March Newsletter

Device Profile
Sonablate®-500: transrectal
high-intensity focused
ultrasound for the treatment of
prostate cancer
Rowland Illing† and Mark Emberton
CONTENTS
Overview of the market
How the device works
Conclusion
Expert commentary
Future developments
Five-year view
Key issues
References
Affiliations
†
Author for correspondence
The Clinical Effectiveness Unit,
The Royal College of Surgeons of
England, 35/43 Lincolns Inn
Fields, London, WC2A 3PE, UK
Tel.: +44 207 869 6600
Fax: +44 207 869 6644
[email protected]
KEYWORDS:
ablation, cancer, focused
ultrasound, HIFU, prostate,
visually directed
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Prostate cancer (PCa) is the most common cancer in men and the second leading cause
of death from malignancy in the UK. The number of men diagnosed with PCa is increasing,
due in part to an increased willingness of men to visit their family doctors with lower urinary
tract symptoms, and also a willingness of physicians to test for it. As the demographic of
men diagnosed with PCa becomes younger and better informed, so the demand for a
less-invasive alternative to standard therapies becomes greater. The Sonablate®-500 is
one of only two high-intensity focused ultrasound (HIFU) devices commercially available
to treat PCa. HIFU is an attractive treatment option as it is the only form of therapy that
neither involves direct instrumentation of the prostate nor ionizing radiation. This article
describes the unique features of both the Sonablate®-500 system hardware and software,
and the outcome data from this device in the context of current standard therapies. Finally,
a view into the future attempts to outline where this technology is heading and how a
paradigm shift in the way that PCa is considered may make HIFU even more relevant.
Expert Rev. Med. Devices 3(6), 717–729 (2006)
Prostate cancer (PCa) is the most common
cancer in men and the second leading cause of
death from malignancy in the UK [1]. The
mainstay of treatment remains radical surgery
or radiation therapy; however, there are several
minimally invasive treatments now under evaluation that may prove to be of equivalent
oncological effectiveness in the long term [2].
The most common radical therapy – surgical excision of the prostate – has been shown
to have a modest impact on disease-specific
survival in men with cancer confined to the
prostate [3]. Over a 10 year period, surgery
offered a 5% increase in survival over observation alone (decreasing the disease specific mortality from 14 to 9%). Consider also that the
side effects of the most common radical treatments are high – they include amongst others
deterioration in urinary, sexual and bowel
function [4,5]. The profile and probability of
these harmful outcomes depend to a large
extent on the type of radical treatment, but all
10.1586/17434440.3.6.717
occur as a consequence of damaging tissue or
structures that exist outside the prostate gland
– the external sphincter, the neurovascular
bundles and the rectal mucosa, respectively.
Refinements in the traditional radical therapies
(conformal or intensity modulated radiation
therapy on the one hand vs laparoscopic or
robotic radical prostatectomy on the other)
have had little impact on the key treatment
related morbidities [6,7].
The desirable attributes for a new technology
in this field have been outlined previously
(BOX 1) [8]. What is required is a truly conformal, noninvasive means of performing radical
treatment for PCa; reducing the side-effect profile while maintaining oncological efficacy.
Transrectal high-intensity focused ultrasound
(HIFU) has the potential to meet these requirements [9]. HIFU relies on the physical properties of ultrasound within tissues. For therapeutic purposes ultrasound energy is focused by
either an acoustic lens, bowl-shaped transducer
© 2006 Future Drugs Ltd
ISSN 1743-4440
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Illing & Emberton
or electronic phased array. As ultrasound propagates through tissue, zones of high and low pressure are created. When the
energy density (in W/cm2) at the focus is sufficiently high (during the high pressure phase), tissue damage (protein denaturation) may occur as a result of thermal coagulation necrosis,
whereas acoustic cavitation may occur in the pressure nadirs.
Tissue water boiling may occur as a result of both the heating
and cavitation effects [10]. As shown in FIGURE 1, the volume of
a HIFU generated lesion at the focal point is small (typically
10–12 mm long by 3 mm wide, in a cigar shape orientated
along the long axis of the beam). To ablate a continuous volume of tissue, individual HIFU lesions are placed overlapping
next to each other in order to provide a continuous zone of
necrosis. HIFU has been used on an experimental and clinical
basis as noninvasive therapy for clinically localized PCa since
the 1990s [9].
Overview of the market
The market for devices used in the treatment of organ-confined
PCa is expanding. The number of men diagnosed with PCa is
increasing, due in part to an increased willingness of men to
visit their family doctors with lower urinary tract symptoms,
and also a willingness of physicians to test for it [11]. In 2005,
approximately 232,000 new cases of PCa were diagnosed in the
USA and approximately 30,000 deaths from PCa occurred [12].
It is estimated that the lifetime risk for a man diagnosed with
PCa is approximately 40%, and this realization has led to a
great increase in the use of screening tests. In the state of
Ontario, Canada the use of prostate specific antigen (PSA) testing has increased by 388% between 1996 and 2000, and in some
American states over 40% of men over the age of 40 now
undergo PSA screening [13]. Despite there being concerns over
the use of PSA as a screening tool, it is a fact that as men become
more informed, the detection rates of small, early-stage PCa will
continue to rise. That having been said, there is now a movement
by some oncologists and urologists not to immediately treat all
Box 1. Desirable attributes of a new tissue ablation
technology for prostate cancer.
• Administered with the patient under local anesthesia
• Real-time monitoring of treatment
• Excellent oncological efficacy (destruction of all
prostate cancer)
• Minimal inflammatory response
• No adverse effect on pretreatment erectile function
• No adverse effect on pretreatment urinary continence
• No injury to adjacent structures (rectum, bladder)
• Repeatable
• Low cost
• Outpatient treatment
Taken from [8].
