Download MR-guided focused ultrasound for cancer of the brain, liver, bone

Health Policy Advisory Committee on
Technology
Technology Brief: Update
MR-guided focussed ultrasound for cancer of the brain,
liver, bone, breast and prostate
November 2013
© State of Queensland (Queensland Health) 2013
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Technology, Company and Licensing
Register ID
WP048
Technology name
(MRgFUS)
Magnetic resonance-guided focussed ultrasound
Patient indication
For the treatment of patients with cancer of the
brain, liver, bone, breast and prostate.
Reason for assessment
Innovative, less invasive treatment with major expected health benefits to a large
patient group. MRgFUS (or MR-guided high intensity ultrasound, MRgHIFU) may
reduce the number or severity of adverse events associated with conventional
cancer treatment options (open surgery, chemotherapy and/or radiotherapy) and in
so doing, may reduce inpatient hospital stay and patient recovery time. In addition,
MRgFUS can provide real-time evaluation of the treatment.1
Stage of development in Australia
…
Yet to emerge
…
Experimental
_
Investigational for these
indications
…
Nearly established
Technology type
Device
Technology use
Therapeutic
…
Established
…
Should be taken out of use
Patient Indication and Setting
Speciality
Oncology and radiotherapy
Technology setting
Specialist hospital
Impact
Alternative and/or complementary technology
Substitution technology: New technology is a direct substitute for current
technology, or will substitute to a great extent.
Diffusion of technology in Australia
Unchanged since writing the original Brief.
Cost infrastructure and economic consequences
Unchanged since writing the original Brief.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
1
Evidence and Policy
Safety and effectiveness
Prostate cancer
Focal therapies for the treatment of prostate cancer include cryotherapy, laser and
photodynamic therapy, and ultrasound or MR-guided high intensity focussed
ultrasound (HIFU).2 Focal therapy for prostate cancer relies on the assumption that
treatment of the index lesion will prevent disease recurrence, whilst at the same
time reducing damage to surrounding tissues and organs. Current treatment options
for prostate cancer include radical prostatectomy or radiotherapy, which may result
in high rates of erectile dysfunction (30–90%), incontinence (5-20%) and rectal
toxicity (5–20%).3 Results of studies evaluating ultrasound-guided HIFU focal therapy
have reported markedly reduced rates of adverse events post-treatment including
urinary incontinence, reported in approximately one per cent of men, and erectile
dysfunction in 5–10 per cent3, 4 after treating the entire gland. Although the majority
of clinical experience of focal therapy for prostate cancer has been with ultrasoundguided HIFU, the technique is limited by the inability to monitor temperature
distribution in the prostate gland during treatment.5
In May 2013 the Urological Society of Australia and New Zealand issued a position
statement on the use of focal therapy to treat prostate cancer. The Society
concluded that “due to the lack of long-term data on focal therapy regarding the
ability to accurately target a lesion, on the long-term cancer control, on the side
effects of treatment , and on the ability to provide safe salvage options should
treatment failure occur – USANZ believes that focal therapy for prostate cancer
remains an experimental technique.”6
MRgFUS for prostate cancer is a relatively new procedure, with MRI providing
improved spatial and contrast resolution when compared to guidance provided by
ultrasound. It is thought that MRgFUS provides a good alternative for the
surveillance of patients with low-risk prostate cancer, especially those with localised
disease and those not suitable, or those who refuse radical prostatectomy.1 MRI,
with its superior anatomical resolution, can be used to accurately identify the index
lesion in addition to accurately guiding the ablation.1, 7
MRgFUS for prostate cancer was first performed under general anaesthesia but is
now usually performed using a spinal block.7 To date, two methods have been used
and it is unclear which method is most favoured, with both methods having some
advantages. In one method, a transurethral ultrasound transducer is inserted with
the patient lying in a supine position until located in the prostate gland (Figure 1). A
water-filled balloon inserted into the rectum provides cooling to the transducer as a
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
2
means of protecting the rectal wall during ablation. This method only allows
treatment of angular sectors within the prostate gland but treatment time is shorter
compared to method two due to the ability to treat continuously. However, only this
method can provide real-time thermometric monitoring during treatment.5 Method
two involves the insertion of an endorectal coil while the patient is lying in a supine
position. The coil is surrounded by a water-filled balloon, providing cooling to the
rectal wall during ablation (Figure 2).7 The transrectal approach uses a highly focused
beam which allows selective treatment of small volumes of the prostate (<0.1 mL).
However, long treatment times of up to 3-4 hours may result if a larger volume
requires treatment due to delays between exposures that are required to avoid
thermal damage to the rectum.5 Unlike ultrasound guided HIFU, MRgFUS is used for
targeted ablation, rather than treating the whole prostate gland.7
Figure 1
The ultrasound transducer is inserted via the urethra until positioned in the
5
prostate gland
Water-filled balloon
for cooling of coil
during ablation
Figure 2
The endorectal probe in position, with MRI guiding the ultrasound beam to
7
the area of interest
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
3
To date, there have only been a few, small case series published describing the
results of MRgFUS of the prostate in humans, with the majority of published studies
reporting on the results in canines.
An early feasibility study was conducted to assess the accuracy of MRgFUS for the
ablation of the prostate using the transurethral approach, building on the early work
in canines and five patients that were reported in 2010 by the same authors.8 Eight
patients (mean age 60 years, range 49-70 years) with localised prostate cancer
(Gleason score ≤7, PSA1 ≤15 μg/L) were recruited (level IV intervention evidence). All
patients were scheduled to undergo radical prostatectomy within 2-hours of
MRgFUS. A 1.5 tesla (1.5-T) MRI unit was used to locate the ultrasound transducer in
the prostate and to guide treatment. A target temperature of a maximum of 55°C at
the prostate boundary was attained using temperature feedback provided by the
MR, using images acquired every 5-seconds. 5
All patients tolerated the procedure without pain or discomfort. The overall
treatment time ranged from 104 to 218 minutes, which included administration of
anaesthesia, device insertion, device localisation, treatment planning, treatment
delivery and post-treatment imaging. Total time spent in the MR unit was an average
of 106 minutes (range 62-143 minutes). One patient experienced a 3 mm shift in the
position of the prostate between the time treatment planning images were obtained
and the time treatment commenced. A biopsy was conducted on the resected gland,
indicating that thermal coagulation was continuous and confined to the area of
treatment. The mean treatment rate was 0.5 ± 0.1 mL/min, with a mean targeting
accuracy of -1.0 ± 2.6 mm, which the authors stated indicated a tendency for under
treatment. The mean temperature measured along the boundary of thermal
coagulation was 52.3 ± 2.1°C. 5
A similar feasibility study was conducted by Napoli et al, who reported on the use of
an endorectal probe to perform MRgFUS using the ExAblate system and a 3-T MRI.
Five consecutive patients (median age 65.4 years, range 50-75 years) with biopsyproven localised prostate cancer (Gleason score 6/7) consented to undergo MRgFUS
prior to scheduled radical prostatectomy (level IV intervention evidence). The
endorectal probe was inserted under spinal anaesthesia and a threshold
temperature of 65°C was set in the target area. Radical prostatectomy took place an
average of nine days (range 7-14 days) post-MRgFUS treatment. 9
The average procedure time was 84 minutes (range 30-120 minutes) with no
technical difficulties or severe patient complications reported. The mean maximum
temperature measured in the target lesions was 81 ± 2°C, with a rectal wall
1
PSA= prostate-specific antigen
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
4
temperature of 35°C. The number of sonications required for each patient ranged
between seven and eleven, with a mean time of 13 seconds for each sonication. A
single pathologist examined the resected glands and results indicated negative
surgical margins in all cases. No residual viable tumour tissue was evident in the
ablation area or along the safety margins, however three patients had nonsignificant residual tumour and two had significant bilateral tumour visible outside
the treated area.9
These small case series demonstrated that MRgFUS of the prostate, using either the
transurethral or endorectal approach, is feasible and safe for patients, with accurate
thermal control and ablation. MRgFUS did not affect the morbidity and oncological
outcome of a subsequent radical prostatectomy. However, no conclusions can be
made on the effectiveness of MRgFUS on disease progression and patient outcomes
as these studies were designed to determine if surgery could be safely adopted after
treatment with MRgFUS, rather than using MRgFUS as an alternative treatment
option to surgery.
In their review, Zini et al referred to the largest case series to date of 18 patients
with localised prostate cancer treated with MRgFUS alone, reported by Cheng2 et al
to the European Congress of Radiology conference in 2011. A copy of this abstract
could not be obtained.10
Turkevich et al (2012) presented an abstract to the World Conference on
Interventional Oncology on the use of the ExAblate system with a 1.5 T MRI in
patients with localised, low-risk prostate cancer (Gleason score <6, PSA <10
ng/mL).11 Seven patients underwent eight MRgFUS treatments under epidural
anaesthesia with conscious sedation (level IV intervention evidence).
One patient required an additional treatment session for a newly detected
cancerous focus at 6-month follow-up. Adverse events such as haematuria, perineal
pain, post-treatment urinary incontinence or bowel related symptoms were not
reported by any of the patients. Before treatment, six patients were potent, and four
patients had returned to baseline sexual and erectile function within 3-months of
treatment.
Ongoing research: prostate cancer
Three ongoing or completed non-comparative studies describing the use of MRgFUS
for the treatment of prostate cancer were identified on the Clinical Trials database.
