort of 100 patients after previous negative TRUS biopsy.
World J Urol. 2012;30:213-218.
53.
Franiel T, Stephan C, Erbersdobler A, et al. Areas suspicious for prostate cancer: MR-guided
biopsy in patients with at least one transrectal US-guided biopsy with a negative finding-multiparametric MR imaging for detection and biopsy planning. Radiology. 2011;259:162-172.
23
Introduction
carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 1993;27:31-37.
49.
Chapter 1
diffusion-weighted MR imaging and 3D 1H MR spectroscopic imaging--correlation with
J Magn Reson Imaging. 2012;35:20-31
2
Predictive value of MRI
in the Localization, Staging,
Volume estimation, Assessment
of Aggressiveness, and Guidance of
Radiotherapy and Biopsies
in Prostate cancer.
Yakar D
Debats OA
Bomers JG
Schouten MG
Vos PC
van Lin E
Fütterer JJ
Barentsz JO
Abstract
Multi-parametric MR imaging has the potential of being the ideal prostate cancer
(PCa) assessment tool. Information gathered with multi-parametric MR imaging
can serve therapy choice, guidance of interventions, and treatments.
The purpose of this review is to discuss the potential role of multi-parametric
MR imaging in focal therapy with respect to patient selection and directing
(robot guided) biopsies and intensity modulated radiation therapy.
Multi-parametric MR imaging is a versatile and promising technique. It
appears to be the best available imaging technique at the moment in localizing,
staging (primary as well as recurrent disease, and local as well as distant
disease), determining aggressiveness, and volume of PCa. However, larger
study populations in multi-centre settings have to confirm these promising results.
However, before such studies can be performed, more research is needed in
order to achieve standardized imaging protocols.
26
Introduction
In the diagnosis of PCa parameters such as location, TNM stage, aggressiveness
(represented by the Gleason score), and volume estimation are essential to both
treatment choice as well as its success. Urologists base their every day decision
making on nomograms which have incorporated these parameters (1).
However, the generally used diagnostic methods, like digital rectal examination
(DRE), prostate specific antigen (PSA) level, and gray scale transrectal ultrasound
(TRUS)-guided biopsy, which are the input for the nomograms, are imperfect.
DRE misses a substantial proportion of cancers and identifies predominantly
tumours when they are large and in a more advanced pathologic stage (2;3).
PSA is considered as the most useful tumour marker for diagnosis, staging and
stages in most cases, but due to low specificity it cannot accurately stage an
individual patient, as there is large overlap between different tumour stages (4).
Shortcomings of gray scale TRUS-guided prostate biopsy are an inherently low
sensitivity for detection of PCa (5), a high false-negative biopsy rate and over- or
underestimating of true Gleason score (1;6). More rigorous biopsy schemes such
as three dimensional (3D) template-guided transperineal saturation biopsies -up
such drastic biopsy methods have many drawbacks for like patient discomfort,
the need of anaesthetics, and intensive pathologic processing.
In summary, PSA, DRE, and TRUS guided biopsy do not have the ability to
correctly localize, stage, determine volume, and aggressiveness of PCa. In the
new era of more precise therapy forms such as intensity modulated radiation
therapy (IMRT) and focal ablative therapies (e.g. cryosurgery, high-intensityfocused ultrasound, thermal therapy, and radiofrequency ablation), this
information is of utmost importance.
The ideal PCa assessment tool should be able to gather this information in a
non-invasive way. This information can then serve therapy choice, guidance of
interventions, and treatments. Multi-parametric MR imaging has the potential of
being such a tool.
The purpose of this review is to discuss the potential role of multi-parametric
MR imaging in focal therapy with respect to patient selection and directing
(robot guided) biopsies and IMRT.
27
MRI in Prostate cancer
to 80 cores-, have shown to augment cancer detection rates (7-9). Nevertheless,
Chapter 2
monitoring of PCa. It correlates well with advanced clinical and pathological
Localizing PCa
Screening, detection and localization
MR imaging has been applied in the assessment of PCa for multiple purposes. It
has been used for screening, detection in patients with elevated PSA level and
multiple negative TRUS-guided biopsy sessions, recurrent disease, localization,
and staging local as well as distant.
The reported diagnostic performance of T2-weighted (T2-w) imaging in
the detection and localization of PCa has a wide range with sensitivities and
specificities between 47.8 – 88.2% and 44.3 – 81%, respectively (10-14). Therefore,
the incremental value of multi-parametric MR imaging such as dynamic contrastenhanced (DCE-MRI), diffusion weighted imaging (DWI), and MR spectroscopic
imaging (MRSI) has been investigated. Studies reporting on the combination
of these techniques describe the additional value in diagnostic performance
(11;12;14- 20). Fütterer et al. reported an area under the curve (AUC) of 0.90 when
T2-w, DCE-MRI and MRSI were combined in localizing PCa. It is recommended to
perform multi-parametric MR imaging consisting of at least T2-w, DCE-MRI, and
28
DWI. However, the lack of consensus in imaging protocols (e.g. with/without
endorectal coil, field strengths, b-values, post-processing methods) makes
defining definite guidelines troublesome. Hence, the next focus point in future
studies should be optimizing these protocols and reaching consensus.
Staging
Local
T2-w, endorectal coil imaging, according to a meta-analysis by Engelbrecht et al.
reported a maximum combined sensitivity and specificity of 71% in distinguishing
clinical stages T2 and T3 at a 1.5T MR system (18). More recent studies, report maximum
sensitivities and specificities of between 80%-88% and 96%-100%, respectively at a 3T
MR system (22;23). Adding metabolic information obtained with MRSI to T2-w imaging
improves staging accuracies (24). Conjunction of this information with nomograms,
used in daily clinical practice by urologists, in evaluating extracapsular extension
and seminal vesicle invasion in staging PCa yields higher accuracies (25-27). In less
experienced readers of MR imaging in staging PCa also DCE-MRI appears to be of
added value (28). Presumably, the extra information collected with DCE-MRI, DWI,
and MRSI draws the attention of the reader, more than T2-w imaging alone, to areas
where extracapsular extension could be the case (Figure 1).
Skeletal
Assessment of skeletal metastases is mostly done by performing a technetium99m-diphosphonate bone scintigraphy. Although bone scintigraphy is considered
as the gold standard for skeletal imaging, its low positive yield makes its use
controversial (29). Several studies have evaluated the role of this technique
compared to MR imaging in detecting skeletal metastases (30-33), but only one
study conducted this in a patient group with only prostate cancer as primary
cancers (33). According to this study, MR imaging when used alone, is superior
in detecting bone metastases with a sensitivity and specificity of 100% and 88%,
compared to bone scintigraphy combined with targeted X-rays with a sensitivity
and specificity of 63% and 64%. However, the highest specificity of a 100% (at the
cost of a lower sensitivity of 88%) was reported when bone scanning together with
what the best approach in clinical practice should be. Noteworthy, limiting MRI
to the axial skeleton will suffice as the probability of finding solitary metastases
outside this area is negligible (34;35). New insights for DWI concerning skeletal
metastases could possibly lead to even higher detection rates (Figure 2) (36-38).
Chapter 2
targeted X-rays and MR imaging was performed. Larger trials can possibly clarify
29
MRI in Prostate cancer
a
b
30
c
d
Figure 1: A 65 years old patient, with a PSA of 6.1. With transrectal ultrasound guided prostate biopsy this
patient was staged as a T1c with a Gleason score of 3+4 on histopathology. On the multi-parametric
staging MRI, the axial T2-weighted image (a) showed extracapsular extension (EPE) (white arrows) in
cancer suspicious region (CSR) number 1. On the diffusion weighted imaging (DWI) derived apparent
diffusion coefficient (ADC)-map (b) this CSR (red circle) was also visible, which appeared to be a
intermediate grade (4+3). The low grade lesions (3+4 and 3+3) 2 and 3 were not visible on the ADC map.
On the dynamic contrast-enhanced MR image (DCE-MRI) (Ktrans) (c) two additional areas showed
focal enhancement, CSRs number 2 and 3 (white circles). The histopathologic slide (d) confirmed the
presence of prostate cancer (PCa) in CSRs 1,2, and 3, and the presence of EPE (red arrows).
a
b
Chapter 2
31
d
e
f
Figure 2: A 70 years old patient with a rising PSA after brachytherapy. Bone scintigraphy (a) and
conventional X-ray (b) revealed no skeletal metastases. MR imaging (c) showed a suspicious region
for a skeletal metastases (white arrow), which was followed up, and was even more obvious on (d) the
second MR imaging examination after 2 months (white arrow), suggesting progression of the metastases.
A CT guided biopsy was performed (e, f) and revealed a PCa skeletal metastases (white arrows).
MRI in Prostate cancer
c
Lymph node
CT and MRI demonstrate an equally poor performance in the detection of lymph
node metastases from PCa, especially concerning sensitivity (39). For this reason,
two other MR techniques have been developed: MR Lymphography (which uses
a lymph node-specific contrast agent, based on Ultra-small Superparamagnetic
Particles of Iron Oxide (USPIO)) and DWI-MRI (Figure 3).
In 1998, Bellin et al reported on the initial clinical experience with MRL and
found a perfect sensitivity of 100% at 80% specificity (40). In another prospective
study with 334 lymph nodes in 80 patients, sensitivity and specificity were 90.5%
and 97.8%, respectively (41). More recently, it has been shown that MRL is
significantly more accurate than Multi Detector-row CT (42, and that in 41% of
PCa patients, MRL can detect lymph node metastases outside the surgical area
of routine Pelvic Lymph Node Dissection (43). Although these results are very
promising, MRL has not yet become available for widespread clinical use, due to
the lack of an FDA-approved lymph node-specific contrast agent.
The added value of DWI compared to USPIO-MRL does not improve accuracy
32
but rather reduces reading time (44). However, one study did report a good
accuracy based on the apparent diffusion coefficient (ADC) map value alone,
with a sensitivity of 86.0% and a specificity of 85.3% (45).
a
b
c
Figure 3: A 59 years old patient with PCa and lymph node metastases. Coronal T1- weighted gradient
echo (GRE) (a) 24 hour post Ultra-small Superparamagnetic Particles of Iron Oxide (USPIO) injection
showed 2 normal sized nodes (arrows). The right one is black (horizontal arrow), suggesting presence of
Ultra-small Superparamagnetic Particles of Iron Oxide (USPIO)-loaded macrophages, which indicates
that this node is normal. The left one is gray (vertical arrow), due to the absence of USPIO. Fusion of T1GRE image with T2*- weighted (sensitive to iron) image (orange) (b), and fusion of T1-GRE image with
DWI (b=600, orange) (c) respectively. On both images the node on the left side showed T2*-signal, and
high diffusion signal due to absence of USPIO contrast, thus indicating metastasis.
Volume measurement
For focal therapy, merely localizing PCa is not enough. Determining cancer foci
volume is of paramount importance for targeting this form of therapy. Studies
regarding this matter are few in number and not consistent (46-49). In 2002 the value
of MRSI in measuring tumour volume in nodules greater than 0.5 cm3 was assessed
and researchers found that it was positively correlated with histopathologic tumour
volume with a Pearson correlation coefficient of 0.59 (50). More recently, DCE-MRI
and DWI have as well been investigated and some promising results have been
presented (51;52).
Aggressiveness
The Gleason grading system remains one of the most effective prognostic
role in therapy decision making. They have been associated with biochemical
failure, local recurrences, and distant metastases such as skeletal and lymph
node metastasis after prostatectomy or radiation therapy (54-58). Since Gleason
scores of 3+4 - or lower - are associated with lower disease progression rates, and
Gleason scores of 4+3 - or higher - are associated with higher disease progression
rates (59), a test differentiating between both is meaningful.
are scarce (60), with DWI a significant negative correlation between Gleason
grade and ADC values has been found (61-63). Furthermore, choline plus
creatine-to-citrate ratios determined by using MRSI have also been correlated
with Gleason grade (64;65). One study even reported on the correlation of signal
intensities on T2-w imaging with Gleason grade (66). More research needs to
be done as regards to what role multi-parametric MR imaging can play in the
assessment of PCa aggressiveness.
Recurrences
Recurrence of local PCa
The majority of patients with PCa is either treated with radical prostatectomy
(RP) or radiotherapy (RT). Approximately 30% will experience recurrent disease
(67). Currently, PSA elevation after RP or RT is the best indicator of biologically
active tumour (68;69). Whenever such an elevation of PSA has taken place, the
main objective is to find out whether the increase in PSA is due to local or distant
33
MRI in Prostate cancer
Although studies reporting on association of Gleason grade with MR imaging
Chapter 2
factors in PCa (53). Gleason score, PSA level, and clinical stage have a major
recurrent disease. Imaging is required as further detailed information about the
site of recurrence is needed.
After RT the prostate will be characterized by a diffuse low signal (70;71). For this
reason, T2-w imaging is less helpful in localizing recurrence of PCa. Gadoliniumbased contrast agents are of added value. Studies evaluating DCE-MRI after
RT report sensitivities between 70%-74% and a specificities between 73%-85%
(72;73). Subsequently, a targeted MR-guided biopsy can be performed (Figure
4) (74). The incremental value of MRSI in localizing PCa after RT has also shown
to be useful (75;76). Although DWI after radiotherapy can be supportive (77;78),
after RP it is of limited value because of surgical clips (left behind by the urologist
during surgery) causing magnetic field inhomogeneities. After RP DCE-MRI and
MRSI provide promising results (Figure 5) (79-81).
34
a
d
b
c
e
Figure 4: A 69 years old patient, with a PSA rise (25 ng/mL) after external radiation beam therapy. A
multi-parametric MRI was performed. The T2-w image (a) showed no CSR. DCE-MRI (Ktrans) (b) showed
CSR number one (white circle), DWI derived ADC-map (c) showed restriction in another CSR number
2 (red circle). Of both CSR an MR-guided biopsy was obtained (d + e) and histopathology revealed a
leason 3+4.
b
c
d
Chapter 2
a
35
Figure 5: A 71 years old patient with a PSA of 0.39 ng/mL after a radical prostatectomy in 2007. A multiADC-map (c) with inhomogeneities of the magnetic field due to surgical clips (white arrows). A MRguided biopsy (d) of this CSR revealed a PCa with a Gleason score of 3+5.
Computer aided diagnosis
Computer assisted technologies have been developed to help interpret the often
multi-dimensional and multi-parametric data. In mammographic detection of
breast cancer such aids have been successfully developed and have become
part of routine clinical work (82). Applications to the prostate are emerging.
Two types of computer assisted technologies exist: Computer aided detection
(CAD) and computer aided diagnosis (CADx). CAD provides, fully automatically,
feedback on zero or more locations containing malignant cancers. It is CAD that
has been used in mammographic screening, whereas CADx, often confused
with CAD, only provides a probability of malignancy of a user identified lesion.
CAD and CADx both contain a supervised pattern recognition module trained
on annotated cases. Although companies provide prostate MR specific tools with
MRI in Prostate cancer
parametric MRI, consisting of a T2-w image (a), a DCE-MRI (b) with a CSR (white circle), a DWI derived
the name CAD in it, neither CAD nor CADx is currently commercially available for
prostate MR.
CADx research for prostate is still limited. The main focus in CADx is to have
objective features or thresholds for the pattern recognition system of PCa. Studies
using simple raw image derived methods report lower AUCs of 0.72 (83-85) than
studies using quantitative features (AUCs of 0.81) (86;87). Combining quantitative
features from all available sequences (multi-parametric MR imaging) is currently
lacking, but first attempts are promising (AUC of 0.89) (88;89). An important
obstruction for prostate MR CAD and CADx, to become widely available, is the
lack of standardized sequences and objective quantitative features of PCa.
Furthermore, without evidence of effectiveness of CAD or CADx in clinical
situations clinical use should be avoided.
Intra-prostatic high dose
modulated radiotherapy
boosting
with
intensity-
In the treatment of PCa, RT has evolved from the use of rectangular beams to
36
3-dimensional (3D) conformal beams, and eventually to segmentation and dose
intensity modulation of these beams known as IMRT. IMRT allows the radiation
oncologist to plan a precise dose distribution in the targeted organ. Potentially
this results in a high dose escalation in the targeted cancer foci (dominant
intraprostatic lesion (DIL)), while lowering treatment induced toxicity to noncancerous prostate tissue and organs abut the prostate, and thus expectantly
improving the therapeutic ratio (90-95). This is achieved by using an inverse
treatment planning method consisting of defining the desired dose distribution to
the target volume and dose restriction to uninvolved tissue or organs (96).
For such a treatment planning strategy a reliable imaging technique is an
essential necessity. Computed tomography (CT) is probably most frequently used
as treatment planning technique. CT has some benefits over MRI as it is helpful in
RT dose calculations, because of the accurate electron densities provided by it,
and its deficit of geometric distortion. Some promising efforts have been made to
overcome both matters concerning MRI (97;98). Still there is more work necessary
in the consideration of performing focal high-dose DIL-IMRT planning with MRI
alone. The faultiness of CT compared to MRI is that it lacks sufficient soft tissue
contrast to precisely delineate the prostate gland, especially in the apex of the
prostate, consequently overestimating prostate volume (99-102). Furthermore,
CT struggles with significantly higher interobserver variability than MRI (101). In
addition to all the foregoing, MRI as opposed to CT has the ability to localize the
cancer foci in the prostate (see Localization of PCa). Eventually, with a precise
dose delivery technique such as DIL-IMRT, one has to bear in mind that its success
rate is highly dependent on the accurate delineation of the target volume.
Future developments will probably make it possible to use MRI directly in the
treatment planning of RT. Until then we need to combine both techniques and
use all assets provided by both of them by the method of fusion. By using a gold
marker-based 3D fusion of CT and MRI it is feasible to plan a safely delivered
intraprostatic high radiation-dose DIL-IMRT, where a DIL volume for example can
be defined by using DCE-MRI and MRSI (Figure 6 and 7) (92;103). With the help of
special software programs merging of MR and CT images can be realized with
Other efforts in finding new fiducial markers for this fusion process have been
made (105).
Chapter 2
fusion inaccuracies with a mean of 1.1 mm at the border of the prostate (104).
37
MRI in Prostate cancer
38
a
b
c
d
e
f
Figure 6: DCE-MRI and 1H-spectroscopic (MRSI) results for a 71 years old patient with a PSA of 5.8
ng/mL with biopsy proven PCa. Axial T2-weighted MR image (a) with decreased signal intensity in
right peripheral zone (arrows), without evidence of capsular invasion. DCE-MRI results (b,c). Start-ofenhancement parameter (b) demonstrated earlier enhancement in part of low-signal-intensity lesion
(arrows) compared with left peripheral zone. Volume transfer constant (Ktrans) (c) was elevated in lowsignal-intensity lesion (arrows) indicating tumour tissue. MRSI (d) detected elevated choline and low
citrate peaks in seven voxels. Blue box indicates voxel from which spectrum (Fig. 6e) originated. 1H-MRI
spectrum (e) from voxel in right peripheral zone. Increased choline (Cho) plus creatine (Cr)/citrate (Ci)
ratio indicated prostate cancer. Strongly interpolated (Cho +Cr)/Ci map (f) was used to visualize MRSIbased tumour nodule.
Figure 7: Dominant intraprostatic lesion-intensity-modulated radiotherapy treatment volumes for same
patient as in figure 6. Three-panel (transverse, sagittal, and coronal view) computed tomography
line) were delineated with margin of 5 and 7 mm, for planning target volume with prescription dose of
90 Gy (red line) and prescription dose of 70 Gy (orange line), respectively. Central gold marker indicated
in yellow.
MR guided biopsy and robotics
Cancer suspicious regions (CSRs) seen on multi-parametric MRI can be targeted
for biopsy. This can be done by either performing a TRUS-guided biopsy, a TRUS-MR
comparing these different biopsy methods. MR-guided prostate biopsies have
shown to improve cancer detection rate in subjects with an elevated PSA and
repetitive negative TRUS-guided biopsies (106-108).
So far, the only commercially available MR-guided prostate biopsy device
is a manually adjustable standard for needle guide positioning (106;109). The
radiologist has to adjust the needle guide into the direction of the region of
interest by hand, based on MR images (109). Consequently, the patient has to
be withdrawn from the scanner bore each time to adjust the direction of the
needle guide. It is conceivable that during these time consuming manoeuvres,
there is abundance of time for movement of the patient as well as movement
of the prostate, possibly leading to less accuracy. Furthermore, one can imagine
that this procedure is unpleasant for the patient.
For these reasons MR-compatible robots for transrectal prostate biopsy are
being developed. Preliminary results found in phantom and patient feasibility
studies are promising (110-114). In future studies robotics can for instance also
39
MRI in Prostate cancer
fusion guided biopsy, or an MR-guided biopsy. No studies have been performed
Chapter 2
treatment planning image: dominant intraprostatic lesion volume (red color wash) and prostate (black
play an important role in guiding focal treatment of PCa. But before robot assisted
MRI guided focal therapy can be realized further extensive research needs to be
done.
Conclusion
In conclusion, multi-parametric MR imaging is a versatile, and promising
technique. It appears to be the best available imaging technique at the
moment in localizing, staging (primary as well as recurrent disease, and local as
well as distant disease), determining aggressiveness, and volume of PCa. With
this information guidance of focal therapy, IMRT and biopsy can be realized.
However, larger study populations in multi-centre settings have to confirm
these promising results. Yet before such studies can be performed, more research
is needed in order to achieve standardized imaging protocols regarding issues in
obtaining data (e.g. b-values in DWI, T1-w or T2*-w in DCE-MRI, 1.5T vs. 3T, the use
40
of an endorectal coil) and quantifying and determining objective parameters or
thresholds (e.g. ADC values in DWI, calculating pharmacokinetic parameters in
DCE-MRI ) for PCa. As a consequence, supportive techniques such as computeraided diagnosis can be developed further.
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Chapter 2
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Invest Radiol. 2011;46:301-306
3
Initial Results of 3-dimensional 1HMR Spectroscopic Imaging in the
Localization of Prostate Cancer at
3 Tesla: Should we use an Endorectal
Coil?