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2000 W/cm2
10 W/cm2
Focus Surgery, Inc.
Figure 1. Typical high-intensity focused ultrasound beam. Adapted with
permission from Focus Surgeons Inc. (IN, USA).
early-stage PCa, but rather place these patients under ‘active
surveillance’ until there is definite evidence of disease
progression [14].
How the device works
The Sonablate®-500 (SB-500; Focus Surgery, Inc., IN, USA)
ablates the prostate via a probe inserted into the rectum while
the patient is anaesthetized. The probe contains elements that
both image and treat the prostate noninvasively through the
intact rectal wall.
Hardware
The SB-500 system as shown in FIGURE 2A consists of a console, printer, flat screen monitor and a transrectal probe
incorporating two transducers of different focal lengths.
Main accessories include an articulated probe arm and a
chiller unit.
The mobile operator’s console consists of a main unit housing the ultrasound generator, flat panel 17” Active Matrix TFTLCD color monitor, keyboard with integral mouse buttons and
trackball, and a housing for a printer.
The SB-500 probe consists of probe tip, front housing,
probe body and probe cable connector (FIGURE 2B). It is made
from polyurethane; is just under 60 cm in length, has a tip
diameter of 3.45 cm, a neck diameter of 1.8 cm and weighs
3.2 kg. The probe tip contains two ultrasound transducers of
differing focal lengths mounted back-to-back (FIGURE 2C). The
transducers are made from a proprietary piezoceramic and
have the capability to both image and deliver HIFU treatment
pulses through the acoustic window opening in the probe tip.
The transducer moves in a longitudinal direction to provide
saggital images of the prostate and oscillates in the transverse
plane for transverse (sector) imaging. An elastomeric sheath
(latex and latex-free versions available) surrounds the probe
tip, and is secured to the probe tip via two O-rings. This
allows degassed and chilled water to circulate around the
transducer inside the probe tip, providing the necessary
coupling of the ultrasound energy for imaging and therapy to
the patient, as well as rectal wall cooling. The probe body,
Expert Rev. Med. Devices 3(6), (2006)
Sonablate®-500
B
A
C
D
Figure 2. (A) The Sonablate®-500 (SB-500) mobile console, articulated Probe Arm, Probe, and Sonachill™ cooling unit. (B) The SB-500 probe (here seen held by the
articulating probe arm). (C) Cutaway section through the probe tip showing the arrangement of the two transducers with different focal lengths for treating tissue
at different depths. (D) The SB-500 Probe features a wide 90° treatment field; the next generation of probes feature the choice of longer focal length transducers.
connected to the tip by the front housing, contains the inline
rotary motor for moving the transducers for transverse
imaging, and a linear actuator for saggital movement.
The standard probe produced by Focus Surgery incorporates transducers with focal lengths of 30 and 40 mm, and a
90° treatment window (FIGURE 2D); however, probes are now
available with the longer focal length of 45 or 50 mm to
accommodate larger glands.
The articulated arm is a universal probe holder that can be
attached to most operating tables. It has a simple locking mechanism to tighten three integral joints and a separate ring
through which the probe is inserted, allowing probe
positioning flexibility. This arrangement allows treatments with
the SB-500 system to be performed in any setting where an
operating table is available.
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The Sonachill™ device circulates degassed water through the
probe to cool the rectal wall and HIFU transducer. It is
connected to the back panel of the SB-500 console via a solid
connector cable and to the probe with hollow connecting
tubes. The solid connection provides the power supply to the
Sonachill and temperature feedback to the system while the
hollow tubes allow water circulation.
Figure 3. Tabbed pages on the user interface.
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Illing & Emberton
Figure 4. Screenshot from the Sonablate®-500 during therapy showing treatment of the preplanned anterior zone of the prostate.
The three main components of the chiller are:
• Liquid-to-air active cooling unit
• Peristaltic pump
• Water reservoir
An important function of the Sonachill is to remove the
closed system of any air bubbles before starting the procedure.
The water reservoir has a connector on the sidewall, which is
connected to a syringe. This is used to adjust the volume of
the sheath by pushing water in or removing it, inflating and
deflating, respectively. Fine adjustment between the transducer’s focal zones and the treatment regions is achieved using
this syringe.
The SB-500 records treatment images either to a digital
graphic printer or to the system’s hard disk. This allows the
physician to record (and later review) the entire
HIFU treatment.
Patient selection & preparation
A CE mark has been awarded for the treatment of patients
with primary PCa or recurrent PCa following prior therapy.
Exclusion criteria include: evidence of metastatic disease;
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previous rectal surgery (excluding surgery for hemorrhoids);
anal stenosis; metal implants or stents in the urethra; history
of prostatitis in the last 6 months; or active urinary tract
infection. Relative contraindications include: bleeding
disorders; extensive microcalcification within the prostate;
gland calcification greater than 1 cm in diameter; gland size
greater than 40 ml or an antero–posterior diameter of greater
than 4.0 cm when using a probe with maximum focal length
of 5 cm.
Prior to therapy, patients are prepared with two phosphate
enemas to empty the rectum. They then undergo
spinal/epidural or general anesthesia and are placed in the
lithotomy position. Prior to treatment a suprapubic catheter
(SPC) may be inserted under direct vision using a
cystoscope. The anal sphincter is gently dilated and the
treatment probe is introduced with a covering of ultrasound
gel to couple it to the rectal mucosa and then held in position by the articulated arm attached to the theatre table. A
16ch Foley urethral catheter is inserted under sterile technique, and a 10 ml balloon can be inflated to allow accurate
visualization of the bladder neck and median saggital plane,
if required.
