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10.1245/s10434-006-9326-z
Annals of Surgical Oncology 14:1540-1550 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Magnetic Resonance–Guided Focused Ultrasound Surgery for the Noninvasive Curative Ablation of Tumors and Palliative Treatments: A Review

Doron Kopelman, MD1,2 and Moshe Papa, MD3,4

1 Department of Surgery B, "HaEmek" Medical Center, Afula, Israel
2 Technion, Israel Institute of Technology, Haifa, Israel
3 Department of Surgery C, Sheba Medical Center, Tel-Hashomer, Israel
4 Tel-Aviv University, Tel-Aviv, Israel

Correspondence: Address correspondence and reprint requests to: Doron Kopelman, MD; E-mail: kopelmand{at}bezeqint.net


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE BEGINNING OF FUS
 DISCUSSION
 REFERENCES
 
This article reviews and discusses the up-to-date data on and feasibility of focused ultrasound surgery. This technique uses high-energy ultrasound beams that can be directed to penetrate through the skin and various soft tissues, focus on the target, and destroy tumors by increasing the temperature at the targeted tissue volume. The boundaries of the treatment area are sharply demarcated (focused) without causing damage to the surrounding organs. Although the idea of using sound waves to ablate tumors was first demonstrated in the 1940 s, only recent developments have enabled this technology to become more controlled and, hence, more feasible. The major breakthrough toward its clinical use came with coupling the thermal ablative process to advanced imaging. The development of magnetic resonance as the foundation to guide and evaluate the end results of focused ultrasound surgery treatment, the image guidance of the ultrasound beam, and the development of a reliable method for tissue temperature measurement and real-time feedback of the extent of tissue destruction have pushed this novel technology forward in oncological practice.

Key Words: Focused ultrasound • Focused ultrasound surgery • Magnetic resonance–guided focused ultrasound surgery • Thermal ablation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE BEGINNING OF FUS
 DISCUSSION
 REFERENCES
 
The concept that many types of cancer become a systemic disease from their early stages, thus necessitating local control with adjuvant systemic treatment, has gained popularity in the last few decades. Treatment trends have changed from radical surgery to less aggressive surgery focusing on local tumor excision with negative surgical margins attempting to preserve organ function and cosmetic appearance as the preferred therapeutic strategy in many malignancies. Advances in imaging, new therapeutic technologies, and the increase in the use of screening methods for early cancer detection have made it possible to treat tumors in situ without surgery. Locoregional therapeutic and ablative techniques include minimally invasive surgical procedures, minimally invasive or noninvasive thermal ablative modalities, new radiation technologies, and regional chemotherapy. Such strategies can also be applied to the treatment of locally advanced and recurrent tumors, both with curative and palliative intentions.

The minimally invasive technologies provide treatment options that are physiologically, cosmetically, and psychologically more acceptable to the patient. Many of these still need further investigation before they become an accepted sound practice. The idea behind the use of thermal energy for tumor ablation is to cause cellular damage and, thus, tumor destruction. The various technologies differ in the way the energy is generated and applied to the tissue. The main challenges with using these technologies are to target and destroy the tumor while ensuring in real time a complete ablation of the tumor with negative margins, as well as minimal damage to the surrounding healthy tissue. Because of the tissue destruction, one needs to obtain all necessary pathologic and biological information, such as markers and receptors, before treatment.

This article reviews and discusses the up-to-date data and feasibility of focused ultrasound surgery (FUS). This technique uses high-energy ultrasound beams that can be directed to penetrate through the skin and various soft tissues, focus on the target, and destroy tumors by increasing the temperature at the targeted tissue volume. The boundaries of the treatment area are sharply demarcated (focused) without causing damage to the surrounding organs. Although the idea of using sound waves to ablate tumors was first demonstrated in the 1940 s, only recent developments have enabled this technology to become more controlled and, hence, more feasible. The major breakthrough toward its clinical use came with coupling the thermal ablative process to advanced imaging. The development of magnetic resonance (MR) as the method to guide and evaluate the end results of FUS treatment, the image guidance of the ultrasound beam, and the development of a reliable method for tissue temperature measurement and real-time feedback of the extent of tissue destruction have pushed this novel technology forward in oncological practice.


