Introduction
Over the past years, radiological imaging methods such as MRI, US and CT/X-ray have
become an integral part of therapeutic interventions such as percutaneous and transarterial
procedures to treat vascular and oncological diseases. Imaging allows treatment planning,
provides spatial guidance to reach the targeted tissue and facilitates real-time monitoring
of the intervention itself, thus ensuring increased safety and improved outcome. Furthermore,
treatment can be evaluated in the same session using appropriate imaging protocols
thereby providing a prognostic readout for efficacy.
Thermal ablation of tumors or metastases, for example, in the liver is currently performed
with minimally invasive procedures under X-ray or CT guidance using percutaneous radiofrequency
or microwave applicators that are inserted into the tumor. Yet, the above methods
suffer from poor temperature control and insufficient target coverage especially for
larger or irregular-shaped tumors. Furthermore, proximity to crucial structures sometimes
prohibits insertion of the probe. A promising noninvasive alternative is high-intensity
focused ultrasound (HIFU). Ultrasound presents a mechanical wave that can be focused
inside the patient on one spot, where absorption and subsequent energy dissipation
cause rapid and focal heating of the target tissue. Temperatures over 55 °C basically
induce coagulative necrosis instantaneously with sharp margins between treated and
healthy tissue. HIFU can therefore be considered as a thermal knife, however without
having to perform open surgery and to remove the tissue. Current HIFU treatments are
performed under either ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) imaging
guidance, thus offering integrated therapy planning, real-time control (spatial and
temperature guidance) and evaluation. The choice of imaging method depends on the
exact application and treatment scheme. This review explains the underlying principles
of HIFU therapy and presents an overview of the established clinical applications
(part 1), while emerging applications that are in a translational or early clinical
phase will be reviewed in a future second part (MR-Guided High-Intensity Focused Ultrasound
(MR-HIFU): Overview of Emerging Applications (Part 2)).
Principles
The biological effect of ultrasound was first described by Wood et al. in 1927 upon
noticing the detrimental effects of high-intensity ultrasound on animals [1 ]. Lynn et al. succeeded in focusing high-intensity ultrasound and recognized its
thermodestructive potency when applied to an ex vivo tissue sample as well as in vivo
when targeting the brain transcranially in cats and dogs [2 ]. Fry et al. were able to produce focal lesions within the central nervous system
in several animal experiments after the skull was removed to avoid extensive heating
of the bone surface [3 ]. Nonetheless, the clinical application of HIFU remained unsuccessful largely due
to the lack of heating control and spatial targeting.
For the latter, HIFU was combined early on with diagnostic ultrasound B-mode imaging
for improved spatial targeting. Combining HIFU with MR (MR-HIFU) imaging presented
a challenge as the transducer needs to be MR-compatible and was first realized by
Hynynen et al. [4 ]. The soft-tissue contrast of MRI and its ability for noninvasive temperature monitoring
strongly improved procedure planning, and targeting of the focus spot, which contributed
to the safety and efficacy of the procedure and paved the way to broader clinical
application of MR-HIFU.
For HIFU ablation, typically frequencies in the range of 0.8 – 4 MHz are employed
with intensities between 400 – 10 000 W/cm2 (ITA – time-averaged intensity) and pressure amplitudes of up to 10 MPa [5 ], depending on the particular application. In contrast to HIFU, conventional diagnostic
ultrasound usually uses a frequency spectrum between 2 and 15 MHz, intensities between
0.004 and 7.5 W/cm2 (ISPTA – spatial peak temporal average intensity) and pressure amplitudes of up to
5.5 MPa depending on the mode being used with the lowest values in B-mode and the
highest values in Doppler mode [6 ].
In contrast to diagnostic ultrasound transducers emitting parallel or divergent ultrasonic
pressure waves, HIFU transducers typically have a concave shape to focus the waves
on one spot. The high intensity in combination with ultrasound absorption within the
focus spot leads to a sudden and localized rise in temperature. Heating of tissue
to temperatures above 55 °C induces coagulation necrosis within seconds. The exact
size of the focus spot depends on the transducer geometry such as aperture and focal
length as well as frequency and has typical dimensions of a few millimeters with respect
to the diameter and length. Displacing the transducer for repeated sonication or using
a phased array transducer with the ability for electronic beam steering allows ablation
of larger volumes [7 ]. The boundary between viable and ablated tissue consists of only a few cell layers.