Expert Rev. Med. Devices 3(6), (2006)
Sonablate®-500
Figure 5. The neurovascular bundle identification screen.
Software
The custom SB-500 application program runs on a Windows
XP™ platform. It is written in C2+ and Java, uses Snag-It software
to manage treatment recording and Sonablate Information
Management System (SiMS™) to manage SB-500 access control.
The SB-500 HIFU Prostate Therapy software allows ultrasonic
imaging of the prostate in both transverse and saggital planes
(with 3D reconstruction), on-screen treatment planning and
HIFU therapy within user-defined treatment zones. At start-up
an automatic system check commences which verifies the circuits
and treatment cycle properties. Simple image and therapy verification functionality tests can be performed by the user or service
personnel to verify proper unit function as part of a regular
maintenance schedule, or after unit transportation to a new site.
The operator interfaces with the software through multiple
tabbed pages – Prepare, Image, Plan, Volume and Therapy
(FIGURE 3). Axial and saggital images are taken through the
prostate using the transducer in the imaging mode. Treatment
planning is carried out using proprietary software that allows
the prostate to be divided into treatment regions – anterior,
middle and posterior, on both right and left sides if necessary
(FIGURE 4). A specific program [15] allows detection of the
periprostatic vessels, thought to be related to the neurovascular
bundles. This can be used should the physician wish to attempt
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to perform a ‘nerve-sparing’ treatment to preserve erectile function (FIGURE 5). The software directs the transducer to move
automatically in the region prescribed by the physician during
the treatment plan mode so that the acoustic focus is moved
sequentially through each point in the treatment plan. Each
acoustic pulse ablates a volume of 3 × 3 × 10–12 mm by heating the tissue to 80–98oC almost instantaneously [16], and individual lesions overlap slightly to ‘paint out’ the entire volume,
using a combination of 3 s exposures (‘on’) time and 3 or 6 s
pauses (‘off ’) time, during which real-time visualization of the
gland takes place. The longer focal length probe is used to treat
anterior and the mid-part of the gland, and the 3 cm probe
used to treat the anterior block.
Box 2. Features unique to the Sonablate®-500.
• User directed power input
• Neurovascular bundle identification (FIGURE 5)
• 3D image reconstruction (FIGURE 6B)
• Intraprocedure therapy plan modification using the
Stack feature
• Reflectivity index measurement monitoring
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Illing & Emberton
Following therapy, patients may leave
the hospital the same day with the SPC
in place. A minimal amount of oral
analgesia is usually required. Trial of
voiding may be carried out using a flipflow valve, and patients return in one or
more weeks for removal of the SPC.
A
Features
The SB-500 has some unique features
that differentiate it from other systems
available. The most important feature, as
discussed previously, is the ability to
monitor the HIFU treatment in real
time and respond to tissue changes by
adjusting the input power according to
the particular characteristics of the gland
being treated. This and other features are
listed in BOX 2. The reflectivity index
measurement (RIM) is an important
safety feature that analyzes the real-time
B-mode image of the rectal wall
immediately in front of the transducer
and digitally compares it to the stored
image taken prior to therapy. The RIM is
a composite score that alerts the user to
any differences between these two images
either caused by patient movement or
gland swelling. If the score is greater
than a certain threshold then the device
will automatically stop and alert
the clinician.
Other important safety features include
real-time rectal wall distance monitoring,
rectal wall temperature monitoring, reverberation detection (to alert the user to the
presence of trapped air bubbles), independent HIFU monitoring via watchdog
timer circuitry and an emergency stop
button to disable HIFU delivery at any
time during the treatment.
B
Sonablate® Information
Management System
Figure 6. (A) Multisliced, from base to the apex, treatment planning screen. (B) 3D treatment planning
screen with transverse, saggital and coronal plane imaging.
As the software is semi-automated, however, control over the
amount of energy that is administered to the prostate remains
under the control of the user. A method of treatment termed
‘visually directed’ HIFU has been suggested, the early results of
which show it to be potentially more efficacious than other
techniques and systems currently available [17]. Visually directed
HIFU takes into account both inter- and intraprostatic differences in acoustic and thermal properties, and allows the user to
respond in real-time to the therapy.
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The SiMS software provides a controlled
interface to the Prostate Therapy software, and has been designed with the longer term aim of
patient tracking (as part of a registry) and user training.
There are three main features: login control that ensures that
only those who have been accredited may use the system;
data entry, which creates a database of demographic preoperative features of all patients treated; and a training module
that will allow users to run through treatments in a controlled manner, either during primary training or as part of
refresher courses.
Expert Rev. Med. Devices 3(6), (2006)
Sonablate®-500
Table 1. Current training requirements for users of the Sonablate®-500.
Observation
Minimum of three cases at a recognized center
Off-line training
On the device using the Sonablate® Information Management System software
Didactic lectures
A series of lectures covering the principles of high-intensity focused ultrasound,
techniques of treatment, follow-up strategies and trouble-shooting
Proctored cases
An accredited trainer visits the users’ center and oversees treatment. An experienced
device specialist teaches the theater support staff device set-up, preparation and patient
safety. This may be a variable number of sessions until the user is deemed competent
Supervision by experienced applications specialist To help trouble-shoot and answer questions
Independent practice
Following ‘sign off’ by a different accredited trainer
Cost–effectiveness
Training, waste disposal & equipment required
The current training requirements for clinicians wishing to use
the SB-500 are given in TABLE 1.
