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REFRESHER COURSES |
1 From the Department of Clinical Focused Ultrasound, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. Presented as a refresher course at the 2007 RSNA Annual Meeting. Received May 4, 2007; revision requested May 16 and received July 25; accepted August 3. The author has received support from and is a consultant for Insightec. Address correspondence to the author (e-mail: ctempany{at}bwh.harvard.edu).
One of the most recent additions to the methods for image-guided therapy is magnetic resonance (MR)-guided focused ultrasound. 
This method represents a unique closed-loop therapy, with planning, guidance, control, and direct feedback (called MR thermometry), which work together to ensure an effective therapy. The focused ultrasound induces focal tissue destruction by thermocoagulation in a noninvasive manner. MR also enables real-time thermometry to be performed during each and every sonication. These characteristics make MR-guided focused ultrasound an exciting new approach for treating fibroids. Fibroids are diagnosed based on findings from the patient’s physical examination supplemented by imaging results. MR imaging is preferred to other imaging modalities because it enables the fibroids and the entire pelvis to be fully examined. After individual fibroids are identified and the target area is defined by the radiologist, the target volume is analyzed in a three-dimensional assessment to ensure the patient’s safety. The procedure begins with the delivery of low-power sonication, and the power is gradually increased until the therapeutic dose is reached. After the procedure, postcontrast images are acquired; these should demonstrate tissue necrosis. The results of clinical trials have shown that the treatment is safe, effective, and highly acceptable to patients.
© RSNA, 2007
The use of image-guided therapy has expanded considerably since it was first introduced with x-ray fluoroscopy to guide placement of intravascular catheters and to observe flow of contrast material in angiographic procedures. Image-guided therapy is now one of the most rapidly expanding fields of medicine, encompassing the expertise of many different fields of science (1). There are multiple components to any image-guided therapy program, which may vary from site to site, but the critical elements include expertise in imaging, image processing, visualization, and display. A typical image-guided therapy clinical research program includes radiologists, surgeons, radiation oncologists, and other clinical specialists. The expertise for image processing and display draws from the domains of computer science, bioengineering, and medical physics (2). Beyond the hospital and clinical research environment, there are important industrial counterparts in device manufacturing, imaging system vendors, and regulatory agencies such as the Food and Drug Administration and National Institute of Standards and Technology.
One of the most recent additions to the modalities and methods for image-guided therapy is magnetic resonance (MR)-guided focused ultrasound. It combines MR imaging to define the target and to control and monitor the ablation, and a transducer to control and deliver the focused ultrasound beam. MR-guided focused ultrasound is a unique closed-loop system that allows planning, guidance, control, and direct feedback of the effectiveness of thermal therapy. This last component, called MR thermometry, is perhaps the most innovative, and exploits the ability of MR imaging to measure temperature changes in real time. Focused ultrasound is the only known method that can induce local or focal tissue destruction by thermal coagulation with an ultrasound beam in a completely noninvasive manner. Early clinical applications of this method of ablation (or high-intensity focused ultrasound) have used diagnostic US to guide delivery of the beam and therapeutic US for thermocoagulation. This article reviews MR-guided focused ultrasound as applied in the treatment of uterine leiomyomas; the role of imaging in diagnosis and treatment of uterine fibroids is also discussed.
Focused ultrasound uses ultrasound waves to induce focal thermal effects, ablation, or thermocoagulation at a specified location in living tissue. The therapeutic use of sound waves has a relatively long history that dates back to 1942, when Lynn et al (3) first generated and used US as a therapeutic tool in the liver. Ultrasonographic (US)-guided high-intensity focused ultrasound has been used around the world for many years and for many different diseases. The work of many individuals, including the Fry brothers, has pioneered this form of thermocoagulation for medical therapy (4,5). Although there are several other forms of thermal therapy used in clinical practice today such as cryotherapy, laser, and radiofrequency waves, therapeutic ultrasound is the only one that does not require a percutaneous probe or other invasive device to access the target organ or lesions. It is completely noninvasive; the sound waves pass through the skin and tissue to focus on and deliver their energy to the target. Thus, therapeutic ultrasound can be used with relative ease in many clinical applications and with a high safety profile.