Ablation efficacy can be assessed directly after the procedure by measuring the non-perfused
volume (NPV) using contrast-enhanced ultrasound or MR imaging.
Before a HIFU procedure can be performed, acoustic access to the targeted lesion needs
to be ensured, with proximity to gas-filled intestines or reflecting structures such
as arteriosclerosis (calcifications), bone, lung or foreign matter being contraindications
as they may lead to scattering and reflections of the ultrasound waves with excessive
heating of the surrounding tissue as a consequence. Proper patient selection and preparation
are therefore strictly required.
Ultrasound guidance of HIFU procedures allows real-time visualization of tissue ablation
showing an emerging hyperecho during and after ablation and furthermore provides continuous
information about the acoustic beam path and potential obstructions. However, diagnostic
ultrasound cannot obtain precise enough temperature information and therefore gives
no readout of the achieved absolute temperature or the thermal dose that is deposited
in the target tissue. Consequently, adaptive heating strategies with e. g. a power
feedback or longer heating times are lacking, which may lead to incomplete ablation
especially in areas where perfusion causes faster heat dissipation or near large vessels.
MR-HIFU allows planning of sonication based on MR images with fine anatomic detail
and high intrinsic soft-tissue contrast. Furthermore, MR-thermometry provides a near
real-time temperature map during sonication to track the heating pattern in the focus
spot and surrounding tissue which can be used as a feedback to the HIFU transducer
([Fig. 1 ]). The closed-loop feedback ensures deposition of a thermal dose sufficient to cause
coagulative necrosis across the entire targeted area. Furthermore, the temperature
feedback is a key factor in hyperthermia applications, where temperatures of approximately
42˚C need to be maintained over a prolonged period of time.
Fig. 1 Schematic overview of an MR-HIFU system. MR guidance offers the possibility for procedure
planning based on high contrast soft-tissue images, near real-time MR-thermometry
for therapy control, and subsequent treatment assessment based on contrast-enhanced
T1 scans. The latter is used to calculate the NPV after thermal ablation of tissues.
MR-thermometry provides near real-time temperature maps which allow a feedback loop
to the HIFU transducer to ensure deposition of a well-defined thermal dose in the
target tissue, or to maintain prolonged hyperthermia at a constant temperature. The
responsible radiologist has access to all anatomical images as well as superimposed
temperature maps and can plan each sonication through the Planning Console which embeds
sophisticated software for optimal energy disposition. Differently sized tissue volumes
can be heated using electronic beam steering, and even larger volumes can be reached
by displacing or tilting the transducer with the help of a motion robot. Source: Hijnen
N, Langereis S, Grüll H. Magnetic resonance guided high-intensity focused ultrasound
for image-guided temperature-induced drug delivery. Adv Drug Deliv Rev 2014; 72: 65 – 81
[rerif].Abb. 1 Schematischer Überblick über ein MR-HIFU-System. Die Steuerung des HIFU-Systems mittels
MRT ermöglicht die Therapieplanung anhand von Bildern mit hohem Weichteilkontrast,
schafft die Therapiekontrolle mittels MR-Thermometrie in nahezu Echtzeit und erlaubt
schlussendlich mithilfe einer KM-unterstützten T1-gewichteten Sequenz, Aussagen über
den Therapieerfolg zu machen. Diese Sequenz wird auch zur Berechnung des NPV nach
Thermoablation des Gewebes verwendet. Die MR-Thermometrie liefert nahezu Echtzeit-Temperaturkarten
mit Rückkopplung zum HIFU-Transducer, um sicherzustellen, dass die thermale Dosis
im Zielgewebe erreicht wurde, alternativ um eine prolongierte Hyperthermie mit einer
konstanten Temperatur aufrechtzuerhalten. Der verantwortliche Radiologe kann auf alle
anatomischen Bilder sowie die überlagerten Thermometrie-Daten zugreifen und anhand
dieser jede Sonikation an der Planungskonsole mit der speziellen HIFU-Software planen,
um eine optimale Energiedisposition zu erreichen. Unterschiedlich große Gewebsvolumina
können erhitzt werden mittels Steuerung des Fokuspunktes; größere Volumina können
abladiert werden, indem der Transducer mithilfe eines Bewegungsroboters verschoben
bzw. abgekippt wird. Quelle: Hijnen N, Langereis S, Grüll H. Magnetic resonance guided
high-intensity focused ultrasound for image-guided temperature-induced drug delivery.