The device has very few disposables. On top of a urological
day-case suite with cystoscopy facilities, degassed water (<3 ppm
oxygen) and nonsterile sheaths are all that are required.
Clinical profile & postmarketing findings
Phase I, II & III
The SB-500 has been granted CE marking in Europe and US
FDA-approved clinical trials are currently on-going. The results
of a multicenter Japanese trial were published in 2005 [18] and a
multicenter European trial assessing the SB-500 is currently
underway, which should report back in 2007. Transrectal
HIFU for PCa was reviewed by the National Institute for
Health and Clinical Excellence in 2005 and, following its
report, was cleared for use in the UK within the National
Health Service [101].
A problem facing all new technologies used to treat organconfined PCa is the length of time required to generate outcome data. True figures regarding the disease-specific mortality
following radical prostatectomy have only recently become
available, and these show only a modest improvement in
survival at 10 years after treatment versus watchful waiting [3].
Owing to this, proxy measures of outcome must be used, with
biopsy negativity and American Society for Therapeutic Radiology and Oncology (ASTRO) criteria the most common. A
recent paper has shown that a low PSA nadir following treatment is strongly correlated with good outcome on subsequent
post-treatment biopsy [19], and evidence of persistent enhancement on post-treatment contrast-enhanced magnetic resonance
also strongly predicts both failure on biopsy and subsequent
PSA nadir [20].
The largest case series of patients treated with the SB-500
comes from Uchida’s group in Japan. This group have shown
that they were able to achieve a biopsy negative rate of 87%
6 months after treatment in men with presumed localized
PCa [21], with a PSA nadir of less than 1 ng/ml in 72% of
patients treated (63 patients). At a mean of 5-years follow-up
they showed a freedom from biochemical recurrence (based on
ASTRO criteria) of 78% [22], in particular, patients with a pretreatment PSA of 10 ng/ml or less demonstrated 94 and 77%
biochemical disease free survival at 4- and 5-years follow-up,
respectively (181 patients). It is important to note that this
group were not using visually directed HIFU in their series;
they used predetermined power levels defined from in vitro and
in vivo experimentation [22]. This series compares very favorably
Table 2. Comparison of mean PSA nadirs achieved following trans-rectal HIFU using different devices.
Study
Device
Treatment
method
Patient no.
PSA nadir target % achieving
(ng/ml)
Mean nadir
ng/ml
Chaussy and Thüroff
Ablatherm
Algorithm
184
≤0.5
61
1.65
[42]
Gelet et al.
Ablatherm
Algorithm
82
≤1.0
56
1.02
[41]
Thüroff et al.
Ablatherm
Algorithm
402
Not given
Not given
1.85
[43]
Blana et al.
Ablatherm
Algorithm
137
≤0.1
≤0.5
56
83
Not given
[44]
Uchida et al.
SB-500
Algorithm
63
≤0.2
≤1.0
32
72
1.38
[22]
Illing et al.
SB-500
Visually directed 25
≤0.2
84
0.15
[17]
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Ref.
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Illing & Emberton
Table 3. Competing minimally invasive devices and technologies in the field of organ confined prostate cancer.
Technique
Background
Ref.
Ablatherm-HIFU
Only other transrectal HIFU device in this field. Uses three preset algorithms for primary, radiation
failure or prior HIFU failure treatments
[43]
Low dose rate brachytherapy
Permanently implanted radioactive seeds. Widely used in the USA and Europe for primary disease in
combination with external beam radiotherapy
[44]
High dose rate brachytherapy Temporary insertion of radioactive sources. Used mainly for high risk disease
[45]
Cryotherapy
Mainly used for recurrent disease following other forms of therapy. Criticized for adverse event rate
[46]
Radiofrequency ablation
Investigational for recurrent prostate cancer
[47]
Photodynamic therapy
Investigational for primary and recurrent prostate cancer
[48]
Interstitial rods
Stalled in development
[49]
HIFU: High-intensity focused ultrasound.
with a recent study by Potters and colleagues that compared
seven year outcome data between cohorts undergoing radical
surgery (RP) (746 patients), external beam radiotherapy
(EBRT) to a minimum 70 Gy (340 patients) and low-dose rate
seed brachytherapy (LDR BT) (733 patients) [23] . The oncological outcome was defined as freedom from biochemical
recurrence (FBR) based on ASTRO criteria for EBRT and
LDR-BT, and PSA of less than 0.2 for RP. FBR was similar in
all three groups; 74, 77 and 79% at 7 years for LDR-BT, EBRT
and RP, respectively.
Proponents of visually directed HIFU suggest that lower PSA
nadirs may be achieved using direct visual feedback to tailor
treatment to the individual [17]. Comparison of mean nadirs
achieved between visually directed HIFU and other HIFU
devices (or indeed with the SB-500, when using the pre-set
energies) is given in TABLE 2. An example of images taken before
and after visually directed HIFU are given in FIGURE 7.