   THE BEGINNING OF FUS
TOP
 ABSTRACT
 INTRODUCTION
 THE BEGINNING OF FUS
DISCUSSION
 REFERENCES
 
The use of focused ultrasound energy as a tissue-ablative modality has been known for decades. The ability of high-intensity ultrasound to induce biological effects in tissue was first studied in unicellular organisms, frogs, and fish by Wood and Loomis1 in 1927. Gruetzmacher2 succeeded in focusing the ultrasound beam by placing a concave surface to a piezoelectric generator. Thermal lesions deep in bovine liver were produced by Lynn et al.3 in 1942 without damaging surrounding tissue. Fry et al.4 were among the pioneers of this fascinating technology and its medical applications. Their significant contribution to implementing FUS is evidenced by numerous valuable publications that appear as references in this review. They produced focal lesions in cat brains by using a device that mechanically aligned four focused ultrasound generators. Their research during the 1950 s demonstrated the ability to perform noninvasive thermal ablation of localized regions in the central nervous system of cats by using FUS.5–7 Human clinical studies began in 1959; FUS was used to produce lesions in the pallidofugal and nigral complexes in the brains of patients with hyperkinetic and hypertonic disorders.8

Experiments were also performed by using FUS on malignant disease. From the early 1930 s to the 1970 s, several attempts were made at FUS ablation of malignancies such as melanoma, thyroid carcinoma, and breast tumors.9–21

In 1975, Lele22 described FUS as a superior non-invasive technology: "Focused ultrasound technology meets the requirements of an ideal surgical tool. It has the demonstrated ability to destroy pre-selected targets located deep within tissue without any damage to the tissue in the path or surrounding the lesions." Encouraging reports were published during the 1980 s in the field of ophthalmology regarding treatment by FUS of pathologies such as retinal detachment, glaucoma, and traumatic capsular tears.23–25 Further research by several groups led by Hynynen, Jolesz, ter Haar, Yang, Gelet, Chapelon, Vallancien, and others led to a pioneering breakthrough in the development of image-guided FUS.26–38 It was then recognized that image guidance is of the greatest value toward the development of the ideal noninvasive surgical "knife."

Several imaging techniques were suggested and evaluated experimentally, such as fluoroscopic guidance, which has been used for extracorporeal shock-wave lithotripsy and even computed tomographic (CT) guidance. These methods gained no success because of a lack of accuracy, suboptimal anatomical resolution, use of ionizing radiation, and inability or poor ability regarding thermal mapping.39 Currently two imaging techniques can be used to guide the FUS: ultrasound imaging and MR.

Ultrasound-Guided FUS
Animal and human feasibility studies of the ultrasound-guided "extracorporeal pyrotherapy" (FUS) demonstrated that precise focal ablations of benign prostatic hyperplasia and of kidney and liver metastases were possible. 30,33,35 The tissue necrosis corresponded to the dimensions of the focal area as verified by histopathology. Efficacy was further supported by the tumor vessel destruction resulting from ultrasound-guided FUS that was demonstrated in patients with solid malignancies.40 Side effects included a transient increase in serum creatine phosphokinase with longer sonication durations and skin burns. Skin burns could be avoided by determining the relationship between sonication durations and the distance from the skin to the focal point.38

FUS is currently in clinical use for the treatment of benign prostatic hypertrophy and prostate cancer.41–46 The device designed by Sanghvi et al.46 involves an ultrasound transducer that switches between imaging and therapy, both at 4 MHz. Transrectal ultrasound probes with differing focal depths are used to treat tumors of varying sizes and shapes. These authors conducted a multicenter study involving 62 patients with benign prostate hypertrophy. Efficacy was evaluated by measuring changes in the urinary peak flow rate, quality of life, and the International Prostate Symptoms Score. According to these criteria, the authors considered the study a success.

Liver
Ter Haar et al.28 induced focal lesions in porcine liver in vitro in 1989. Since then, several research groups have explored the use of ultrasound-guided FUS technology for the ablation of liver tumors. Yang et al.29 showed improved survival rates in FUS-treated rats with hepatomas. Researchers in France demonstrated significant liver tumor size reduction in both animal and human studies.31,32 Other pioneering human studies were published in the late 1990 s: MR imaging (MRI) and histological evaluation and the preliminary results of a dose-escalation clinical trial using ultrasound-guided FUS in the treatment of localized tumors.36,47,48 In China, ultrasound-guided FUS is widely used for the treatment of oncological liver pathologies. Wu et al.49 claimed that ultrasound-guided FUS treatment is safe, effective, and feasible in a study of 164 patients with liver cancer, breast cancer, malignant bone tumor, and soft tissue sarcoma. FUS in this study was performed with partial imaging guidance by diagnostic ultrasound or with no imaging at all, without temperature monitoring, and with no real-time control or feedback regarding the deposited thermal dose.