Adv Drug Deliv Rev 2014; 72: 65 – 81 [rerif].
The most frequently used clinical systems around the world are the US-HIFU “JC” developed
by HAIFU (Chongqing, China) and the MR-HIFU “ExAblate” by InSightec (Haifa, Israel)
and “Sonalleve” by Profound Medical (Mississauga, Canada). Additionally, several other
HIFU systems from various companies exist or are under development for dedicated applications.
Established applications for MR-HIFU and US-HIFU are accounted for licensed procedures
under EU regulations (FDA approval, CE-certified) with an overview provided in [Table 1 ].
Table 1
Overview of currently most relevant applications for MR-HIFU and US-HIFU depending
on their status of approval worldwide adapted from an overview of approved applications
from the Focused Ultrasound Foundation (https://www.fusfoundation.org/diseases-and-conditions-all/overview ).Tab. 1 https://www.fusfoundation.org/diseases-and-conditions-all/overview ).
application
regulatory approval by region
MR-HIFU
US-HIFU
oncological
NA, EU, Ru, Ch, In, Ja, ME, SA
no approval
Ru, Ko
EU, Ru, Ch, SA
no approval
EU, Ru, Ch, SA
Ch, Ko
EU, Ru, Ch, Ko, SA
Ch, Ko
EU, Ch, Ko, SA
NA, EU, Ru, SA
NA, EU, Ru, In, Ko, SA
no approval
EU, Ru, Ch, SA
neurological
Ko
no approval
NA, EU, Ru, Ja, Ko, ME
no approval
EU, Ru, Ko, ME
no approval
Ko
no approval
EU, Ru, Ko, ME
no approval
women’s health
no approval
EU, Ko
EU, Ch
EU, Ru, Ch, SA
NA, EU, Ru, Ch, In, Ja, Ko, ME, SA
EU, Ru, Ch, Ko, SA
musculoskeletal
EU
no approval
EU
EU, Ru, Ch, SA
cardiovascular
no approval
EU
endocrine
no approval
EU
NA = North America (USA + Canada), EU = Europe, Ru = Russia, Ch = China, In = India,
Ja = Japan, Ko = Korea, ME = Middle East, SA = South America.
1 Obsessive-compulsive disorder.
For this review we concentrated on the current status of MR-HIFU as well as a few
selected potential future applications mostly related to oncology.
Established applications
Uterine fibroids
Symptomatic uterine fibroids are found in 20 – 40 % of all women of childbearing age,
causing dysfunctional uterine bleeding, infertility or mass effects on the bladder,
intestines or nerves. Classical treatment schemes comprise medicamentous as well as
operative (hysterectomy, myomectomy) or interventional therapies (UAE, HIFU). The
noninvasive treatment of uterine fibroids using HIFU is increasingly used in equipped
centers as it is an organ-preserving, partly outpatient method with low complication
rates and fast recovery. A typical MR-HIFU treatment comprises three steps with an
MRI prescan for delineation of the uterine fibroids and subsequent HIFU treatment
planning ([Fig. 2a ]), the HIFU treatment as such ([Fig. 2b ]), and a contrast-enhanced MR post-treatment scan to evaluate the treated volume
([Fig. 2c ]). The latter is typically congruent with the tissue in which a high enough thermal
dose was achieved to induce thermal necrosis ([Fig. 2b ]) and correlates to the non-perfused volume (NPV) observed in contrast-enhanced MR
scans ([Fig. 2c ]). HIFU allows fast treatment of even large fibroid volumes of up to 500 ml with
approximately 240 ml being the average volume [8 ]. A high NPV is of clinical importance as the reduction of symptoms correlates with
increasing NPV ratios [9 ]. Thus, the NPV is considered to be a measure of technical success with newer MR-HIFU
studies achieving NPV ratios of 60 – 90 % [10 ].