Yakar D
Heijmink SW
Hulsbergen-van de Kaa CA
Huisman H
Barentsz JO
Fütterer JJ
Scheenen TW
Abstract
Purpose
The purpose of this study was to compare the diagnostic performance of 3 Tesla
(3T), 3-dimensional (3D) MR spectroscopic imaging (MRSI) in the localization of
prostate cancer (PCa) with and without the use of an endorectal coil (ERC).
Materials and Methods
Our prospective study was approved by the institutional review board, and
written informed consent was obtained from all patients. Between October 2004
and January 2006, 18 patients with histologically proven PCa on biopsy and
scheduled for radical prostatectomy were included and underwent 3D-MRSI
with and without an ERC. The prostate was divided into 14 regions of interest
(ROIs). Four readers independently rated (on a five-point scale) their confidence
that cancer was present in each of these ROIs. These findings were correlated
with whole-mount prostatectomy specimens. Areas under the receiver operating
52
characteristic curve (AUC) were determined. A difference with a P < 0.05 was
considered significant.
Results
A total of 504 ROIs were rated for the presence and absence of PCa. Localization
of PCa with MRSI with the use of an ERC had a significantly higher AUC (0.68) than
MRSI without the use of an ERC (0.63) (P = .015).
Conclusion
The use of an ERC in 3D MRSI in localizing PCa at 3T slightly but significantly
increased the localization performance compared to not using an ERC.
Introduction
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous form
of cancer in men and is the second largest cause of cancer related mortality in
this population (1). Like many cancers, PCa is treated most effectively if localized
and staged correctly. Thus, reliable knowledge of the location and spatial extent
of the disease within and beyond the gland is crucial.
The most frequently used diagnostic tools in daily clinical practice (e.g. digital
rectal examination (DRE), prostate specific antigen (PSA) level, and transrectal
ultrasound (TRUS) guided biopsy) are often inaccurate or inadequate. DRE misses
a substantial proportion of cancers, PSA alone cannot accurately stage an
individual patient, and TRUS suffers from major sampling errors (2-6).
Magnetic resonance (MR) imaging is a noninvasive examination, which can
provide anatomical, functional, and metabolic information. MR spectroscopic
imaging (MRSI), that generates metabolic spectra, has been investigated
before for cancer localization. Some promising results have been reported with
sensitivities and specificities of 63-80% and 75-84%, respectively (7;8). In addition,
MRSI and MR imaging are still evolving techniques where recent insights about
new metabolic markers such as polyamines (9;10), and new approaches with
improve its localization ability (11-14) .
The use of an endorectal coil (ERC) as an essential part of the optimal prostate
MR imaging protocol is still a matter of debate. The obvious advantage of using
the ERC is the increase in signal-to-noise ratio compared to non-ERC MR imaging.
Even though several authors have demonstrated the advantages of the use of
such an ERC for localizing and staging PCa on T2-weighted MR imaging (15;16),
the direct comparison between ERC and non-ERC MR examinations has not
been investigated for PCa localization with three-dimensional (3D) MRSI.
We hypothesized that the use of an ERC will increase the diagnostic
performance of MRSI in localizing PCa. Therefore, the purpose of this study was to
compare the diagnostic performance of 3 Tesla (3T), 3D MRSI in the localization
of PCa with and without the use of an ERC.
53
MRSI with and without ERC
dynamic contrast-enhanced and diffusion-weighted MR imaging could further
Chapter 3
Materials and Methods
Patients
Our prospective study was approved by the institutional review board, and written
informed consent was obtained from all patients. During the time period in which 3D
MRSI at 3T was firstly initiated and performed at our institution (between October 2004
and January 2006), 18 consecutive patients with histologically proven PCa on biopsy
and scheduled for radical prostatectomy were included and underwent 3D-MRSI (at
least three weeks after biopsy) with and without an ERC. Patient characteristics were
as follows: median age 66 years (range 56-75 years), median PSA 4.9 ng/mL (range
3.6-24.6 ng/mL), median time between TRUS guided biopsy and MR examination
64 days (range 21-104 days), median time between MR examination and radical
prostatectomy 7 days (range 1-89 days), and median Gleason score, based on
prostatectomy specimens, 6.5 (range 5-9). Exclusion criteria were previous hormonal
therapy and contraindications to MR imaging (e.g., cardiac pacemakers, intracranial
clips, prior anorectal surgery).
54
MR Imaging Protocol
MR imaging of the prostate was performed using a 3T whole body MR system
(Siemens Trio Tim, Erlangen, Germany) with the spine array and body array coil
elements, with a total examination time of between 45-50 minutes. Bowel peristalsis
was suppressed with an intramuscular injection of 1 mg of glucagon (Glucagen,
Novo Nordisk, Bagsvaerd, Denmark). At first, patients were imaged without the use
of an ERC according to the following MR imaging protocol sequences: T2-weighted
fast spin echo sequence in three orthogonal planes, with the field of view of the axial
plane obtained perpendicular to rectal wall, (TR/TE, 3700/124 msec; field of view,
220 x 220 mm; matrix size, 512 x 512; slice thickness, 4 mm; number of averages, 2;
total acquisition time per plane, 4-5 minutes), followed by 3D 1H-MRSI of the entire
prostate with a point-resolved spectroscopy pulse sequence (15) (TR/TE, 750/145
msec; acquisition bandwith, 1250 Hz; voxel resolution, 7 x 7 x 7 mm; total acquisition
time, approximately 9 minutes).
Subsequently, in the same patient an ERC was inserted rectally and filled with 40
ml perfluorocarbon liquid (Fomblin, Solvay-Solexis, Milan, Italy). After a quick series
of images obtained to depict ERC position and ERC adjustment if necessary, a T2weighted fast spin echo sequence in three planes (TR/TE, 5000/153; field of view, 200
x 100 mm; matrix size, 768 x 384; slice thickness, 2.5 mm; number of averages, 1; total
acquisition time per plane, 2-3 minutes) was obtained, with the field of view of the
axial plane obtained perpendicular to rectal wall, followed by 3D 1H -MRSI (TR/TE,
750/145 msec; acquisition bandwith, 1250 Hz; voxel resolution, 6 x 6 x 6 mm; total
acquisition time, approximately 9 minutes).
Data Postprocessing
Semi-automatic postprocessing of all voxels within the prostate was performed with a
software work-in-process package (Metabolite report, Siemens, Erlangen, Germany).
A basic set of simulated complex model signals of choline, creatine, and citrate
was fitted to the time domain signals of the voxels after a frequency shift, residual
water removal, and remodeling of the first five data points to handle baseline
(choline+creatine)-to-citrate ratio (CC/C) and the choline-to-creatine ratio (C/C). A
similar approach has been used before (17).
Scoring and Evaluation of Data
All MRSI datasets were evaluated overlaid on the T2-weighted datasets. The prostate
was divided into 14 regions of interest (ROIs) (Figure 1). The T2-weighted images were
this with pathology. Four readers (reader I (Radiologist), II (Radiologist), III (Radiologist),
and IV (Spectroscopist) with 0, 4, 6, and 8 years of experience in MRSI data evaluation,
respectively) independently rated cancer presence in each of these ROIs on a five-point
scale, using a standardized scoring system (18). This scale was based on the cholinecreatine-to-citrate (CC/C) and choline-to-creatine (C/C) ratios for the peripheral zone
and the central gland determined before by Scheenen et al. (19) (Table 1).
All datasets were anonymized, and readers were blinded to all clinical parameters.
They were only aware of the fact that all patients were histopathologically diagnosed
with PCa. First, all MRSI examinations without the ERC were rated. For each ROI, all
spectra were read and interpreted and the final score for that ROI was based on the
highest CC/C present within the ROI, and adjusted based on the C/C ratio for the
corresponding voxel (Table 1). Second, after a period of 4 weeks, during a different
reading session, MRSI with the ERC were rated likewise. Readers were allowed to rate
ROIs as non-rateable if ratios were not reliably fitted due to low signal-to-noise ratios of
the metabolite spectra (more than 50% of the voxels within a certain ROI).
55
MRSI with and without ERC
only used for transfer of the 14 ROIs to the MRSI data and subsequently correlating
Chapter 3
artifacts. The amplitudes of the individually fitted signals were used to calculate the
Figure 1: A schematic overview of the 14 regions of interest in which the prostate was divided into.
Table 1
Five-point scale
Score and Score definition
PZ CC/C ratio
CG CC/C ratio
C/C ratio adjustment
1: Definitely benign tissue
≤0.34
≤0.48
If C/C ratio ≥2, then: adjust 3
2: Probably benign tissue
>0.35-0.46
>0.49-0.62
and 2 into 4.
3: Possibly malignant tissue
>0.47-0.58
>0.63-0.76
4: Probably malignant tissue
>0.59-0.70
>0.77-0.90
5: Definitely malignant tissue
≥0.71
≥0.91
If C/C ratio < 2, then: adjust 5
into 4 and 4 into 3.
Source: Reference (17). PZ= peripheral zone, CG= central gland, CC/C = choline-creatine-to-citrate,
56
C/C = choline-to-creatine.
Histopathological Analysis
Prostatectomy specimens were fixed overnight in 10% neutral buffered
formaldehyde and coated with India ink. These prostatectomy specimens were
sliced at 4-mm intervals at a plane parallel to the axial T2-weighted images
(perpendicular to rectal wall). All slices were routinely embedded in paraffin.
Tissue sections of 5 µm thickness were prepared from the slices and stained with
hematoxylin-eosin. A single genitourinary histopathologist (C.A.H. van de K.) with
18 years of experience who was blinded to the MR imaging results determined
the exact localization, extent, Gleason score, and volume of each cancer focus.
Data Analysis
After evaluating and scoring all MRSI data, one Spectroscopist (T.W.J.S.) and two
of the Radiologists (J.J.F. and D.Y.) in consensus transferred the histopathologic
evaluation (standard of reference) of the prostatectomy specimens to the
14-segment prostate ROI-scheme. This transfer was realized by matching the
pathological slice to the level of the T2-weighted images by its location between
the apex and the base of the prostate. Subsequently, landmarks such as benign
prostatic hyperplasia nodules and the urethra were used to match cancer foci to
their corresponding ROIs. The T2-weighted images were only used for correlating
pathology to the cancer region relative to the 14-segment ROI-scheme. A ROI
was considered true-positive if cancer was present and if this cancer focus was
0.5 cm³ or larger in volume (20). All smaller cancer foci were excluded from further
analysis. Each of the 14 ROIs for every prostate were classified as containing
either cancer or healthy tissue.
Statistical Analysis
For statistical analysis (SPSS version 16.0), the sensitivity, specificity, negative
predictive value (NPV) and positive predictive value (PPV) were calculated by
dichotomizing (cut-off point of 3 and above was considered malignant) the
comparison between these AUCs were determined by using an ROI-ROC analysis
(21) with a bootstrap estimation of diagnostic accuracy (22) and a Bonferroni
correction. These statistical methods have been used before in studies that
collected data according to the ROI paradigm (8;15). All P values reported were
derived at one-sided tests. P values of .05 or less were considered significant.
Eighteen patients were included. A total of 504 ROIs (18 patients with 14 ROIs
each, 252 ROIs with and 252 ROIs without ERC) were rated for the presence and
absence of PCa (Figure 2). From the histopathologic standard of reference,
81/252 (32%) ROIs were assigned as containing PCa. Thirty-one of these 81
ROIs containing PCa, were excluded due to low cancer volume (<0.5 cm³).
Of the remaining 50 ROIs classified as containing PCa, 72% (36/50) comprised
peripheral zone cancers while 28% (14/50) comprised central gland cancers.
These remaining cancer foci had a median volume of 1.1 cm³ (range 0.5-12.9
cm³) (Figure 3).
Overall, there were significantly more ROIs non-rateable on MRSI with ERC, 14%
(146/1008), than without ERC, 12% (121/1008), (P = .007) for all readers together
(Table 2).
57
MRSI with and without ERC
Results
Chapter 3
readings. Areas under the receiver operating characteristic curve (AUC) and
Descriptive statistics of PCa localization with and without an ERC per reader
were summarized in Table 3. For the more experienced readers (i.e. readers II, III,
and IV) MRSI with an ERC had a high specificity (82%-92%), but a low sensitivity
(20%-57%). For the novice reader (reader I), MRSI with the use of an ERC had a
high sensitivity (80%) and a low specificity (34%). For all readers, the negative
predictive values were high (82%-89%) while the positive predictive values were
low (20%-45%) for both imaging with and without ERC.
The AUCs increased with the experience of the reader (Table 4). The most
experienced reader (reader IV) had the highest AUC (0.72) for localization of
PCa with MRSI with an ERC. Overall AUCs were calculated for reader II, III, and IV
together. Localization of PCa with MRSI with the use of an ERC had a significantly
higher AUC (0.68) than MRSI without the use of an ERC (0.63) (P = .015) (Figure 4).
58
a
b
d
d
e
Figure 2: Presentation of how readers were able to evaluate and score the data in one view. MR images
of a 73-year-old man with a PSA of 5.0 ng/mL. From left to right: Overlaid on transverse T2-weighted
multiple-spin-echo image (TR/TE 3700/124) spectral fits (a), choline+creatine-to-citrate ratio (CC/C)
(b),choline-to-creatine ratio (C/C) (c), and voxel number (d). Magnified view of metabolite spectrum
of the voxel at the red arrow, which had the highest CC/C ratio of region of interest (ROI) number 10.
Measured spectrum (white line), overlaid with fit (red line), and residual between data and fit (green
line) (e). This voxel had a CC/C ratio of 0.83 in the peripheral zone of the prostate. The C/C ratio was 1.06
so, according to Table 1 this voxel, representing segment 10, was classified as probably malignant tissue.
Histopathology revealed prostate cancer in this segment with a Gleason score of 3+3.
9
8
7
Number
6
5
4
3
1
0
0.5-1.0
1.1-1.5
1.6-2.0
2.1-2.5
2.6-3.0
10.0-15.0
Volume cm³
Figure 3: Cancer foci volume distribution on histopathology. Median tumor volume 1.1 cm3, range 0.5-
Table 2
Number of non-rateable ROIs
MRSI -
MRSI +
Reader I
3%
0%
Reader II
18% (50/252)
22% (62/252)
Reader III
8%
(20/252)
14% (36/252)
Reader IV
18% (45/252)
19% (48/252)
(6/252)
MRSI - = MR spectroscopic imaging without an endorectal coil, MRSI + = MRSI with an endorectal coil.
P = .007.
59
MRSI with and without ERC
12.9 cm3.
Chapter 3
2
Table 3
Diagnostic performance in localizing prostate cancer with MRSI with and without an ERC
MRSI -
MRSI +
Sensitivity
Specificity
NPV
PPV
Sensitivity
Specificity
NPV
PPV
65%
43%
84%
20%
80%
34%
89%
21%
(26/40)
(76/178)
(76/90)
(26/128)
(33/41)
(62/183)
(62/70)
(33/154)
Reader II
30%
88%
85%
37%
20%
92%
82%
39%
(13/43)
(164/186)
(164/194)
(13/35)
(9/44)
(159/173)
(159/194)
(9/23)
Reader III
33%
70%
82%
20%
32%
87%
85%
37%
(14/43)
(133/189)
(133/162)
(14/70)
(13/41)
(153/175)
(153/181)
(13/35)
42%
74%
83%
30%
57%
82%
85%
45%
(18/43)
(122/164)
(122/147)
(18/60)
(24/46)
(129/158)
(129/151)
(24/53)
Reader I
Reader IV
MRSI - = MR spectroscopic imaging without endorectal coil, MRSI + = MRSI with endorectal coil.
Table 4
AUC’s for localizing prostate cancer with MRSI with and without an ERC
MRSI +
AUC
AUC
Reader I
0.55
0.61
.047*
Reader II
0.62
0.65
.151
Reader III
0.59
0.68
.014*
Reader IV
0.67
0.72
.056
Overall (II, III, and IV)
0.63
0.68
.015*
P value
MRSI - = MR spectroscopic imaging without endorectal coil, MRSI + = MRSI with endorectal coil.
* = considered significant.
100
100
80
80
Sensitivity
Sensitivity
60
MRSI -
60
Reader II MRSI - = AUC
0.62 (95% CI 0.54−0.70)
40
a
0
20
40
60
1-Specificity
80
Reader III MRSI + =
AUC 0.68 (95% CI
0.59−0.76)
20
Reader IV MRSI - = AUC
0.67 (95% CI 0.59−0.74)
0
Reader II MRSI + =
AUC 0.65 (95% CI
0.57−0.72)
40
Reader III MRSI - = AUC
0.59 (95% CI 0.51−0.67)
20
60
Reader IV MRSI + =
AUC 0.72 (95% CI
0.64−0.80)
0
100
b
0
20
40
60
80
100
1-Specificity
Figure 4: ROI-ROC curves for the experienced readers for localizing prostate cancer with MR
spectroscopic imaging without an endorectal coil (MRSI -) (a), and with an endorectal coil (MRSI +) (b).
Discussion
In the localization of PCa with MRSI at 3T, the use of an ERC provided a significantly
(P = .015) higher AUC (0.68) for experienced readers compared with not using an
ERC (AUC 0.63) (Figure 4). Despite the fact that this difference was statistically
significant, such a small increase in the AUC should make one think whether using
the ERC is worth the effort, cost and patient discomfort. When calculating the
general AUCs for all readers together we excluded the results from reader I. This
was done because of the vastly different level of experience of this reader (no
experience) for evaluating MRSI data compared to the other three readers (at
least 4 years of experience), as evidenced by the contrasting descriptive statistics
compared to the other readers. All other readers had high specificities and low
In general the AUCs for localization with or without the use of an ERC were low
compared to earlier published studies in localizing PCa with MR imaging (7;8).
Only one previously published multi-centre study on the localization of PCa with
MRSI at 1.5T presented even lower AUCs compared to our study (23). Some of
their main arguments for such low AUCs, such as low image quality and limited
experience in obtaining data are somewhat shared by us. The results of our study
commenced acquiring MRSI on a 3T system. The high number of non-rateable
ROIs (Table 2) clearly illustrated this limited experience in 3T data acquisition. With
matured technology (improved shimming), better coils and more experienced
technicians, current data quality in clinical practice is expected to be improved,
possibly resulting in an increased signal to-noise-ratio of the spectra and less nonrateable regions in the prostate. Furthermore, in our study the experience level
of the reader was also shown to be of influence by the fact that the highest AUC
(0.72) was achieved by the most experienced reader (reader IV). Altogether
this emphasizes the importance of experience in both acquiring and reading
spectroscopic data. Future studies should therefore focus on training radiologists
to read spectroscopic data (with possible pitfalls such as false positives due to
high choline signals from seminal vesicles, and unreliable fits due to low signal-tonoise ratios) as well as technicians in obtaining high image quality data.
Nonetheless, it is important to note that the main purpose of our study was to
compare the performance of MRSI in the localization of PCa with and without an
61
MRSI with and without ERC
were based partly on MRSI data that were obtained in 2004 when we had just
Chapter 3
sensitivities, whereas reader I had a high sensitivity and a low specificity.
ERC. The low overall AUCs did not interfere with our conclusion that the use of the
ERC only marginally, but significantly, improves localization performance.
More ROIs were judged non-rateable on MRSI with the use of an ERC than in
the set of images without the use of an ERC. In one other study (15), the authors
established that there was a higher presence of motion artefacts in the ERC
group (compared to the non-ERC group) which could explain the higher amount
of non-rateable ROIs in the ERC group (compared to the non-ERC group) in our
study. It is very difficult to assess motion during the MRSI measurements. As the
MRSI part of the protocol is performed after T2w MRI in three directions (larger
time gap from pre-examination glucagon injection), and takes longer than one
T2w series alone, motion during MRSI cannot be ruled out and may indeed be a
source of error. Even the absence of these artefacts on T2w MRI cannot rule out
motion during MRSI. Also, this difference in non-rateable ROIs in favour of the ERC
group could be accounted for by decreased signal-to-noise ratio at distances
further away from the coil, in the ventral part of the prostate.
Limitations of this study were initially, the low number of patients included,
62
although this was partially compensated for by the 14 ROIs per prostate that were
used and the multiple number of readers that were involved. Second, poor SNR
and therefore the high number of non-rateable ROIs in these patients, because
of this being the first patient cohort. Third, in this study we did not use T1-weighted
images to assess the amount of haemorrhage after biopsy in the prostate gland.
Instead, to diminish this haemorrhage effect as much as possible, the time
between biopsy and MR examination was kept to a minimum of three weeks
(24;25). Worth noting, any still existing haemorrhage effect would have affected
the endorectal group as well as the non-endorectal group equally. Fourth, the
readers rating these data were able to see which set of images concerned the
MRSI data with the use of an ERC as well as without the use of an ERC. Ideally,
data in comparative studies should be presented in a blinded fashion. Blinding
the use of an ERC is problematic, because it is very difficult to hide the increased
SNR, especially at the dorsal aspect of the prostate, and the deformed prostate/
rectum from a good radiologist or spectroscopist.
In conclusion, the use of an ERC in 3D MRSI in localizing PCa at 3T slightly but
significantly increased the localization performance compared to not using an
ERC.
Acknowledgements
The authors thank J. Wang (Department of Radiology, Changhai Hospital,
Shanghai), J. G. R. Bomers, and M. G. Schouten for their contributions.
Chapter 3
63
MRSI with and without ERC
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Invest Radiol. 2010;45:121-125
4
Feasibility of 3T dynamic contrastenhanced MR-guided biopsy in
localizing local recurrence of
prostate cancer after external
beam radiation therapy
Yakar D
Hambrock T
Huisman H
Hulsbergen-van de Kaa CA
van Lin E
Vergunst H
Hoeks CM
van Oort IM
Witjes JA
Barentsz JO
Fütterer JJ
Abstract
Purpose
The objective of this study was to assess the feasibility of the combination of MRguided biopsy (MRGB) and diagnostic 3T magnetic resonance (MR) imaging in
the localization of local recurrence of PCa after external beam radiation therapy
(EBRT).
Materials and Methods
Twenty-four consecutive men with biochemical failure suspected of local
recurrence after initial EBRT were prospectively enrolled in this study. All patients
underwent a diagnostic 3T MR examination of the prostate. T2-weighted and
dynamic contrast-enhanced MR images (DCE-MRI) were acquired. Two
radiologists evaluated the MR images in consensus for tumour suspicious regions
(TSRs) for local recurrence. Subsequently, these TSRs were biopsied under MRguidance and histopathologically evaluated for the presence of recurrent PCa.