Wu et al.50 have recently published their experience of ablating primary liver tumors with ultrasound-guided high-intensity focused ultrasound. The ultrasound-guided high-intensity focused ultrasound is not accurate enough, and the efficacy of the treatment becomes evident only during clinical follow-up. In many patients, the authors used several sessions of transcatheter arterial chemoembolization, including 10 to 20 mL of iodinated oil, 2 to 4 weeks before high-intensity focused ultrasound treatment to decrease tumor blood flow and increase the energy deposition in the target region. Fourteen patients who had partial treatment in the first session, as was proven in the follow-up imaging studies, had some ribs resected to enable an "acoustic window" for further high-intensity focused ultrasound treatment. The intraprocedural ultrasound study showed increased grayscale changes in the treated area in some patients. These changes became less evident and sometimes disappeared within a few minutes. Obviously these changes are not used as an integral part of the treatment process. The follow-up imaging studies—Doppler ultrasound, CT, or MRI—were performed 3 to 6 months after the procedure: these could assess the combined late effects of the different treatment modalities used for these patients. There was no real-time temperature mapping or imaging feedback that could be used during the treatment to change the treatment parameters and achieve more accurate results. Other groups in China are using ultrasound-guided FUS to treat bone, liver, pancreas, and other malignant lesions at various sites.51–54

When summarizing the work performed by the Chinese, several points of interest should be noted:

  1. In many patients, the authors used transcatheter arterial chemoembolization, including 10 to 20 mL of iodinated oil, 2 to 4 weeks before high-intensity focused ultrasound treatment to decrease tumor blood flow and increase the energy deposition in the target region.
  2. Some patients needed ribs removed to enable an acoustic window for further high-intensity focused ultrasound treatment.
  3. The intraprocedural ultrasound study showed increased grayscale changes in the treated area. These changes became less evident and sometimes disappeared within a few minutes. The follow-up imaging studies—Doppler ultrasound, CT, or MRI—performed 3 to 6 months after the procedure could assess the combined late effects of the treatment
  4. Neither real-time temperature mapping nor imaging feedback was used during the treatment to change the treatment parameters and achieve better results.
  5. To properly target the sonication to a liver lesion, the tissue should be immobile; respiratory movement of the liver thus creates a problem for focusing during sonication. Visioly et al.48 trained their patients to hold their breath during sonication.

Kidney
Several animal studies of high-intensity focused ultrasound were performed during the 1990 s: ablation of rabbit kidney tumors and ablation of the kidney in a large animal model.34,37 These led to advanced human studies of partial kidney ablation by using ultrasound-guided FUS for the treatment of renal carcinoma.55,56 An 18-mm laparoscopic FUS probe that allows real-time ultrasound imaging was used. Partial renal pole ablation was performed in 13 Yucatan minipigs. The median operative time was 180 minutes, the average high-intensity focused ultrasound activation time was 18.3 minutes, and the created lesion size was 23 x 17 x 11 mm. No effect on renal function was seen in treated versus untreated kidneys. Pathologic examination at 14 days revealed homogenous and complete tissue necrosis throughout the entire volume of the lesion, with sharp demarcation from adjacent normal tissue. The authors concluded that partial renal ablation with a laparoscopic approach is feasible and safe and results in homogenous, complete, and reproducible lesions.

MR-Guided FUS
Because B-mode ultrasound guidance lacked precision and did not provide thermal feedback from the targeted tissue, Hynynen et al.57 proposed FUS surgery with MRI to guide and monitor tissue damage. The first study that used MR-guided FUS for tumor ablation in rabbit skeletal muscle was performed in 1995 by Cline et al.58 The authors concluded that MRI provided accurate target definition and control for thermal therapy in a variety of tissues with variable perfusion rates and good thermal imaging feedback.

The single-element transducer used would be inconvenient for treatment of larger volumes because of the required cool-down time between sonications, which results in lengthy procedures. Jolesz and Hynynen et al.59 proposed an increase in acoustic focal volume to decrease the number of required sonications. This was accomplished by using a phased-array FUS system (InSightec Ltd., Haifa, Israel). This system is composed of many individual channels driving transducer elements that are individually excited by using a timing scheme to achieve the desired focusing. In addition, this technology offers the flexibility to electrically move the focal spot without physically moving the transducer.