The one completed study (June 2012) built on the earlier work by Napoli et al, and
enrolled 12 men with localised prostate cancer, with a Gleason score <7 and PSA
Cheng CWS, Kwek JW, Thng CH, Lau W, Ho H, Khoo JBK. Initial experience with MRg FUS focal
therapy for low risk prostate cancer. European Congress of Radiology 2011; Mar 3-7; Vienna, Austria
2
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
5
levels <10 ng/mL. All patients were scheduled for radical prostatectomy and the
study was designed to determine if surgery could be safely adopted after treatment
with MRgFUS, rather than using MRgFUS as an alternative treatment option to
surgery (ClinicalTrials.gov Identifier: NCT01522118). The two remaining ongoing
feasibility studies were sponsored by the manufacturer, InSightec and are currently
recruiting patients. One is a multicentre study expecting to recruit a total of 80
patients from five centres: Toronto, Canada; Tel Hashomer, Israel; Rome, Italy;
Singapore and London, United Kingdom (NCT01226576). Patients must be aged
between 50 and 75 years with localised, low-risk prostate (Gleason score <6, PSA <10
ng/mL). Patients will be followed-up for a total of 24-months, with the primary
outcomes measured at six months being:
safety of the procedure – the number of adverse events related to the
procedure; and
the effectiveness of the procedure - adequate tumour control.
At 24-months patients will be assessed for quality of life issues including function
and satisfaction with the procedure, in addition to effectiveness of the procedure,
i.e. tumour control as measured by periodic PSA measurements and transperineal
biopsy. The study expects to be finalised by December 2013. The last study is being
conducted in the United States of America (USA) and expects to recruit 40 patients
(NCT01657942). The inclusion criteria are similar the previous study, however safety
and effectiveness follow-up of treatment-related incontinence and impotence as
well as tumour control (confirmed by transperineal biopsy results) at only 6-months.
Expected completion date of this study is December 2014.
An additional study was identified that was currently recruiting patients to be
treated with MRI guided focal prostate cancer laser ablation, aiming to recruit 60
men (NCT01094665).
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
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Breast cancer
No studies describing the use of MRgFUS for breast cancer have been published
since the 2011 Brief. One study reported on the effect of MRgFUS ablation and
thermal exposure on cadaver breast tissue. Ablations were performed in three nonembalmed cadaveric breast specimens. Anatomical images were obtained and breast
tissue temperature was measured. Following ablation the breast tissue samples
underwent histopathology. The authors concluded that as MRgFUS could
successfully be used to monitor tissue ablation and that cell death occurred after 5minutes at 75°C, MRgFUS is feasible as a non-invasive treatment of breast tumours.12
Another study reported on the use of MRgFUS as a surgical guide for non-palpable
breast tumours cadaveric breast tissue.13
Previously published studies describing the use of MRgFUS for breast cancer have
used the ExAblate system, which consists of a spherically-shaped transducer
embedded in a water bath, built into an MR table top .Ultrasound waves are directed
at the breast anteriorly using a “point-by-point” method. Merkel et al. (2013)
described the development of a dedicated MRgFUS breast platform, the Sonalleve
(Philips Healthcare, Finland), a system currently used for the ablation of uterine
fibroids and for pain palliation for patients with bone metastases. As with the
ExAblate, patients are positioned on the MR table with their breast inside a cup that
is filled with water to ensure conduction of the ultrasound beams to the breast
(Figure 3a). The breast cup, however, consists of eight separate focused ultrasound
modules with 32 transducer elements, which means that 270° of the breast is
surrounded by the structure (Figure 3b). The breast is laterally targeted by the
ultrasound, which has the effect of increasing the focal point to rib cage, heart and
lungs, reducing heating of critical structures (Figure 4). Results in women with breast
cancer treated with this system have yet to be reported.14
Figure 3
a
(a) The MRI table
top, demonstrating
the placement of
14
the breast cup (b)
b
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
7
a
Figure 4
b
a) Conventional breast MRgFUS demonstrating the short distance between
focal point and ribs
b) Lateral targeting of the breast, demonstrating a greater distance between
14
focal point and ribs
A group from the USA recently reported on refinements to published techniques for
the treatment of breast cancer with MRgFUS. Previously described techniques use a
single coil around the breast, positioned at the chest wall, which has the advantage
that it does not interfere with the ultrasound beam during treatment. However, this
technique has a relatively low signal-to-noise ratio and gives limited coverage of the
breast. This study used a dedicated 11-channel radiofrequency phased array coil that
was incorporated into a breast MRgFUS apparatus, for use in a 3-TMRI unit. Phased
arrays will improve signal-to-noise ratios and the multiple channels provide an
increase in signal sensitivity, which enables parallel image acquisition techniques.
Temporal resolution of temperature monitoring in the breast tissue should be
enhanced tissue, which may reduce motion artefacts such as breathing. The array
was tested in breast phantoms and five normal human volunteers. Signal-to-noise
ratios were improved in the phantom studies when the 11-channel breast coil was
compared to the single chest-loop coil. There was a 131 per cent improvement at the
centre of the breast, a 295 per cent improvement at lateral edge of the breast, and a
173 and 108 per cent improvement at the superior and inferior edge of the breast,
respectively. In addition, there was a 247 per cent improvement at the nipple area.
In the normal volunteers, the 11-channel breast coil provided better signal-to-noise
ratio coverage over the entire breast region. The increase in signal-to-noise ratio
translates to improved spatial and temporal resolution. In addition, the 11-channel
coil gave more precise temperature measurements throughout a larger volume of
the breast tissue compared to the single chest-loop coil.15
Of interest is the proof-of-concept study by Oerlemans et al. (2011), who described
using a combination of fluorescein-containing liposomes which, when the dye is
released by the heat of MRgFUS, acts as a means of lesion demarcation making
surgical resection of non-palpable breast lesions easier. To date, this technique has
only been used in phantoms.16
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
8
Ongoing research: breast cancer
Although no ongoing trials were identified on the United States’ National Institutes
of Health clinical trials database, the manufacturer advises that they are sponsoring
two ongoing trials: BC004 (excision-less trial) and BC006 (treat and resect protocol).
In addition, InSightec advise that several hospitals around the world (mainly Japan
and Europe) are currently treating patients under these protocols (personal
communication).
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
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Bone metastases
In October 2012, the United States’ Food and Drug Administration (FDA) approved
the use of the ExAblate MRgFUS system for pain palliation of metastatic bone cancer
in patients for whom radiation therapy is not an alternative. This is only the second
clinical indication that the system has obtained FDA approval for, after uterine
fibroids.17 In addition, the ExAblate 2100 system received CE Mark approval in June
2013 for the treatment of bone metastases, multiple myeloma, local tumour control,
bone denervation for local treatment of cancerous and benign primary and
secondary bone tumours or facet joint syndrome.
One peer-reviewed study and three conference abstracts were identified for
inclusion in this Brief, in addition to the safety and effectiveness data submitted to
the FDA for the approval of the ExAblate system for the treatment of bone
metastases. The non-comparative study by Napoli et al. (2013) enrolled 18
consecutive patients (mean age 62.7 ± 11.5 years) with painful bone metastases
from primary tumours of the lung (n=5), breast (n=4), kidney (n=3), prostate (n=3),
colon/rectum (n=2) and melanoma (n=1) (level IV intervention evidence). Seven
patients had a single bone lesion. In four patients the bone was the only secondary
organ involved, with the remaining 14 patients having additional metastatic disease
to the brain, lung or liver. All patients were undergoing chemotherapy at the time of
enrolment and 11 patients had undergone resection of the primary tumour.
Computed tomography and MR imaging were performed to determine the size and
location of the lesions to be treated. MRgFUS was performed using the ExAblate
2100 system and a 3-T MRI unit.18
Treatment was performed as a day procedure with patients anaesthetised (deep
sedation (n=5), epidural (n=8) or general anaesthesia (n=5)) for pain management
and to avoid patient movement. Patients were placed on the specially designed MR
table, with the transducer attached to the patient’s skin using a moist gel pad to
exclude any air which may interfere with the ultrasound signal. A single lesion per
patient was treated and ablation at the focal point was considered successful when
the temperature reached at least 60 to 70 C. Patients were monitored for one to
two hours before discharge. All patients were followed up at 1- and 3-days, 1- and 2weeks, and at 1-, 2- and 3-months post-MRgFUS treatment. The mean number of
sonications was 23.5 ± 4 (range 15-29) with a mean maximum sonication energy
used per sonication of 2736.8 ± 911.4 Joules (range 980-6677 Joules). The total time
spent in the treatment room ranged between 55 and180 minutes.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
10
Pain severity and pain interference scores were assessed3 at baseline and at followup, in addition to the non-perfused volume of tumour. Pain severity was assessed
using a 10-point scale questionnaire, where one corresponds to the absence of pain
and 10 to the worst pain experienced, with a decrease of two points considered to
be clinically significant. Pain interference score relate to the degree in which pain
interferes with the patient’s feeling and function across seven daily activities: general
activity, walking, work, mood, enjoyment of life, relations with others and sleep. The
non-perfused volume of tumour was assessed using contrast-enhanced MR images
by a blinded radiologist and defined as the volume of cancer tissue enhancing at
baseline that did not show any contrast uptake after treatment.