Fig. 2 Representative MR images obtained during HIFU treatment of a uterine fibroid (Sonalleve,
Profound Medical, Mississauga, Canada). a T2-weighted planning image (coronal view) with a representative treatment cell (green
circle) placed in the center of a uterine fibroid; b MR-thermometry map obtained in a coronal slide at a depth of the treatment cell overlaid
on the respective anatomical image; c contrast-enhanced T1-weighted image showing successfully ablated tissue as a hypointense
area in the fibroid due to lack of perfusion (arrows). The ratio of total fibroid
volume and non-perfused volume (NPV) is a measure for ablation efficacy.Abb. 2 Repräsentative MR-Bilder während einer HIFU-Therapie eines Uterusmyoms (Sonalleve,
Profound Medical, Mississauga, Canada). a T2-gewichtetes Planungsbild (koronare Darstellung) mit einer charakteristischen Therapiezelle
(grüner Kreis), die im Zentrum eines Uterusmyoms platziert wurde; b MR-Temperaturkarte in koronarer Darstellung im Bereich der Therapiezelle überlagert
mit einem entsprechenden anatomischen Bild; c Bild einer KM-unterstützten T1-gewichteten Sequenz, welches die erfolgreiche Gewebsablation
als hypointenses Areal innerhalb des Myoms aufgrund ausbleibender Perfusion zeigt
(Pfeile). Das Verhältnis vom Gesamtvolumen des Myoms und des nicht perfundierten Volumens
(NPV) gilt als Maß für die Ablationseffizienz.
The indication for HIFU treatment must be well considered as a good selection of patients
leads to a higher success rate with lower complication rates.
In order to determine if a patient qualifies for a MR-HIFU therapy, T2-weighted and
dynamic contrast-enhanced T1-weighted MR images are acquired to assess the size, quantity,
location, signal intensity on T2-weighted images, and perfusion of the fibroids. The
assessment of T2-weighted images is of clinical importance as fibroids with a higher
signal intensity relative to skeletal muscle, also known as Funaki Type III fibroids,
are more resistant to heating and generally excluded from MR-HIFU [11 ]. In addition, a recent study has shown that the presence of a peripheral rim with
a high signal intensity around the fibroids on T2-weighted images, which could be
associated with dilated veins, lymphatic vessels, and/or edema, significantly lowered
the therapeutic response to MR-HIFU [12 ].
Exclusion criteria can include the presence of organs such as a voided bladder, intestines
or nerves in the beam path. Preparations have to be made accordingly such as bladder-filling,
manipulation of the intestines and the uterus, fasting or enema. Contraindications
are suspicion of malignancy, pregnancy, an acute inflammatory process, pedunculated
subserosal fibroids in addition to the general HIFU and MRI contraindications [13 ]. Uterine fibroids with a diameter greater than 10 cm, more than 5 myomas, large
scars in the acoustic window, e. g. after a c-section, and myomas in the posterior
wall or near the Os sacrum count as relative contraindications [13 ]. When patients have the wish to become pregnant, myomectomy should be the first
choice. However, this does not count as a contraindication for HIFU therapy as previous
documented cases (> 120) report pregnancies after HIFU, but patients need to be informed
about possible complications and pregnancy should not be attempted for 6 months after
therapy [13 ].
Many studies confirm MR-HIFU as a safe, feasible and effective alternative treatment
option for myomas [8 ]
[14 ]
[15 ]
[16 ]. Also, from an economic healthcare point of view, MR-HIFU may reduce the overall
treatment costs and disease management thanks to fewer complications, shorter hospitalization
and accelerated rehabilitation rates [17 ].
Complications may include pain, temporary vaginal discharge of necrotic material,
cramps, skin burns and rarely nerve lesions [13 ].