68
Descriptive statistical analysis was applied.
Results
Tissue sampling was successful in all patients and all TSRs. The positive predictive
value (PPV) on a per patient basis was 75% (15/20) and on a per TSR basis 68%
(26/38). The median number of biopsies taken per patient was 3 and the duration
of an MRGB session was 31 minutes. No intervention related complications
occurred.
Conclusions
The combination of MRGB and diagnostic MR imaging of the prostate was a
feasible technique to localize PCa recurrence after EBRT using a low number of
cores in a clinically acceptable time.
Introduction
Approximately 30% of the patients diagnosed with prostate cancer (PCa) are
treated with external-beam radiation therapy (EBRT) as initial definitive treatment (1).
Of these patients, between 20 to 60% develop biochemical failure (2). Biochemical
failure is considered to represent cancer recurrence (3) and correlates well with
clinical progression as evidenced by local clinical control rates after 5 years in
patients with and without biochemical failure of 86% and 99%, respectively (4).
The diagnosis of recurrent PCa entails a prostate specific antigen (PSA) test, digital
rectal examination (DRE), transrectal ultrasound (TRUS)-guided prostate biopsy and a
bone scan. However, each of these diagnostic tools have definite shortcomings (5).
The PSA nadir, PSA half-life, time interval from treatment to PSA nadir, and PSA
there is no absolute cut-off value to accurately discriminate on an individual basis,
between local recurrence and distant metastases (7).
Diagnosing local recurrence after EBRT by DRE is challenging due to radiation-
induced fibrosis and shrinkage of the prostate, whereas the sensitivity and specificity
of TRUS after radiotherapy was found to be 49% and 57%, respectively (8).
Magnetic resonance (MR) imaging of the prostate is a well established
is restricted because of treatment-induced changes, resulting in homogeneously
low signal on T2-w images (9, 10). Hence, MR imaging of the prostate after EBRT is
much more challenging. Functional imaging techniques, like dynamic contrastenhanced MR imaging (DCE-MRI) (11, 12), diffusion weighted-imaging and proton
MR spectroscopy can improve the accuracy of localizing recurrence after EBRT
(13-15). This diagnostic information can be used for directing biopsies to tumour
suspicious regions (TSRs). Thus far, TRUS is the most widely used imaging modality
and systematic sextant TRUS-guided biopsy is considered the gold standard for
histological assessment of a local recurrence, with a positive predictive value
(PPV) of only 27% (8). However, this may be improved by DCE-MRI with a PPV
of 46%-78% (11, 12). To our knowledge there are no studies available on 3T MRguided biopsy (MRGB) in the localization of local recurrence of PCa after EBRT.
The purpose of our study was to assess the feasibility of the combination of
MRGB and diagnostic 3T MR imaging in the localization of local recurrence of
PCa after EBRT.
69
DCE-MRGB in PCA recurrence
modality for accurately localizing PCa. Evaluation of the radiated prostate gland
Chapter 4
doubling time are all associated with both clinical and biochemical failure (6). Yet,
Materials and Methods
Patients
This study was approved by the ethics review board of our institution and informed
consent was obtained.
From October 2006 to March 2009, 24 consecutive patients (median age
70 years; range 60-83) with biochemical failure (using the ASTRO definition of 3
consecutive rises in PSA after reaching PSA nadir) after initial EBRT were enrolled
in this prospective study. Patients were referred for MR imaging of the prostate
followed by MRGB. Exclusion criteria were contraindications to MR imaging
(eg, cardiac pacemakers, intracranial clips). The pre- and post-radiotherapy
characteristics of the patients are given in Table 1.
Table 1. Patient characteristics
70
Characteristic
Datum (range)
Median age (yr)
70 (60-83)
No. of missing data
Preradiotherapy pathologic stage*
T1
3
T2
4
T3
13
Median preradiotherapy Gleason score
7 (5-9)
2
Median preradiotherapy PSA (ng/mL)
15.6 (6.1-96.0)
1
Median radiation therapy dose (Gy)
67.5 (66.0-78.0)
3
No. of patients who received hormonal
15
therapy
Median PSA nadir (ng/mL)
0.26 (0.0-6.3)
Median PSA level (ng/mL) prior to MR imaging
4.4 (1.1-13.4)
Median time (yr) between radiation therapy
4.4 (1.1-13.4)
completion and MR examination
Median time (wk) between MR examination
4.1 (1.3-10.00)
and biopsy
* Data are numbers of men (n=20) with the given cancer stages.
MR Imaging protocol
MR imaging of the prostate was performed using a 3T MR scanner (Siemens Trio Tim,
Erlangen, Germany) with the use of an endorectal coil (ERC) (Medrad, Pittsburgh,
U.S.A) and a pelvic phased array coil. The endorectal coil was inserted and filled
with either a 40 ml perfluorocarbon or water preparation (FOMBLIN, SolvaySolexis, Milan, Italy). Peristalsis was suppressed with an intravenous injection of
20 mg butylscopolaminebromide (BUSCOPAN, Boehringer-Ingelheim, Ingelheim,
Germany), intramuscular injection of 20 mg butylscopolaminebromide and 1 mg
of glucagon (GLUCAGEN, Nordisk, Gentofte, Denmark).
The imaging protocol included the following sequences: T2-weighted turbo
spin echo sequences were acquired (TR 4260 ms/ TE 99 ms; flip angle 120; 3 mm
slice thickness; echo train length 15; 180 x 90 mm field of view and 448 x 448
matrix; voxel size 0.2 mm x 0.4 mm x 3 mm) in axial, coronal and sagittal planes. A
3-dimensional (3D) T1-weighted gradient echo sequence (TR 4.90 ms/ TE 2.45 ms;
flip angle, 10; 176 slices per 3D slab; 0.9 mm slice thickness; 288 x 288 field of view
and 320 x 320 matrix; voxel size 0.9 mm x 0.9 mm x 0.9 mm) was used to assess
sequence (TR 800 ms/ TE 1.47 ms; flip angle, 14; 3 mm slice thickness; field of view
230 x 230 and 128 x 128 matrix; voxel size 1.8 mm x 1.8 mm x 3 mm) was used to
obtain proton-density images, with the same positioning angle and centre as
the axial T2-weighted sequence (to allow calculation of the relative gadolinium
chelate concentration curves), followed by 3D T1-weighted spoiled gradientecho images (TR 38 ms/ TE 1.35 ms; flip angle, 14; 10 transverse partitions on a 3D
size 1.8 mm x 1.8 mm x 3 mm; GRAPPA parallel imaging factor 2; 2.5s temporal
resolution; and 2 minutes 30 seconds acquisition time) acquired during an
intravenous bolus injection of a paramagnetic gadolinium chelate—0.1 mmol of
gadopentetatedimeglumine (DOTAREM, Guerbet, Paris, France) per kilogram of
body weight. This was administered with a power injector (Spectris; Medrad) at
2.5 ml/sec and followed by a 20-ml saline flush.
MR Data Analysis
The prostate images of all patients were read in consensus by two radiologists
with respectively two and five years of experience in prostate MR imaging.
Functional dynamic imaging parameters were estimated from a fitted general
bi-exponential signal intensity model for each MR signal enhancement–time
curve, as described previously (16, 17). The pharmacokinetic parameters (Ktrans,
Ve, Kep, and WashOut) were computed using the standard two-compartment
model (18) and the arterial input function was estimated using the reference
71
DCE-MRGB in PCA recurrence
slab; 3 mm section thickness; 230 x 230 mm field of view; 128 x 128 matrix; voxel
Chapter 4
lymph node and skeletal status. Finally, an axial 3D T1-weighted gradient echo
tissue method (19) and automated per-patient calibration (20). Finally, these
parameters were projected as colour overlay maps over the T2-weighted images.
This patented procedure (21) for calculating pharmacokinetic parameters is
being used in multiple centres. For the first two patients lesions were identified as
suspicious purely if a focally enhancing region with DCE-MRI was seen irrespective
of the degree of enhancement. To determine if regions enhancing in the prostate
were representing tumour, we applied a lesion directed biopsy approach. To
establish a “cut-off” in the colour coding of the pharmacokinetic maps we used
the “normal” regions of these two patients as a cut-off for future colour coding.
Above this “normal” threshold, radiologists then defined suspicious regions as
focally enhancing spots shown on the colour maps. The criterion for TSRs on DCEMRI in the peripheral zone, the central gland and the seminal vesicles was a
cut-off value of 3.5 (minute-1) for Ktrans and -0.225 [AU] for washout. The criterion
for TSRs on T2-weighted MR images was a low signal-intensity region within the
prostate.
72
Per patient, the T2-w images were evaluated for TSRs individually and in colour
overlay (DCE-MRI). To locate the TSRs the prostate was divided into 22 different
axial and sagittal segments, in order to make a 3D spatial position estimation of
the identified TSRs which was used during the second MRGB-session. A similar
translation technique was described before by Hambrock et al. (22).
MR-guided biopsy
After the initial tumour localization MR examination (median time between biopsy
and initial localization MRI was 4.1 weeks; range 1.3-10.0), patients underwent an
MRGB using an MR-compatible biopsy device (Invivo, Schwerin, Germany) at
3T. All patients received oral ciprofloxacin 500 mg (CIPROXIN, Bayer, Leverkusen,
Germany) the evening before, on the morning of the biopsy and 6 hours post
biopsy.
Relocation of the TSRs (by using the 3D spatial position estimation) determined
during the first MR imaging localization was done by obtaining T2-weighted
anatomical images in the axial direction. Prostate biopsies were performed with
the patient in prone position and a needle guider inserted rectally which was
attached to the arm of the biopsy device. The needle guider was pointed towards
the TSR before obtaining the biopsy specimen (22). All biopsies were supervised by
one experienced radiologist (4 years of experience) with MRGB of the prostate.
Histopathology
Samples were subsequently processed by a routine fixation in 10% buffered
formalin, embedded in paraffin, stained with hematoxylin-eosin, before being
evaluated by an experienced genitourinary pathologist (18 years experience
of PCa histopathology) for the presence of tumour. The biopsies were classified
as negative if there was no evidence of carcinoma or residual indeterminate
carcinoma with severe treatment effect, defined as isolated tumour cells or
poorly formed glands with abundant clear or vacuolated cytoplasm. All positive
biopsies were assigned a Gleason score.
Statistical analysis
Descriptive statistical analysis was applied. The positive predictive value (PPV)
and range) were calculated by using SPSS 16.0.
Results
Three patients with contraindications to an ERC (e.g., anorectal surgery,
Metastatic disease was evident on MR imaging in 4 out of 24 patients. One
patient had multiple low signal intensity areas in the left iliac and sacral bone
and multiple enlarged lymph nodes (diameter greater than 10 mm) next to the
right internal iliac artery. Two patients had multiple enlarged lymph nodes next to
the right internal iliac artery. One patient had multiple areas with focal low signal
intensities in the body of L4, the right acetabulum and in the right anterior superior
iliac spine. These patients received hormonal therapy and were excluded in the
further analysis.
In the remaining 20 patients, a total of 38 TSRs were identified on combined T2-
weighted and DCE-MRI and subsequently biopsied with MRGB. All TSRs that were
identified on T2-weighted imaging were also identified on DCE-MRI. With DCE-MRI 8
TSRs, in 5 patients, were identified that were not identified on T2-weighted imaging.
One patient had a hyperintense region compared to uninvolved prostate tissue as
TSR on T2-weighted MR imaging and increased permeability on DCE-MRI (Figure 1),
which turned out to be recurrent PCa on histological examination.
73
DCE-MRGB in PCA recurrence
inflammatory bowel disease) were scanned with a pelvic phased array coil only.
Chapter 4
of TSRs seen on MR images was calculated. The patient characteristics (median
Median MRGB time was 31 minutes (range 18-47) per patient and a median of 3
biopsy cores per patient (range 2-5) was obtained. Median number of biopsies
per TSR was 2 (range 1-4). The MRGBs were tolerated well and no procedure
related complications occurred. Tissue sampling was successful in all patients
and TSRs.
Histologically proven local recurrence was evident in 15 patients (Figure
2). These patients were either treated with salvage cryosurgery (5 patients),
salvage prostatectomy (1 patient), wait and see (1 patient), hormonal therapy
(2 patients), were lost to follow up (4 patients), or died (2 patients). Of the 38
different TSRs identified on MR imaging, 26 contained histologically proven
recurrence (68%), 8 revealed radiotherapy induced atypia in preexisting glands
(21%), 1 contained residual indeterminate PCa with severe radiation changes
(3%) and the remaining 3 contained fibrosis (8%).
The PPV of MRGB for detecting local recurrence on a per patient basis and per
TSR basis was 75% (15/20) and 68% (26/38), respectively. There was no significant
difference of the PPV when peripheral, central gland and seminal vesicles were
74
considered separate and also the use of a pelvic phased array coil only had no
influence on these results. Gleason score 10 was present in 2/26 (8%), Gleason
score 9 in 8/26 (31%), Gleason score 8 in 3/26 (12%), Gleason score 7 in 9/26 (35%)
and Gleason score 6 in 4/26 (15%) TSRs.
The site of recurrence within the prostate was present in the apical region in
6 out of 26 TSRs, in the apex-mid in 5, in the mid in 9, in the mid-base in 3, in the
base in 1 and in the seminal vesicle in 2 TSRs. The local recurrence was identified
in the peripheral zone in 19 out of 26 (73%) TSRs and in the central gland in 7 of 26
(27%) TSRs.
Three of the five patients with negative histology received hormonal therapy,
one underwent salvage cryosurgery and one underwent a follow up MR
examination. The patient with the follow up MR had unchanged MR findings in
combination with a declining PSA (PSA during the first MR examination was 6.4
ng/mL and during the follow up MR imaging it was 3.7 ng/mL).
a
b
c
Figure 1: MR images obtained from a 70 year old man with a TSR seen in the right ventral part in the
mid-prostate, with a PSA of 0,4 ng/mL. The T2-weighted images showed a hyperintense TSR in the right
ventral part in the mid-prostate (arrow) (a), also on DCE-MRI there was a TSR (high Ktrans) visible (arrow)
(b). During a second session, an MRGB was performed, the needle guider was pointed towards the TSR
in axial (TRUE-FISP image) (c) plane and subsequently biopsied. Histopathology revealed a Gleason 9
prostate cancer recurrence.
Chapter 4
a
b
c
75
Figure 2: MR images obtained from a 68 year old man with a tumor suspicious region (TSR) seen in the
contrast-enhanced MR imaging (DCE-MRI) there was a TSR (high Ktrans) visible (arrow) (b). During a
second session, an MRGB was performed, by pointing the needle guider towards the TSR in axial (TRUEFISP image) (c) plane and subsequently biopsied. Histopathology revealed a Gleason 7 prostate cancer
recurrence.
DCE-MRGB in PCA recurrence
right peripheral zone at the apex-mid, with a PSA of 2,1 ng/mL. The T2-weighted images showed a
diffuse low signal intensity of the entire prostate and no TSR was detectable (a), however on dynamic
Discussion
Results of our study show that local recurrence after EBRT could be localized
with the combination of MRGB and diagnostic MR imaging in a substantial
proportion of patients (PPV of 68% and 75% on a per TSR and a per patient basis,
respectively). With a median intervention time of 31 minutes, and no procedure
related complications, MRGB can be considered a feasible method in localizing
local PCa recurrence following EBRT.
MRGB was not able to assess the effect of false negatives i.e. areas of
prostate cancer which did not enhance, because of the relative time-consuming
character of this procedure. However, previous studies that have used six core
TRUS-guided biopsy as the standard of reference in localizing radiation therapy
recurrence, including from regions that did not enhance on DCE-MRI, have
shown that the negative predictive value of this technique is between 78%-95%
(11,12). Undoubtedly six core TRUS-guided biopsies have many limitations when
used as the gold standard (e.g. high false negatives and underestimating of true
76
Gleason score). Which probably means that these negative predictive values
of the above mentioned studies are somewhat overrated. Correlating DCE-MRI
with radical prostatectomy samples would be the best option and should be
the next step in correlating recurrent disease seen on DCE-MRI. Nonetheless,
when selecting patients with prostate cancer recurrence the mostly followed
treatment strategy is still some form of whole-gland salvage therapy. Hence,
false negatives are less of a problem. Merely detecting a recurrence, rather
than mapping the recurrent tumour, will suffice for this particular group of
patients. Thus, only biopsying TSRs seen on DCE-MRI should be considered as an
advantage rather than a disadvantage of MRGB biopsies. MRGB is capable of
detecting a recurrence with only three biopsies per patient omitting TRUS biopsy
core schemes (with a positive predictive value of 27% (8)) that use between 6-12
cores per patient. Consequently, it may lead to higher patient satisfaction.
The main advantage of TRUS-guided biopsy over 3T DCE-MRGB is that the
expertise and the technique itself are more generally available in routine clinical
practice. Probably, performing MR-TRUS fusion for targeted biopsies by combining
the high spatial resolution of MR imaging with the wide-spread availability of TRUS is
the most optimal strategy as evidenced by promising results in two different studies
(23, 24). However, MRGB has the advantage of being directed towards TSRs using
the same imaging modality used for localization. This way spatial misregistration
between MR imaging and the biopsy core can be reduced to a minimum, which
probably makes it a more precise method. Unfortunately, randomized controlled
trials comparing MRGB, TRUS-guided biopsy and MR-TRUS fusion are not available
yet.
Future studies should focus on inclusion of a larger number of patients and in
order to improve the reproducibility of quantitative pharmacokinetic parameters
(25) as well as to limit the subjectiveness of reader evaluation an automated perpatient arterial input function estimation which was shown in a recent publication
to be superior to fixed input models (20) is more preferred.
The widely known and accepted criterion for prostate cancer on T2-weighted
MR imaging, a region of low signal intensity, was used by us for localizing
hyperintense region compared to surrounding prostate tissue as a TSR which
was confirmed on histological evaluation as PCa recurrence. This indicates that
after EBRT a recurrence can also have a hyperintense character compared
to surrounding prostate tissue on T2-weighted MR imaging. Furthermore, future
studies may include other functional MR imaging techniques such as diffusion
weighted imaging (26) and MR spectroscopy in guiding MRGB after EBRT. This
Limitations of our study are related to the relatively small number of patients
included and the incomplete data concerning patient characteristics, which
was due to patient referral from outside our university hospital. In our study, we
did not have any patient with a negative DCE-MRI on local prostate level. In other
words, each patient we imaged had at least one TSR in the prostate detected
with DCE-MRI. This can be interpreted as a selection bias. However, this is not
surprising because of the inclusion criteria being 3 consecutive rises of PSA after
reaching PSA nadir. Only three patients were examined without the use of an
ERC. Due to the small number of this group no further conclusions can be drawn
from this result. Because our current study is prospective and no other studies exist
on defining true pharmacokinetic cut-off values for the irradiated prostate we
had to base our cut-off values on the first two patients we imaged and biopsied.
Defining a cut-off for tumour is impossible with only two patients. These two
were only used to define a cut-off for “normal”. Above this “normal” threshold,
radiologists then defined suspicious regions as focally enhancing spots shown on
77
DCE-MRGB in PCA recurrence
may lead to a higher detection rate with a minimum number of biopsy cores.
Chapter 4
recurrence of PCa. It is interesting to note that we had a specific case with a
the colour maps. To define true pharmacokinetic cut-off values for tumour vs.
benign enhancing spots vs. normal in the irradiated prostate is subjective of a
future publication and can only be determined retrospectively on a larger group
of patients.
Salvage therapies can offer a possibility of cure in selected patients. This
underlines the importance to select the patients who would benefit from it
carefully (27). Unfortunately, the conventional methods for diagnostic workup
of PCa recurrence (e.g. DRE, PSA, TRUS, bone scan) all have their limitations.
Therefore, there is a need for more accurate and versatile diagnostic tools like
MR imaging, which has the advantage that both local and distant prostatic
disease can be evaluated at the same time. Moreover, the addition of other
functional MR imaging techniques such as DWI can even possibly play a role in
the assessment of tumour aggressiveness (28).
In conclusion, the combination of MRGB and diagnostic MR imaging of the
prostate was a feasible technique to localize PCa recurrence after EBRT using a
low number of cores in a clinically acceptable time.
78
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Kim CK, Park BK, Lee HM. Prediction of locally recurrent prostate cancer after radiation therapy:
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Futterer JJ, Heijmink SW, Scheenen TW, et al. Prostate cancer localization with dynamic contrastenhanced MR imaging and proton MR spectroscopic imaging. Radiology. 2006;241:449-458.
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Huisman HJ, Engelbrecht MR, Barentsz JO. Accurate estimation of pharmacokinetic contrastenhanced dynamic MRI parameters of the prostate. J Magn Reson Imaging. 2001;13:607-14.
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Chapter 4
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Top Magn Reson Imaging. 2008;19:291-295
5
MR-guided biopsy of the prostate,
feasibility, technique and clinical
applications
Yakar D
Hambrock T
Hoeks C
Barentsz JO
Fütterer JJ
Abstract
Purpose
To describe the technique of magnetic resonance (MR)-guided biopsy as
performed in our institution and highlight trends from current literature.
Materials and Methods
Local protocols for MR prostate cancer localization and its image data analysis is
described. Acquisition of a 3D localization for a tumour suspected region (TSR) and
its re-identification on a second MR-guided biopsy session are being explained.
Furthermore, detailed information about the procedure, biopsy technique itself
and current trends are being discussed and highlighted.
Results
MR-guided biopsies (MRGBs) have a higher tumour detection rate of prostate
cancer in patients with clinical suspicion of prostate cancer and repeated
84
negative transrectal ultrasound guided biopsies (TRUS-GB). It is a feasible and an
accurate technique.
Conclusion
Performance of MR guided prostate biopsies, using suggested techniques,
protocols and equipment is a feasible and accurate technique. It has proven to
be an accurate method for detection of significant prostate cancer in men with
repetitive previous negative biopsies.