No treatment related adverse events were reported. The 3-month follow-up results
are summarised in Table 1. Mean pain severity scores decreased significantly at one
and three month follow-up when compared to baseline values. A pain severity score
of zero, requiring no medication intake, was reported in 13/18 (72.2%) of patients
(responders). Of the remaining five patients, three reported a partial response with a
pain reduction of at least two points without an increase in analgesic intake. Two
patients reported pain recurrence requiring a 25 per cent increase in pain
medication when compared to baseline (non-responders). Both of these patients
had a complete response at 2-months but presented with disease progression at 3months. Similarly, the pain interference scores decreased significantly at one and
three months when compared to baseline. The non-perfused volumes remained
stable after treatment when compared to imaging taken immediately after MRgFUS
treatment. There was no difference in the non-perfused volume when responders
were compared to partial or non-responders.18
Table 1
Evaluation of pain and tumour volume at baseline and follow-up
Baseline
1-month follow-up
3-month follow-up
Pain severity
score
7.1 ± 2.08, range 4-10
95% CI [6.07, 8.15]
2.5 ± 1.4, range 0-5
95% CI [1.81, 3.2],
p=0.001
1 ± 1.1, range 0-3
95% CI [0.0, 1.85],
p=0.001
Pain
interference
score
4.8 ± 1.8, range 2.1-8.7
95% CI [3.86, 5.67]
1.8 ± 1.0, range 0.3-4.6
95% CI [1.32, 2.32],
p=0.001
0.7 ± 0.6, range 0-2.6
95% CI [0.06, 0.92],
p=0.001
45.2 ± 22.1%, range 20-93%
95% CI [34.19, 56.14],
p=0.08
43.7 ± 21.3%, range 20-93%
95% CI [33.17, 54.38],
p=0.08
Non-perfused
volume
3
18
Pain scores were assessed using the Brief Pain Inventory-Quality of Life criteria
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
11
This small study demonstrated that MRgFUS was a safe and effective tool for pain
palliation in patients with painful bone metastases, however longer follow-up would
be required to determine the length of effect time.
A recent conference abstract reported on the results of a multicentre study4 that
randomised patients 3:1 to treatment with MRgFUS (n=107) or sham treatment
(n=35) (level III-1 intervention evidence – method of randomisation was unclear). All
patients had painful bone metastases where radiation therapy was ineffective or
contraindicated. Patients in the sham arm who did not report any pain relief within
2-weeksof treatment were allowed to cross over for salvage MRgFUS treatment. The
primary outcome was pain response and quality of life5, in addition to safety of the
procedure.19
At 3-month follow-up, 67 per cent (95% CI[57.5, 76.0%]) of patients in the MRgFUS
treatment arm reported a clinically significant improvement in pain scores compared
to 20 per cent of the patients in the sham arm (p<0.0001). At baseline, both groups
had a median pain score of 7.0, whereas at 3-month follow-up median pain scores
for the MRgFUS group were reduced to 2.0 compared to 6.0 in the sham group.
Similarly, the MRgFUSgroup reported a clinically significant improvement in pain
scores compared to the sham arm, with an average decrease in pain score of 2.4
versus 0.2 (p<0.0001). No adverse events associated with the treatment were
reported.19
The same research group reported on the same patients at a different conference.20
However, only the results from 122 patients treated for 125 lesions with MRgFUS
were reported, which may possibly include the results from some of patients in the
sham group who crossed over (this was not explicitly stated). Responders were
considered to be those patients who reported a reduction of two or more points on
the pain scale, without a significant increase in pain medication (<25% difference
from baseline).
Using these criteria, 87 treatments produced a response. Univariate and multivariate
analyses identified five factors that were related to response rate:
sex (p<0.001), with a higher likelihood of response associated with being
female (odds ratio (OR) = 4.55, 95% CI [1.63, 12.68]);
history of radiation therapy (p=0.001), associated with a decreased likelihood
of response (OR = 0.33, 95% CI [0.12, 0.91]);
4
Philadelphia, Tampa, Boston, San Diego and Virginia, USA; Rostov-on-Don and St Petersburg,
Russia; Toronto, Canada; Haifa and Ramat-Gan, Israel; and Rome, Italy.
5
Pain scores were assessed using the Brief Pain Inventory-Quality of Life criteria (BPI-QOL) and
quality of life (QOL) by the numerical rating scale (NRS)
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
12
primary tumour site (p=0.009), with metastases from breast cancer (n=46)
showing the best response at 87 per cent;
treated tumour location (p=0.021) with a higher likelihood of response
associated with osteoblastic tumour (OR = 4.0, 95% CI [1.13, 14.2]);and
treatment energy (p<0.001), with higher energy densities associated with an
increased chance of a response.20
This study was the pivotal study in the application for approval from the FDA. 21
Although the conference abstracts reported no adverse events, the safety and
effectiveness data in the FDA application is more comprehensive, with a total
number of 82 adverse events reported in 62 patients. Results were divided into
those patients from the Russian cohort (ExAblate n=50, sham n=18) and the nonRussian cohort (ExAblate n=83, sham n=19). All of the Russian patients were treated
under general anaesthesia, whereas patients in the non-Russian cohort were treated
under local or conscious sedation. This resulted in a much higher number of adverse
events reported in the non-Russian cohort that were related to pain during the
procedure. A total of 77 adverse events in 57 patients were reported in the nonRussian cohort, of which 48 per cent were transient pain and discomfort during
treatment. A total of 71 patients (53%) experienced no adverse events. Four
significant adverse events were reported, including a third degree skin burn, leg
neuropathy in one patient and two events of fracture, which may be considered a
complication of bone metastases rather than as a result of treatment. Interestingly, a
higher proportion of patients in the Russian cohort were responders (Table 2). These
patients were treated with a higher mean energy compared to the non-Russian
cohort (6.9 ± 2.8 versus 4.5 ± 3.0 Joules/mm2); however their treatment time was
less (54 ± 38.8 versus 78.1 ± 48.5).
Table 2
Proportion of responders in the pivotal FDA study
Responders
N
ExAblate
Sham
Non-Russian
cohort
83
55% (35/64)
26% (5/19)
p=0.04
Russian cohort
56
90% (36/40)
13% (2/16)
p<0.0001
Opioid medication use at 3-months was compared to baseline intake for those
patients considered responders. The majority of responders in the non-Russian
cohort either stopped (10/35, 29%) or reduced (10/35, 29%) their medication, with
43 per cent reporting no change. In contrast, the majority of responders in the
Russian cohort reported no change in their medication (25/36, 69%).
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
13
The FDA concluded that data from this study supported that the ExAblate system
was safe and effective for the palliation of pain resulting from bone metastases, and
does not represent an increased risk to patients who are already at significant risk
due to their underlying disease. In approving the ExAblate system, the Center for
Devices and Radiological Health required that the performance of the device
continue to be monitored in actual clinical use, requiring a post-approval study to
evaluate the safety and effectiveness when the device is used in the intended
patient population.21
The results from another small case series (n=31) were presented at the World
Conference on Interventional Oncology (level IV intervention evidence). Patients
(mean age 55 years, range 19-76 years) with painful bone metastases resulting from
primary tumours of the breast (n=19), stomach (n=4), bronchus (n=2), bladder (n=2)
and other (n=4) were treated with MRgFUS and follow-up for 3-months. No
treatment-related adverse events were reported. Three patients died during the
follow-up period from progression of their disease. Of the remaining 28 patients, all
reported a clinically significant reduction in pain as described in previous studies at
3-months. The mean worst pain score decreased gradually over time from a baseline
value of 6.9 to 0.9 at 3-months (Figure 5). As with other studies, MRgFUS appeared
to be effective at reducing pain, however longer term follow-up is required to
ascertain length of treatment effect and if re-treatment would be required.22
Figure 5
Average pain score reduction versus time
22
Of interest are two small case series that describe the innovative use of MRgFUS for
the treatment of chronic musculoskeletal pain (level IV intervention evidence). Izumi
et al. (2013) reported the results of eight patients with osteoarthritis (OA) of the
knee (mean age 78 ± 6.4 years). All patients had grade 4 medial knee OA and were
eligible for a total knee replacement. The primary outcome measure was VAS 6 scores
6
VAS = visual analogue scale
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
14
during walking, with zero representing no pain and 100 representing maximum pain,
with a 50 per cent decrease in pain scores considered to be a successful response.
The mean treatment time was 74 minutes (range 50-120 minutes), with a mean
number of sonications of 12.4 (range 10-20) per patient. Six of the eight patients
were considered responders with a decrease in VAS scores at one month follow-up
compared to baseline values. However, two patients proceeded to a total knee
replacement and one patient switched to opioid therapy at one month. Four patients
had long lasting pain alleviation with a mean VAS reduction of 72.6 per cent at 6months.23
Weeks et al. described the use of MRgFUS to treat chronic pain emanating from
facet joint OA of the lower back (level IV intervention evidence). Although 18
patients (mean age 48.2 years, range 33-60 years) with chronic back pain underwent
treatment, only 13 patients were enrolled for follow-up. Patients underwent
treatment in an outpatient setting with the ExAblate 2000 system, with (n=10) or
without (n=3) sedation. Five patients reported claustrophobia when first placed
inside the MRI unit; however this was resolved after administration of sedation. Four
patients with a body mass index >30 reported discomfort despite sedation due to
difficulty fitting them into the MRI aperture. The mean time spent in the MR unit was
188 minutes (range 102-265) and the mean treatment time was 97 minutes (range
58-186). Treatment consisted of a mean of 23 sonications (range 10-35).24
No adverse events related to the treatment were reported. Pain and quality of life
scores were reported at baseline and 1-week, and 1-, 2-, 3- and 6-months. At
baseline, the average NRS pain score was 6.42, with a worst pain score of 7.96. At 6months there was a reduction of 3.87 (60.2%) in the average pain score and the
reported worst pain score was 4.08, a reduction of 51 per cent. At the same time,
improvements in the Oswestry Disability score were noted (45.88%) and a reduction
in the BPI-QOL score (61.9%). These results indicate that MRgFUS may be a safe
treatment option for patients with chronic facet joint pain with treatment effects
lasting for at least 6-months. Ideally this pilot study should be followed up with a
larger, randomised controlled trial.24
Ongoing research: Bone metastases cancer
Three InSightec-sponsored trials have been identified. One small randomised trial
identified in the 2011 Brief (ClinicalTrials.gov Identifier: NCT01091883) comparing
MRgFUS to external beam radiation therapy for the palliation of pain in patients with
metastatic and myeloma bone tumours was last updated in September 2012. The
estimated study completion date was March 2013, however the current status of the
trial is unclear. A Phase IV study (NCT01833806) aims to study the safety and efficacy
of ExAblate treatment of metastatic bone tumours for the palliation of pain. The
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
15
primary outcome of the study is the proportion of responders at 3-months, i.e. those
patients with reduced pain after treatment. The secondary outcome is the number
and type of adverse event associated with the treatment. This study intends to
recruit 70 patients beginning September 2013, with an estimated completion date of
October 2016. Another small phase IV post approval registry study (BM019-Registry)
(NCT01834937) aims to examine adverse events reported in patients undergoing
ExAblate treatment for palliation of pain from metastatic bone tumours during the
first 2-years of commercial experience in the USA. Although the planned start date
was June 2013, the study has not yet started recruitment, which is estimated to be
50 patients. The estimated study completion date is December 2015.