The current applications of US-guided high intensity focused ultrasound are performed with two different transducers—one for the diagnostic applications and one for therapeutic use. This thermal method has a long history of use in clinical care (6), ranging from treatment of liver metastases to bone tumors (7). It is relatively easy to perform, is practically pain free and easy on the patient, and is relatively inexpensive. Unfortunately, it has not been widely accepted, especially in the United States, primarily due to a lack of accurate monitoring of the temperature changes. In the early 1990s, a revolutionary approach was introduced in which MR was used to both guide and monitor delivery of the ultrasound beam (8,9). This technique allowed, for the first time, accurate, real-time measurement of the tissue temperature changes, either directly at the focal spot or anywhere in the tissue being ablated or in the volume being imaged.
MR Thermometry
The major advantage of using MR is that it enables real-time thermometry to be performed during delivery of an individual sound wave or sonication. This is done by exploiting the fact that the proton resonance frequency of water changes in response to changes in temperature. This method was first described by Ishihara et al in 1995 (10). Thus, when a single sonication is delivered to a focal spot, molecular vibrations or mechanical changes will occur and the local temperature in the tissues will change. This change can be measured by repeatedly performing phase-difference fast-spoiled gradient-echo MR imaging, or "phase map" imaging, at the targeted region before, during, and immediately after sonication. These images are used to calculate maps of thermal dose and may be rapidly acquired; the average sonication is delivered in 20 seconds and is followed by a cool-down period of 60–90 seconds. The use of MR thermometry provides several unique features: (a) when performed after low-power delivery, it localizes individual sonications; (b) when higher powers are used, it enables measurement of the delivered thermal dose; and (c) most important, it provides instant feedback on the effectiveness of the sonications. If the MR thermometry does not indicate that an appropriate thermal dose was delivered, the parameters of the sonication may be changed to improve effect (eg, the power may be increased). There are, however, some limitations to this form of thermometry: It does not work in tissue that contains fat, motion seriously compromises its effectiveness, and it does not provide absolute temperature measurements. Despite these limitations, it is the best imaging method currently available for real-time monitoring of thermal dose delivery and effect.
Clinical Overview
MR-guided focused ultrasound, or "scalpelless" surgery as it is sometimes called, appeals to both patients and physicians. Patients prefer a noninvasive treatment because it offers a simpler approach and avoids the risks of complications and prolonged hospital stays associated with open surgery. However, the medical community has been relatively slow to adopt new techniques such as MR-guided focused ultrasound for many reasons. Thus, the introduction of this approach into routine clinical care is neither simple nor straightforward. Appropriately, the assessment of all new technologies is a complex process, and it takes investigation, time, effort, and money to collect the mandatory evidence that the procedures are safe, efficacious, and better than the current conventional approaches. MR-guided focused ultrasound has been assessed at many of these levels to date.
MR-guided focused ultrasound was initially used to treat focal lesions of the breast because of its accessibility for transcutaneous delivery of focused ultrasound and because focal breast lesions can be well visualized with MR imaging and are easily accessible. Thermometry may also be performed in the breast; this has been demonstrated in the treatment of breast fibroadenomas (11) and breast cancer (12). This ablative technique is now an established method and is used to treat breast cancer in several centers around the world.
The next major clinical target was to use MR-guided focused ultrasound to treat uterine leiomyomas. This application was selected for several reasons. Uterine leiomyoma is a common benign disease that is currently treated with hysterectomy, myomectomy, uterine artery embolization, or medication. Its true prevalence is difficult to calculate, but at least 25% of women are thought to have symptomatic leiomyomas. Symptoms include excessive uterine bleeding, bulk or pressure symptoms, and infertility in younger women. These problems cause otherwise healthy women to lose time from family and work. The social and economic cost of fibroids has been estimated to be several billion dollars each year.
Pathologically, fibroids are benign, smooth muscle neoplasms and are composed of tightly packed smooth muscle cells in a whorl-like configuration with a tight outer capsule. As they enlarge and age with varying hormonal stimulation, their internal makeup changes. In general, they begin to shrink after menopause, and they can grow quickly during pregnancy. They may also bleed into themselves, degenerate, become cystic, calcify, or undergo sarcomatous degeneration (in less than 1% of cases).