Introduction
Prostate cancer was the most frequently diagnosed cancer in men in the United
States in 2008, accounting for 25% of all cancers (1). Early detection is very
important because localized disease can be treated effectively (2). Digital rectal
examination (DRE) and measuring the prostate specific antigen (PSA) level are
the mostly widely used tests for the diagnosis of prostate cancer (PCa). However,
the gold standard remains histopathological evaluation of tissue obtained during
prostate biopsy.
Systematic transrectal ultrasound guided biopsy (TRUS-GB) is the most
frequently used technique for detecting PCa in men, clinically suspect for
malignancy. However, limitations of TRUS-guided biopsy, such as high falsehave led to a search for other localization and biopsy techniques. Furthermore
gray scale transrectal ultrasound inherently has a low sensitivity for localizing PCa
(5). Urologists are constantly faced with the dilemma of how to best manage
a patient with an elevated PSA in which repeat TRUS-GB reveal no cancer, as
these patients could still be harbouring clinically significant tumours. Among
others, repeat biopsies and radical techniques like saturation biopsies have been
repeat TRUS-GB and saturation biopsy have been described (6, 7).
As a consequence of the poor performance, other techniques with higher
sensitivities for localizing PCa are needed. MRI with its proven high sensitivity
for tumour localization appears to fulfil this need and has been used to direct
biopsies under direct MR guidance( 8, 9).
The current literature on MRGB of the prostate however, is limited and the
few studies available have included small number of patients, excessively long
imaging and biopsy times, and only used conventional T2-weighted (T2-w) MR
imaging to localize TSRs (10-12). Multi-modality MRI has proven to increase the
localization accuracy of PCa (13, 14). In our institution we use the multi-modality
approach to maximize detection capabilities.
The objective of this article is to describe the technique of MR-guided biopsy
as performed in our institution and highlight trends from current literature.
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MRGB Review
performed to overcome these limitations. Detection rates of between 9-34% for
Chapter 5
negative biopsy rate(3) or over- or underestimating of true Gleason score (4),
Materials and Methods
Localization MRI
Before biopsy, an MR localization protocol is performed to identify possible PCa
locations. A 3T MR scanner (Siemens Trio Tim, Erlangen, Germany) was used
together with an endorectal coil (Medrad, Pittsburgh, U.S.A) and pelvic phased
array coil. The endorectal coil is inserted and filled with a 40 ml perfluorocarbon
preparation (FOMBLIN, Solvay-Solexis, Milan, Italy). A localization MRI can also
be performed without an endorectal coil, using the pelvic phased array coil for
signal reception only, especially when there are contra-indications to endorectal
coil insertion (such as anorectal surgery, inflammatory bowel disease). However,
despite a reduced signal-to-noise-ratio, at 3T imaging with the pelvic phased
array coils is of proven feasibility. Peristalsis is suppressed with an intravenous
administration of 20 mg of butylscopolaminebromide (BUSCOPAN, BoehringerIngelheim, Ingelheim, Germany), an intramuscular administration of 20 mg
butylscopolaminebromide and 1 mg of glucagon (GLUCAGEN, Nordisk,
86
Gentofte, Denmark) intramuscular.
The imaging protocol was as follows: after fast evaluation of correct endorectal
coil position with fast gradient echo imaging, T2-w turbo spin echo sequences
are performed (TR 4260 ms/ TE 99 ms; flip angle 120; 3 mm slice thickness; echo
train length 15; 180 x 90 mm field of view and 448 x 448 matrix) in axial, coronal
and sagittal planes, covering the prostate and seminal vesicles. Subsequently,
diffusion weighted imaging (DWI) is acquired with a single-shot echo-planar
imaging sequence with diffusion modules and fat suppression pulses. Water
diffusion in 3 directions is measured using b-values of 0, 50, 500 and 800 s/mm2
(TR of 2400 ms/ TE of 81 ms; 3 mm slice thickness; 204 x 204 field of view and 136
x 136 mm matrix). Apparent Diffusion Coefficient (ADC)-maps are automatically
calculated by the scanner software. Finally, in order to perform dynamic contrastenhanced MRI ( DCE-MRI), transverse 3D T1-weighted gradient echo sequence
(TR 800 ms/ TE 1.47 ms; flip angle 14; 3 mm slice thickness; field of view 230 x 230
and 128 x 128 matrix) are used to obtain proton-density images, with the same
positioning angle and centre as the transverse T2-weighted sequence (to allow
calculation of the relative gadolinium chelate concentration curves), followed
by 3D T1-weighted spoiled gradient-echo images (TR 38 ms/ TE 1.35 ms, flip angle
14, 10 transverse partitions on a 3D slab, 3 mm section thickness, 230 x 230 mm
field of view, 128 x 128 matrix, GRAPPA parallel imaging factor 2) acquired during
an intravenous bolus injection of a paramagnetic gadolinium chelate—0.1 mmol
of gadopentetate dimeglumine (DOTAREM, Guerbet, Paris, France) per kilogram
of body weight, administered with a power injector (Spectris; Medrad) at 2.5 ml/
sec and followed by a 20-ml saline flush. With these two sequences, a 3D volume
with 10 partitions is acquired every 2.5 seconds.
Localization MR data analysis
For image evaluation, the acquired images are viewed on an analytical software
workstation. The calculated pharmacokinetic DCE-MRI parameters and the
calculated ADC-maps from DWI are projected as colour overlay maps over the
T2-w images (15). A manual co-registration tool built into the software is used if
The criterion for tumour suspicious regions (TSR) on T2-w images is a relative low
signal intensity region within the prostate. On DCE-MRI features of tumour (high
Ve, Ktrans, Kep and negative WashOut) as defined by Engelbrecht et al. (16)
and Fütterer et al. (14) are being used to detect TSRs as well as areas of restriction
on ADC maps (17). Eventually, information from T2w-imaging, DCE-MRI and
DWI are combined and used to determine the three most suspicious TSRs. The
a 3D spatial position estimation of the identified TSR. Sagittally, the prostate is
divided into 5 different slabs respectively: apex, apex-mid, mid, mid-basis, basis.
Axially, the apical and basal slabs are divided into simple quadrants, while the
remaining three are divided into left and right peripheral zone with subdivisions
of anterior horn, dorsolateral region and paramedian region. The transition
zone is furthermore subdivided into quadrants (Figure 1). Also the left and right
seminal vesicles are considered as two separate regions. Thus, for each TSR, the
exact location sagittally and axially is noted. During a second session this spatial
information is used to translate and relocate the TSR on the T2-w images and
direct the MR-guided biopsy.
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MRGB Review
prostate is divided into 22 different axial and sagittal regions, in order to make
Chapter 5
patient related movement causes misregistration of the different MRI modalities.
88
a
b
c
d
Figure 1: Endorectal 3T MRI anatomical T2-weighted images with the prostate divided into different
regions in order to make an 3D estimation of the location of the tumour suspicious region. (a) The different
slabs sagittaly, base (B), mid-base (MB), mid (M), apex-mid (AM) and apex (A). Axially, the apical (b)
and basal (d) slabs are divided into simple quadrants, while the remaining three (mid-prostate) (c) are
divided into left and right peripheral zone and left and right transition zone.
MR-guided biopsy
Finally, after the initial tumour localization MRI (preferably within 2 weeks),
patients receive a 3T MR-guided biopsy (Trio Tim, Siemens, Germany) using
a pelvic phased array coil and dedicated FDA approved MR biopsy device
(Invivo, Schwerin, Germany). All patients receive oral ciprofloxacin 500 mg
(CIPROXIN, Bayer, Leverkusen, Germany) the evening before, on the morning of
the biopsy, as well as 6 hours post biopsy as antibiotics prophylaxis. The prostate
biopsies are performed with the patient in the prone position. Pelvic phased array
coils are placed on the patient’s back as well as beneath the hips and pelvis.
Chloorhexidine/lidocaïne gel (Instillagel, FARCO-PHARMA GmbH, Köln, Germany)
is used to facilitate insertion of the needle guider (filled with gadolinium) rectally.
The needle guider is then attached to the arm of the MR biopsy device. Figure 2
shows the MR-guided biopsy device with the patient in the prone position, lying
on the scanner table with the needle guider inserted rectally. The needle guider
can be adjusted to be rotated, moved forward and backward, and changed
in height.
Relocation of the TSR, determined during the first MRI localization, is done
by obtaining T2-w turbo spin-echo images in the axial direction (TR 3500 ms/
TE 116 ms, flip angle 180, slice thickness 3 mm, in-plane resolution 0.7 x 0.7 mm,
number of slices 15) for anatomical visualization of the prostate and it is optional
to obtain a DWI (see for details localization MRI) if the TSR is more evident on
the DWI than on the T2-w images during the first localization MRI. The axial T2-w
slices have a similar angulation relative to the dorsal surface of the prostate as
during the localization MR session. By using the 3D spatial position noted during
transition zone) the desired TSR is re-identified. After relocation of the desired TSR,
adjustments are made to the biopsy device to aim the gadolinium-filled needle
guider exactly towards this region. In order to prevent prostate movement during
examination, it is important to prevent pressure from the needle guider on the
rectum wall before starting T2-w image acquisition. To make sure that this is not
the case, it is possible to obtain fast T2-w TRUE-FISP images primarily. In-between
228 mm field of view, 228 x 228 matrix, slice thickness 3mm) are made in the axial
and sagittal direction (with an imaging time of 11 seconds for each direction) to
visualize correct guider position and to plan further adjustments. After this position
is fixed, tissue samples with an 18-gauge, fully automatic, core-needle, doubleshot biopsy gun (Invivo, Schwerin, Germany) with needle length of 175 mm and
tissue core sampling length of 20 mm, are taken.
After acquiring a biopsy, fast T2-w axial and sagital TRUE-FISP images are again
obtained with the needle left in situ to verify correct needle position relative to
the desired TSR. This is done for each TSR. The number of biopsy cores taken is
dependent on the certainty of correct needle position within the TSR and the size
of the TSR. Up to three different TSRs are biopsied.
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MRGB Review
adjustments, fast T2-w TRUE-FISP images (TR 4.48ms/ TE 2.24; flip angle 70; 228 x
Chapter 5
the first localization MRI (sagitally the slabs and axially left/right peripheral zone/
90
Figure 2: Patient lying in prone position with biopsy device and needle guide inserted rectally.
Histopathology
Samples are subsequently processed by a routine fixation in formaldehyde,
embedded in paraffin, stained with hematoxylin-eosin, before being evaluated
by a histopathologist for the presence of tumour or other benign pathologies.
Results
Results from the few studies that have already been performed on this technique
have proven the feasibility, but imaging and biopsy times vary substantially (1012). Median imaging times of 30 minutes and a median number of 4 biopsies per
patient can be achieved with the above described method. Additionally, as
mentioned before, the method for localization of tumour suspicious regions prior
to biopsy vary with most researchers using T2-w imaging only. We believe that a
multi-modality approach will result in the highest tumour detection rate.
The described method of translation of MRI determined TSRs to T2 weighted
images in order to perform MR guided biopsy is a feasible technique (Figure 3)
(18). In our initial experience we have shown a tumour detection rate of 38%
but this increased to 59% after gaining more experience (Hambrock et al. The
Value of 3 Tesla Magnetic Resonance Imaging Guided Prostate Biopsies in Men
with Repetitive Negative Biopsies and Elevated PSA. Submitted). Furthermore our
latest results indicate that for patients with PSA < 20 and prostate volumes < 65
cc, MRGB significantly outperforms repeat TRUS-GB session in tumour detection.
Of note is also that MRI for tumour localization and MRGB does not appear
to overdiagnose indolent cancers, a fear that is justified as a higher tumour
localization implies a higher chance of detecting clinically insignificant tumours.
Of all our tumours detected 93% were of clinical significance (Hambrock et al.
The Value of 3 Tesla Magnetic Resonance Imaging Guided Prostate Biopsies in
higher field strength of 3T for both tumour localization and biopsy, offers improved
image quality and acquired in a shorter time frame, 1.5T will however also be
suitable for both localization and detection.
Chapter 5
Men with Repetitive Negative Biopsies and Elevated PSA. Submitted). Using a
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MRGB Review
92
a
b
c
d
Figure 3: Shows pelvic phased array coil 3T MR images of a 70 year old male (PSA 35 ng/ml) in which
six previous TRUS-guided biopsies failed to detect the transition zone tumour. This area showed low
signal intensity on T2-weighted axial images (a), restriction on the ADC map (b) and a high Ktrans on
DCE-MRI (c). An MR guided biopsy of this region was obtained (d) and histopathology revealed an
adenocarcinoma with a Gleason score of 6.
Discussion
Using state-of-the-art multi-modality MRI for tumour localization a definite
diagnosis of prostate cancer can be made in a substantial number patients
with clinical suspicion of prostate cancer based on elevated PSA values and
repeated negative TRUS-GB. MRGB has been shown to be of added value in
this particular group of patients (10-12,19) and can help urologists to improve
their biopsy outcome. In addition, biopsy under direct MR guidance, is not only
feasible, but also leads to a high number of patients being identified with clinically
significant tumour. MRGBs are limited by the restricted general availability of
the required hardware and therefore other methods such as TRUS-MRI fusion
(20) could be considered. Nevertheless, MRGB is probably the most accurate
technique because translation of a tumour suspicious region (TSR) to another
imaging modality is not required.
Performance of MR guided prostate biopsies, using suggested techniques,
protocols and equipment is a feasible and an accurate technique. MRI is
deemed essential in the work-up of all patients with suspicion of cancer but
repeat negative TRUS-GBs. MRGB can offer a value method to accurately
validate findings of multi-modality MRI in these patients. It can be a valuable
addition in the arsenal of clinicians in managing these problematic patients with
repetitive previous negative biopsies (19).
Chapter 5
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MRGB Review
References
1.
Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96.
2.
Tewari A, Divine G, Chang P et al. Long-term survival in men with high grade prostate cancer: a
comparison between conservative treatment, radiation therapy and radical prostatectomy--a
propensity scoring approach. J Urol 2007;177:911-5.
3.
Rabbani F, Stroumbakis N, Kava BR et al. Incidence and clinical significance of false-negative
sextant prostate biopsies. J Urol 1998;159:1247-50.
4.
Chun FK, Steuber T, Erbersdobler A et al. Development and internal validation of a nomogram
predicting the probability of prostate cancer Gleason sum upgrading between biopsy and
radical prostatectomy pathology. Eur Urol 2006;49:820-6.
5.
Halpern EJ, Strup SE. Using gray-scale and color and power Doppler sonography to detect
prostatic cancer. AJR Am J Roentgenol 2000;174:623-7.
6.
Roehrborn CG, Pickens GJ, Sanders JS. Diagnostic yield of repeated transrectal ultrasoundguided biopsies stratified by specific histopathologic diagnoses and prostate specific antigen
levels. Urology 1996;47:347-52.
7.
94
Stewart CS, Leibovich BC, Weaver AL et al. Prostate cancer diagnosis using a saturation needle
biopsy technique after previous negative sextant biopsies. J Urol 2001;166:86-91.
8.
Prando A, Kurhanewicz J, Borges AP et al. Prostatic biopsy directed with endorectal MR
spectroscopic imaging findings in patients with elevated prostate specific antigen levels and
prior negative biopsy findings: early experience. Radiology 2005;236:903-10.
9.
Yuen JS, Thng CH, Tan PH et al. Endorectal magnetic resonance imaging and spectroscopy for
the detection of tumor foci in men with prior negative transrectal ultrasound prostate biopsy.
J Urol 2004;171:1482-6.
10.
Anastasiadis AG, Lichy MP, Nagele U et al. MRI-guided biopsy of the prostate increases
diagnostic performance in men with elevated or increasing PSA levels after previous negative
TRUS biopsies. Eur Urol 2006;50:738-48.
11.
Beyersdorff D, Winkel A, Hamm B et al. MR imaging-guided prostate biopsy with a closed MR
unit at 1.5 T: initial results. Radiology 2005;234:576-81.
12.
Engelhard K, Hollenbach HP, Kiefer B et al. Prostate biopsy in the supine position in a standard
1.5-T scanner under real time MR-imaging control using a MR-compatible endorectal biopsy
device. Eur Radiol 2006;16:1237-43.
13.
Kim CK, Park BK, Lee HM et al. Value of diffusion-weighted imaging for the prediction of prostate
cancer location at 3T using a phased-array coil: preliminary results. Invest Radiol 2007;42:842-7.
14.
Futterer JJ, Heijmink SW, Scheenen TW et al. Prostate cancer localization with dynamic contrastenhanced MR imaging and proton MR spectroscopic imaging. Radiology 2006;241:449-58.
15.
Futterer JJ, Engelbrecht MR, Huisman HJ et al. Staging prostate cancer with dynamic contrastenhanced endorectal MR imaging prior to radical prostatectomy: experienced versus less
experienced readers. Radiology 2005;237:541-9.
16.
Engelbrecht MR, Huisman HJ, Laheij RJ et al. Discrimination of prostate cancer from normal
peripheral zone and central gland tissue by using dynamic contrast-enhanced MR imaging.
Radiology 2003;229:248-54.
17.
Xu J, Humphrey PA, Kibel AS et al. Magnetic resonance diffusion characteristics of histologically
defined prostate cancer in humans. Magn Reson Med 2009.
18.
Hambrock T, Futterer JJ, Huisman HJ et al. Thirty-two-channel coil 3T magnetic resonanceguided biopsies of prostate tumor suspicious regions identified on multimodality 3T magnetic
resonance imaging: technique and feasibility. Invest Radiol 2008;43:686-94.
19.
Hambrock T, Somford DM, Hoeks C et al. Magnetic resonance imaging guided prostate
2010;183:520-7.
20.
Singh AK, Kruecker J, Xu S et al. Initial clinical experience with real-time transrectal
ultrasonography-magnetic resonance imaging fusion-guided prostate biopsy. BJU Int
2008;101:841-5.
Chapter 5
biopsy in men with repeat negative biopsies and increased prostate specific antigen. J Urol.
95
MRGB Review
Book chapter in: Interventional Magnetic
Resonance Imaging. Springer-Verlag 2012
6
Clinical Applications in Various
Body Regions: MRI-Guided Prostate
Biopsies
Yakar D
Fütterer JJ
Abstract
In men with an elevated prostate-specific antigen and/or abnormal digital rectal
examination biopsy is the gold standard for prostate cancer (PCa) diagnosis.
Random systematic transrectal ultrasound guided prostate biopsy (TRUSGB) is the
most widely applied and available PCa diagnosis method. Detection rates of
PCa in random systematic TRUSGB do not exceed 44% and 22% for the first and
second biopsy session, respectively (2,3). Consequently other biopsy methods
have been explored. One of these methods is MR guided biopsy (MRGB) of the
prostate which has detection rates after previous negative TRUSGB sessions of
between 38-59% (18-23). These rates are higher compared to repeat TRUSGB.
MRGB typically consists of two sessions. In the first session a diagnostic multiparametric MR of the prostate is acquired and subsequently cancer suspicious
regions (CSR) are determined. In the second session these CSR will be targeted
for MRGB. The use of multi-parametric MR imaging in PCa diagnosis could
prevent patients from undergoing unnecessary biopsies and consequently avoid
98
unnecessary treatment delay.
In conclusion, MRGB has a high PCa detection rate in patients with previous
negative TRUSGB sessions. For this reason MRGB will probably become more and
more available in daily practice. However, the lack of standard protocols for MR
imaging of the prostate is an important issue. For the optimal biopsy technique
there is still more research necessary. Robotics may optimize MRGB regarding
target accuracies and procedure time.
Introduction
In men with an elevated prostate-specific antigen and/or abnormal digital rectal
examination biopsy is the gold standard for prostate cancer (PCa) diagnosis.
Random systematic transrectal ultrasound guided prostate biopsy (TRUSGB) is
the most widely applied and available PCa diagnosis method. According to
the guidelines of the European Association of Urology on PCa, depending on
prostate volume, a minimum of 8 cores should be sampled with a maximum of 12
cores (1). Detection rates of PCa in random systematic TRUSGB do not exceed
44% and 22% for the first and second biopsy session, respectively (2,3). This ‘blind’
prostate sampling often results in under sampling of the anterior prostate and
apex. As a result of this ‘blind’ biopsy strategy (36% negative predictive value (4)),
Consequently other biopsy methods have been explored. Saturation biopsies,
either transperineal or transrectal, have been proposed in patients with multiple
prior negative TRUSGB sessions. The term saturation biopsy is used to describe
biopsy schemes with a minimum of 20 cores. Even with such drastic biopsy
schemes, detection rates of only maximally 34% have been reported in patients
with negative previous biopsy sessions (5). Moreover, such biopsy schemes can
hematuria requiring treatment (6). Furthermore there is an ongoing debate on
whether the risk of detecting more insignificant tumours is higher in saturation
biopsy (7). In all probability, it is not the number of biopsy cores which makes
TRUSGB imprecise, rather the random way of sampling the prostate without
any sensitive imaging technique. There is a real need for an adequate imaging
technique, which ideally localizes, determines PCa aggressiveness and estimates
tumour volume in a non-invasive fashion. Subsequently, this information can serve
for targeting biopsies and e.g. for focal therapy.
MR imaging of the prostate, with its multi-parametric approach, is the best
available technique for PCa detection and localization (8-10). Areas under
the curve of 0.90 have been described when T2-weighted imaging (T2-w),
dynamic contrast-enhanced (DCE-MRI) and spectroscopic imaging (MRSI) were
combined (10). Moreover, adding diffusion weighted imaging (DWI) revealed a
significant negative correlation between Gleason grade and apparent diffusion
coefficient (ADC) values (11-13), implicating that it can serve as targeting the
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MRGB Book Chapter
be associated with increased patient morbidity, such as urinary retention and
Chapter 6
many men are falsely reassured that they are free of cancer when they are not.
most aggressive part of the PCa during biopsy. Although the number of studies
are scarce, there is accumulating evidence that multi-parametric MR imaging is
also sensitive to measuring tumour volume (14-16).