Two studies sponsored by Phillips were identified. A small pilot study (NCT01309048)
aims to confirm the safety and technical of MRgFUS for palliation for pain of skeletal
metastases. The primary outcome measures include reduction of pain score,
reduction of pain medication use, and complications and adverse events at 90 days.
Secondary outcomes are changes in bone density and quality of life measure at 90
days. The study enrolled 10 patients and has been completed, however no results
have been published to date. Another ongoing multi-centre, non-comparative study
is evaluating MRgFUS for palliation of painful skeletal metastases. The primary
outcome is pain response to therapy using the BPI questionnaire at 30 days after
treatment. Secondary outcome measures include the total number of adverse events
at 90 days after treatment, quality of life at baseline (before treatment) and at 7, 14,
30, 60, and 90 days after treatment, pain response in radiation-naïve patients at 30
days and temporal evolution of pain response during the first 30 days after
treatment. The study began in September 2012 and hopes to recruit 64 patients with
an estimated completion date of December 2014.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
16
Diseases of the brain
No recent published studies since the original Brief reporting the use of MRgFUS for
the treatment of brain cancer were identified. However, several novel potential
intracranial applications of MRgFUS have been described in the literature including
the treatment of: chronic neuropathic pain, essential tremor, clot lysis in ischaemic
stroke, epilepsy, trigeminal neuralgia and hydrocephalus.25
Lipsman et al. (2013) reported the results of a proof-of-concept study, using MRgFUS
to treat four patients (mean age 70.8 years, range 58-77 years) with medication
resistant essential tremor. Surgical options for these patients included thalamotomy,
gamma knife treatment or deep brain stimulation. The mean duration of illness in
the four patients was 17.8 years, with a range of 6-25 years. Although 10 patients
were originally screened for inclusion in the study, six were excluded due to age,
minimal tremor severity or previous neurosurgery. Patients were followed up for 3months and the primary effectiveness outcome was tremor severity and functional
impairment, in addition to any adverse events from the procedure.26
The thalamus contralateral to the most disabled hand was targeted. Although
patients were awake during the procedure, a local anaesthetic was used to fix the
stereotactic frame to the skull. Treatment was performed with the ExAblate system
in conjunction with a 3-T MRI scanner. The mean number of sonications was 22.5,
with a range of 12-29. The procedure lasted 5-6 hours including fitting of the frame,
positioning of the patient, pre- and post-treatment imaging, as well as treatment
time.26
All four patients demonstrated an immediate improvement in tremor in the
dominant hand, which was sustained over the 3-month follow-up period. Mean
reduction in tremor score of the treated hand was 89.4 and 81.3 per cent at one and
three month follow-up, respectively. Patients also had improvements in their selfrated functional impairment scores, with a reduction of 51 per cent in their
perceived functional disability relating to their tremor. One patient developed a
lower limb deep vein thrombosis at 1-week after the treatment which may have
been related to the length of the procedure. No other adverse events were reported.
An example of functional ability before and after treatment is given in Figure 6, with
the patient demonstrating a clear improvement post-treatment in their ability to
draw free-hand and to follow pre-existing lines. This study demonstrates the
potential for the non-invasive treatment of essential tremor with MRgFUS, however
larger studies are required, with longer follow-up.26
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
17
Figure 6
Functional ability pre-and post-treatment. A: One patient completed a freehand drawing before treatment (LHS) and immediately after treatment
(RHS). In addition patients were asked to draw between the lines of the
diagrams in B before treatment (LHS) and immediately after treatment
26
(RHS).
A similar study was conducted by Elias et al (2013) who enrolled 15 patients (mean
age 66.6 ± 8.0 years, range 53 to 79 years) with medication resistant essential
tremor. Patients were excluded if they had previously undergone stereotactic or
cranial surgery or if they had another neurological condition such as Parkinson’s
disease. Patients had a mean history of tremor of 32.0 ± 21.3 years (range 4 to 60
years), with a mean baseline score on the Clinical Rating Scale for Tremor (CRST) of
54.9 ± 14.4. The procedure was conducted using a 3T MRI and the ExAblate Neuro.
Follow-up assessments were performed at 1-day, 1-week, 1, 3 and 12-months.27 It
should be noted that although this study was funded by the Focused Ultrasound
Surgery Foundation, InSightec made financial contributions to this foundation and
oversaw the study.
As with the previous study, patients were awake during the procedure and a local
anaesthetic was used to fix the stereotactic frame to the skull. Patients received a
mean number of 17.9 ± 4.6 (range 11 to 26) sonications. Final sonication energies of
10,320 ± 4,537 J (range 6,500 to 20,800) which produced a maximal temperature
voxel of 58.5 ± 2.5°C in the lesion.
A number of adverse events were reported, some of which were transient and
related to the use of the stereotactic frame (headache, scalp numbness). In addition,
transient adverse events related to sonication and MRI were reported in a number of
patients including nausea (n=5), head pain (n=9) and syncope (n=1). Of those adverse
events related to thalamotomy, the most common was paresthesia of the lip (n=9) or
fingers (n=5). At 12-months follow-up, four patients experienced persistent
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
18
paresthesia. In addition, four patients experienced ataxia that resolved by one
month and one patient dysmetria for the same time.
There was a significant improvement in tremor in the contralateral hand from a
mean baseline CRST score of 20.4 ± 5.2 to a score of 4.3 ± 3.5 at 3-months and 5.2 ±
4.8 at 12-months (p=0.001), representing a 75 per cent reduction from baseline at
12-months (Figure 7). There was no significant difference in tremor score for the
ipsilateral hand from baseline to 12-months. Total tremor scores were also reduced
significantly from 54.9 ± 14.4 at baseline to 24.3 ± 14.8 at 12-month follow-up
(p=0.001). Disability scores improved from 18.2 to 2.8 (p=0.001) and patient’s
perception of their quality of life improved with scores reduced from 37 to 11 per
cent (p=0.001). 27
As with the previous study, these results are encouraging but further randomised
controlled trials are required to assess the clinical effectiveness of this procedure.
Figure 7
Individual hand tremor CRST scores
27
A small case series reported on the use of MRgFUS to treat chronic therapy-resistant
neuropathic pain using the ExAblate 4000 system with a 3-T MRI. Patients were aged
between 45 and 75 years with a duration of pain ranging from 1.5 years to 21 years.
Pain was located in the face (n=3), thorax (n=1), lower extremity (n=3), upper
extremity (n=4). The cause of pain varied. As in the previous studies, the patient’s
head was immobilised in a stereotactic frame. The posterior of the thalamic central
lateral nucleus was targeted. Patients were fully awake during the procedure. The
procedure was performed unilaterally in five patients and bilaterally in six.28
Pre and post-treatment data is summarised in Table 3. In the first two patients the
therapeutic lesions were too small, and therefore only the results of nine of the 11
patients deemed to have successful treatment are presented. Pain was assessed
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
19
using the visual analogue scale, with 1 representing the least amount of pain and 100
representing the worst pain. At baseline, the mean VAS score was 59.5, which was
reduced at 3-month and maintained at 1-year follow-up. This translated to an
approximate 40 per cent post-operative improvement. Significant pain relief was
reported immediately following treatment, however this diminished over time. Of
the eight patients with data available at 1-year follow-up, five had stopped taking
pain relief medication; however three patients had an unchanged medication
regimen.28
During the procedure, one patient experienced a displacement of the head frame,
which was repositioned without any negative consequences. In addition, one patient
experienced a bleed with ischaemia in the motor thalamus.28
Table 3
Summary of the post-treatment data of the 11 patients who underwent
MRgFUS for neuropathy
Pain relief (%)
Patient
VAS score (lowest-highest, mean)
1-year
drug
intake
Acute
2-days
3month
s
1-year
Baseline
3-months
1-year
1
100
70
0
LFU
70-80
16-79
UN
Reduced
2
30
30
0-30
LFU
72-100
40-70
UN
No
change
3
10
100
80
80
52-73, 62.5
5-20, 12.5
9-16, 12.5
Ceased
4
70
50
50
95
40-80, 60
0-72, 36
9-36, 22.5
Ceased
5
100
80
0
Died
12-78, 45
0-50, 25
UN
UN
6
30
100
90
100
39-62, 50.5
0-11, 5.5
0
Ceased
7
30
50
50
40
22-85, 53.5
15-84, 49.5
21-86, 53.5
No
change
8
100
100
70
50
56-85, 70.5
13-80, 46.5
77
No
change
9
0
10
0
0
67-90, 78.5
54-89, 71.5
11-84, 47.5
No
change
10
100
75
90
80
44-91, 67.5
0-14, 7
0-28, 14
Ceased
75
15
10
25-70, 47.5
30-80, 55
30-80, 55
Ceased
71.1
49.4
56.9
59.5
34.3
35.3
UN
11
Overall
mean*
55
* The mean values were only calculated for cases 3-11
LFU = lost to follow-up, UN = unavailable, VAS = visual analogue scale
Although the ExAblate 4000 transcranial MR system has not received FDA approval
for the treatment of brain cancer, in December 2012 it received the CE Mark for the
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
20
thermal ablation of targets in the thalamus, subthalamus and pallidum regions of the
brain. To this end, it can be used for the treatment of neurological disorders such as
essential tremors and tremor dominant idiopathic Parkinson’s disease; and
neuropathic pain in the brain.