The Sapareto and Dewey equations were described in 1984 to relate the dose to the probability of complete cell necrosis.60 The critical thermal dose is described in terms of tissue temperature and length of exposure. Thermal effects are quantified by calculating the thermal dose (time and temperature history) correlated with a volume of tissue and comparing this with a threshold to allow the prediction of thermal necrosis of the volume. A reference temperature of 43°C has been arbitrarily chosen to convert all thermal exposures to equivalent lengths of time in order to determine prognostic ability. The temperature mapping by the MRI enables evaluation of the average tissue volume ablated per sonication. It can be described as a closed-circle ablation with real-time feedback and control over the expected results. The ablative thermal energy in FUS is usually deposited during a few seconds only (5–20 seconds). This relatively rapid and steep gradient of tissue temperature in comparison to other thermal ablation modalities, such as radiofrequency ablation, is less dependent on the specific blood perfusion parameters. Sonication, as performed by the MR-guided FUS technique, achieves a relatively precise ablation of a predetermined area of tissue.

Focused ultrasound therapy is mainly based on tissue heating to induce coagulation. MR-guided FUS was found to be an effective technique for treating tumors in vivo, and MRI thermometry and dosimetry provide a way to predict the threshold for tissue damage in vivo. This offers improved online control and allows more accurate target volume coagulation. Techniques previously developed for treatments in homogeneous tissue volumes are applicable in the more complicated tumor environment if MR temperature feedback is available to modify treatment-delivery parameters. This feedback control mechanism is claimed to be the most significant advantage of MR guidance over ultrasound-guided FUS.61–65 Heat can be achieved through linear and nonlinear mechanisms. The linear mechanism is based on linear wave propagation and the absorption of energy through molecular friction. The nonlinear mechanisms include higher harmonics generation and multiple reflections by cavitation (implosion of microbubbles), thus resulting in significantly higher focal absorption of the energy; hence, the treatment rate will be higher. This interaction is less stable and less predictable compared with the linear mechanism, and nontargeted tissue at the interfaces could be damaged. To overcome the limitations and benefit from the enhanced treatment rate, a real-time monitoring and control based on MR thermometry was developed. The focal volume can be shaped by using temporal and spatial control of the focus. In vivo studies have recently demonstrated a two- to three-factor improvement in coagulated volume by enhanced ultrasound emission regimen, for the same transmitted acoustic energy with approximately 40% less energy propagating to the far field. The location of the ablated volume by enhanced sonication was predictable, pear shaped, and on average 1.8 times larger than that of a regular sonication of the same energy. Pathology results showed the same thermally induced damage patterns for both enhanced and regular sonications. This new enhanced sonication technology may significantly reduce the length of time required for tumor ablation procedures by MR-guided FUS.66

Organ-Specific MR-Guided FUS Animal Studies
Liver
We proved that MR-guided FUS under general anesthesia is a safe, completely noninvasive technology for the ablation of liver tissue. Liver tissue can be ablated in a very accurate manner, exactly according to the pretreatment planning on the MRIs. The MRI characteristics, including real-time temperature mapping, enable real-time control of every step of the ablation process. Mechanical ventilation with intermittent apnea periods overcomes the problem of the respiratory movements of the liver. The ablation of large volumes of liver tissue is still time consuming and requires hours of treatment under general anesthesia.67–69

MR-guided FUS ablations were performed in 15 pig livers under general anesthesia with the ExAblate 2000 system (InSightec). Different foci were chosen in the liver. Real-time imaging and temperature mapping (Signa Twinspeed 1.5 T; General Electric Healthcare, Milwaukee, USA) enabled the immediate evaluation of results of each sonication. These mock lesions were ablated by several sonications, each of them performed during 20 to 30 seconds of apnea. Between sonications, the pigs were ventilated normally. The pigs were sacrificed 3 to 30 days after the procedure, and their livers were examined.