In 2010 Hambrock et al. (17) published a study on detection rates in
transrectal MR guided prostate biopsy (MRGB) in men with at least 2 negative
prior TRUSGB sessions. Targeted biopsies were performed based on preceded
3 tesla diagnostic multi-parametric MR examination. With a median of 4 cores
per patient they reported a detection rate of 59%. In 68% of the cases PCa was
detected in the anterior aspect of the prostate, which is not sampled standardly
in random TRUSGB. Ninety three percent of the detected cancers on MRGB were
clinically significant. Also other authors have provided data of MRGB in patients
with previous negative TRUSGB (18-23) (Table 1). MRGB can also be applied
to detect local recurrences after radiotherapy (24). MRGB of the prostate is
becoming more and more available. However there is no consensus on the
optimal technique. Recent studies describing the role of robotics in prostate
biopsy have been published (25-27).
100
This chapter will give an overview on the pre-biopsy planning session of
detecting cancer suspicious regions (CSR) in the prostate, how to perform MRGB,
and the role of robotics in MRGB.
Table 1
Overview on MRGB literature
Authors
Patient group
Field strength
Diagnostic
Detection rate
imaging protocol
Patients with previous
Radiology 2005
TRUSGB
Engelhard et al. Eur
Patients with previous
Radiol 2006
TRUSGB
Anastasiadis et al. Eur
Patients with previous
Urol 2006
TRUSGB
Hambrock et al. IR
Patients with previous
2008
TRUSGB
Hambrock et al. J
Patients with previous
Urol 2010
TRUSGB
Yakar et al. IR 2010
Patients with suspicion
1.5T
T2-w
45%
1.5T
T2-w
39%Z
1.5T
T2-w
55%
3T
T2-w, DWI, DCE-
38%
MRI
3T
T2-w, DWI, DCE-
59%
MRI
3T
T2-w, DCE-MRI
75%
1.5T
Partly T2-w, partly
52%
of post-radiotherapy
recurrence
Patients with previous
Urol 2011
TRUSGB
Franiel et al.
Patients with previous
Radiology 2011
TRUSGB
T2-w, DWI, DCEMRI, MRSI
1.5T
T2-w, DWI, DCE-
39%
MRI, MRSI
MRGB= MR guided prostate biopsy, TRUSGB= transrectal ultrasound guided prostate biopsy, T2-w= T2
weighted, DWI= diffusion weighted imaging, DCE-MRI= dynamic contrast-enhanced MRI, MRSI= MR
spectroscopic imaging
Pre biopsy planning session
MRGB typically consists of two sessions. In the first session a diagnostic multiparametric MR of the prostate is acquired. Although there is an ongoing discussion
on the optimal imaging protocol, such a protocol should include at least T2-w,
DWI, DCE-MRI and/or MRSI (21). Additionally, CSR detected on these MR images
need to be reported structurally. A structured report is of paramount importance
to enable a successful transfer of these CSR to the MRGB session. During a MRGB
session the two most suspicious CSR should be biopsied (as a minimum). Figure 1
shows an example of a first diagnostic multi-parametric MR imaging session with
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MRGB Book Chapter
Roethke et al. World J
Chapter 6
Beyersdorff et al.
an example of a structured report. Most practical is to score for every CSR for
each different MR parameter the likelihood of cancer being present. A scale of
1-5 can be used, where a score of 1 indicates no cancer present and a score
of 5 indicates that cancer is highly likely to be present. Although it is beyond the
scope of this chapter (see chapter on prostate MRI for more detailed information),
criteria per parameter for scoring cancer presence in short are; a focal area of
low signal intensity on T2-w, on the DCE-MR images a focally enhancing region
on the volume transfer constant map and/or washout map, and on the DWI a
focally low-signal intensity region on the apparent diffusion coefficient map in
combination with a high-signal-intensity region on the image obtained with a
high b value (e.g. 800 sec/mm 2).
102
b
a
c
Summary of findings (NA = Not available, 1 = def. no tumour, 5 = def. tumour)
T2
DWI
DCE
Total
Extracapsular
Extension
Finding marking 1
5/5
5/5
5/5
15/15
d
e
Figure1: Multi-parametric MR images, comprising T2-weighted (a), diffusion weighted-derived apparent
diffusion coefficient map images (b), and dynamic-contrast enhanced images (K-trans) (c), in a 75
year old patient, with a PSA of 15 ng/mL, and a history of 2 negative transrectal ultrasound guided
prostate biopsy sessions. The white circle depicts the areas suspicious for malignancy. These findings
were summarized in a structured report. Firstly the cancer suspicious area was scored for the likelihood
of cancer being present on 1-5 scale (d). Secondly, a 3 dimensional position estimation was determined
(e) for targeting purposes during the MR-guided biopsy session.
Patient preparation
It is advisable to prepare patients preventively with oral or intravenous
quinolones. Patients with indications for endocarditis prophylaxis and patients
on anti-coagulation medication should be recognized, and if necessary further
adjustments should be made depending on hospital protocols. No further
preparation is necessary, such as special diets or enema’s. Patients should be
instructed not to move during the intervention. The first MRGB were performed
in open-bore MR systems. Open-bore MR systems suffer from low signal to noise
ratios (due to low field strength) and consequently from low image quality.
Therefore, ideally MRGB should be performed in a closed bore system (≥ 1.5
Tesla). At the same time the hindrance of a closed bore system is the limited
space one has to position the patient, perform specific manoeuvres and handle
till a certain level with newer MR systems with larger and shorter bores. Moreover
robotics can also assist in overcoming these above-mentioned problems.
As for biopsy routes, the transrectal approach is probably the most preferable
one. Even though transgluteal and transperineal biopsy methods have been
described and seem feasible, the transrectal approach is the only method where
anaesthetics can be omitted (28,29).
involved in TRUS biopsy of the prostate is well tolerated, without the need for
anaesthesia (29). In addition, the rectum is the shortest way to reach the prostate
and therefore technically the most straightforward approach. It will suffer the
least from e.g. needle deflection. Concerning complication rates transrectal and
transperineal biopsy are equally safe (28,30). There are no studies comparing
morbidity rates between the three biopsy routes.
How to perform MR guided prostate biopsies
Beyersdorff et al. (18) were the first to describe a transrectal MRGB in a closed
MR system by using only T2-w MR images as part of a pre-biopsy planning. More
recently, Hambrock et al. (17) and Franiel et al. (23) described transrectal MRGB in
a closed MR system by using a multi-parametric MR pre-biopsy planning method.
There are currently two commercially available devices for MRGB (Figure 2 and
3). The latter device has 5 degrees of freedom (rotation, forward and backward,
change in height). Patients are placed in a prone or supine position on the MR table
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MRGB Book Chapter
In a placebo-controlled, double-blind study, the authors concluded that pain
Chapter 6
instruments required for certain interventions. Such problems may be overcome
where a needle guider filled with gadolinium is inserted rectally, after lubricating
it with lidocaine gel. A body phased-array coil is placed on the patient (Figure 4).
Once the patient is in the MR scanner the CSR determined during the diagnostic
MR session need to be relocated. For this, these CSR need to be translated to the
T2-w images obtained during the biopsy session by using anatomical landmarks
and a relative 3 dimensional position estimation (Figure 1e) (21). In certain cases
it is advisable to obtain a DWI sequence just before the biopsy. In this way the
most aggressive part of the CSR can be targeted (11-13). After relocation of the
CSR the needle guider is adjusted towards the desired target area, a fast T2-w
true fast imaging with steady state precession verification image in at least two
planes (preferably in the axial and the sagittal plane) is acquired to determine
the needle guider’s position relative to the targeted area. Both commercially
available systems have software systems for correct alignment of needle guider
with target area. When satisfied with its location a biopsy can be performed and
a verification image with the needle left in situ can be obtained (Figure 5). An
18-gauge, fully automatic, MR-compatible, core needle, double-shot biopsy gun
104
with a needle length of 150/175 mm and tissue core sampling length of 17 mm
can be used for this. Depending on how confident one is about the accuracy
of the biopsy relative to the CSR, additional biopsies can be taken. A procedure
time of 35 minutes (17,22) is reachable, after a learning curve of probably 30-40
cases.
The expected morbidity after MRGB are more or less comparable to random
TRUSGB, which are hematospermia (for about 4 weeks after the procedure),
hematuria (for about a week after the procedure), and anal bleeding (one or
two days after the procedure). Sporadically sepsis can develop (<1%). Even
though it is conceivable that MRGB will have less complications due to the lower
number of cores taken per patient, no studies report on the comparison of MRGB
and TRUSGB complications.
Chapter 6
Figure 2: Biopsy device for patient positioning (Invivo, Schwerin, Germany).
105
MRGB Book Chapter
Figure 3: Biopsy device for patient positioning (Hologic, Toronto, Canada). Photo courtesy of Hologic,
Inc. © 2011. All rights reserved.
106
Figure 4: Patient lying in prone position with biopsy device and needle guider inserted rectally.
a
b
Figure 5: During a second session, a MR-guided biopsy was performed of the cancer suspicious area
depicted at figure 1. The needle guider was pointed towards the cancer suspicious region in axial (a)
and sagittal plane (b) and subsequently biopsied. Verification images with the needle guider left in situ
was obtained. Histopathology revealed a Gleason 4+4 prostate cancer.
Robotics
MRGB as described above is a manual procedure where the needle guider
movements have to be adjusted by hand. Since access within the closed bore
MR scanner is limited for manual manipulation of instruments, every adjustment
requires the patient to be moved in and out of the scanner. As a consequence a
great amount of time is spent on instrument adjustment. Robotics or manipulators
can be very practical in such situations. However, designing a MR-compatible
robot which can be used in the restricted space and environment of the MR scanner
is a very challenging task. Several demanding issues have to be considered, such
as selecting MR-compatible materials, constructing MR-compatible actuators
and position sensors, and designing a robot to image registration system that
allows guidance of the robot based on MR image feedback (31).
bore systems for prostatic interventions have been investigated. Most of these
studies have focused on transperineal needle or brachytherapy seed placement
(25-27). Two studies reported on the feasibility of MRGB with the aid of robotics
(32,33). One of these studies examined the transgluteal approach in biopsying
suspicious prostate lesions (32). The other study used the transrectal approach
(without the use of anaesthesia) where manipulation time of moving the needle
are promising and the use of robotics in MRGB may eventually lead to lesser
biopsy procedure time and higher target accuracies. Nevertheless, with only 4
studies reporting on this subject, there is still more research necessary in order to
proof the utility of robotics in MRGB.
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MRGB Book Chapter
guide from CSR to CSR had a median of 2.5 minutes (33). These preliminary results
Chapter 6
At the moment there are only 3 sites where MR-compatible robotics in closed
Discussion
The detection rates for MRGB after previous negative TRUSGB sessions range
between 38-59% (18-23) (Table 1). These rates are higher compared to repeat
TRUSGB, which has a detection rate of maximally 22% in a second session (2,3).
Also noteworthy in Table 1, is the general trend towards higher detection rates
in multi-parametric MR imaging preceded MRGB compared to only anatomical
T2-w MR imaging preceded MRGB.
MRGB has the advantage of being a targeted procedure, directed by the
preceding diagnostic MR session with promising localization performance. Also
the excellent soft tissue contrast during the biopsy itself is a major advantage of
this technique. The use of multi-parametric MR imaging in PCa management
could prevent patients from undergoing unnecessary biopsies and consequently
avoid unnecessary treatment delay. The lack of standard protocols for MR
imaging of the prostate is an important issue, however it is still the best available
imaging technique in PCa localization, determining aggressiveness and tumour
108
volume. Another advantage of multi-parametric MRI is the low sensitivity for low
grade and/or low volume disease, therefore potentially only detecting clinically
significant disease. As more studies concerning multi-parametric MR imaging
in PCa will follow, it will only be a matter of time till standardized protocols will
be developed. Another major argument of opponents of MR imaging in the
management of PCa is the supposedly high costs involved. Of interesting note,
the costs involving saturation biopsy has been an estimated $5000 more than
standard TRUS biopsy (6).
TRUSGB is more available worldwide compared to MRGB. The information
obtained from the diagnostic MR session could be used to direct TRUSGB. This
information can be visually transferred to the TRUS images. It is conceivable
that this method will suffer a great deal from spatial misregistration. To reduce
this misregistration fusion algorithms are currently developed. Currently, MR
localization information can also be fused with the help of commercially
available software packages with TRUS images (34), which is a work in progress.
Concerning target accuracies it is imaginable that MRGB will suffer the least
from spatial misregistration because the same two techniques are being used
for localization and biopsy. However, there are no studies comparing target
accuracies between TRUS-MR imaging fusion and MRGB.
Furthermore, robotics will most likely play a larger future role in MRGB and
interventions. However, there is still more research necessary in order to define
the optimal technique. Future studies should concentrate on determining what
the most accurate, fastest, and cost-effective technique is.
In conclusion, MRGB has a high PCa detection rate in patients with previous
negative TRUSGB sessions. For this reason MRGB and/or TRUS-MR fusion guided
biopsy will probably become more and more available in daily practice. For the
optimal biopsy technique there is still more research necessary. Robotics may
optimize MRGB regarding target accuracies and procedure time.
Chapter 6
109
MRGB Book Chapter
References
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Presti JC Jr, O’Dowd GJ, Miller MC, Mattu R, Veltri RW. Extended peripheral zone biopsy schemes
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Stewart CS, Leibovich BC, Weaver AL, Lieber MM. Prostate cancer diagnosis using a saturation
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Futterer JJ, Heijmink SWTPJ, Scheenen TWJ et al. Prostate cancer localization with Dynamic contrastenhanced MR imaging and Proton MR spectroscopic imaging. Radiology 2006;241:449-458.
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Hambrock T, Somford DM, Huisman HJ et al. Relationship between apparent diffusion
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Villers A, Puech P, Mouton D, Leroy X, Ballereau C, Lemaitre L. Dynamic contrast enhanced,
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Coakley FV, Kurhanewicz J, Lu Y et al. Prostate cancer tumor volume: measurement with
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Mazaheri Y, Hricak H, Fine SW et al. Prostate tumor volume measurement with combined T2weighted imaging and diffusion-weighted MR: Correlation with pathologic tumor volume.
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Hambrock T, Somford DM, Hoeks C, et al. Magnetic resonance imaging guided prostate
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Beyersdorff D, Winkel A, Hamm B, Lenk S, Loening SA, Taupitz M. MR imaging-guided prostate
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Anastasiadis AG, Lichy MP, Nagele U, et al. MRI-guided biopsy of the prostate increases
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Hambrock T, Futterer JJ, Huisman HJ, et al. Thirty-two-channel coil 3T magnetic resonance-
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Franiel T, Stephan C, Erbersdobler A, Dietz E et al. Areas suspicious for prostate cancer: MRguided biopsy in patients with at least one transrectal US-guided biopsy with a negative finding-multiparametric MR imaging for detection and biopsy planning. Radiology 2011;259:162-172.
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Yakar D, Hambrock T, Huisman H et al. Feasibility of 3T Dynamic Contrast-Enhanced Magnetic
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26.
Fischer GS, Iordachita I, Csoma C et al. MRI-compatible pneumatic robot for transperineal
prostate needle placement. IEEE/ASME Transactions on Mechatronics 2008;13:295-305.
111
MRGB Book Chapter
guided biopsies of prostate tumor suspicious regions identified on multimodality 3T magnetic
Chapter 6
biopsy with a closed MR unit at 1.5 T: initial results. Radiology 2005;234:576-581.
19.
27.
van den Bosch MR, Moman MR, van VM et al. MRI-guided robotic system for transperineal
prostate interventions: proof of principle. Phys Med Biol 2010;55:N133-N140.
28.
Hara R, Jo Y, Fujii T, et al. Optimal approach for prostate cancer detection as initial biopsy:
prospective randomized study comparing transperineal versus transrectal systematic 12-core
biopsy. Urology 2008;71:191-195.
29.
Ingber MS, Ibrahim I, Turzewski C, Hollander JB, Diokno AC. Does periprostatic block reduce pain
during transrectal prostate biopsy? A randomized, placebo-controlled, double-blinded study.
Int Urol Nephrol 2010; 42:23-27.
30.
Miller J, Perumalla C, Heap G. Complications of transrectal versus transperineal prostate biopsy.
ANZ J Surg 2005;75:48-50.
31.
Fütterer JJ, Misra S, Macura KJ. MRI of the prostate: potential role of robots. Imaging Med
2010;2:583-592.
32.
Zangos S, Melzer A, Eichler K. MR-compatible assistance system for biopsy in a high-field-strength
system: initial results in patients with suspicious prostate lesions. Radiology 2011;259:903-10.
33.
Yakar D, Schouten MG, Bosboom DG, Barentsz JO, Scheenen TW, Fütterer JJ. Feasibility of a
Pneumatically Actuated MR-compatible Robot for Transrectal Prostate Biopsy Guidance.
Radiology 2011;260:241-247.
34.
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Singh AK, Kruecker J, Xu S et al. Initial clinical experience with real-time transrectal ultrasonographymagnetic resonance imaging fusion-guided prostate biopsy. BJU Int 2008;101:841-845.
Radiology. 2011;260:241-247
7
Feasibility of a Pneumatically
Actuated MR-compatible Robot
for Transrectal Prostate Biopsy
Guidance
Yakar D
Schouten MG
Bosboom DG
Barentsz JO
Scheenen TW
Fütterer JJ
Abstract
Purpose
To assess the feasibility of using a remote-controlled, pneumatically actuated
magnetic resonance (MR)-compatible robotic device to aid transrectal biopsy
of the prostate performed with real-time 3-T MR imaging guidance.
Materials and Methods
This prospective study was approved by the ethics review board, and written
informed consent was obtained from all patients. Twelve consecutive men
who were clinically suspected of having prostate cancer and had a history of
at least one transrectal ultrasonography guided prostate biopsy with negative
results underwent diagnostic multi-parametric MR imaging of the prostate. Two
radiologists in consensus identified cancer-suspicious regions (CSRs) in 10 patients.
These regions were subsequently targeted with the robot for MR imaging–guided
prostate biopsy. To direct the needle guide toward the CSRs, the MR-compatible
116
robotic device was remote controlled at the MR console by means of a controller
and a graphical user interface for real-time MR imaging guidance of the needle
guide. The ability to reach the CSRs with the robot for biopsy was analyzed.
Results
A total of 17 CSRs were detected in 10 patients at the diagnostic MR examinations.
These regions were targeted for MR imaging–guided robot-assisted prostate
biopsy. Thirteen (76%) of the 17 CSRs could be reached with the robot for biopsy.
Biopsy of the remaining four CSRs was performed without use of the robot.
Conclusion
It is feasible to perform transrectal prostate biopsy with real-time 3-T MR imaging
guidance with the aid of a remote-controlled, pneumatically actuated MRcompatible robotic device.
Introduction
In patients clinically suspected of having prostate cancer—that is, those with
suspicious digital rectal examination findings and/or an elevated prostate
specific antigen level—transrectal ultrasonography (US)–guided prostate biopsy
is recommended (1). Transverse US–guided biopsy, despite the systematic course
of sampling involved, reportedly has relatively low sensitivity (33%–44%) and a
considerably high false negative result rate (23%) (2–4). Thus, persistent suspicion
of prostate cancer after repeated transverse US–guided biopsies with negative
results is common (5,6) and can create emotionally stressful situations. Physicians
and patients are faced with the dilemma of determining whether they are
dealing with missed cancer or benign disease.
biopsy of the prostate has been proposed. Some promising results, including high
tumour detection rates and a minimal number of biopsy core specimens per
patient, have been published (7–9). A major advantage of MR imaging–guided
biopsy is the use of diagnostic MR imaging, which not only yields excellent
soft-tissue contrast to localize cancer-suspicious regions (CSRs) but also can
help guide the intervention. MR imaging is considered a reliable technique for
Performing multi-parametric MR imaging, the preferred approach, involves
obtaining T2-weighted, diffusion-weighted, MR spectroscopic, and dynamic
contrast material–enhanced images (10–16).
The use of robotics during an MR imaging–guided intervention can be very
helpful. Robot use has been investigated for neurosurgical applications (17,18)
and prostatic interventions such as needle and seed placement in brachytherapy
(19–21). For MR imaging–guided prostate biopsy procedures, which are typically
performed with a manually adjustable device (22), robotics can be valuable for
aligning the needle guide with the target area. The majority of the procedure
time in MR imaging–guided prostate biopsy is spent repeatedly moving the
patient in and out of the MR unit for device manipulation to facilitate correct
alignment of the needle guide with the CSR.
In contrast to the investigators in the aforementioned studies of robotassisted transperineal prostatic interventions (19–21), we used the transrectal
approach for prostate biopsy in the current study. For biopsy in particular, this
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Robot for MRGB
localizing prostate cancer and is now being performed in many institutions.
Chapter 7
For these reasons, lesion-directed magnetic resonance (MR) imaging–guided
approach might be more advantageous because of the possibility to perform
biopsy without the need for anaesthetics. In a recently published randomized
placebo-controlled, double- blind study, the investigators concluded that the
pain involved in transrectal US–guided biopsy of the prostate is well tolerated,
without the need for anaesthesia (23). Furthermore, when the transrectal and
transperineal approaches were compared (in 246 patients) in a randomized
controlled trial, no significant differences in complication rates were found (24).
The purpose of this study was to assess the feasibility of using a remote-controlled,
pneumatically actuated MR-compatible robotic device as an aid in performing
transrectal biopsy of the prostate with real-time 3-T MR imaging guidance.
Materials and Methods
Patients
This prospective study was approved by the ethics review board of our
118
institution, and written informed consent was obtained from all patients. From
September 2009 to March 2010, 12 patients with a prostate-specific antigen
level of 4 ng/mL or higher and a history of at least one transverse US–guided
prostate biopsy procedure with negative results were referred for diagnostic
multi-parametric MR examination of the prostate. Ten of these patients, who
had CSRs, were prospectively enrolled in our study. In a second MR examination,
the CSRs were targeted with an in-house–developed MR-compatible robot
(Bosboom Engineering, Vriezenveen, the Netherlands) that was used as an aid
in performing MR imaging– guided prostate biopsy. The exclusion criteria were
contraindications to MR imaging (e.g., cardiac pacemakers, intracranial clips).
Diagnostic MR Imaging
MR imaging of the prostate was performed by using a 3-T MR system (Siemens
Trio Tim; Siemens Healthcare, Erlangen, Germany) and a pelvic phased-array
coil. Peristalsis was suppressed by means of intravenous injection of 20 mg of
butylscopolamine
bromide
(Buscopan;
Boehringer-Ingelheim,
Ingelheim,
Germany) and 1 mg of glucagon (Glucagen; Nordisk, Gentofte, Denmark).