Ongoing research: brain cancer
One InSightec-sponsored single-group study evaluated the safety and feasibility of
ExAblate in the treatment of glioma or metastatic brain tumours (ClinicalTrials.gov
Identifier: NCT01473485), with an intended patient number of 10. No primary or
secondary outcome measures have been reported. The last update of the study
(March 2012) indicated that the study is currently recruiting however the intended
finishing date was April 2012. Although not listed on the National Institutes of Health
clinical trials database, the manufacturer advises they are sponsoring a large, doublearm blinded study (treatment vs. sham) to evaluate the effectiveness and safety of
ExAblate transcranial MRgFUS thalamotomy in the treatment of medication
refractory essential tremor (IDE number G120246) (personal communication).
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
21
Cancer of the liver
In the 2011 Brief, no human studies describing the use of MRgFUS for the ablation of
liver cancer were identified despite several reviews discussing the possibility. Since
that time, de Senneville et al. have reported on the use of MRgFUS in porcine
livers.29 One group in Italy described the results of ultrasound-guided HIFU in 22
patients with mixed indications, including pancreatic solid lesions, and liver and/or
bone metastases from breast cancer. The effect of treatment was assessed by MRI.30
Ongoing research: liver cancer
No ongoing trials identified.
Economic evaluation
No economic evaluation of MRgFUS for an indication other than uterine fibroids
could be identified. Economic evaluations, especially on the use of MRgFUS for the
treatment of bone metastases are required.
Summary of findings
MRgFUS potentially offers a unique, non-invasive, radiation-free way of treating
many types of cancer, which would appeal to many patients. However, apart from
the pain palliation for patients with bone metastases, the technology remains
immature. In the treatment of prostate cancer, research is still ongoing to decide
which method is more effective and/or acceptable to patients: the endorectal or
transurethral approach. Only small human case series have been published. Several
non-comparative studies for prostate cancer are ongoing. Similarly with breast
cancer, methods of imaging and technique are still developing. There appeared to be
no advancement of the evidence base for the use of MRgFUS to treat liver cancer.
Although this was also true for the treatment of brain cancer, the interest in
neurology appears to lie in the use of MRgFUS for the treatment of other conditions
such as essential tremor and neuropathic pain. The small proof-of-concept studies
included in this Brief indicate that the use of MRgFUS for these conditions may be a
feasible option, however larger comparative studies are required.
The most mature evidence base was that for the palliation of pain from bone
metastases. The FDA approved the use of the ExAblate system for this indication in
late 2012, based on the results of a RCT. It would appear that not all patients will
respond to this treatment, with pain relief reported in 67-100 per cent of patients,
with a corresponding reduction in intake of pain medication. All case series and the
RCT included in this Brief only reported on the effectiveness of treatment, that is, a
reduction in pain at 3-months post treatment. Longer-term follow-up would be
required to determine the length of treatment effectiveness. There were differences
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
22
in treatment modality reported when the RCT was stratified into those patients
treated in Russian and non-Russian centres. These differences included the method
of sedation, which impacted on the amount of procedure pain reported by patients,
and the level of energy used for the sonications. These differences in technique need
to be clarified. Of interest is the potential use of MRgFUS for the treatment of
osteoarthritis.
HealthPACT assessment
The evidence base for the use of MRgFUS to treat cancers is currently immature,
requiring more studies to demonstrate its effectiveness, especially in terms of longterm follow-up of patients. The use of MRgFUS to treat neurological conditions, such
as essential tremor, appears to be promising. It is likely that, as the technology
matures; further evidence will be published and identified by routine horizon
scanning activities. Therefore it is recommended that no further research on behalf
of HealthPACT is warranted at this time.
Number of studies included
All evidence included for assessment in this Technology Brief has been assessed
according to the revised NHMRC levels of evidence. A document summarising these
levels may be accessed via the HealthPACT web site.
Total number of studies
Total Level IV intervention evidence studies for prostate cancer
Total number of studies for breast cancer
Total level IV intervention evidence studies for bone metastases cancer
Total level III-1 intervention evidence studies for bone metastases cancer
Total number of studies for liver cancer
Total number of Level studies for brain cancer
8
3
0
4
1
0
0
References
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2.
Da Rosa, MR, Trachtenberg, J et al (2011). 'Early experience in MRI-guided
therapies of prostate cancer: HIFU, laser and photodynamic treatment'.
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3.
Dickinson, L, Ahmed, HU et al (2013). 'A multi-centre prospective
development study evaluating focal therapy using high intensity focused
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Trials, 36 (1), 68-80.
4.
Ahmed, HU, Freeman, A et al (2011). 'Focal therapy for localized prostate
cancer: a phase I/II trial'. J Urol, 185 (4), 1246-54.
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5.
Chopra, R, Colquhoun, A et al (2012). 'MR imaging-controlled transurethral
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6.
USANZ (2013). Position Statement on Focal Therapy for Prostate Cancer.
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Ellis, S, Rieke, V et al (2013). 'Clinical applications for magnetic resonance
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8.
Siddiqui, K, Chopra, R et al (2010). 'MRI-guided transurethral ultrasound
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9.
Napoli, A, Anzidei, M et al (2013). 'Real-time magnetic resonance-guided
high-intensity focused ultrasound focal therapy for localised prostate cancer:
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10.
Zini, C, Hipp, E et al (2012). 'Ultrasound- and MR-guided focused ultrasound
surgery for prostate cancer'. World J Radiol, 4 (6), 247-52.
11.
Turkevich, VG, Nosov, AK et al (2012). 'Preliminary clinical experience with
the use of the exablate magnetic resonance guided focused ultrasound
surgery (MRgFUS) system for focal treatment of organ-confined low-risk
prostate cancer'. Journal of Vascular and Interventional Radiology,
Conference: World Conference on Interventional Oncology, WCIO 2012
Chicago, IL United States 23 (6), 853.e20.
12.
Merckel, LG, Deckers, R et al (2013). 'The effects of magnetic resonance
imaging-guided high-intensity focused ultrasound ablation on human cadaver
breast tissue'. Eur J Pharmacol, 717 (1-3), 21-30.
13.
Bitton, RR, Kaye, E et al (2012). 'Toward MR-guided high intensity focused
ultrasound for presurgical localization: focused ultrasound lesions in
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14.
Merckel, LG, Bartels, LW et al (2013). 'MR-guided high-intensity focused
ultrasound ablation of breast cancer with a dedicated breast platform'.
Cardiovasc Intervent Radiol, 36 (2), 292-301.
15.
Minalga, E, Payne, A et al (2013). 'An 11-channel radio frequency phased
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16.
Oerlemans, C, Nijsen, F et al (2011). 'A novel approach to identify nonpalpable breast lesions combining fluorescent liposomes and magnetic
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17.
FDA (2012). Magnetic Resonance guided Focused Ultrasound Surgery System
(MRgFUS), ExAblate Model 2000/2100 - P110039. [Internet]. US Food and
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http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/Device
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ApprovalsandClearances/Recently-ApprovedDevices/ucm327521.htm
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Napoli, A, Anzidei, M et al (2013). 'Primary pain palliation and local tumor
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Hurwitz, M, Meyer, JE et al (2013). 'Magnetic resonance guided focused
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Meyer, JE, Pfeffer, R et al. Pain Palliation of Bone Metastases Using Magnetic
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Turkevich, VG, Savelyeva, VV et al (2012). 'Result of Treatment Painful Bone
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23.
Izumi, M, Ikeuchi, M et al (2013). 'MR-guided focused ultrasound for the
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24.
Weeks, EM, Platt, MW&Gedroyc, W (2012). 'MRI-guided focused ultrasound
(MRgFUS) to treat facet joint osteoarthritis low back pain--case series of an
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25.
Monteith, S, Sheehan, J et al (2013). 'Potential intracranial applications of
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26.
Lipsman, N, Schwartz, ML et al (2013). 'MR-guided focused ultrasound
thalamotomy for essential tremor: a proof-of-concept study'. Lancet
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27.
Elias, WJ, Huss, D et al (2013). 'A pilot study of focused ultrasound
thalamotomy for essential tremor'. N Engl J Med, 369 (7), 640-8.
28.
Jeanmonod, D, Werner, B et al (2012). 'Transcranial magnetic resonance
imaging-guided focused ultrasound: noninvasive central lateral thalamotomy
for chronic neuropathic pain'. Neurosurgical focus, 32 (1), E1.
29.
Denis De Senneville, B, Ries, M et al (2011). 'Non-invasive thermotherapy of
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30.