MR-guided FUS created complete tissue destruction of mock lesions chosen in different areas of the pig livers (Fig. 1Go). There was no morbidity. Minor postprocedural elevations in the liver transaminases, bilirubin, creatine phosphokinase, and lactate dehydrogenase were detected. In addition to the ablation of mock lesions within healthy pig livers, a huge canine hepatocellular adenoma was treated by MR-guided FUS. Four procedures were performed with general anesthesia with the ExAblate 2000 system integrated with the ventilator. The exact location and volume of the ablated areas were planned on the MRIs. Real-time MRI and temperature mapping enabled the immediate evaluation of the effect of each sonication. Different areas were ablated within the tumor. The dog was operated on 21 days after the fourth ablative procedure. The MR-guided FUS created necrosis with continuous areas of complete tissue destruction within the liver tumor, in full accordance with the planning. The ablation of significant volumes of a highly vascular liver tumoral tissue was achieved.


Figure 1
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  		FIG. 1. Sharply demarcated ablated tissue within the right lobe of a pig’s liver. Tissue intimately adjacent to large vessels is thermally ablated. Portal vein (PV).

 
Brain MR-Guided FUS Phantom and Animal Studies
To determine the feasibility of the use of temperature-sensitive MRI for the detection of local temperature elevations at the focus of a low-power ultrasound beam in the brain, the brains in 28 rabbits were sonicated in a few different locations at different acoustic power levels in each rabbit. Ninety-three percent of the lowest-power (3.5 W) sonications were visible on temperature-sensitive MRIs and did not result in any short- or long-term histological or MRI evidence of tissue damage. These experiments demonstrated that temperature elevations induced by means of focused ultrasound exposures can be detected by temperature-sensitive MRI.70

Vykhodtseva et al.71 and Hynynen et al.72 investigated, using a rabbit model, the ability of MR-guided FUS to ablate tumors in the brain. The skull presents a major obstacle to the ultrasound beam. Advances in ultrasound transducer array and amplifier technologies have prompted many intriguing scientific proposals for ultrasound therapy. These include both mildly invasive and noninvasive techniques to be used in ultrasound brain surgery through the skull. The same authors have shown how a 500-element hemisphere-shaped transducer could correct the wave distortion caused by the skull with a transducer that operates at a frequency near .8 MHz. A new system using hemispheric phased array has been developed (InSightec) with optimized acoustic parameters. The system was tested by focusing ultrasound through ex vivo human skulls and into a brain phantom. Simultaneously, the procedure was monitored by MRI thermometry. The ultrasound focus of a 500-element, 30-cm-diameter, .81-MHz array could be steered electronically through the skull over a volume of approximately 30 x 30 x 30 mm. Furthermore, temperature monitoring of the inner and outer surfaces of the skull showed that the array could coagulate targeted brain tissue without causing excessive skull heating. The successful outcome of these experiments indicated that intensities high enough to destroy brain tissue can be produced without excessive heating of the surrounding areas and without producing large MR noise and artifacts.73 These studies represent the greatest potential and promise for future human intracranial noninvasive ablation of tumoral lesions.

Bone MR-Guided FUS—Animal Studies
The pioneering works of Hynynen and associates26,27 in the late 1980 s using FUS for the ablation of soft tissue adjacent to bone led to the MR-guided FUS bone studies. The purpose of these studies was to determine the ability of MR-guided FUS to accurately and safely target and ablate soft tissue at its interface with bone, with minimal collateral damage to nontargeted bone and soft tissue. Pigs were treated by the ExAblate 2000 system (InSightec). Heat-ablated lesions were created at the hind leg of each pig by applying a series of short high-power bursts of ultrasonic energy. During energy deposition, the temperature increase at the soft tissue was monitored by using real-time thermal images generated by the MRI. After 4 to 8 weeks, soft tissue lesion sizes were in the range of .8 x 1.2 cm to 1.6 x 2.6 cm on post-treatment MRI images. Nuclear imaging demonstrated a small photopenic area in the adjacent bone with evidence of initial resolution on its margins. MRI demonstrated mild enhancement of the treated tissue. Histopathologic examination of all lesions showed focal damage to the tissue at its interface with bone and localized damage to the outer cortex of the bone on the side closer to the targeted tissue. There was no damage to nontargeted tissue. MR-guided FUS can be used to produce controlled well-localized damage to soft tissue in close proximity to bone.74

MR-guided FUS Clinical Trials
Breast—Benign and Malignant Tumor Ablation by MR-Guided FUS
The in situ ablation of benign breast tumors has the advantage of saving patients from surgery and unnecessary scars. In 2001, Hynynen et al.75 concluded that noninvasive coagulation of breast fibroadenomas can be safely performed with noninvasive MR-guided FUS. The researchers used temperature-sensitive phase difference–based MRI to monitor focus localization and offline calculation of temperature changes. Eleven fibroadenomas were treated in nine patients under local anesthesia. The treatment was successful in 8 of 11 fibroadenomas, as demonstrated by a complete or partial lack of perfusion on the posttreatment MR contrast imaging.