Bone-related applications
Bone is the most common target site for the formation of distant metastases, which
eventually occur in 70 – 80 % of all patients suffering from solid tumors such as
breast, lung and prostate cancer [18 ]. Bone metastases are often associated with strong pain and can lead to pathological
fractures. At this stage, the disease is virtually incurable with a limited life expectancy,
reduced mobility and strongly reduced quality of life. Treatment options in the management
of bone metastases are palliative and directed at alleviating pain and comprise systemic
therapies such as chemotherapy, hormonal therapy and bone-seeking bisphosphonates,
as well as local treatments such as surgery, radiation therapy and thermal ablation
using radiofrequency (RFA) or HIFU [19 ]
[20 ]
[21 ]. Radiotherapy, which is the current standard of care for the local treatment of
painful metastases, achieves a response rate in ⅔ of all patients within 2 – 8 weeks,
but in ¼ of treated patients pain eventually recurs after radiotherapy [22 ]
[23 ]. Retreatment with radiotherapy has a reduced response rate of about 60 % and is
limited by radiation dose. The mechanisms of pain relief after radiation therapy of
bone metastases, however, are poorly understood [24 ]. As an alternative, thermal treatments aim at denervation of the highly sensitive
periosteum to interrupt pain signaling [25 ]. HIFU has been used for pain palliation of bone metastases with a promising outcome
[26 ]
[27 ]. As the bone cortex absorbs about 50 times more ultrasound energy than soft tissue,
lower acoustic powers are sufficient to adequately heat the bone surface and cause
periosteal denervation [28 ]. Furthermore, as HIFU does not involve ionizing radiation and is virtually free
of side effects, treatment can be repeated if needed.
MR-HIFU treatment protocols depend on the specific lesion morphology. In case an intact
cortical bone surface is present, the high absorption of ultrasound in bone causes
rapid heating even at moderate ultrasound energy exposures. The latter acts as a secondary
heat source which causes local ablation of the periosteum adjacent to the bone. A
commonly accepted treatment protocol for these lesions is the near-field approach,
where the focus spot of HIFU is placed behind the cortical surface [29 ]. However, the effect of the interplay between sonication power and length of sonication
on the ablation of soft tissue in front of the bone surface as well as the reached
ablation depth within the bone is still under discussion [30 ]. As MR thermometry based on proton resonance frequency shift (PRFS) does not allow
direct temperature mapping within the bone, heating of the adjacent soft tissue is
commonly monitored as a secondary readout for successful heating of the bone surface
([Fig. 3a, b ]). The treatment strategy for osteolytic lesions depends on the residual bone tissue
left in the tumor lesion. The near-field approach may not lead to sufficient heating
to achieve pain relief. Instead, the focus spot should be directed at the tumor mass
eroding the bone to achieve soft tissue tumor ablation besides pain relief.
Fig. 3 Treatment of an osteolytic bone lesion for pain palliation (Sonalleve, Profound Medical,
Mississauga, Canada). a Treatment cell (yellow ellipsoid) placed on the cortical bone and soft tissue interface.
b MR thermometry map showing temperature increase along the cortical surface and in
the adjacent muscle (black arrow).Abb. 3 Therapie einer osteolytischen Knochenläsion zur Schmerzlinderung (Sonalleve, Profound
Medical, Mississauga, Canada). a Therapiezelle (gelbe Ellipse), die auf die Kortikalis und die angrenzenden Weichteile
platziert wurde. b MR-Thermometrie-Karte, die eine Temperaturzunahme entlang der kortikalen Oberfläche
und den angrenzenden Muskel zeigt (schwarzer Pfeil).