Orgera, G, Monfardini, L et al (2011). 'High-intensity focused ultrasound
(HIFU) in patients with solid malignancies: evaluation of feasibility, local
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MRgFUS for cancer of the brain, liver, bone and breast: November 2011
26
TECHNOLOGY BRIEF 2011
Register ID:
WP048
Name of Technology:
MRI guided, high intensity focussed
ultrasound
Purpose and Target Group:
For indications other than uterine fibroids,
including cancer of the brain, liver, breast
and bone
Stage of Development (In Australia):
…
Yet to emerge
…
Experimental
_
Investigational for these
indications
…
Nearly established
…
Established
…
Should be taken out of use
Australian Therapeutic Goods Administration approval
Yes
ARTG number (s)
118009 MEDITRON P/L - Hyperthermia
system, ultrasound
128137 GE Medical Systems Australia Pty
Ltd - Hyperthermia system, ultrasound
No
Not applicable
International Utilisation:
COUNTRY
LEVEL OF USE
Trials Underway
or Completed
Limited Use
Widely Diffused
Liver
Korea
9
Germany
9
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
1
Bone
Canada
9
China
9
Israel
9
United States
9
Korea
9
United States
9
Breast
Brain
Prostate
9
Impact Summary:
In August 2008, an horizon scanning update was completed on the use of MRIguided, high-intensity focussed ultrasound (MRgFUS) for the treatment of
symptomatic uterine fibroids. The Royal Woman's Hospital, Melbourne, Australia,
began treating women in September 2008 using a 3T MRI and the ExAblate 2000
with a uterine fibroids application. All data on patient treatment and outcomes are
being collected for future analysis. There has been a great deal of interest in the use
of MRgFUS for the treatment of other indications including cancer of the breast,
liver, prostate, brain and bone. This summary will present a brief overview of the
evidence for these indications. Currently there are two high-intensity focussed
ultrasound systems registered on the TGA: one distributed by Meditron Pty Ltd
(Victoria) and manufactured by Focus Surgery (Indianapolis, USA), which was
registered on the ARTG in 2005 (ARTG 118009); the other is distributed by GE
Healthcare Australia Pty Ltd and manufactured by InSightec Ltd (Israel), registered on
the ARTG in 2006 (ARTG 128137). This technology would be made available through
specialised hospitals by interventional radiologists in conjunction with a treating
specialist.
Background
High-intensity focussed ultrasound (FUS) is a non-invasive means of focusing thermal
energy to ablate deep soft tissue targets such as tumours, which otherwise may only
be excised using open surgery. The high-intensity ultrasound deposits localised
energy, causing rapid vibration of molecules within the focal spot. This results in
localised heating (65-95°C) at the focal point of the target tissue, avoiding damage to
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
2
the surrounding tissue but resulting in tissue necrosis, apoptosis and cell death of
the target. Magnetic resonance imaging (MRI) is superior for imaging soft tissue
compared to other modalities, in addition to being able to monitor temperature and
tissue coagulation and therefore avoid damage to the surrounding normal tissue.
MRI clearly visualises the boundaries between the normal and cancerous tissue and
when combined with FUS allows for precise targeting of tumours. In addition, MRI
does not utilise radiation, which safely allows for repeat procedures to be performed
if required.1, 2
InSightec Ltd manufactures three systems for the use of magnetic resonance guided
FUS (MRgFUS):
the ExAblate One, which uses a transducer embedded in the patient bed for
the treatment of uterine fibroids, adenomyosis and breast cancer (requires a
special coil). The depth and angle of focus of the ultrasound beam can be
altered by adjusting the position of the transducer within the water bath
using a robotic system;
the ExAblate OR, which has separate cradles and accessories depending on
the indication. Cradle 1 is used for uterine fibroids, bone and breast cancer
and uses the transducer embedded in the patient bed. Cradle 2 is used for
prostate cancer and uses a 990-element endorectal transducer. The
treatment of liver and pancreatic cancer currently uses the transducer
embedded in the patient table, however it is expected that specialised
transducers will have to be developed for these indications. A conformal
transducer, which is strapped to the body, may be used to treat bone cancer.;
and
the ExAblateNeuro, which uses a helmet-like 1000-element transducer. This
system cannot be upgraded from the ExAblate One or ExAblate OR (personal
communication InSightec Ltd).
The main components of the ExAblate system are the MR scanner (1.5 or 3.0 T) and
the focused ultrasound table, which contains a transducer and cooling water bath. In
addition, the FUS work station is linked to the MR work station, with all electronics
stored in a large equipment cabinet, which resides in the MRI equipment room. All
systems use a transducer (as described above), which focuses the ultrasound energy.
Detachable cradles, which contain the transducers, are connected to the patient
table to hold the area of clinical interest in place. Good acoustic coupling must be
maintained between the part of the body to be treated and the transducer in order
to minimise the presence of residual gas bubbles. The entire assembly of patient
table and detachable cradle is then moved into the MRI scanner. The patient table
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
3
and detachable cradles must be MR compatible. Prior to treatment, a full MRI scan is
conducted targeting the tissue of interest and the margins for the procedure are
planned on the FUS work station, targeting the tumour and sparing normal tissue. A
phase-shift MR thermal map, which requires a specialised software add on to the
basic MRI, is used to measure the result of the FUS sonications and monitor progress
in near real-time. Each heating period or sonication lasts approximately 20 seconds
followed by a cooling period, however during this cooling time treatment may
continue in another, not adjacent, area, which reduces treatment time. Total
treatment time will vary according to the organ and size of the area being treated
and may consist of multiple sonications, with the brain, bone and prostate requiring
fewer sonications compared to uterine fibroids. Patients are treated under conscious
sedation allowing for communication between patient and the interventional
radiologist, especially in regard to any discomfort that may be experienced.2,
3
Existing MRI scanners may be upgraded to be used with the ExAblate system, and
can be used interchangeably for diagnostic and therapeutic use, taking
approximately 10 minutes to change from diagnostic to ExAblate mode. Of
importance to note is that the ExAblate system can only currently be used with GE
MRI scanners (personal communication InSightec Ltd).
Clinical Need and Burden of Disease
The most commonly diagnosed cancer in females in 2007 was breast cancer, with
12,567 cases at an age-standardised incidence rate (ASR) of new breast cancer cases
109.2 per 100,000. The leading cause of burden of disease from cancer in females
during 2010 was breast cancer, representing a total of 24 per cent of the total cancer
burden and four per cent of the total burden of disease in Australia, accounting for
61,100 DALYs.7 In 2007, breast cancer was the second most common cancer causing
death in Australian females, accounting for 2,680 deaths with an ASR of 22.1 per
100,000. The 5-year relative survival for breast cancer in females has increased from
72 per cent in 1982–1986 to 88 per cent in 1998–2004.4
In comparison, cancer of the brain was the 8th ranked cancer in terms of burden of
disease in females, associated with 8,800 DALYs and four per cent of the total cancer
burden. The overall ASR for cancer of the brain was 6.7 per 100,000, with the rate
slightly higher in males (8.6) compared to females (5.0). Death from cancer of the
brain was ranked the 9th most common cancer in Australian females with an ASR of
3.9 per 100,000, accounting for a total of 457 deaths in 2007. The ASR for the same
period was higher for males at 6.3 deaths per 100,000. Although 5-year relative
7
DALYs = disability affected life year
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
4
survival rates for many cancers have improved over time, the 5-year relative survival
rate for brain cancer has remained low at approximately 20 per cent.4
In 2007, the ASR for cancer of the liver was 8.0 and 2.7 per 100,000 for males and
females, respectively and this rate was expected to increase in 2010. Cancer of the
liver is associated with a poor prognosis and contributes to a high burden of disease
due to premature death. During the same period, cancer of the liver was the 10th
most common cancer causing death in males with 717 attributed deaths and an ASR
of 6.9 per 100,000.4
Cancer of the bone represents a small proportion of the total burden of cancer
disease with 195 new cases reported in 2007 at an ASR of 0.9 per 100,000. Death
from bone cancer remains relatively high in comparison to many cancers, with 118
deaths reported in the same year at a rate of 0.5 per 100,000. 4
In New Zealand in 2007, the number of new breast cancer cases registered was 90.3
per 100,000 females, representing 2,575 women diagnosed with the disease. The
number of deaths from breast cancer in the same year was 643 at an ASR of 20.8 per
100,000. As in Australia, rates for liver cancer were markedly higher in males than
females with an ASR of 6.1 compared to 2.3 per 100,000, respectively. Similar high
rates of mortality were observed for cancer of the liver, with an ASR of 5.3 for males
and 1.8 for females per 100,000. The age-standardised incidence rate for cancer of
the brain was similar for males and females in New Zealand, with an overall rate of
5.3 per 100,000. Rates of mortality also remain high for these patients with an
overall ASR of 4.2 per 100,000. The number of new registrations for cancer of the
bone was relatively small at 38 cases (ASR 0.9 per 100,000), however mortality
remains high with 22 deaths in 2007.5
Diffusion
There are currently two ExAblate systems operating in Australia: one situated in The
Royal Woman's Hospital, Melbourne and the other situated at the private clinic
Future Medical Imaging, Melbourne. Both centres currently treat women with
symptomatic uterine fibroids or adenomyosis. The clinic at Future Medical Imaging
has also recently started treating painful bone metastases. The Royal Women’s
Hospital is currently in final preparations prior to the launch of a breast cancer
clinical trial. Both systems could be upgraded for additional treatment applications
for other indications (personal communication InSightec Ltd).
Comparators
In the majority of cases of brain, breast and liver cancer, the only alternative to
MRgFUS would be invasive surgery combined with post-surgical chemotherapy
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
5
and/or radiotherapy. Bone metastases are associated with a high degree of pain and
palliative therapy is offered as a means to improve the quality of life of patients.
External beam radiation would be considered the standard therapy; however 20-30
per cent of patients would not gain sufficient pain relief using this modality. Other
therapeutic options may also include chemotherapy, hormonal therapy,
pharmaceuticals including bisphosphonates and opiates for pain management,
radiation, surgery, cryotherapy and radiofrequency percutaneous ablation.6
Safety and Effectiveness Issues
Breast cancer
In 2007, MRI was approved by the Medical Services Advisory Committee for interim
public funding for the diagnosis of breast cancer in young, high-risk, asymptomatic
women. When used in this group of women, MRI was found to be more sensitive
and less specific compared to mammography.7 Using MRgFUS therefore allows for
accurate targeting of breast lesions for ablation as the breast may be isolated
relatively easily, avoiding potential damage to other organs and structures (Figure 8).