Invasive breast carcinomas were treated with the ExAblate system (InSightec) a year later. Gianfelice et al.76,77 (St. Luc Hospital, Montreal, Canada) and researchers at Brigham and Women’s Hospital (Boston, MA) conducted a feasibility study on 12 patients with breast cancer. All patients were treated with MR-guided FUS before tumor resection. The resected mass and the surrounding tissue were analyzed histopathologically. Thermal ablation efficacy was determined from the histopathology findings. Efficacy differed depending on which of two FUS systems was used: a single-element transducer–equipped system with a fixed focal point or a phased-array transducer–equipped system with three-dimensional planning and monitoring capabilities that allowed the operator to vary the depth and size of focus in real time. The phased-array system was more effective. Residual tumor was mostly located in the periphery of the tumor mass. These results indicated the need to include a margin of healthy breast tissue around the tumor to increase the probability of complete tumor ablation. Another study included 24 breast carcinoma patients who were considered to be at increased surgical risk or who had refused surgery. These women underwent MR-guided FUS as an adjunct to their chemotherapeutic regimen or tamoxifen. Follow-up included routine studies to rule out metastatic disease and MR studies with and without contrast material infusion in the treated breast (10 days and 1, 3, and 6 months after the treatment session). Percutaneous biopsy was performed after 6-month follow-up, and if residual tumor was present, a second MR-guided FUS was performed, followed by repeat biopsy 1 month later.

Twenty-three of 24 patients completed the protocol, with only 1 minor complication: a second-degree skin burn that resolved with local treatment. Follow-up MR studies demonstrated a varying hypointense treatment margin (range, 1–11 mm), which represents destruction of tissue beyond the visible tumor. Absence of enhancement was thought to be an indicator of tumor destruction (18 of 19 patients with negative biopsy results), whereas persistent enhancement suggested tumor residue (3 of 5 patients with residual tumor). Overall, 19 (79%) of 24 patients had negative biopsy results after 1 or 2 treatment sessions. In both studies, the authors concluded that MR-guided FUS is a safe, repeatable, and promising method of focal tumor destruction. From 2002 to 2004, Papa et al. conducted a phase I trial for the evaluation of MR-guided FUS in ablating both breast carcinoma and fibroadenomas. Seven to ten days after the procedure, all patients with carcinoma underwent subsequent lumpectomy and axillary sampling to complete standard treatment and to allow pathologic evaluation of the procedure. Patients with fibroadenoma were observed. The authors concluded that although this type of ablation is still in its infancy, its future role in breast cancer and other tumors is promising. Furusawa et al.78 in Breastopia Namba Hospital, Miyazaki, Japan, treated 30 patients from April 2004 to February 2005. The aim of this study was to analyze the pathologic efficacy and clinical safety of MR-guided FUS for stage I and II breast cancer. The treatment was discontinued in one case as a result of patient stress. MR-guided FUS successfully ablated most targeted tumors by thermal coagulation and lytic necrosis. Several residual tumoral lesions were found. Third-degree skin burn, which was a treatment-related adverse event, developed in one case. The authors concluded that MR-guided FUS was a potentially effective breast-conserving treatment.

Uterine Fibroid Ablation and Symptom Relief by MR-Guided FUS
Uterine fibroids, benign tumors of the uterus, are symptomatic in 25% of women of childbearing age. Symptoms include excessive bleeding, pain, bloating, and incontinence. Up to 250,000 women in the United States undergo hysterectomy each year as a result of uterine fibroids. Uterine fibroids are to date the most prevalent tumors treated by MR-guided FUS. Approximately 2300 symptomatic women were treated around the world, with up to 36 months of follow-up. Of these, 71% to 79% reported significant symptom relief.