The adverse event rate for this procedure has been described by
Uchida and colleagues [22]. Having treated 181 patients, they
found a presphincteric stricture rate of 22%, epidiymitis occurring in 6%, a rectourethral fistula in 0.5%, erectile dysfunction in
previously potent men of 20% and no stress incontinence lasting
more than 1 month. In the cases of presphincteric strictures all
were managed with periodic urethral dilatation. The experience of
UK clinicians using visually directed HIFU is similar – at a recent
meeting of European users of the SB-500, a cohort of 81 patients
treated in London was described in which the stricture rate was
15%, infection rate 6% and erectile dysfunction in previously
potent men of 25%. In this group, grade 1 stress incontinence
persisted more than 3 months in 4% of those treated [LESLIE TA,
PERS. COMM.]. Overall, these figures are very acceptable compared
with other radical therapies such as radical prostatectomy, which
even in the hands of high volume surgeons may have a long-term
incontinence rate (requiring surgical intervention) of almost
7% [24]. It has been the experience of those using the Ablatherm®
device that the postprocedure stricture rate is reduced by the
administration of a preprocedural transurethral resection of the
prostate (TURP). In one study, additional de-obstruction
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procedures were required in 27% of those undergoing HIFU
alone and in 8% of those with combined resection [25]. This must
therefore be considered by the physician – should 100% of
patients undergo the risks associated with transurethral resection,
rather than only those who require intervention subsequently?
In an attempt to further reduce the impotence rates, the
‘neurovascular bundle’ detection system has been developed (see
Patient selection & preparation). This relies upon the assumption that neurological mechanism for erection is related anatomically to the vascular bundles lying antero–lateral to the prostate
capsule. While this is possible, there are no clinical studies yet
available that demonstrate this association. A further caveat
remains that by deliberately undertreating portions of the gland,
the risk of residual disease is greater.
Alternative devices
See TABLE 3.
Conclusion
Viewpoint
It has been shown that HIFU using the SB-500 has many of
the desirable attributes of a new ablative technology (BOX 1),
incorporated into a highly mobile and expandable treatment
platform. It may be administered under local/regional anesthesia; however, the trend, certainly in Europe, is to use general
anesthesia. Real-time monitoring of the treatment may be performed, but more importantly, the information gained from
the monitoring may be used by the clinician to guide therapy in
a ‘visually directed’ manner. This is the key feature that differentiates it from other transrectal HIFU devices currently available. So far the oncological data looks promising – although
long-term results are not available, 5-year data is now emerging
that appears comparable with all of the current mainstream
modalities for the treatment of organ-confined PCa. The sideeffect profile also appears very promising – reported
incontinence, erectile dysfunction and infection rates all appear
better than current modalities. The urethral stricture rate is
high and currently under evaluation [LESLIE TA, PERS. COMM.].
Expert Rev. Med. Devices 3(6), (2006)
Sonablate®-500
Further attractions of HIFU are that it is repeatable, of
relatively low running cost and does not provide a therapeutic impasse – surgery and radiotherapy, as well as further
HIFU sessions, are possible following initial treatment
failure [22].
One of the concerns regarding population screening for PCa
in the healthy population is that the available therapies for it
may cause significant harm to the patient. This goes against one
of the five key principles of an effective screening program –
that the benefits of treatment for a condition must outweigh
A
B
C
D
Figure 7. An example of a Sonablate®-500 treatment follow-up. Axial, T1-weighted gadolinium contrast-enhanced magnetic resonance (MR) images taken
1 min post injection of a patient with T2b prostate cancer. 58-year-old male, pretreatment PSA 7.42, prostate volume 20 ml, Gleason score 3+4, 2/6 cores positive;
left peripheral zone at mid-gland and base. (A) Pretreatment image showing an enhancing region suspicious of cancer in the left peripheral zone; (B) 2 weeks
after treatment, lack of contrast uptake within the prostate consistent with coagulation necrosis; (C) 2 months after treatment, shrinkage of the necrotic volume
and typical 'double rim'; and (D) 6 months after treatment, no residual prostate tissue on MR, unrecordable PSA and no evidence of residual disease on transrectal
ultrasound guided biopsy of 7.5 ml tissue seen abutting the sphincter at ultrasound.
PSA: Prostate specific antigen.
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Illing & Emberton
the risks [26]. Not taking into account the problematic nature of
the PSA test itself, having a potential therapy that can offer
comparable oncological efficacy with a lower adverse event rate
may encourage more men to come forward for screening, thus
increasing the diagnostic pick-up.
A
B
C
D
Expert commentary
The trend in all surgical disciplines is for less-invasive treatments. Open surgery has given way to laparoscopic procedures
in many areas, and needle-ablative therapies (such as cryotherapy and radiofrequency ablation) are gaining ground [27,28].
The next conceptual change is the ability to treat entirely
noninvasively – and in HIFU this is realized.
The key difference between the SB-500 and other current
transrectal HIFU technology is the ability for the user to
tailor treatment to the individual. Other systems may have
real-time imaging, however, if the treatment delivered is
derived from a preset algorithm, any input from the user over
defining the margins of the prostate is obviated. Clinicians
familiar with transrectal ultrasound will acknowledge that
the characteristics of prostate glands differ between patients.
Even men who have had no prior therapy may have glands of
different density and with different patterns of micro- or
macrocalcification. Just as the amount of pressure that is
required to exert on the scalpel is based upon the real-time
characteristics of the tissue it is passing through, so is the
amount of energy required to cause ablation within the prostate gland. It is hoped that the early outcomes based on PSA
nadir [17] can be translated into medium-term biochemical
and histological freedom from disease, and ultimately
survival benefit.
Future developments
There is a great deal of work underway in the field of focused
ultrasound, both clinically and in the laboratory. In 2006, investigation into aspects of HIFU have generated over 1 million
pounds in UK government research grants from the Engineering
and Physical Sciences Research Council alone [102,103].
Considerable work has already taken place into the development of probes for other HIFU applications and phased array
transducer technology [29]. Most clinical devices in use have
either single-element therapeutic transducers or multielement
arrays that act as a single element. Transducers with annular
arrays, allowing the focal point to be electronically moved
towards and away from the transducer face, and 2D arrays
that allow horizontal, lateral and vertical translation of the
focal point without moving the transducer itself, have already
been constructed for experimental purposes (FIGURE 8). Coupled with this, speckle tracking technology is in development,
which may allow software to follow the movement of a target
over time such as through the respiratory cycle, or if the target
organ changes shape during the procedure due to edema [30].