The diagnostic MR examination took 17 minutes and included the following
sequences: T2-weighted turbo spin-echo imaging was performed by using 3070–
4010/104–107 (repetition time msec/echo time msec), a flip angle of 120°, a
section thickness of 3–4 mm, an echo train length of 15, a field of view of (180–256)
x (180–222) mm, and a matrix of (320–448) x (320–448) in the sagittal, coronal, and
axial planes. Axial diffusion-weighted imaging was performed by using 2300/61, a
section thickness of 4 mm, a field of view of 256 x 216 mm, a matrix of 128 x 128,
and b values of 50, 500, and 800 sec/mm 2 with construction of apparent diffusion
coefficient maps. Before the administration of contrast material (gadoterate
meglumine, Dotarem; Guerbet, Paris, France), a three-dimensional proton
density– weighted sequence was performed by using 800/1.47, a flip angle of 8°,
a section thickness of 4 mm, a field of view of 230 x 230, and a matrix of 128 x 128.
After the intravenous bolus injection of 15 mL of gadoterate meglumine, dynamic
contrast-enhanced MR imaging was performed by using a three-dimensional T1following parameters: 32/1.47, a flip angle of 10°, a section thickness of 4 mm, a
field of view of 230 x 230 mm, and a matrix of 128 x 128, with 35 measurements
performed in 2 minutes 43 seconds.
MR Data Analysis
Two radiologists (J.O.B., J.J.F., 16 and 6 years of experience, respectively,
results were interpreted at an analytical software workstation, where dynamic
contrast-enhanced
MR
imaging–derived
pharmacokinetic
parameters
were calculated by using the standard two compartment model (25) and
the reference tissue method for arterial input function estimation (26) and
diffusion weighted imaging–derived apparent diffusion coefficient maps were
calculated with the mono-exponential decay fit to the signal versus b value.
Both the pharmacokinetic parameters and the apparent diffusion coefficient
maps were projected as colour maps overlaid on the T2-weighted MR images.
A CSR was defined as such when abnormal findings were present on at least
one of the following images: on T2-weighted images a relatively low signalintensity region, on the dynamic contrast-enhanced volume transfer constant
map and/or washout map a focally enhancing region, and on the diffusion
weighted imaging apparent diffusion coefficient map a focally low-signal
intensity region in combination with a high-signal-intensity region on the image
obtained with a b value of 800 sec/mm 2. For each CSR, the location was
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Robot for MRGB
reading prostate MR images) in consensus identified the CSRs. All MR imaging
Chapter 7
weighted spoiled gradient-echo sequence with equal spatial resolution and the
annotated by using three-dimensional spatial position estimation. For these
annotations, the prostate was divided into 22 axial and sagittal segments on
the T2-weighted images (22). This information was used to relocate the CSRs
during the biopsy procedure.
MR-Compatible Robotic System
The robotic system was developed in house and de novo. The robot was
designed to function with the patient in any standard closed-bore clinical MR
system. The entire device was constructed of MR-compatible (i.e., nonmagnetic
and nonconductive) materials to prevent MR image artefacts due to distortion of
the magnetic field and to ensure patient safety. The robotic system consisted of
the robot itself (Figure 1, d) and a controller unit (comprising a computer, motion
control elements, and electropneumatic and electronic interfaces) located
outside the MR radiofrequency shield. Compressed air for the pneumatic motors
that was generated in a compressor outside the MR imaging room was delivered
to the robot through plastic tubes. Therefore, no electricity was required inside
120
the MR imaging room. Clicking on the corresponding arrow required to prompt a
certain movement initiated motion of the needle guide: The corresponding valve
was opened and generated a wave of pressure to the corresponding motor. On
a separate screen, a graphical user interface IFE enabled real-time MR image
monitoring of the intervention.
The robotic system enables positioning of the needle guide with five degrees
of freedom, with translations in three directions (anterior-posterior, inferiorsuperior, and lateral) and rotations in two directions (inferior-superior and lateral).
The angle of the needle guide in relation to the main magnetic field could range
from 30° to 55° in the inferior- superior direction and plus or minus 26° in the lateral
direction (27). To ensure patient safety and meet standard safety requirements for
use in a medical environment, the needle guide had a built-in mechanical safety
mechanism consisting of a suction cup. Only a maximal set amount of force was
allowed to be exerted on the patient, after which the safety mechanism was
released (27).
Biopsy Procedure
During the second part of the MR examination, with the patient in the closedbore 3-T MR system, the CSRs were targeted with the robot by using a transrectal
approach. One radiologist (D.Y.) operated the robotic device; however, either
two radiologists or a radiologist and a technician were required to position the
patient and set up the system. All patients received 1000 mg of ciprofloxacin
(Ciproxin; Bayer, Leverkusen, Germany) orally the evening before the biopsy, the
morning of the biopsy, and 6 hours after the procedure.
Biopsy was performed with the patient in the prone position and the needle
guide (Invivo, Schwerin, Germany) inserted rectally. The needle guide was
attached to the arm of the robotic device (Figure 2). A pelvic phased-array coil
was placed on the buttocks of the patient. To relocate the annotated CSR, a
sagittal T2-weighted half-Fourier single shot turbo spin-echo image (2180/116, 120°
flip angle, 6-mm section thickness, echo train length of 15, 350 3 317-mm field of
view, matrix of 256 x 205, imaging time of 31 seconds) and a coronal T2-weighted
train length of 15, 256 x 252-mm field of view, matrix of 256 x 256, imaging time of
3 minutes) were acquired. The coronal T2-weighted turbo spin-echo sequence
was used to select the section that corresponded to the exact location of the
CSR, which was subsequently exported to the IFE monitor. In addition, a real-time
true fast imaging with steady-state precession sequence (894/2.3, 60° flip angle,
5-mm section thickness, 300 x 300-mm field of view, 192 x 192 matrix, imaging time
performed repeatedly in the coronal, sagittal, and axial planes. These images
were exported to the IFE monitor in real time for visualization of the movement
of the needle guide. The robot controller, located on a separate computer
next to the IFE monitor, was used to remotely change the position of the needle
guide. After the needle guide was correctly aligned with the targeted CSR, a
T2-weighted true fast imaging with steady-state precession image (4.48/2.24, 70°
flip angle, 3-mm section thickness, 228 x 228-mm field of view, 228 x 228 matrix,
imaging time of 11 seconds) was acquired in the axial direction, from behind the
MR console, to measure the biopsy depth (Figure 1).
Finally , the actual biopsy procedure was performed manually. For this, the
patient had to be removed from the bore, and an MR-compatible, 18-gauge fully
automatic core-needle double-shot biopsy gun (Invivo) with a needle length of 175
mm and a tissue core sampling length of 17 mm was used. After the biopsy, the
patient had to be moved back into the bore, with the needle left in situ. Another T2weighted true fast imaging with steady-state precession image was then obtained
121
Robot for MRGB
of 0.9 second per plane [total imaging time for all three planes, 2.7 seconds]) was
Chapter 7
turbo spin-echo image (3540/102, 120° f lip angle, 4-mm section thickness, echo
to verify the position of the needle relative to the desired CSR. All biopsies were
performed by one radiologist (D.Y.) with 1½ years of experience performing manual
MR imaging– guided biopsy of the prostate. After verification of the needle position
relative to the desired CSR and with the needle still in situ, the number of biopsy
samples per CSR was determined on the basis of the certainty of the correct needle
positioning. For each patient, the setup time (including robot setup and patient
positioning), the time from movement of the needle guide from one CSR to another
CSR, and the duration of the entire biopsy procedure were noted.
Histopathologic Analysis
The biopsy samples were subsequently processed. They were routinely fixed in
10% buffered formalin, embedded in paraffin, and stained with hematoxylineosin
before being evaluated for the presence of prostate cancer or benign
abnormalities. All biopsy samples that were positive for prostate cancer were
assigned a Gleason score.
122
d
a
c
b
Figure 1: Robotic system setup, including MR console, interactive front end (IFE) monitor, robot software
controller, and robotic device itself. After patient positioning in MR unit, imaging is started from the
console (a) , and the image is sent to the IFE monitor (b), where, on the basis of the real-time image
fi ndings, the needle guide is adjusted and directed toward the CSR by using the controller (c). This
eventually results in motion of the robot (d).
system.
Results
(Figures 3, 4) in 10 patients. A median of 1.5 CSRs (range, 1–2) per patient were
identified, a median of two biopsy samples per CSR were taken (range, 1–3), and
a median of three biopsy samples (range 1–5) per patient were obtained. Four
CSRs, two of which were in the same patient, were not reachable with the robot
for biopsy: One patient who had two CSRs, in the apex and in the base of the
prostate, was not positioned correctly; he was positioned outside the pivoting
point of the needle guide, and this resulted in a limited range of movements of
the needle guide in the rectum. The remaining two CSRs, in two patients, were
located in the apex of the prostate gland. To reach these apical regions, the
robot had to rotate the needle guide more caudally in the sagittal plane, and
this could be achieved only by means of cranial movement of the angulation
rail. However, cranial movement of the angulation rail was restricted by the size
of the magnet bore (60 cm).
Ultimately, four of the 17 CSRs, in one of the 10 patients, were manually
123
Robot for MRGB
Patient characteristics are listed in the Table. A total of 17 CSRs were identified
Chapter 7
Figure 2: Rectal insertion of needle guide attached to robot, after patient is positioned prone in the MR
sampled without use of the robot and thus were excluded from further analysis in
this study. There were no complications related to the prostate biopsy procedure
in terms of bleeding, infection, sepsis, or other medical conditions.
Procedure Time
The entire biopsy procedure was completed within a median time of 76.5 minutes
(range, 45–105 minutes). This was exclusive of the median setup time (e.g., for
robot setup, patient positioning), which took an average of 15 minutes (range,
10–20 minutes) per patient. The median time for movement of the needle guide
from CSR to CSR was 2.5 minutes (range, 1–5 minutes).
Table 1
Patient Characteristics
Characteristic
Datum (range)
Total number of patients
9
Median age (y)
69 (59-72)
Median number of negative TRUS guided biopsy
3 (1-4)
procedures per patient
124
Median PSA (ng/mL)
19.5 (10-26)
Median time between diagnostic MRI and robot MR-
53 (14-119)
guided biopsy (days)
TRUS = transrectal ultrasound, PSA = prostate specific antigen
Histopathologic Findings
On a patient-by-patient level, five (56%) of nine patients received a diagnosis
of prostate cancer. On a CSR-by-CSR level, six of 13 CSRs contained prostate
cancer (Gleason scores: 3 + 3, 3 + 3, 3 + 4, 3 + 4, 3 + 5, and 4 + 4), and all of them
were located in the ventral aspect of the prostate. Three of 13 CSRs contained
prostatitis; two, hyperplasia; and two, high-grade prostatic intraepithelial
neoplasia.
a
b
c
Figure 3: Multi-parametric MR imaging in axial plane performed in 59-year-old man with prostatespecific antigen level of 10 ng/mL and history of three negative-result transrectal US–guided prostate
biopsy procedures. (a) T2-weighted image, (b) diffusion-weighted imaging–derived\apparent diffusion
coefficient map, and (c) dynamic contrast-enhanced volume transfer constant image. Outlined areas
are suspected to be malignancy and were targeted by the robot for biopsy.
Chapter 7
125
a
b
c
controller consists of multiple arrows corresponding to directions of potential needle guide movements.
In this example, needle guide is moved to left by selecting arrow corresponding to this direction
(highlighted in blue). (c) Confirmation axial MR image was obtained with biopsy needle in situ to verify
position of needle (dashed red line) relative to desired CSR (dashed yellow oval). Histopathologic
analysis revealed prostate cancer with Gleason score of 3 + 4.
Robot for MRGB
Figure 4: Magnified views of (a) real-time axial MR image on the IFE and (b) robot controller. To align
needle guide with suspicious region (depicted in Figure 3), needle has to be adjusted to left. (b) Software
Discussion
In this study, we demonstrated the feasibility of adjusting the movement of the
needle guide remotely throughout a transrectal prostate biopsy procedure.
Although the detection rate is not a crucial issue in feasibility studies, our cancer
detection rate was 56% in patients with CSRs, which is in concordance with the
results reported in other lesion-directed MR imaging–guided prostate biopsy studies
(7–9). In our study, the median remote-controlled manipulation time for moving the
needle guide from CSR to CSR was 2.5 minutes (range, 1–5 minutes).
Other study investigators have reported on MR imaging–guided robotic
systems for prostate interventions in closed-bore systems (19–21). Muntener
et al described a proof of principle for a fully automated robotic device for
transperineal brachytherapy seed placement in dogs (19). van den Bosch et al
recently conducted a proof of principle study, in which they used automated
transperineal seed placement in one patient (21). In these studies, the perineum
was used for seed placement during brachytherapy; this is a more desirable
126
approach for increasing the therapeutic ratio in brachytherapy. For prostate
biopsy, however, the transrectal approach is more favorable because it facilitates
the possibility to perform biopsy without using anesthetics and increasing patient
discomfort and complications (23,24). In addition, because using the transperineal
approach requires a longer distance to the prostate than does the transrectal
approach, errors due to needle deflection (28) and small deviations during the
needle insertion may become more pronounced at farther distances from the
insertion point, potentially decreasing biopsy accuracy. Our robotic system was
specifically designed for prostate biopsy and consists of an automated needle
guide manipulation mechanism, whereas the transrectal biopsy itself had to be
performed manually by the radiologist.
For practical reasons, because transverse US–guided prostate biopsy is far more
accessible worldwide in terms of availability and skill in performing the procedure,
the prostate cancer localization information attained with multi-parametric MR
imaging can be used to direct transverse US–guided biopsies. However, visually
converting the localization information acquired with MR imaging to gray-scale
US data is associated with many difficulties—most likely at the expense of target
accuracies. A solution could be automated transverse US–MR imaging fusion.
Some preliminary published results with this technique have been promising
(29,30); however, more research with larger study populations is needed to
demonstrate its clinical value. In terms of target accuracies, it is conceivable that
MR imaging–guided biopsy eventually will be the least adversely affected by
spatial misregistration because the same two techniques are used for localization
and biopsy. Yet comparisons of target accuracy among the different biopsy
techniques, such as transverse US–MR imaging fusion– guided biopsy versus MR
imaging–guided biopsy, are lacking.
Our study had a number of limitations. The robotic device that we used in this
preliminary study had restrictions related to the limited range and the size of the
robot. Biopsies performed in patients positioned outside the pivoting point of the
needle guide were not feasible with the robot.
Also, owing to the size of the robot, some geometric limitations were
unreachable for biopsy. We also encountered some delays due to system
integration issues. The image data were exported to the IFE monitor in the procedure
room. However, a number of required tasks—for example, measurement for biopsy
depth planning and verification of the needle position after biopsy—were possible
from behind the MR console only. As a result, the operator had to repeatedly
switch between the MR console and the IFE monitor during the procedure. We
minutes. In addition, target volumes were not calculated during the localization of
the CSRs on the diagnostic MR images. As a result, we were unable to determine if
the target volumes influenced the ability to successfully target these CSRs.
In future studies, after further optimizations of the robot (with a larger range of
motion and a reduced robot size) and the system setup, investigation of biopsy
accuracy and decreasing the biopsy procedure time seem to be the next logical
steps. After a few adjustments, the robot may also be used in studies to investigate
emerging treatments such as focal cryosurgery (31) and laser ablation (32) because
it was designed to interact with a patient inside any standard closed-bore clinical
MR system. These therapies might benefit considerably from the superior softtissue contrast and temperature mapping ability (33) provided with MR imaging
for guiding intervention. In conclusion, it is feasible to perform transrectal prostate
biopsy with real-time 3-T MR imaging guidance by using a remote-controlled,
pneumatically actuated MR-compatible robotic device as an aid.
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Robot for MRGB
believe that these factors increased the procedure time by as much as 30–40
Chapter 7
encountered—specifically, some targets at the apex of the prostate were
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Schouten MG , Ansems J , Renema JK , Bosboom D , Scheenen TW , Fütterer JJ. The accuracy
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Robot for MRGB
study. Int Urol Nephrol 2010;42:23-27.
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prostate needle placement. IEEE/ ASME Trans Mechatron 2008;13:295-305.
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Singh AK , Kruecker J , Xu S , et al. Initial clinical experience with real-time transrectal
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Lambert EH , Bolte K , Masson P , Katz AE. Focal cryosurgery: encouraging health outcomes for
unifocal prostate cancer. Urology 2007;69:1117-1120.
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Lindner U , Lawrentschuk N , Weersink RA , et al. Focal laser ablation for prostate cancer
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130
Rieke V , Butts Pauly K. MR thermometry. J Magn Reson Imaging 2008;27:376-390.
Accepted with revision; Radiology 2012
8
MR-guided focal cryoablation in
recurrent prostate cancer patients
Bomers JG
Yakar D
Sedelaar JPM
Vergunst H
Barentsz JO
de Lange F
Fütterer JJ
Abstract
Purpose
The objective of this study was to assess the feasibility of magnetic resonance
(MR)-guided focal cryoablation at 1.5 Tesla (T) in patients with locally recurrent
prostate cancer (PCa) after initial radiotherapy.
Materials and Methods
The need of informed consent was waived by the Institutional Review Board.
Ten consecutive patients with histopathologically proven locally recurrent PCa
without evidence for distant metastases were treated with cryoablation under
general anaesthesia in a 1.5T MR scanner. A urethral-warmer was inserted and
a transperineal template was placed against the perineum. Cryoneedles were
inserted under real-time MR imaging. After correct placement of the needles, a
rectal warmer was inserted. Iceball growth was continuously monitored under MR
image guidance. Two freeze-thaw cycles were performed. Follow-up consisted
134
of PSA-level measurement every three months and a multi-parametric MRI (MPMRI) after 3 and 6 months. Potential complications were recorded.
Results
All patients were successfully treated with MR-guided focal cryoablation. In
one patient the urethral-warmer could not be inserted and the procedure was
cancelled. Two months later the patient was successfully treated. No other
complications were recorded.
Follow-up is known for the first 6 patients. After three months, PSA levels of all
patients had decreased and MP-MRI showed no signs of tumour recurrence.
After six months, one patient had a local recurrence and was retreated with MRguided cryoablation.
Conclusion
Transperineal MR-guided focal cryoablation of recurrent PCa after radiotherapy
is feasible and safe. Initial results are promising, however longer follow-up is
needed and more patients have to be included.
Introduction
Prostate cancer (PCa) is the most common form of cancer in the western male
population and has a significant socio-economic impact (1). Around 25–33%
of newly diagnosed PCa patients undergo a form of radiotherapy. Of these
patients 26–52% develop biochemical signs of tumour recurrence within 5 years
after treatment (2-4). After radiotherapy recurrence salvage prostatectomy is
a frequently used therapy option. However, high rates of incontinence (0-67%)
or rectal injury (0–8%) (5;6) have led to the search for other salvage treatment
options. For this reason, ablative techniques such as cryoablation, high intensity
focused ultrasound, and photodynamic therapy have been developed.
Cryoablation, performed under transrectal ultrasound (TRUS)-guidance is
recurrent PCa (7). A large study describing the results of salvage TRUS-guided
cryoablation in 279 patients, reported an incontinence rate of 10.2%, and a rectourethral fistula rate of 1.1% (8). Other studies, concerning cryoablation under TRUS
guidance, have described comparable results (9-11).
Furthermore, cryoablation has the ability to be used for focal therapy purposes.
To our knowledge, only one study described TRUS-guided salvage hemi-ablation
However, to be able to perform focal therapy, accurate and adequate image
guidance is a prerequisite. TRUS is unable to provide accurate PCa localization
and has major limitations in monitoring the iceball during cryoablation due to
acoustic shadowing. Multi-parametric magnetic resonance imaging (MPMRI), comprising of T2-weighted, dynamic contrast enhanced, and diffusion
weighted imaging is currently the best technique available for PCa localization.
For detection and localization of PCa with MP-MRI, area’s under the curve of
respectively 0.94–0.98 (13-15) and 0.71–0.95 (16-19) have been reported. During
cryoablation, MR image guidance enables accurate lesion targeting as well
as three-dimensional monitoring of iceball growth, such that the PCa is treated
completely and nearby critical structures are kept within a safe distance from the
ice formation (20).
Nonetheless, MR-guided prostate cryoablation is very uncommon. Two studies
described the first results of whole gland MR-guided cryoablation in patients with
respectively newly diagnosed PCa or local recurrence after radiotherapy or
135
MR guided focal cryo-ablation
of the prostate (12).
Chapter 8
an established treatment option for both men with newly diagnosed as well as
radical prostatectomy (21;22).
In contrast to the aforementioned studies which performed whole gland MRguided cryoablation, this study describes initial results in focal MR-guided salvage
cryoablation. To our knowledge this is the first study to describe this. The purpose of
this study was to assess the technical feasibility of MR-guided focal cryoablation
at 1.5T in patients with locally recurrent PCa after initial radiotherapy.
Materials and Methods
Preoperative Evaluation and Selection
From May 2011 to February 2012, 10 consecutive patients (median age, 67
years; range, 52-76) with histopathologically proven PCa recurrence after initial
radiotherapy and one patient with primary PCa were enrolled in this prospective
study. All patients underwent a MP-MRI examination (3T MAGNETOM Skyra,
Siemens, Erlangen, Germany) with the use of a pelvic phased-array coil to
136
localize recurrent cancer (Figure 1) and to exclude bone- and node metastases.
The need for informed consent was waived by the Institutional Review Board.
a
b
c
Figure 1: Multi-parametric MRI Pre cryoablation. From left to right; Axial T2-weighted image of the
prostate, axial ADC map, axial Dynamic Contrast-Enhanced MR image. Arrows pointing at the recurrent
tumour.
MR-guided cryoablation
All patients were admitted in the hospital on the night before the cryoablation.
Patients were prescribed antibiotics prophylaxis (CIPROXIN, Bayer, Leverkusen,
Germany) for fourteen days, starting on the day before the cryoablation. Prior
to the cryoablation they were instructed to give a self-administered cleansing
enema to eliminate gas and remove faeces.