The first clinical trial of MR-guided FUS surgery for uterine fibroids proved its feasibility and safety and was published in 2003 by Tempany et al.79 Temperature evolution in the focus of each sonication was visualized and confirmed by real-time MR thermal images. All focal necrotic lesions were detected as nonperfused volumes in the immediate posttreatment contrast-enhanced T1-weighted images. Five lesions were pathologically confirmed. A separate multicenter study of noninvasive MR-guided FUS treatment of uterine fibroids, aiming at the alleviation of symptoms, included 55 women with clinically significant uterine fibroids.80 All MR-guided FUS treatments were conducted in an outpatient setting. Pain and complications were assessed prospectively, and MRI was used to monitor the anatomical effects of the treatment. In three of the five centers, patients underwent planned hysterectomy after the treatment, thus providing a pathologic correlation. No major complications were reported. Pathologic examination of uterine fibroids after hysterectomy showed that MR-guided FUS provided accurate delivery of effective levels of energy to the targeted regions. It seems in different studies81–83 that the larger the treatment volume, the greater the symptom improvement. Odds of a 10-point improvement in the symptom severity score at 12 months were 2.6 times greater for women with a nonperfused volume ratio ≥30% compared with women with a nonperfused volume ratio <30%. In general, it can be concluded that MR-guided FUS advantages are fewer days of missed work, a quicker return to normal activity, fewer days in bed, lower use of medical resources compared with total abdominal hysterectomy, 66% fewer additional procedures, and 66% fewer additional diagnostic tests. Significant device-related adverse events were one case of temporary nerve damage that resolved naturally (after protocol revision, no such events occurred) and five cases of skin burn with ulceration of the skin. Large fibroids (>10 cm) pretreated with gonadotropin-releasing hormone achieve symptom improvement similar to that with smaller fibroids.84

Liver Tumor Ablation by MR-Guided FUS
On the basis of the aforementioned liver MR-guided FUS animal studies and the first two human cases in which foci of primary liver hepatocellular carcinoma were ablated by MR-guided FUS, Jolesz et al.85 anticipated that the increased accuracy of treatment with thermal mapping combined with the cost savings of ambulatory treatment might lead to significant changes in the treatment of primary malignant liver tumors. Several problems still need to be overcome before MR-guided FUS can be used clinically to treat liver tumors on a widespread basis. MR-guided FUS under general anesthesia with intermittent apnea ventilation is time consuming. Large tumors will require faster MR-guided FUS systems. Currently the rib cage blocks much of the liver from the ultrasound beam. Next-generation phased-array transducers and advanced MRI methods are currently being developed for these needs.

Bone Metastasis—Pain Relief by MR-Guided FUS
Pain management is the most important goal in the treatment of patients with bone metastases. Palliative treatments such as localized irradiation, chemotherapy, oral bisphosphonates, systemic strontium 89, radioisotope therapy, surgery, or drugs have either efficacy problems or significant unwanted side effects. Percutaneous CT and ultrasound-guided radiofrequency ablation have recently proved to be of palliative value.

Currently a multicenter study of MR-guided FUS as a palliative modality is being conducted. The objective of the study is to evaluate the efficacy of MR-guided FUS in the treatment of bone metastases for pain relief. This palliative treatment is meant to become an alternative to failures of radiotherapy. Fewer than 10 patients with bone metastatic disease were treated by MR-guided FUS for pain relief (Fig. 2Go). The preliminary results in terms of significant reductions in pain and use of narcotics are promising.86


Figure 2
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  		FIG. 2. Schematic representation of magnetic resonance–guided thermal ablation of a bone lesion for the palliation of pain. The focused ultrasound surgery transducer is embedded within the magnetic resonance imaging (MRI) bed. The ultrasound beam (in red) is aimed at a focus "behind" (distal to) the target itself. All energy is absorbed by the bony tissue.

 
Brain Tumor Ablation—MR-Guided FUS
On the basis of previous phantom and animal studies, MR-guided FUS was shown to have the potential for precise image-guided thermocoagulation of intracranial lesions. A phase I clinical study was initiated to treat patients with recurrent glioma. Three patients with histologically verified recurrent glioblastoma multiforme were treated with MR-guided FUS. All patients underwent craniectomy 7 to 10 days before therapy to create a bony window for the ultrasound treatment. Sonications were applied to induce thermocoagulation of the enhancing tumor mass. MR-guided FUS treatment resulted in immediate changes in contrast-enhanced T1, T2, and diffusion-weighted MRI in the treated regions with subsequent histological evidence of thermocoagulation. MR-guided FUS was demonstrated to be a potentially effective means to destroy tumor tissue by thermocoagulation, although with an associated morbidity, and the inherently invasive nature of the procedure requires creation of a bone window.87