This paves the way for a system that does not have to physically move during the treatment, but also accounts for any
intraoperative changes automatically.
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Figure 8. (A) Annular array electrode laser-scribed on convex side. (B)
Annular array installed in Sonablate®-500 HIFU probe. (C) Cylindrical 2D array
electrode laser-scribed on convex side of piezocomposite material prior to
forming, and (D) completed cylindrical HIFU array transducer assembled
from [29].
HIFU: High-intensity focused ultrasound.
Visual changes are not the only method of real-time feedback. Tissue elastography [31] and ultrasound thermometry [32]
are in development, but remain experimental; magnetic resonance imaging (MRI) [33] may accurately detect temperature
changes, however, MRI devices are costly, do not provide feedback as instantaneously as B-mode ultrasound and have not
been used clinically in the setting of transrectal prostate HIFU.
Novel methods enhancing the effect of focused ultrasound
are in development. Injected microbubbles have not only been
used as a contrast agent, but also to enhance ablation [34] and
aid the delivery of genes and chemotherapy [35]. Added to this
are the potential synergistic effects of combining focused ultrasound with ionizing radiation, which have yet to be explored,
but which may have a role in the treatment of high-risk or
locally advanced disease.
Lastly, interest in the effect of ablative technologies on immune
upregulation [36], potentially provoke the body into producing an
innate antitumor response following treatment, is growing.
Five-year view
In 5-years’ time the field of PCa therapy may have altered radically. Not only will new drugs and devices have emerged (possibly
based on those areas outlined above), but there may also have
been a paradigm shift in the way that early disease is viewed.
Whatever the modality, the current treatment for organ-confined
disease is ‘radical’ – the whole gland is treated, as well as the PCa
within it. The reasons for this are straightforward; PCa may be
multifocal in nature, detection of small foci of disease has been
difficult and the tools to perform such precise treatment were
missing. Already this picture has changed – a range of new modalities for targeted treatment have emerged, of which HIFU is arguably the most promising [37], and improvements in imaging and
biopsy technique allow greater levels of confidence that all significant foci of disease have been accounted for [38]. There is no doubt
that PCa can be multifocal, but if the targeting and treatment
Expert Rev. Med. Devices 3(6), (2006)
Sonablate®-500
methods are sufficiently accurate there is the potential for a ‘male
lumpectomy’, much in the same way as radical mastectomy has
been superseded by lumpectomy for early-stage breast cancer in
women [39]. This has the potential to greatly reduce the associated
side effects of radical treatment for PCa, and indeed trials are
currently underway to assess the feasibility of this approach.
• The Prostate Cancer Charity
www.prostate-cancer.org.uk
• Focus Surgery
www.focus-surgery.com
• UK HIFU
www.ukhifu.co.uk
Information resources
Conflict of interest
• The International Symposium for Therapeutic Ultrasound
www.istus.org
• Cancer Research UK
www.cancerhelp.org.uk
Rowland Illing is supported by a grant from Misonix. Mark
Emberton has acted as a paid consultant to Misonix. Misonix
is the European manufacturor and distributor of the
Sonablate device.
Key issues
• High-intensity focused ultrasound (HIFU) is a noninvasive therapy that has the potential to treat prostate cancer in a
radical manner.
• The Sonablate®-500 is the only transrectal device currently available that uses intraoperative feedback to guide treatment and to
tailor it to the individual.
• Early data from this technique look promising with medium-term outcome data from less tailored treatments looking similar to
results from standard therapies.
• The published side-effect profile following Sonablate-HIFU is better than current standard therapies.
• There is a great deal of interest in this field and developments are underway to refine both the conduct of therapy and the devices
in use.
• There is potentially a paradigm shift in the way early-stage prostate cancer is treated – more accurate diagnosis coupled with the
accuracy of HIFU could pave the way to widespread use of focal therapy for early-stage disease.
References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
7
Hoznek A, Menard Y, Salomon L,
Abbou CC. Update on laparoscopic and
robotic radical prostatectomy. Curr. Opin.
Urol. 15(3), 173–180 (2005).
1
Cancer Research UK. UK prostate cancer
incidence statistics. (2000).
8
2
Ahmed S, Lindsey B, Davies J. Emerging
minimally invasive techniques for treating
localized prostate cancer. BJU Int. 96(9),
1230–1234 (2002).
Gillett MD, Gettman MT, Zincke H,
Blute ML. Tissue ablation technologies for
localized prostate cancer. Mayo. Clin. Proc.
79(12), 1547–1555 (2004).
9
Kennedy JE. High intensity focused
ultrasound in the treatment of solid
tumours. Nat. Rev. Cancer 5, 321–327
(2005).
An excellent overview of the principles of
high-intensity focused ultrasound (HIFU)
and the scope of diseases currently
being treated.
3
Bill-Axelson A, Holmberg L, Ruutu M
et al. Radical prostatectomy versus
watchful waiting in early prostate cancer.
N. Engl. J. Med. 352(19), 1977–1984
(2005).
4
Steineck G, Helgesen F, Adolfsson J et al.
Quality of life after radical prostatectomy
or watchful waiting. N. Engl. J. Med.
347(11), 790–796 (2002).
5
Penson DF, McLerran D, Feng Z et al.
5-year urinary and sexual outcomes after
radical prostatectomy: results from the
prostate cancer outcomes study. J. Urol.