A phase 3 randomized trial including 112 patients showed pain relief with average
onset three days after MR-HIFU treatment with a response rate of 64.3 % compared to
20 % in the placebo group [31 ]. Pain relief after HIFU treatment was long lasting, i. e., up to six months and
longer. Furthermore, 27 % of all responding patients could completely discontinue
pain medication, while an additional 17 % required less medication. Another prospective,
single-arm research study including 18 patients examined pain relief from MR-HIFU
in a first–line treatment setting. Here, 72.7 % of all patients reported complete
pain relief while omitting all pain medication and 16.7 % of all patients reported
partial pain relief while keeping pain medication constant. Remarkably, local tumor
control was observed after MR-HIFU treatment in about 33.3 % of all patients with
restoration of bone integrity [32 ]. The clinical outcome of pain relief is supported by current preclinical studies
pointing at thermal denervation of the bone and periosteum as the most prominent mechanism
for pain relief [25 ]. Despite thermal ablation of the bone itself, there is no indication in clinical
and preclinical studies that HIFU treatment could lead to an additional reduction
of mechanical stability of weight-bearing bones or increase the risk of fractures
[33 ]. HIFU-related complications can be comprised of skin burns or intramuscular edema
with consecutive reduced mobility of the affected extremity directly after treatment
that usually resolves within days.
The bone application space has been broadened to include the treatment of benign bone
lesions such as osteoid osteomas or sub-cortical desmoids [34 ]
[35 ]
[36 ]
[37 ]
[38 ]
[39 ]
[40 ]. In a recent study, Sharma et al. demonstrated that MR-HIFU ablation of osteoid
osteomas yields a comparable clinical response to radiofrequency ablation with the
added benefit of being free of incisions and ionizing radiation [40 ].
Another interesting application is the treatment of pain related to facet joint arthritis
[41 ], where HIFU offers a completely noninvasive alternative to standard treatments including
minimally invasive RF ablation, medications (e. g., NSAIDs, topical analgesics), or
local injections (e. g., steroids, analgesics).
Neurological diseases
Although the treatment of brain diseases was envisioned as one of the first clinical
HIFU applications in the 1950 s [3 ], FDA approval for the treatment of essential tremor was first given in 2016. While
early HIFU studies required a craniotomy, a noninvasive therapy through the skull
was finally made possible with a transducer covering the whole calvaria [42 ]. Corrections for scattering and refraction of ultrasound at the skull based on models
derived from prior CT scans and using an improved HIFU transducer having 1024 beams
(ExAblate Neuro, InSightec, Haifa, Israel) allow precise MR-guided focal ablation
within the central part of the brain nowadays. To date, several non-oncological applications
such as noninvasive ventriculostomy [43 ], thalamotomy to treat Parkinson’s disease [44 ] and therapy for refractory neuropathic pain [45 ] have been described with first successes in clinical studies. A first study showed
convincing results of a noninvasive cerebellothalamic tractotomy for the treatment
of 21 patients with therapy-refractory essential tremor [46 ] and describes transcranial HIFU to be effective and safe. A randomized trial published
by Elias et al. finally provided safety and efficacy data that led to the above-mentioned
FDA approval of this method [47 ].
Ultrasound-induced cavitation in combination with intravenously administered microbubbles
(i. e., ultrasound contrast agents) was also recognized for its potential to reversibly
open the blood brain barrier [48 ]. That effect allows molecules to extravasate into the brain tissue that would normally
be confined to the vascular system, though extent and time span depend on the size
of the molecule and ultrasound parameters [49 ]. The approach was preclinically applied to improve drug delivery to brain cancer
and also to treat neurological disorders such as Alzheimer disease. Recently, Lipsman
et al. were able to demonstrate the safety and feasibility of opening the blood-brain
barrier using MR-HIFU in a phase I safety trial which included five patients with
Alzheimer’s disease [50 ].
Conclusion
Currently, the clinical use of MR-HIFU is restricted to the thermal ablation of tissues
and is well established for the treatment of uterine fibroids and for pain alleviation
in patients suffering from bone metastases. For the treatment of uterine fibroids,
MR-HIFU has been shown to be a patient-friendly, safe and effective therapeutic option,
with reduced overall healthcare spending thanks to fewer complications, shorter hospitalization
and accelerated rehabilitation rates. The use of MR-HIFU for pain palliation caused
by bone metastasis offers the advantage of fast treatment response and the possibility
for repeated treatment as HIFU does not involve ionizing radiation. Local tumor control
after HIFU treatment has been reported in a few cases using MR-HIFU for first-line
treatment but needs broader statistical evidence. As a first application in neurological
disorders, MR-HIFU recently gained approval for the treatment of essential tremor.
Other neurological applications are currently being investigated.