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 THE BEGINNING OF FUS
 DISCUSSION
REFERENCES
 
Focused ultrasound technology captured the imagination of physicians and researchers many years ago as a result of its noninvasive nature: it brings the ablative energy to its target without cutting or stabbing the body to destroy pathologic tissue, leaving the coagulated remnants to the natural disposal and healing physiological processes of the body. These advantages depend on the ability to accurately focus the beam, and this is not an easy task. Patient and system characteristics have a significant influence on the behavior of the beam. Tissue aberrations are yet of an unexpected nature, as are different absorbance quotients of energy along the beam path and in the target. Phased-array transducers are required to achieve better control of the beam. Advances in material science, mechanical and electronic engineering, processing power, and acoustic modeling were needed. The lack of all these abilities made the acceptance of FUS modality somewhat slow during the last decades. Parallel advances in the imaging world enabled pioneers to begin using diagnostic ultrasound guidance. This was the beginning of image-guided noninvasive surgery. Yet diagnostic ultrasonography has significant limitations in terms of real-time control of the thermal processes that are the very essence of FUS. Real-time thermal mapping made MRI a perfect solution for the next generation of FUS.88 MR guidance and control give the physician for the first time the ability to see the actual accumulation of thermal energy, the ablating process itself, in real time on a high-resolution MRI. MR-guided FUS is an advanced noninvasive image-guided and controlled procedure.

Advantages Versus Limitations of MR-Guided FUS
A totally noninvasive thermal ablative modality is an obvious advantage over invasive surgical and minimally invasive thermal ablative modalities. Most treatments that require not more than conscious sedation of the patient are of an ambulatory nature. If general anesthesia is required, as is currently the case with MR-guided FUS of liver tumors, the length of hospital stay is dramatically reduced in comparison to open surgery. Iatrogenic trauma and infectious complications due to penetrating the body and dissecting healthy tissue on the way to and around the target are avoided. The healthy tissue on the beam pathway is not affected, nor is the tissue surrounding the target. This is why the thermal dose is not limited as long as the temperature of tissue along the beam pathway does not increase. Also, recurrent treatment sessions are possible, unlike with other common modalities such as surgical interventions or radiotherapy. Access to deep targets is limited mainly by bone, cartilage, and other calcified tissue, which absorb most of the ultrasound energy, as well as by all air-containing organs (lung and bowel) that reflect the ultrasonic energy, impair the efficacy of the treatment, and endanger heat-sensitive neighboring organs. The advantages of MR-guided FUS in terms of access arise mainly due to the real-time image guidance of the procedure. Access to tumors located deep in the parenchymal organs (such as the liver) obviates the need for extensive surgical dissection. Comparing MR-guided FUS with minimally invasive ablative procedures such as radio-frequency, cryotherapy, and ethanol injections raises other issues besides the degree of invasiveness: the accuracy and comprehensiveness of tumor margin ablation are compromised unless there is a real-time control mechanism of the desired effect. MR-guided FUS makes this possible on the basis of MRI and real-time thermal imaging of the ablative process. Accurate, real-time thermal and anatomical verification of the ablation act itself enable the operator to adjust the system, change the treatment parameters, and overcome unexpected tissue aberrations. This makes a closed-loop verification of the ablative procedure.

Morbidity
The morbidity related to FUS is mainly the result of unexpected behavior of the ultrasonic beam due to tissue aberrations, absorbance of energy in tissue interfaces such as skin and bone, unexpected reflections from gastrointestinal air bubbles, and so on. These may cause skin burns and thermal damage to any other sensitive organ, such as the nerves and bowel wall. The MR real-time control of the process significantly diminishes these risks.

Future of MR-Guided FUS
Future applications include curative ablation of soft tissue tumors in different parenchymal organs, as well as palliative treatments for debulking or pain relief. Ablating large tumors by this modality is still time consuming. Future advanced systems should be faster and enable different access directions to the target. The combined effect of multiple transducers—extracorporeal, endocavital, endoluminal, rigid and flexible, and of different shapes—may improve the access and increase the efficacy of MR-guided FUS. Fast tissue tracking will enable the treatment of moving targets faster and will obviate the need for general anesthesia, used today for some applications.

Received for publication September 4, 2006. Accepted for publication December 1, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 THE BEGINNING OF FUS
 DISCUSSION
 REFERENCES
 

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