173(5), 1701–1705 (2005).
6
Khoo VS. Radiotherapeutic techniques for
prostate cancer, dose escalation and
brachytherapy. Clin. Oncol. R. Coll. Radiol.
17(7), 560–571 (2005).
www.future-drugs.com
••
10
•
11
ter Haar GR. Ultrasonic biophysics. In:
Physical Principle of Medical Ultrasonics.
Hill CR, Bamber JC, ter Haar GR (Eds).
John Wiley & Sons Ltd, Chichester, UK,
350–406 (2004).
Benchmark textbook describing the
physics behind therapeutic ultrasound
in detail.
Han PKJ, Coates RJ, Uhler RJ, Breen N.
Decision making in prostate-specific
antigen screening: National Health
Interview Survey. Am. J. Prev. Med. 30(5),
394–404 (2006).
12
American Cancer Society. Cancer facts
and figures. American Cancer Society, GA,
USA (2005).
13
Dyche DJ, Ness J, West M, Allareddy V,
Konety BR. Prevalence of prostate specific
antigen testing for prostate cancer in
elderly men. J. Urol. 175(6), 2078–2082
(2006).
14
Hardie C, Parker C, Norman A et al. Early
outcomes of active surveillance for
localized prostate cancer. BJU Int. 95(7),
956–960 (2005).
15
Chen W, Carlson RF, Fedewa R et al. The
detection and exclusion of prostate
neurovascular bundle (NVB) in
automated HIFU treatment planning
using a pulsed-wave doppler ultrasound
system. Procedings from the 4th
International Symposium on Therapeutic
Ultrasound. Kyoto, Japan, 23–26 (2005).
16
Madersbacher S, Pedevilla M, Vingers L,
Susani M, Marberger M. Effect of highintensity focused ultrasound on human
prostate cancer in vivo. Cancer Res. 55(15),
3346–3351 (1995).
17
Illing RO, Leslie TA, Kennedy JE,
Calleary JG, Ogden CW, Emberton M.
Visually directed HIFU for organ confined
prostate cancer – a proposed standard for
727
Illing & Emberton
••
18
the conduct of therapy. BJU Int. 98(6),
1187–1192 (2006).
Details the conduct of visually directed
HIFU and provides the rationale for
its use.
Uchida T, Baba S, Irie A et al. Transrectal
high-intensity focused ultrasound in the
treatment of localized prostate cancer: a
multicenter study. Acta Urol. Jpn 51,
651–658 (2005).
19
National Institute for Health and Clinical
Excellence. High-intensity focused
ultrasound for prostate cancer.
20
Uchida T, Illing RO, Cathart PJ,
Emberton M. To what extent does PSA
Nadir predict subsequent treatment failure
following trans-rectal HIFU for presumed
localized adenocarcinoma of the prostate?
BJU Int.98(3), 537–539 (2006).
First paper to define the association
between PSA nadir following prostate
HIFU and outcome.
•
21
22
•
23
•
24
25
26
Kirkham APS, Hoh I, Illing RO,
Freeman A, Emberton M, Allen C.
Magnetic resonance imaging of the prostate
after high intensity focused ultrasound.
Presented at the Annual Radiological Society
of North America (RSNA), Chicago, USA,
November 2006.
Uchida T, Ohkusa H, Nagata Y, Hyodo T,
Satoh T, Irie A. Treatment of localized
prostate cancer using high-intensity focused
ultrasound. BJU Int. 97(1), 56–61 (2006).
Provide the largest case series of patients
treated with the Sonablate®-500 (SB500).
Uchida T, Ohkusa H, Yamashita H et al.
Five years experience of transrectal highintensity focused ultrasound using the
Sonablate device in the treatment of
localized prostate cancer. Int. J. Urol. 13(3),
228–233 (2006).
Provide the largest case series of patients
treated with the SB-500.
Potters L, Klein EA, Kattan MW et al.
Monotherapy for stage T1-T2 prostate
cancer: radical prostatectomy, external
beam radiotherapy, or permanent seed
implantation. Radiother. Oncol. 71(1),
29–33 (2004).
27
Wilson JMQ, Junger G. Principles and
practice of screening for disease. WHO,
Geneva, Switzerland (1968).
28
Davol PE, Fulmer BR, Rukstalis DB. Longterm results of cryoablation for renal cancer
and complex renal masses. Urology 68(Suppl.
1), S2–S6 (2006).
Chaussy C, Thuroff S. High-intensity
focused ultrasound in prostate cancer:
results after 3 years. Mol. Urol. 4(3),
179–182 (2000).
42
Gelet A, Chapelon JY, Bouvier R et al.
Transrectal high-intensity focused
ultrasound: minimally invasive therapy of
localized prostate cancer. J. Endourol. 14(6),
519–528 (2000).
29
Lucey BC. Radiofrequency ablation: the
future is now. Am. J. Roentgenol. 186(Suppl.
5), S237–S240 (2006).
43
30
Seip R, Chen W, Carlson R et al. Annular
and cylindrical phased array geometries for
transrectal high-intensity focused ultrasound
(HIFU) using PZT and piezocomposite
materials. Kyoto, Japan: AIP (2005).
Thuroff S, Chaussy C, Vallancien G et al.
High-intensity focused ultrasound and
localized prostate cancer: efficacy results
from the European multicentric study.
J. Endourol. 17(8), 673–677 (2003).
44
31
Bercoff J, Pernot M, Tanter M, Fink M.
Monitoring thermally-induced lesions with
supersonic shear imaging. Ultrason. Imaging
26(2), 71–84 (2004).