All patients were treated under general anaesthesia. After patients were
anaesthetized a catheter was inserted in the urethra, which was later during
the procedure exchanged for a urethral warmer. Patients were positioned in
a lithotomy position on the scanner table and cushions were used to maintain
proper positioning and to make the patient as comfortable as possible. A pelvic
phased array coil was placed over the patient’s pelvis. All procedures were
performed by one interventional radiologist (JJF) using the MRI SeedNet System
(Galil Medical, Yokneam, Israel) in a closed bore 1.5T MR system (MAGNETOM
Avanto, Siemens, Erlangen, Germany). All image parameters of the used
sequences are described in Table 1.
A transperineal template, attached to a flexible arm (Invivo, Schwerin,
Germany) was placed against the perineum of the patient. The template was
moistened with sterile gel at forehand to improve its visibility on the MR images.
were acquired to re-localize the recurrent tumour and the transperineal grid.
Cryoneedles (IceSeed and/or IceRod, Galil Medical, Yokneam, Israel) were
transperineally inserted in the tumour using real-time balanced steady-state free
precession sequences which were projected onto a white screen in the MR room.
Images were obtained in at least two directions to get an accurate impression
of the needle position. After placement of all cryoneedles a rectal warmer was
(43° Celsius) to protect the urethra and the rectal wall from freezing. The number
and type of inserted cryoneedles was dependent on the size of the recurrent
tumour, determined on the MP-MRI obtained during preoperative evaluation.
Both needle types have distinct freezing characteristics. After ten minutes freezing
the lethal zone of the IceSeed and IceRod are respectively 1x2 cm and 1.5x4 cm.
Iceball growth was continuously monitored using near real-time T1-weighted
volumetric interpolated gradient echo MR imaging (Figure 2). The size and
shape of the iceball were regulated by adjusting the gas flow to each individual
cryoneedle. The iceball had to cover the total lesion with a definite safety margin.
This safety margin was limited by avoiding contact of the iceball with the rectal
wall. In total two freezing cycles were performed. Each freezing period lasted
10 minutes, or as long as the iceball remained within a safe distance from the
critical structures. This safety distance was determined by carefully monitoring the
position of the hyper intense iceball rim. Active or passive thawing was continued
until the cryoneedles were visible again on the MR images.
137
MR guided focal cryo-ablation
inserted in the rectum. Both warmers were continuously flushed with warm saline
Chapter 8
Next, for cryoneedle placement, T2-weighted images in three directions
After the second thawing period the cryoneedles were removed. The urethral
warmer was flushed with warm saline for another 20-30 minutes to avoid strictures.
Warming catheters were removed and another catheter was inserted in the
urethra to avoid any temporary urinary incontinence or retention. This catheter
could be removed after one or two days. Patients were asked to score potential
pain according the Numeric Rating Scale (NRS) when they were back on the
nursing ward. When no complications occurred, patients were discharged the
day after the procedure. Patients were prescribed movicolon (Norgine, Uxbridge,
UK) for 3 weeks to ease defecation and were advised to drink a substantial
amount of water in order to rinse the bladder. Follow-up consisted of a MP-MRI of
the prostate (Figure 3) and a visit to the urologist after 3 and 6 months, to check
for complications (i.e. urine retention, incontinence and rectal fistula), PSA level
and local recurrence.
In all procedures, total procedure- and treatment times were annotated. The
total procedure time was defined as from the moment the patient entered the
MR suite and anaesthetization was started until anaesthetization was ended and
138
the patient left the MR suite. Treatment time was defined as from the moment of
the first MR image acquisition until the moment the last image acquisition was
finished.
Table 1 Imaging parameters MR guided cryoablation protocol
PROTOCOL
Sequence
TR (ms)
TE
Flip angle
Voxel size
FOV
Acquisition
Temporal
(ms)
(degrees)
(mm×mm×mm)
(mmxmm)
Time
resolution
607
0.99
70
2.5x2.5x8.0
480x480
8.2 s
n.a.
5000
107
150
0.7x0.6x3.0
160x160
3:37 m
n.a.
465.92
1.82
70
2.7x2.7x10
350x350
n.a.
0.46
494.08
1.93
70
3.1x3.1x4.0
400x400
n.a.
0.49
4.81
1.96
6
1.3x1.3x2.5
250x250
0:50 m
n.a.
(s)
GRID
Balanced
DETECTION
Steady-State
T2WI
Axial, coronal
Free Precession
and sagittal TSE
BEAT IRT
Axial
Balanced
Steady-State
Free Precession
Coronal/ Sagittal
Balanced
Free Precession
T1 VIBE
Axial volumetric
interpolated
gradient echo
T2WI = T2-weighted MR imaging, VIBE = volumetric interpolated breath hold examination, TSE = turbo spin echo, GE =
gradient echo, TR = repetition time, TE = echo time, FOV = Field of view
b
139
c
d
Figure 2: a: Axial T2-weighted image of the cryoneedles in situ. b-d: Axial T1-weighted VIBE with the
growing ice ball (black signal void), eventually covering the entire tumour.
a
b
c
Figure 3: Multi-parametric MRI 3 months post cryoablation. From left to right; Axial T2-weighted image of
the prostate, axial ADC map, axial Dynamic Contrast-Enhanced MR image. There is no sign of tumour rest.
MR guided focal cryo-ablation
a
Chapter 8
Steady-State
Results
Feasibility
Ten out twenty-three patients met the inclusion criteria and were successfully
treated with MR-guided focal cryoablation. One of these was a patient with
newly-diagnosed PCa. He was previously treated with radiotherapy for testis
carcinoma and for this reason, other therapies (surgery or salvage radiation
therapy) were not possible. Patient characteristics are shown in Table 2.1.
Table 2.1 Patient characteristics
Patient
Age (y)
Months
Before RT
Before cryoablation
between RT
and cryo
140
Gleason
Stage
PSA
Gleason
score
(TNM)
(ng/mL)
score
Stage
PSA
1†
65
80
7
N.A.
5.5
7
3b
2.7
2
66
52
6
3a
4
7
2
3.4
3*
67
N.A.
N.A.
N.A.
N.A.
7
3
0.9
4
52
62
8
2-3
25
N.A.
2
8.7
5
68
76
6
1c
9
N.A.
2
8.4
6
71
55
8
3
19
9
2
7.2
7
60
119
8
2c
18
10
2
4
8
76
16
6
3a
14.6
7
2
7
9
67
30
7
1c
48
7
3b
3.1
10
68
24
7
2
12
N.A.
2
3.6
*Patient with newly diagnosed PCa and previous RT for testis carcinoma.
N.A.= not available
†Patient had local recurrence and was treated again with MR cryoablation.
Procedure and treatment time
The median procedure time was 210.5 minutes (range 179 – 375). The median
treatment time was 133 minutes (range 91 – 242). Noteworthy, the first procedure
had a procedure time and treatment time of respectively 375 and 242 minutes,
the last procedure lasted only 184 and 91 minutes (Figure 4). Considering the total
procedure time and the treatment time of all procedures, a substantial learning
curve was noticed during the first 10 procedures (Table 2.2).
400
350
300
Minutes
250
200
Procedure time
150
Treatment time
100
50
0
1
2
3
4
5
6
7
8
9
10
Figure 4: Plot of the procedure time and the treatment time per patient, showing our learning curve.
Table 2.2 Procedure characteristics
Patient
1†
Procedure parameters
Follow up
Number of
Procedure
Treatment
cryoneedles
time
time
(minutes)
(minutes)
375
242
4
Complications
Mild hema-
Hospitalization
3 months
6 months
days
PSA
MP-MRI
PSA
MP-MRI
3
2.2
No recur-
2.9
Recur-
2
3
300
138
None
rence
2
0.5
No recur-
rence†
0.5
rence
3*
2
240
128
None
2
0.3
No recur-
No recurrence
0.2
-
rence
4
4
255
143
Mild urine
3
n.a.
retention, mild
No recur-
-
rence
perineal pain
5
2
179
93
Urine retention
2
1.3
No recur-
-
-
-
-
-
-
-
-
rence
6
2
180
131
None
2
5.9
No recurrence
7
4
217
135
None
2
-
No recurrence
8
2
186
94
None
2
-
No recurrence
9
3
204
140
None
2
-
-
-
-
10
3
184
91
None
2
-
-
-
-
*Patient with newly diagnosed PCa and previous RT for testis carcinoma.
N.A. = not available, MP-MRI = multi-parametric MRI.
†Patient had local recurrence and was treated again with MR cryoablation.
141
MR guided focal cryo-ablation
tospermia
Chapter 8
Patient
Complications
All patients were satisfied about the treatment and hardly experienced any pain.
In one patient the urethral-warmer could not be inserted due to perforation of
the urethra and the procedure was cancelled. Two months later the patient
was successfully treated with focal MR-guided cryoablation. The first patient
stayed a second night in the hospital at his own request. Another patient had
urine retention and was observed for a second night in the hospital. All other
patients went home one day after the procedure. No other complications, like
incontinence or fistula were recorded (Table 2.2).
Follow-up
Follow-up is known for the first 6 patients. After three months, PSA levels decreased
and MP-MRI showed no presence of recurrent tumour. Two patients suffered
from mild urine retention. After six months, one patient had a local recurrence
just cranial to the previously treated area. This was the first patient treated with
MR-guided cryoablation at our institution, and when retrospectively examining
142
the MR images acquired during the procedure, it was found that treatment had
been too conservative as the iceball did not cover the entire tumour. The patient
was treated again with MR-guided cryoablation and subsequent follow-up is not
known yet.
Discussion
In this study, the feasibility of MR-guided focal cryoablation in patients with
recurrent prostate cancer after radiation therapy was demonstrated. Most
patients were discharged one day after the procedure and did not suffer from
major complications. Patients who undergo salvage radical prostatectomy after
radiotherapy are often hospitalized between 8 – 14 days (23).
A true comparison between the results of our and other studies is difficult to
make, because of the different patient characteristics groups (newly diagnosed
vs. local recurrence) and treatment styles (whole gland vs. focal). In one study,
whole gland MR-guided prostate cryoablation was performed in 7 patients with
newly diagnosed prostate cancer and 2 patients with local recurrence after
radiotherapy in a wide-bore 1.5T MR scanner (21). Per patient 4 – 7 cryoneedles
were used. One major complication was reported, a rectal fistula which
spontaneously healed after 3 months. Some minor complications as hematuria,
dysuria and urine retention were reported as well. Mean hospitalization time was
5.6 days (range 3 – 13). In another study 12 patients with local recurrence of
PCa after radical prostatectomy were treated in a 1.5T wide-bore MR scanner.
Per patient 2 – 5 cryoneedles were used and 2 – 3 freeze-thaw cycles were
performed. No instant complications were seen. However, within 3 months, one
patient reported urine retention and in 2 patients local recurrence was found
contiguous to the urethra (22).
These above mentioned studies differed from our study in one important
aspect. Namely, whole gland treatment as opposed to study focal treatment
in our study. Only the lesion with a certain safety margin around it was ablated.
such as incontinence, impotence, and rectal fistula formation were tried to
keep to a minimum. Also, as a consequence of focal ablation, less needles (2–
4) were needed per patient. Probably for the same reason, the hospitalization
time was shorter as well (2–3 days). When comparing our results with a study
describing TRUS-guided salvage hemiablation of the prostate, they were more
consistent. Per patient 2–4 cryoneedles were used and 2–4 freeze-thaw cycles
a urine-catheter in situ for 2–5 days. Furthermore, an incontinence rate of 6.7%,
an erectile dysfunction rate of 60%, and no rectal fistulas were recorded. One
patient harboured a residual carcinoma (12).
In our study longer term complications are only known for the first 6 patients.
PSA levels decreased severely after three months. MP-MRI showed no presence
of local recurrence. Mild urine retention was observed in two patients. After six
months, the PSA level of one patient was increasing again and MP-MRI showed
a recurrent tumour. Therefore, MR guided focal cryoablation was repeated.
One of main the reasons that MR imaging guided cryoablation is suited
for focal therapy is the potential for exact monitoring of the iceball formation.
Previous studies described the presence of a hyper-intense border around the
hypo-intense ice ball in fast T1-weighted imaging (24). This hyper-intense rim is
caused by shortening of the T1 in cooled but not yet frozen tissue (25;26). By
carefully monitoring this edge, exact ice ball can be monitored. In this way the
tumour can be focally treated and nearby critical structures such as the urethra,
143
MR guided focal cryo-ablation
were performed. Patients were discharged on the day of the procedure with
Chapter 8
By applying focal treatment, we aimed to keep a minimum of complications
the rectal wall and the neurovascular bundle can be avoided. An alternative
approach to obtain temperature information using MRI is to monitor the proton
resonance frequency (PRF) shift. However, to enable MR signal measurements
from cooled tissue TE has to be shortened, which in turn decreases temperature
accuracy. Additionally, the PRF-method is seriously affected by susceptibility
artefacts at the ice-tissue transition (27).
This study encountered some limitations. Foremost, a considerable learning
curve was experienced. A lot of time was lost in finding the optimal workflow
during the first procedures. Preparing the diagnostic MR-room for the procedure
took a lot of time. Furthermore, all MR-guided cryoablation procedures were
performed in a normal sized bore 1.5T MR system (60 cm), which means limited
amount of space for patient positioning as well as instrument handling for the
physician. Proper patient positioning was therefore essential.
For the purpose of creating more space for patient and instrument
handling and improving image quality, the possibility of performing MR-guided
cryoablation in a wide-bore MR scanner should be explored. Other future steps
144
will be to investigate the long term follow-up of the treated patients, to optimize
the workflow, and to perform MR-guided cryoablation in combination with an
MR-compatible robot (28). Workflow optimization and robotic needle placement,
could further decrease the procedure and treatment time.
In conclusion, transperineal MR-guided focal cryoablation of the prostate in
patients with a local recurrence after radiotherapy was feasible and safe. Initial
results are promising, however longer follow-up is needed and more patients
have to be included.
Acknowledgements
The authors would like to thank Professor Afshin Gangi and his team for assisting
during the first MR-guided cryoprocedure in our hospital and Eva Rothgang for
providing the correct MR image sequences.
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27.
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measuring temperature adjacent to ablated tissue using the PRF method . 8th Interventional
MRI Symposium; 2010. Leipzig, Germany
28.
Yakar D, Schouten MG, Bosboom DGH, Barentsz JO, Scheenen TWJ, Futterer JJ. Feasibility of
a Pneumatically Actuated MR-compatible Robot for Transrectal Prostate Biopsy Guidance.
Radiology 2011; 260:241-247.
9
Summary and conclusions
Summary
Chapter 2 discusses the potential role of MP-MR imaging in focal therapy with
respect to patient selection and directing (robot guided) biopsies and IMRT. An
overview of the literature on MRI in the localization, staging, volume estimation,
assessment of aggressiveness, and guidance of radiotherapy and biopsies in
PCa has been provided.
For localization purposes areas under the curve (AUC) of 0.90 have been
reported when T2-w, DCE-MRI and MRSI were combined. For local staging of
PCa studies report maximum sensitivities and specificities of between 80%-88%
and 96%-100%, respectively at a 3T MR system (1, 2). Not just in local staging,
but also in staging of skeletal metastases MR imaging is superior with a sensitivity
targeted X-rays with a sensitivity and specificity of 63% and 64% (3). For lymph
node metastases MR Lymphography (which uses a lymph node specific contrast
agent, based on Ultra-small Superparamagnetic Particles of Iron Oxide) has a
sensitivity of as high as 100% and a maximum specificity of as high as 97.8% 9
(4, 5). DWI-MRI had a sensitivity of 86.0% and a specificity of 85.3% in one study
(6). Studies regarding volume measurement of PCa are few in number and
have been presented (7-9). For determining PCa aggressiveness with DWI a
significant negative correlation between Gleason grade and ADC values has
been found for PCa located in the peripheral zone (10-12). In radiotherapy
planning MRI does not yet have the ability to be used as treatment planning
technique alone, CT is necessary for dose calculations. MRGB of the prostate
has shown to improve cancer detection rate in subjects with an elevated PSA
and repetitive negative TRUS-guided biopsies (13-17).
In conclusion, MP-MR imaging is a versatile, and promising technique.
It appears to be the best available imaging technique at the moment in
localizing, staging (primary as well as recurrent disease, and local as well as
distant disease), determining aggressiveness, and volume of PCa. With this
information guidance of focal therapy, IMRT and biopsy can be realized. It
is recommended to perform MP-MR imaging consisting of at least T2-w, DCEMRI, and DWI. However, larger study populations in multi-centre settings have
to confirm these promising results. Yet before such studies can be performed,
151
Summary
not consistent, however some encouraging results with fair to good correlation
Chapter 9
and specificity of 100% and 88% compared to bone scintigraphy combined with
more research is needed in order to achieve standardized imaging protocols.
This is partly assessed in chapter 3.
In chapter 3 the diagnostic performance of 3T, 3D MRSI in the localization of PCa
was compared with and without the use of an ERC. This was a prospective study
performed in 18 patients with histologically proven PCa on biopsy and scheduled
for radical prostatectomy. All patients underwent 3D-MRSI with and without an
ERC. Readers independently rated their confidence that cancer was present in
the prostate. These findings were correlated with whole-mount prostatectomy
specimens. Localization of PCa (in tumours of 0.5 cm3 or larger in volume) with
MRSI with the use of an ERC had a significantly higher AUC (0.68) than MRSI
without the use of an ERC (0.63) (P = .015). Despite the fact that this difference
was statistically significant, such a small increase in the AUC should make one
think whether using the ERC is worth the effort, cost and patient discomfort.
In chapter 4 the feasibility of 3T DCE-MRGB in localizing local recurrence of
152
PCa after EBRT was evaluated in 24 consecutive men with biochemical failure
suspected of local recurrence. In a first session patients are referred for a
diagnostic MRI of the prostate, followed by, in a different session, MRGB. Tissue
sampling was successful in all patients and all tumour suspicious regions (TSRs).
The positive predictive value on a per patient basis was 75% (15/20) and on a per
TSR basis 68% (26/38). TRUS biopsy core schemes, which is the standard diagnostic
work up in clinical practice in patients with a biochemical recurrence after EBRT,
have a positive predictive value of 27% (18). These schemes use between 6-12
cores per patient. In this study the median number of biopsies taken per patient
was 3 and the duration of an MRGB session was 31 minutes. No intervention
related complications occurred. In conclusion, the combination of diagnostic
MR imaging and MRGB of the prostate was a feasible technique to localize PCa
recurrence after EBRT using a low number of cores in a clinically acceptable time.
In chapter 5 and 6 an overview of the literature, technical details, and future
developments concerning MRGB of the prostate has been given. In men with
an elevated PSA and/or abnormal DRE biopsy is the gold standard for PCa
diagnosis. Random systematic TRUSGB is the most widely applied and available
PCa diagnosis method. Detection rates of PCa in random systematic TRUSGB
do not exceed 44% and 22% for the first and second biopsy session, respectively
(19, 20). Consequently other biopsy methods have been explored. One of these
methods is MRGB of the prostate that has detection rates after at least one
previous negative TRUSGB session of between 38-59% (13-17). These rates are
higher compared to repeat TRUSGB. For this reason MRGB will probably become
more and more available in daily practice. However, the lack of standard
protocols for MR imaging of the prostate is an important issue. For the optimal
biopsy technique there is still more research necessary. Robotics may optimize
MRGB regarding target accuracies and procedure time. This is partly assessed in
chapter 7.
In chapter 7 the feasibility of an MR-compatible robot for MRGB was
patients on the diagnostic multi-parametric MR examinations. These CSRs were
targeted for MR-guided robot assisted prostate biopsy. Thirteen out of seventeen
(76%) CSRs were reachable for biopsy with the robot. The remaining 4 CSRs were
biopsied manually. In future studies, after further optimization of the robot (larger
range of motion and size reduction) and the system set up, investigating biopsy
accuracy and decreasing biopsy session time seem to be the next logical steps.
MR imaging guidance using a remote controlled, pneumatically actuated, MRcompatible, robotic device as an aid.
In chapter 8 the feasibility of MR-guided focal cryo-ablation in recurrent PCa after
radiotherapy was evaluated in 10 patients. All patients had histopathologically
proven recurrent PCa, detected on MP-MRI, without evidence for distant
metastases. They were treated with cryo-ablation under general anaesthesia in
a 1.5T MR scanner. All patients were satisfied about the treatment and hardly
experienced any pain. No major complications were recorded. Follow-up is
known for the first 6 patients. After three months, PSA levels of all patients had
decreased and MP-MRI showed no signs of tumour recurrence. After six months,
one patient had a local recurrence and was retreated with MR-guided cryoablation. Transperineal MR-guided focal cryo-ablation of recurrent PCa after
radiotherapy is feasible and safe. Initial results are promising, however longer
follow-up is needed and more patients have to be included.
153
Summary
In conclusion, it is feasible to perform transrectal prostate biopsy with real-time 3T
Chapter 9
demonstrated. A total of 17 cancer suspicious regions (CSRs) were detected in 10
Conclusions
The following overall conclusions can be made:
1.
Based on the literature, MP-MR imaging appears to be the best
available imaging technique currently in localizing, staging, determining
aggressiveness, and volume of PCa (chapter 2).
2.
Based on the literature, it is recommended to perform MP-MRI for the
localization of PCa consisting of at least T2-w, DCE-MRI, and DWI for the
highest diagnostic yield (chapter 2).
3.
The use of an ERC in 3D MRSI in localizing PCa at 3T only slightly
increases the localization performance compared to not using an
ERC (chapter 3).
4.
Dynamic contrast-enhanced MR targeted MRGB in patients with
a biochemical recurrence after radiotherapy of PCa is a feasible
technique (chapter 4).
5.
154
According to the literature, detection rates of MRGB of the prostate in
patients with a history of previous negative TRUSGB sessions are higher
compared to repeat TRUSGB (chapter 5 and 6).
6.
It is feasible to perform transrectal prostate biopsy with real-time 3T MR
imaging guidance using a remote controlled, pneumatically actuated,
MR-compatible, robotic device as an aid (chapter 7).
7.