MRgFUS may potentially be used to replace surgical procedures such as lumpectomy
and wide local incision, in so doing conserving the breast with the added cosmetic
and psychological benefits.8 Several issues have been identified with the use of
MRgFUS for the ablation of breast cancer, specifically the importance of adequate
tumour-free margins following ablation and appropriate patient selection. Patients
with large tumours >5cm and those with tumours close to the chest wall should not
be selected.9
Figure 8
Positioning of the patient for the treatment of breast cancer
9
with MRgFUS (printed with permission InSightec Ltd)
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
6
A small case series by Zippel et al (2005) enrolled 15 women (mean age 56 years,
range 45-72) with biopsy proven infiltrating breast carcinomas less than 3cm in
diameter (mean size 22mm) (level IV intervention evidence). Lesions were all more
than 10mm away from the skin and chest wall. The MRgFUS procedure was
conducted using the ExAblate 2000 system. The treatment plan included ablation of
a minimum boundary of 0.5cm of healthy tissue in all dimensions from the tumour
edge. The effect of all sonications was monitored with MR thermal mapping.
Although 15 women were enrolled, only 10 completed the protocol with the
procedure halted in five patients who experienced extreme anxiety in the MRI. Total
procedure time was expected to be 240 minutes; however the actual procedure time
was not reported. All patients underwent successful lumpectomy 7-10 days postablation procedure and the resected lesion underwent histopathological
examination. Compete ablation was observed in two patients, with no residual
tumour left behind. Varying degrees of residual tumour were left behind in the
remaining eight patients: three had 10 per cent residual tumour; three had 10-30 per
cent and two had microscopic foci of residual carcinoma. Patients were administered
analgesics for pain during the procedure and one patient experienced a second
degree burn which required skin excision prior to lumpectomy. In addition, the
authors noted that the effect of MRgFUS on sentinel node biopsy is largely unknown,
however there was no difficulty identifying and removing the sentinel node in the
two patients who required this procedure.10
A recent review reported on the results of one of the largest case series of MRgFUS
ablation of biopsy-proven breast cancer to date presented by Furusawa et al at the
International Symposium on MR-guided Focused Ultrasound (results unpublished at
time of writing). Results were presented for 47 out of 57 enrolled women with small
breast tumours ≤ 1.5cm (mean 11mm, range 6.0-15mm) with a distance of more
than 1.0cm from the skin (level IV intervention evidence). All patients underwent
core needle biopsy three weeks after the MRgFUS (1.5T) procedure. Mean MRgFUS
treatment duration was 108 minutes (range 65-209 minutes). Mean follow-up was
44 months (range 3-64 months) with all women with no residual viable tumour
receiving radiation therapy and breast examination by mammography and MRI every
six months. No local recurrences or significant adverse events were reported.11
Bone cancer
Up to 30 per cent of all cancer patients will develop secondaries in the bone and
approximately half of these patients will go on to develop pain from these lesions.
The current treatment option for these lesions is radiotherapy; however 20-30 per
cent of patients will gain no relief from pain from radiotherapy and of those who do
experience relief, 27 per cent will have recurring pain once radiotherapy ceases.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
7
Bone actively absorbs FUS and a large area at the periosteal margin8 of the bone can
be rapidly heated and in so doing may destroy neural pain fibres in the periosteum,
resulting in palliation of painful bone lesions. Large areas of the periosteum may be
treated with a broader portion of the FUS beam rather than adopting the usual
focussed approach described for the ablation of tumours.2, 3 To treat bone
metastases, the patient may be situated above the transducer located within the
cradle (as depicted in Figure 8) or by using a conformal transducer which can be
strapped to the region of interest (Figure 9).
Figure 9
Patient being treated for bone metastases indicating the use
of a strap on transducer (printed with permission InSightec Ltd)
A small case series by Catane et al (2006) reported on the use of MRgFUS for the
palliation of pain in 13 patients with 14 symptomatic bone lesions (level IV
intervention evidence). Patients were treated under conscious sedation with the
ExAblate system, utilising a 1.5T MRI and were followed-up at 3-days, 2-weeks and
one, three and six months (mean follow-up 59 days). One patient underwent two
treatment sessions due to insufficient energy being used in the first treatment, with
another patient undergoing two treatments but targeting two different lesions. All of
the remaining patients underwent only one treatment session. The average time for
15 treatments was 80 minutes (range 22-162 minutes), with an average of 25
sonications delivered at an average acoustic energy of 1080 joules (J).
One patient was unable to tolerate the pain of the MRgFUS procedure and
treatment was halted after 14 sonications and 30 minutes. This patient did not
report an improvement in visual analogue scale (VAS) or a reduction in pain
medication. No other adverse events were reported during or post-treatment.
Follow-up data was not collected from two patients who experienced a rapid
8
Periosteum is a membrane that lines the outer surface of all bones, except at the joints of long bones
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
8
progression of disease after MRgFUS treatment, with one patient dying prior to 3month follow-up. The remaining 10 patients reported a reduction in pain scores and
the use of pain medication.12
The initial results reported by Catane et al (2006) provided the basis for the largest
multicentre case series reported to date. Liberman et al (2009) described the results
of 31 patients who had failed to respond to radiotherapy or refused to undergo
radiotherapy (level IV intervention evidence). Patients were treated under conscious
sedation with the ExAblate system, utilising a 1.5T MRI and were followed-up for
three months. The most common treatment site was the iliac bone (18/31, 58%) and
the most common primary tumour type was breast cancer (11/31, 35%). Thirty-six
treatments in 31 patients with 32 metastatic lesions were administered, with an
average treatment time of 66 minutes (range 22-162 minutes). An average of 17.3
sonications (range 8-32) were delivered at an average acoustic energy of 1,135 J
(range 440-1,890).
The only adverse events reported in this larger study were those reported by Catane
et al. Twenty-five patients received the full treatment and completed the 3-month
follow-up. Overall, pain reported by one patient worsened during the 3-month
follow-up period, six patients (24%) had no response to MRgFUS treatment and 18
patients (72%) reported a significant reduction in VAS scores (>2 points), with nine of
these patients reporting a VAS score of zero. The average VAS score decreased from
5.9 at baseline to 1.8 at three months post-MRgFUS. Over 50 per cent of patients
reported a reduction in pain within three days of MRgFUS treatment. In addition, the
majority of patients reported a decrease in pain medication use, however follow-up
data was incomplete for this outcome. A complete response, defined as a VAS score
of zero without an increase in medication, was observed in nine patients (36%). A
partial response, defined as a decrease in VAS score of two points without a
decrease in pain medication, or a decrease of 25 percent or more in medication use
without an increase in pain score, was reported in nine patients.13
Gianfelice et al (2008) reported the results of 11 consecutive patients (mean age
58.6 years, range 38-84) with painful bone metastases who had exhausted other
treatment options including chemotherapy, radiotherapy and pain medication (level
IV intervention evidence). Primary tumour origins included breast (n=5) kidney (n=4),
lung (n=1) and liver (n=1). MRgFUS was delivered using the ExAblate system and a
1.5T MRI. Patients underwent MRgFUS treatment under conscious sedation in an
outpatient setting and were followed-up at 3-months. Ten patients underwent one
treatment session; however one diabetic patient required a second session due to a
rapid drop in blood sugar during the procedure. Ten patients had a single lesion
treated and one patient had two adjacent lesions treated during the same session.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
9
Treated lesions originated in the iliac (n=7), scapula (n=2), clavicle (n=1) and ischium
(n=1).
No adverse events related to the procedure were reported. Total treatment time
ranged from 28 to 103 minutes, with the number of sonications delivered per patient
ranging from 12 to 18 and the energy of sonications varying between 466 and 1853 J.
Some patients reported pain relief by 3-days post-treatment, however by day 14 all
patients had reported a reduction in pain, with 7/11 (63.6%) patients reported a VAS
score of zero at 3-months. The remaining four patients who experienced some pain
at end of follow-up had a marked reduction in pain ranging from 3.5-6.5 points on
the VAS scale. The average VAS score prior to treatment was 6.0 (range 4-9), which
was reduced by 39 per cent to 3.7 three days post-treatment. Further reductions in
VAS scores were noted at 14 and 30 days post-treatment, with a significant mean
decrease of 92 per cent to a mean VAS score of 0.5 at 3-month follow-up (p<0.01).
Seven patients (63.6%) no longer required pain medication at end of follow-up and
the remaining four patients had reduced their pain medication intake by at least 50
per cent. MR imaging conducted at end of follow-up indicated that the majority of
patients exhibited necrosis of the enhancing medullary component of the
metastases and CT imaging revealed increased bone density at the treated site in
five patients.6
Brain cancer
Previous attempts to use transcranial focused US have been unsuccessful due to the
increase in the acoustic attenuation of the skull, which is 30-60 times higher than in
soft tissue. To avoid this issue, a hemispherical transducer operating at a lower
frequency to produce the US beam, combined with a specialised cradle capable of
holding the head in place in a cooling water bath (15-20°C) has been developed, as
demonstrated by this short video and Figure 10.14
a
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
10
b
Figure 10
Positioning of the patient for transcranialMRgFUS
14
a) , b) printed with permission InSightec Ltd
Only one small phase I feasibility study was identified for inclusion in this assessment
that reported the results of using transcranial MRgFUS for the treatment of three
patients with glioblastoma (level IV intervention evidence). Two patients had
inoperable tumours whilst the remaining patient had recurrent metastatic cancer.