Blana A, Walter B, Rogenhofer S,
Wieland WF. High-intensity focused
ultrasound for the treatment of localized
prostate cancer: 5-year experience. Urology
63(2), 297–300 (2004).
32
Curiel L, Souchon R, Rouviere O, Gelet A,
Chapelon JY. Elastography for the follow-up
of high-intensity focused ultrasound prostate
cancer treatment: initial comparison with
MRI. Ultrasound Med. Biol. 31(11),
1461–1468 (2005).
45
33
Miller NR, Bograchev KM, Bamber JC.
Ultrasonic temperature imaging for guiding
focused ultrasound surgery: effect of angle
between imaging beam and therapy beam.
Ultrasound Med. Biol. 31(3), 401–413
(2005).
Sylvester JE, Blasko JC, Grimm PD,
Meier R, Malmgren JA. Ten-year
biochemical relapse-free survival after
external beam radiation and brachytherapy
for localized prostate cancer: the Seattle
experience. Int. J. Radiat. Oncol. Biol. Phys.
57(4), 944–952 (2003).
46
34
Quesson B, de Zwart JA, Moonen CT.
Magnetic resonance temperature imaging
for guidance of thermotherapy. J. Magn.
Reson. Imaging 12(4), 525–33 (2000).
Demanes DJ, Rodriguez RR, Schour L,
Brandt D, Altieri G. High-dose-rate
intensity-modulated brachytherapy with
external beam radiotherapy for prostate
cancer: California endocurietherapy’s 10year results. Int. J. Radiat. Oncol. Biol. Phys.
61(5), 1306–1316 (2005).
47
Mouraviev V, Polascik TJ. Update on
cryotherapy for prostate cancer in 2006.
Curr. Opin. Urol. 16(3), 152–156 (2006).
48
Shariat SF, Raptidis G, Masatoschi M,
Bergamaschi F, Slawin KM. Pilot study of
radiofrequency interstitial tumor ablation
(RITA) for the treatment of radio-recurrent
prostate cancer. Prostate 65(3), 260–267
(2005).
49
Moore CM, Nathan TR, Lees WR et al.
Photodynamic therapy using meso tetra
hydroxy phenyl chlorin (mTHPC) in early
prostate cancer. Lasers Surg. Med. 38(5),
356–363 (2006).
50
Tucker RD. Use of interstitial temperature
self-regulating thermal rods in the
treatment of prostate cancer. J. Endourol.
17(8), 601–607 (2003).
35
Yu T, Xiong S, Mason TJ, Wang Z. The use
of a micro-bubble agent to enhance rabbit
liver destruction using high intensity
focused ultrasound. Ultrason. Sonochem.
13(2), 143–149 (2006).
36
Mitragotri S. Healing sound: the use of
ultrasound in drug delivery and other
therapeutic applications. Nat. Rev. Drug
Discov. 4(3), 255–260 (2005).
37
Wu F, Wang ZB, Lu P et al. Activated
anti-tumor immunity in cancer patients
after high intensity focused ultrasound
ablation. Ultrasound Med. Biol. 30(9),
1217–1222 (2004).
Bianco JR, Riedel ER, Begg CB,
Kattan MW, Scardino PT. Variations
among high volume surgeonsin the rate of
complications after radical prostatectomy:
further evidence that technique matters.
J. Urol. 173(6), 2099–2103 (2005).
38
Barqawi A, Crawford ED. Focal therapy
in prostate cancer: future trends. BJU Int.
95(3), 273–274 (2005).
39
Carey BM. Imaging for prostate cancer.
Clin. Oncol. R. Coll. Radiol.17(7),
553–559 (2005).
Chaussy C, Thuroff S. The status of highintensity focused ultrasound in the
treatment of localized prostate cancer and
the impact of a combined resection. Curr.
Urol. Rep. 4(3), 248–252 (2003).
40
Onik G. The male lumpectomy: rationale
for a cancer targeted approach for
prostate cryoablation. A review. Technol.
Cancer Res. Treat. 3(4), 365–370 (2004).
728
41
Websites
101
National Institute for Health and Clinical
Excellence.Interventional procedure
guideline 118 – high-intensity focused
ultrasound for prostate cancer – guidence
(2005)
www.nice.org.uk/page.aspx?o=IPG118guid
ance
Expert Rev. Med. Devices 3(6), (2006)
Sonablate®-500
102
103
Engineering and Physical Sciences
Reasearch Council (EPSRC). Funding
Awarded.
http://gow.epsrc.ac.uk/ViewDepartment.
aspx?DepartmentId=2181
Engineering and Physical Sciences
Reasearch Council (EPSRC)
http://gow.epsrc.ac.uk/ViewDepartment.
aspx?DepartmentId=681
www.future-drugs.com
Affiliations
•
Rowland Illing
Honorary Research Fellow, The Clinical
Effectiveness Unit, The Royal College of Surgeons
of England, 35/43 Lincolns Inn Fields, London,
WC2A 3PE;
Clinical Fellow, The Institute of Urology &
Nephrology, University College Hospital,
London WC1E 3DB, UK
Tel.: +44 207 869 6600
Fax: +44 0207 869 6644
[email protected]
•
Mark Emberton
Deputy Director, The Clinical Effectiveness
Unit, The Royal College of Surgeons of England,
35/43 Lincolns Inn Fields, London, WC2A
3PE;
Consultant Urological Surgeon, The Institute of
Urology & Nephrology, University College
Hospital, London WC1E 3DB, UK
Tel.: +44 207 869 6600
Fax: +44 207 869 6644
[email protected]
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