Transperineal MR-guided focal cryo-ablation of recurrent PCa after
radiotherapy is feasible and safe (chapter 8).
Suggestions for future research
Although MR imaging in the management of PCa seems to be a promising
technique most studies have been in single centres and concerned a low
number of patients. These published initial results have to be validated in multicentre trials with larger number of patients. However before such trials can be
performed uniform protocols have to be developed. Moreover a uniform scoring
system concerning detecting/localizing PCa needs to be developed. Recently
the European Society of Urogenital Radiology (21) has published guidelines with
an attempt to define standard imaging protocol requirements and a uniform
scoring system. However, because of the lack of large multi-centre trials they
have only been able to provide minimal requirements. Also a uniform scoring
system has been proposed by them. Further clinical studies need to evaluate
this proposed scoring system. One of the questions that need to be addressed is;
should one of the MP-MRI techniques in a given clinical situation prevail above
the other? In other words, should there be some kind of weighting factor for
certain MP-MRI techniques in certain clinical situations?
Basically this means; which combination of MP-MRI has the highest diagnostic
performance in a certain clinical situation (e.g. primary PCa, recurrent PCa after
radiotherapy (Chapter 4) or after prostatectomy)?
The necessity of the use of an ERC for localizing primary PCa with MRSI is one
serve in guidelines formation. This is an issue that also needs answering in the
context of other MP-MRI techniques. Not only the use of an ERC but also for
example issues concerning the use of a 1.5T versus a 3T MR system need to be
evaluated further.
Furthermore, in our work also some feasibility studies have been demonstrated.
In optimizing the MRGB process the role of robotics has been partly investigated
demonstrated. The next step is to further optimize the biopsy setting and the
robot itself. Also future studies should focus on target accuracies and decreasing
biopsy procedure time.
We demonstrated the feasibility and safety of MR guided focal cryo-ablation
of the prostate (Chapter 8). Future studies should focus on a phase II trial where
a larger group of patients is treated. This should then be compared to the current
standard of care which is whole gland cryo-ablation under TRUS guidance (e.g.
in terms of complication rates, treatment success, hospitalization days, patient
satisfaction, costs etc.).
155
Summary
in chapter 7. The feasibility of MRGB with the aid of a MR-compatible robot was
Chapter 9
the research objectives of my thesis (Chapter 3), the results of this study could
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Beyersdorff D, Winkel A, Hamm B, Lenk S, Loening SA, Taupitz M. MR imaging-guided prostate
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Chapter 9
17.
10
Samenvatting en
conclusies
Samenvatting
Hoofdstuk 2 geeft een overzicht van de literatuur over de rol van MRI in de
lokalisatie, het stadiëren, de volumeschatting, de bepaling van agressiviteit, en
begeleiden van radiotherapie en biopten bij prostaatkanker.
PSA, transrectaal onderzoek (DRE) en transrectale echo geleide biopsie
(TRUSGB) hebben niet de mogelijkheid om prostaatkanker correct te lokaliseren,
stadiëren, het volume en de agressiviteit te bepalen (1-6). In het nieuwe tijdperk
van meer preciezere therapievormen, zoals minimaal focale behandelingen
(bijv. cryochirurgie), is deze informatie van het grootste belang. De ideale
diagnosetechniek bij prostaatkanker moet in staat zijn om deze informatie op
Voor lokalisatie is MRI een nauwkeurige techniek: de zogenaamde gebieden
onder de receiver operating characteristic (ROC)-curve hebben een waarde
van 0,90 wanneer T2-gewogen (T2-w), dynamische contrast versterkende (DCE)MRI en MR spectroscopie (MRSI) werden gecombineerd. Voor lokale stadiëring
van prostaatkanker rapporteren studies een maximale sensitiviteit en specificiteit
van 80% -88% en 96% -100%, respectievelijk op een 3 Tesla (T) MR-systeem (7, 8).
Niet alleen bij lokale stadiëring, maar ook bij het detecteren van skeletmetastasen
van de botscan in combinatie met gerichte conventionele röntgen opnamen met
een sensitiviteit en specificiteit van 63% en 64% (9). Voor lymfkliermetastasen heeft
MR lymfografie (dat een lymfeklier specifieke contrastmiddel gebruikt, op basis
van ultra-kleine superparamagnetische deeltjes van ijzeroxide) een gevoeligheid
van maar liefst 100% en een maximum specificiteit van 97,8% (10, 11). Diffusie
gewogen (DWI)-MRI had een sensitiviteit van 86,0% en een specificiteit van 85,3%
in een studie (12). Studies met betrekking tot volumemeting van prostaatkanker
zijn weinig in aantal en niet consistent. Er zijn echter een aantal bemoedigende
resultaten gemeld (13-15). Voor het bepalen van prostaatkanker agressiviteit
met DWI is een significante negatieve correlatie tussen de Gleason score en
de apparent diffusion coefficient ADC waarde gevonden met betrekking tot
tumoren in de perifere zone van de prostaat (16-18).
Multi-parametrische (MP) MRI is een veelzijdige en veelbelovende techniek.
Het lijkt de beste beschikbare beeldvormende techniek op dit moment in
het lokaliseren, het stadiëren, het bepalen van agressiviteit, en het volume
161
Samenvatting
is MRI superieur met een sensitiviteit en specificiteit van 100% en 88% ten opzichte
Chapter 10
een niet invasieve manier te verzamelen.
van prostaatkanker. Het verdient aanbeveling om MP-MRI bestaande uit
tenminste T2-w, DCE-MRI en DWI uit te voeren. Echter, grotere studie populaties
in meerdere instellingen moeten deze veelbelovende resultaten bevestigen.
Maar voordat dergelijke studies kunnen worden uitgevoerd, is meer onderzoek
nodig om gestandaardiseerde protocollen te kunnen formuleren. Dit wordt deels
onderzocht in hoofdstuk 3.
In hoofdstuk 3 wordt de diagnostische waarde van 3T, 3-dimensionale (3D)
MRSI in de lokalisatie van prostaatkanker vergeleken met en zonder het gebruik
van een endorectale spoel (ERC). Dit was een prospectieve studie uitgevoerd
bij 18 patiënten met een histologisch bewezen prostaatkanker middels biopsie
en gepland voor radicale prostatectomie. Alle patiënten ondergingen een
3D-MRSI met en zonder een ERC. Lezers beoordeelden waar in de prostaat
de kanker aanwezig was onafhankelijk van elkaar. Deze bevindingen werden
gecorreleerd met de radicale prostatectomie bevindingen. Lokalisatie van
prostaatkanker met MRSI met behulp van een ERC heeft een significant hogere
162
ROC-curve (0,68) dan MRSI zonder het gebruik van een ERC (0,63) (P = 0,015).
Ondanks het feit dat dit verschil statistisch significant was, moet een dergelijke
kleine stijging van de ROC-curve afgewogen worden tegen de extra kosten die
hiermee gemoeid zijn en het ongemak voor de patiënt tijdens het inbrengen
van een ERC.
In hoofdstuk 4 wordt de haalbaarheid van 3T DCE-MR geleide biopsie (MRGB)
geëvalueerd in het lokaliseren van een lokaal recidief van prostaatkanker na
radiotherapie bij 24 mannen met biochemische verdenking op een lokaal
recidief. MRGB was succesvol bij alle patiënten en alle tumor verdachte regio’s
(TSR’s). De positief voorspellende waarde op een per patiënt basis was 75%
(15/20) en op een per TSR basis van 68% (26/38). TRUSGB, dat de standaard
diagnosetechniek in de klinische praktijk is, heeft bij patiënten met een
biochemisch recidief na radiotherapie een positief voorspellende waarde
van 27% (19) . Deze techniek maakt gebruik van tussen de 6-12 biopten per
patiënt. In dit onderzoek bedroeg het gemiddelde aantal bioptien per patiënt
3 en de duur van een MRGB sessie was 31 minuten. Er waren geen interventie
gerelateerde complicaties. Deze studie toonde aan dat de combinatie van
MRGB en diagnostische DCE-MRI van de prostaat een haalbare techniek
was in het lokaliseren van prostaatkanker recidief na radiotherapie met
een laag aantal biopten in een klinisch aanvaardbare tijd en een hoge
detectiepercentage.
In hoofdstuk 5 en 6 wordt een overzicht van de literatuur, de technische details,
en toekomstige ontwikkelingen met betrekking tot MRGB van de prostaat
gegeven. Bij mannen met een verhoogd PSA en / of abnormale DRE is biopsie
de gouden standaard voor prostaatkanker diagnose. Willekeurige systematische
TRUSGB is de meest toegepaste en beschikbare diagnose methode. Detectie
percentages bedragen 44% en 22% voor de eerste en tweede bioptie
sessie, respectievelijk (20, 21). Dientengevolge zijn andere biopsie methoden
heeft na ten minste één eerdere negatieve TRUSGB van tussen de 38-59% (2226). Deze percentages zijn hoger in vergelijking met herhaalde TRUSGB. Om deze
reden zal MRGB waarschijnlijk een belangrijke plaats in de dagelijkse praktijk gaan
innemen. Echter, het ontbreken van standaard biopsie protocollen voor MRI van
de prostaat is een belangrijk punt. Voor de optimale biopsie techniek is er nog
meer onderzoek nodig. Robotica kan mogelijk het MRGB proces optimaliseren
met betrekking tot de nauwkeurigheid en de procedure tijd. Dit wordt deels
In hoofdstuk 7 wordt de haalbaarheid van een MR-compatibele robot voor
MRGB onderzocht. Een totaal van 17 kanker verdachte regio’s (CSR’s) werd
aangetroffen in 10 patiënten met MP-MRI. Deze CSR’s werden met behulp van
de MR-compatibele robot gebiopteerd. Dertien van de zeventien (76%) CSR’s
waren biopteerbaar met de robot. De resterende 4 CSR’s werden handmatig
gebiopteerd. In toekomstige studies, na verdere optimalisatie van de robot (groter
bereik van de beweging en verkleining van het model) en de gehele opzet van
het systeem, moet onderzoek gedaan worden naar de nauwkeurigheid en de
snelheid van de robot.
In hoofdstuk 8 wordt de haalbaarheid van MR-geleide focale cryo-ablatie bij
recidief van prostaatkanker na radiotherapie geëvalueerd bij 10 patiënten.
Alle patiënten hadden histopathologisch bewezen recidief van prostaatkanker
dat gedetecteerd was op de MP-MRI, zonder aanwijzingen voor metastasen
163
Samenvatting
onderzocht in hoofdstuk 7.
Chapter 10
onderzocht. Een van deze methoden is MRGB, dat een detectie percentage
op afstand. Zij werden behandeld met cryo-ablatie onder algehele anesthesie
in een 1,5T MR-scanner. Alle patiënten waren tevreden over de behandeling
en hadden nauwelijks pijn ervaren. Er werden geen belangrijke complicaties
geregistreerd. Follow-up is bekend van de eerste 6 patiënten. Na drie maanden
was het PSA van alle patiënten gezakt en MP-MRI vertoonde geen tekenen van
een recidief. Na zes maanden, had een patiënt een lokaal recidief en werd
wederom behandeld met MR-geleide cryo-ablatie. Transperineale MR-geleide
focale cryo-ablatie van recidief prostaatkanker na radiotherapie is haalbaar en
veilig. De eerste resultaten zijn veelbelovend, maar langere follow-up is nodig en
meer patiënten moeten worden geïncludeerd.
conclusies
1.
Op basis van de literatuur, MP-MRI lijkt de beste beschikbare beeldvormende
techniek op dit moment in het lokaliseren, het stadiëren, het bepalen van
agressiviteit, en het volume van prostaatkanker (hoofdstuk 2).
164
2.
Op basis van de literatuur, is het aanbevolen om voor de lokalisatie van
prostaatkanker een MP-MRI te verrichten bestaande uit ten minste T2-w,
DCE-MRI, en DWI (hoofdstuk 2).
3.
Het gebruik van een ERC in 3D MRSI in het lokaliseren van prostaatkanker
op 3T geeft slechts in geringe mate een verbetering in vergelijking met het
niet gebruiken van een ERC (hoofdstuk 3).
4.
DCE-MRI gerichte MRGB bij patiënten met een biochemisch recidief na
radiotherapie van prostaatkanker is een haalbare techniek (hoofdstuk 4).
5.
Volgens de literatuur zijn detectiepercentages van MRGB van de prostaat
bij patiënten met een voorgeschiedenis van eerdere negatieve TRUSGB
sessies hoger dan herhaalde TRUSGB sessies (hoofdstuk 5 en 6).
6.
Het is mogelijk om transrectale prostaatbiopsie uit te voeren met 3T
MRI begeleiding en met behulp van een op afstand bestuurbare MRcompatibele robot als hulpmiddel (hoofdstuk 7).
7.
Transperineale MR-geleide focale cryo-ablatie van prostaatkankerrecidief
na radiotherapie is uitvoerbaar en veilig (hoofdstuk 8).
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A
Appendices
Dankwoord
Dankwoord
Graag wil ik een ieder bedanken die heeft geholpen bij het tot stand brengen
van dit proefschrift. Sommigen van jullie wil ik in het bijzonder bedanken.
Prof. Dr. J. Barentsz, beste Jelle, bedankt voor het mogelijk maken van dit
proefschrift. Ik heb van jou de kans gekregen om me in de volste breedte te
ontwikkelen en te ontplooien. Ik besef me al te goed dat ik geboft heb met jou
als promotor.
Dr. J.J. Fütterer, beste Jurgen, ik wist dat ik altijd op jou kon rekenen. Altijd
gewaardeerd. Van de coachende gesprekken die ik van tijd tot tijd van je heb
gehad heb ik veel geleerd. Bedankt voor je vertrouwen in mij. Ik kan een ieder
alleen maar een co-promotor als jou toewensen.
Dr. Ir. T.W. Scheenen, beste Tom, het was altijd zeer geruststellend wanneer jij
een stuk goedkeurde. Misschien dat we jou in het vervolg de “Firewall” kunnen
stukken altijd weer een stapje beter werden.
Dr. Ir. Henk Jan Huisman, beste Henk jan, jouw ondersteunende rol was erg
belangrijk. Dit bestond uit zowel statistische, analytische als technische (vooral
MRCAD) ondersteuning.
Beste Thomas, bedankt voor de tijd die je hebt genomen om mij de basisdingen
te leren van “het vak”. Het scannen en het biopteren heb ik immers van jou
geleerd. Ook wil ik jou en Stijn bedanken voor het deels beschikbaar stellen van
jullie databases.
Mijn kamergenootjes, beste Joyce, Martijn, Monique, Loes, Caroline, Oscar,
Marcel en Wendy, de tijd die ik met jullie heb doorgebracht was altijd erg
gezellig. En niet alleen voor de gezelligheid heb ik veel aan jullie gehad maar
het was ook waardevol om op het wetenschappelijke vlak over dingen te
173
Dankwoord
noemen. Jouw kritische en analytische blik hebben ervoor gezorgd dat mijn
Appendix
razendsnel met je commentaar op mijn stukken, iets wat ik altijd zeer heb
kunnen brainstormen met jullie. Martijn, bedankt voor je hulp bij de robot en
de presentatie (vooral split-screen truc) die we destijds voor de SCBTMR samen
hadden gemaakt.
Beste prof. dr. J.A. Witjes, dr. I.M. van Oort, dr. J.P. Sedelaar, dr. H. Vergunst, en
dr. E. van Lin bedankt voor de vruchtbare samenwerking. Ook jullie hebben een
belangrijke rol gespeeld bij het includeren van patiënten en het kritisch bekijken
van mijn stukken.
Beste dr. C.A. Hulsbergen-van de Kaa, zonder de gouden standaard zou geen
enkele publicatie mogelijk zijn geweest.
Beste Dennis, wie had dat nou gedacht van te voren, een Radiology publicatie
met de robot!
Beste opleiders prof. dr. M. Prokop, prof. dr. L.J. Schultze-Kool, en Liesbeth,
174
bedankt voor de ruimte die ik van jullie heb gekregen voor de wetenschap
tijdens mijn opleiding.
Beste Marijke en Manita, de wetenschap is toch een stuk gemakkelijker met jullie
als ondersteunend team.
Beste Solange en Leonie, bedankt voor jullie hulp.
Beste Ilke en Laura, ik wist dat ik op jullie kon vertrouwen. Bedankt voor de
eindsprint.
Lieve Nicky, a.k.a. “Nick the çabuk”, zonder jouw steun en inzet had ik dit
proefschrift nooit op tijd af kunnen hebben. Ik hou van je.
Curriculum Vitae
Curriculum Vitae
Derya Yakar werd geboren op 25 april 1981 te Nijmegen. In 1999 behaalde zij
haar VWO diploma aan de Nijmeegse Scholengemeenschap Groenewoud. Na
eerst 2 jaar filosofie te hebben gestudeerd in Nijmegen begon zij in 2002 met
de geneeskunde opleiding aan de Katholieke Universiteit Nijmegen. In 2008
behaalde zij haar arts examen. Een wetenschappelijke stage van 3 maanden bij
de afdeling Radiologie in het Radboud over dynamische contrast versterkende
MRI bij patiënten met een lokaal recidief van prostaatkanker na radiotherapie
resulteerde in een publicatie. Aansluitend werd in 2008 begonnen met het
huidige project over MRI bij prostaatkanker onder leiding van prof. dr. Barentsz,
dr. Fütterer en dr. Scheenen. In juli 2010 begon zij met de opleiding tot radioloog
Appendix
in het Radboud Universiteit Nijmegen.
179
Curriculum Vitae
List of publications and presentations
List of publications and presentations
Publications
Yakar D, Fütterer JJ. Clinical Applications in Various Body Regions: MRI-Guided
Prostate Biopsies. Book chapter in. Interventional Magnetic Resonance Imaging.
Springer-Verlag 2012. Editors: Kahn T, Busse H.
Bomers JGR, Yakar D, Sedelaar JPM, Vergunst H, Barentsz JO, de Lange F,
Fütterer JJ. MR-guided focal cryoablation in recurrent prostate cancer patients.
Accepted with revision; Radiology 2012.
Schouten MG, Bomers JGR, Yakar D, Huisman H, Bosboom D, Scheenen TWJ,
prostate biopsies. Eur Radiol. 2012 Feb;22:476-83.
Yakar D, Debats O, Bomers J, Schouten MG, van Lin E, Fütterer JJ, Barentsz
JO. The predictive value of MRI in the localization, staging, volume estimation,
assessment of aggressiveness, and guidance of radiotherapy and biopsies in
prostate cancer. J Magn Reson Imaging 2012; 35:20-31.
Feasibility in patients of a pneumatically actuated MR-compatible robot for MRguided prostate biopsy. Radiology 2011; 260:241-247.
Yakar D, Heijmink S, Hulsbergen-van de Kaa C, Barentsz JO, Fütterer JJ, Scheenen
T. Initial Results of 3-dimensional 1H-MR Spectroscopic Imaging in the Localization
of Prostate Cancer at 3 Tesla: Should we use an Endorectal Coil? Invest Radiol
2011; 46:301-306.
Hoeks C, Barentsz JO, Hambrock T, Yakar D, Somford D, Heijmink S, Scheenen T,
Vos P, Huisman H, van Oort I, Witjes J, Heerschap A, Fütterer JJ. Multiparametric
MR imaging in detecting, localizing, and staging of prostate cancer: a State of
the Art review. Radiology 2011;261:46-66.
Fütterer JJ, Verma S, Hambrock T, Yakar D, Barentsz JO. High-risk prostate cancer:
183
Publications & Presentations
Yakar D, Schouten MG, Bosboom D, Scheenen TWJ, Barentsz JO, Fütterer JJ.
Appendix
Misra S, Fütterer JJ. Evaluation of a robotic technique for transrectal MRI-guided
value of multi-modality 3T MRI-guided biopsies after previous negative biopsies.
Abd Imaging 2011; [Epub ahead of print].
Yakar D, Hambrock T, Huisman H, Hulsbergen-van de Kaa C, van Lin E, Vergunst
H, Hoeks C, van Oort I, Witjes J, Barentsz JO, Fütterer JJ. Feasibility of 3T dynamic
contrast-enhanced MR-guided biopsy in localizing local recurrence of prostate
cancer after external beam radiation therapy. Invest Radiol 2010;45:121-5.
Hambrock T, Somford D, Hoeks C, Bouwense S, Yakar D, Huisman H, Oort I, Witjes
J, Barentsz JO, Fütterer JJ. The Value of 3 Tesla Magnetic Resonance Imaging
Guided Prostate Biopsies in Men with Repetitive Negative Biopsies and Elevated
PSA. J Urol 2010;183:520-7.
Yakar D, Hambrock T, Hoeks C, Barentsz JO, Fütterer JJ. MR-guided biopsy of
the prostate, feasibility, technique and clinical applications. Topics in Magnetic
Resonance Imaging 2008; 19:291-295.
184
Fütterer JJ, Yakar D, Strijk SP, Barentsz JO. Preoperative 3T MR imaging of rectal
cancer: Local staging accuracy using a two-dimensional and three-dimensional
T2-weighted turbo spin echo sequence. Eur J Radiol. 2008; 65: 66-71.
Blijlevens NMA, Donelly JP, Yakar D, van Die CE, de Witte. Determining mucosal
barrier injury to the oesophagus using CT scan. Support Care Cancer 2007;
15:1105-1108.
Presentations
“Feasibility of a pneumatically actuated MR-compatible robot for MR-guided
prostate biopsy.”
RSNA (oral, 2010), SCBTMR (oral, 2010), ECR (E-poster, 2010)
“3T MR spectroscopic imaging with and without endorectal coil in localizing
prostate cancer.”
RSNA (E-poster, 2010), ISMRM (poster, 2010), ESUR (oral, 2009)
“Predictive accuracy of 3T multi-modal MR imaging guided prostate biopsy
determined Gleason Score and true Gleason Score on prostatectomy.”
RSNA (oral, 2009)
“Dynamic-Contrast Enhanced MRI and MR-guided biopsy for the detection of
Prostate cancer recurrence after Radiation therapy.”
ISMRM (E-poster 2009), ECR (oral, 2009), Dutch Radiology days (oral, 2008), ESUR
(oral, 2008, honourable mention for an excellent presentation )
Appendix
185
Publications & Presentations