The tumours were all located in the thalamus, relatively deep and central within the
brain. All patients underwent chemotherapy and radiation therapy prior to
treatment with MRgFUS. Patients were treated under conscious sedation. Prior to
treatment patients underwent a CT and MRI scan for treatment planning purposes.
Once treatment commenced, MR temperature imaging was used to verify the target
location within the tumour and acoustic power was increased to reach thermal
coagulation at approximately 55°C peak temperature.14
Treatment was limited by the maximum acoustic power available, with one patient
only achieving a maximum power of 650 watts (W) due to software settings. Another
patient reached this power level but due to sonication-related pain higher power
was not reached. The remaining patient reached a maximum of 800 W. Sufficient
tumour ablation was not possible due to the power limitations. Some patient motion
was observed in all patients (2-4mm). Focal heating within the tumour was observed
during 3 of 12, 14 of 16 and 11 of 17 sonications, and the maximum temperature
achieved was 42, 51 and 48°C for patients 1-3, respectively. Ultimate patient
outcomes were not reported, however the authors concluded that transcranial
MRgFUS was feasible but may require further modifications.14
An interesting development in the use of MRgFUS for the treatment of brain
tumours such as gliomas is the potential to deliver therapeutic magnetic
nanoparticles across the blood brain barrier. Low-energy FUS is used to increase the
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
11
permeability of the blood brain barrier in a localised and reversible manner, allowing
for the diffusion of magnetic nanoparticles containing chemotherapeutic agents.
Diffusion of nanoparticles is usually passive, however the application of an external
magnetic force allows concentration of a therapeutic dose at the target site, with
MRI used to monitor the procedure (Figure 11). The integrity of the blood brain
barrier is re-established within 24-36 hours. To date only animal studies have been
conducted.15-17
Figure 11
Schematic of the procedure demonstrating the localised permeability of
the BBB using FUS flowed by the diffusion of the magnetic nanoparticles,
17
which are then guided and concentrated by an external magnetic force
Liver cancer
Invasive radiofrequency or laser ablation has recently been used as a method to
treat local tumours of the liver, with probes being inserted percutaneously into the
target tissue. Application of power causes local heating followed by the thermal
destruction of tissue. MRgFUS has been suggested as a non-invasive approach for
the destruction of localised areas of the liver, especially when underlying liver
disease is present, which is common in patients with hepatocellular carcinoma.
MRgFUS of the liver presents technical difficulties due to the presence of the rib cage
and movement of the liver with respiration. Treating patients under general
anaesthesia overcomes the latter problem, however a MRI-compatible ventilator is
required. Currently MRgFUS treatment can only be applied to areas of the liver not
covered by the rib cage, however it is anticipated that modified transducers will
allow treatment between the ribs in the near future.2, 3
Many reviews describing the potential use of MRgFUS for tumours of the liver,
however no human studies were identified.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
12
Prostate cancer
Phase I and II protocols have been finalised for the treatment of prostate cancer,
with studies set to commence in 2012.
Cost Impact
The cost of the complete ExAblate system varies between AUD$2-4 million
depending on the configuration of the MRI (1.5 or 3 Tesla) (personal communication
CPR Communications on behalf of InSightec Ltd). All ExAblate systems come
complete with the patient table and at least one cradle, depending on the
configuration of the system. If new indications are planned for treatment, systems
may be upgraded to cater for this except for in the case of the ExAblateNeuro, which
is a standalone system. In addition, there would be a cost for the disposable
treatment kits required for each procedure that include gel pads and the degassed
water (personal communication InSightec Ltd).
Ethical, Cultural or Religious Considerations
No issues were identified/raised in the sources examined.
Other Issues
Two studies evaluating the use of magnetic resonance-guided focused ultrasound
surgery in patients with metastatic bone cancer are listed on the Current Controlled
Trials register. One study, a multi-centre (United States, United Kingdom, Canada,
Israel, Italy and Russia) randomised controlled trial, aims to compare the use of the
ExAblate 2000 MRgFUS to a sham procedure for the palliation of pain in adult
patients with metastatic and multiple myeloma bone tumours, who are not
candidates for radiation therapy (ClinicalTrials.gov Identifier: NCT00656305). The
trial, sponsored by InSightec, began recruiting patients in 2008 and aims to be
finalised by December 2011 with 148 patients enrolled. The primary outcome
measure is an improvement in pain scores within three months of treatment, with
the secondary outcome measure being a change in pain medication. A smaller
randomised controlled trial, also sponsored by InSightec, aims to compare MRgFUS
to external beam radiation therapy for the palliation of pain in patients with
metastatic and myeloma bone tumours (ClinicalTrials.gov Identifier: NCT01091883).
The trial is currently recruiting up to 60 Israeli adult patients and aims to be finalised
by March 2012. The primary outcome measure is the number and severity of
adverse events associated with the use of MRgFUS compared to external beam
radiation therapy. Secondary outcome measures include the assessment of pain
relief, determined by a pain scale and by a reduction in the use of pain medication,
and an assessment of quality of life within six months of treatment.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
13
Of interest is a clinical trial that has commenced in the United States using MRgFUS
for the treatment of patients with chronic neurological conditions, including
essential tremor and Parkinson’s Disease.18 It is worth noting that in January 2012,
the Journal of Neurosurgery’s online website magazine will be publishing a special
issue devoted to the use of MRgFUS (personal communication InSightec Ltd).
A summary of talks given at the 2010 Focused Ultrasound Foundation meeting on
MRgFUS may be accessed via this link.
Summary of findings
The use of MRI guided high-intensity ultrasound for the treatment of symptomatic
uterine fibroids is an established technique. This technology brief has presented the
preliminary evidence on the use of MRgFUS for other indications including tumours
of the brain, breast and bone. Small proof of concept studies conducted on patients
with breast and brain cancer indicate that the technique is feasible. However,
patient selection, especially when treating breast cancer, is an important
consideration to ensure optimal outcomes. One of the more interesting and
promising fields of research is the use of MRgFUS to target and deliver magnetic
nanoparticles to tumours of the brain. It would appear that partial or complete
palliation of pain using MRgFUS in patients with painful bone metastases is possible
for the majority of patients, increasing the quality of life in these patients.
Purchasing the various cradles required to use MRgFUS for indications other than
fibroids may increase the utilisation of existing (or those purchased in the future)
MRgFUS units to a maximum level. However, this may raise workforce issues in
relation to the number of trained interventional radiologists capable of performing
this type of procedure, in addition to the role that current specialists (oncologists,
hepatologistsetc) may play in this procedure.
HealthPACT assessment:
Based on the low-level, preliminary evidence it would appear that MRgFUS may be a
useful tool for the treatment of patients with tumours who may have limited
treatment alternatives available to them. The range of applications for this
technology are potentially wide-ranging and therefore HealthPACT have
recommended that a New and Emerging Health Technology Report be commissioned
late-2012 to allow sufficient time for the results from the randomised controlled
trials to be published in addition to the publication of initial studies into the use of
MRgFUS for the treatment of prostate cancer and neurological conditions.
MRgFUS for cancer of the brain, liver, bone and breast: November 2011
14
Number of included Studies
Total number of studies
6
Level IV intervention evidence
Breast
Bone
Liver
6
2
3
0
Brain
1
Search Criteria:
Magnetic Resonance Imaging/ methods
Sonication
Ultrasonic Therapy/adverse effects/ methods
Ultrasonography
Neoplasms
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1.
Fennessy, FM&Tempany, CM (2005). 'MRI-guided focused ultrasound surgery
of uterine leiomyomas'. Acad Radiol, 12 (9), 1158-66.
2.
Gedroyc, WM&Anstee, A (2007). 'MR-guided focused ultrasound'. Expert Rev
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3.
Dick, EA&Gedroyc, WM (2010). 'ExAblate magnetic resonance-guided focused
ultrasound system in multiple body applications'. Expert Rev Med Devices, 7
(5), 589-97.
4.
AIHW&AACR (2010). Cancer in Australia: an overview, 2010, Australian
Institute of Health and Welfare and Australasian Association of Cancer
Registries, Canberra Available from: http://www.aihw.gov.au/publicationdetail/?id=6442472459&tab=2.
5.
Ministry of Health (2010). Cancer: New Registrations and Deaths 2007, New
Zealand Ministry of Health, Wellington Available from:
http://www.moh.govt.nz/moh.nsf/indexmh/cancer-reg-deaths-2007-jun10.
6.
Gianfelice, D, Gupta, C et al (2008). 'Palliative treatment of painful bone
metastases with MR imaging--guided focused ultrasound'. Radiology, 249 (1),
355-63.
7.
Lord, S, Lei, W et al (2007). Breast magnetic resonance imaging, Medical
Services Advisory Committee, Canberra Available from:
http://www.msac.gov.au/internet/msac/publishing.nsf/Content/2CDBC3816
FDE8D20CA2575AD0082FD8E/$File/1098%20%20Breast%20MRI%20Report.pdf.
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8.
Wu, F, ter Haar, G&Chen, WR (2007). 'High-intensity focused ultrasound
ablation of breast cancer'. Expert Rev Anticancer Ther, 7 (6), 823-31.
9.
Schmitz, AC, Gianfelice, D et al (2008). 'Image-guided focused ultrasound
ablation of breast cancer: current status, challenges, and future directions'.
Eur Radiol, 18 (7), 1431-41.
10.
Zippel, DB&Papa, MZ (2005). 'The use of MR imaging guided focused
ultrasound in breast cancer patients; a preliminary phase one study and
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11.
Brenin, DR (2011). 'Focused ultrasound ablation for the treatment of breast
cancer'. Ann Surg Oncol, 18 (11), 3088-94.
12.
Catane, R, Beck, A et al (2007). 'MR-guided focused ultrasound surgery
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MRgFUS for cancer of the brain, liver, bone and breast: November 2011
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