MR Imaging of Leiomyomas
The diagnosis of fibroids is made based on findings from the patient’s clinical history and physical examination, supplemented by either US or MR imaging results. MR imaging offers significant advantages over all other imaging modalities; namely, it enables the fibroids and the entire pelvis to be fully examined. Current techniques for imaging the pelvis include performing T2-weighted sequences in all three orthogonal planes through the uterus and, in most centers, acquisition of a set of images before and after the administration of gadolinium. A typical protocol is outlined in Table 1.
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The MR images of the pelvis allow the radiologist to (a) diagnose the presence of fibroids, (b) correctly locate them, (c) measure their size and volume, (d) characterize the tissue, and (e) diagnose other uterine or pelvic conditions that may be present. All of these aspects should be included in MR imaging reports. The first concern is to diagnose the presence of fibroids (Figs 1, 2). As previously described, fibroids appear as well-defined uterine masses with crisp, clear borders that are easily seen on T2-weighted images as low-signal-intensity masses. The border definition is important, as it allows fibroids to be differentiated from their most common "mimicker," adenomyosis (Fig 3). Adenomyosis (the ectopic location of endometrial tissue within the myometrium) can be either diffuse or focal, and although it may appear masslike, its borders are not well defined.
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MR-guided Focused Ultrasound for Treatment of Uterine Leiomyomas
MR-guided focused ultrasound is currently performed with a system called the ExAblate 2000 (InSightec, Haifa, Israel) in a diagnostic 1.5-T MR imaging unit (General Electric Healthcare, Milwaukee, Wis). The ExAblate device is located in a custom-made table that docks in the magnet like a normal patient table. During the treatment, the patient lies prone on her stomach with her lower pelvis positioned over the transducer. Correct skin coupling is essential for successful treatment and patient safety and ensures a safe acoustic window for the ultrasound beam to pass through the skin into the fibroid. The patient is instructed to prepare for the procedure by removing all hair from the lower abdominal area prior to treatment; any scars are also noted. Extensive scarring is a contraindication for treatment because the scar deflects the ultrasound beam. Treatment through a scar may also cause local heating and burning because the patient has no feeling in the denervated scar.
Procedure Planning.— Prior to the procedure, multiplanar T2-weighted images of the fibroid, uterus, and surrounding pelvis, including the skin and fat of the anterior abdominal wall, are taken. These images are then transferred to the ExAblate planning program, the target area is manually drawn and defined by the radiologist, and the target volume is analyzed with superimposed ultrasound beam paths in all three planes. This three-dimensional assessment is done to ensure the following safety measures: (a) that no beam passes through or near any bowel loops, (b) that no beam passes through the bladder or major scar tissue, and (c) that no distal beam passes within 4 cm of the sciatic nerve or branches in front of the sacrum. During the procedure, the patient receives intravenously infused sedative, which allows her to remain fully conscious and comfortable and with little or no pain for the duration of the procedure. An important aspect of this procedure is continuous communication between the patient and the treating physician. Feedback from the patient regarding what she feels during each sonication is critical; if she feels burning in the skin or pain or stimulation in the sciatic nerve, the treating doctor may need to change the sonication parameters.
Performing the Procedure.— The procedure begins with the delivery of low-power sonication (50–100 W), with real-time thermometry acquired simultaneously. The resultant images provide feedback on location and allow the operator to determine the correct placement of the focal spot. Any alterations in location may be made at this point or after sonications are delivered. If the target location is correct and is clearly illustrated on the phase map, the procedure continues with gradual increases in power until the therapeutic dose is reached.
When the therapeutic dose is achieved, the procedure continues with delivery of all planned sonications. With each sonication, the MR images illustrate the local heating, and the ExAblate screen shows the resultant temperature change (Figs 4, 5). The operator then confirms the patient’s comfort and proceeds with the next sonication. The treatment monitor displays the delivered sonications that have achieved the threshold dose, usually over 60°C. In fact, it is more usual to try to reach 70°C–80°C, which ensures real tissue necrosis. The goal of each procedure is to ablate as much tissue within the selected fibroid as possible.
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Summary of Clinical Trials
The results of the multicenter clinical trials of MR-guided focused ultrasound in the treatment of leiomyomas have been reported several times, dating from the first report in 2003 by Tempany et al (14). Later reports include those of Hindley et al (15), Stewart et al (16), and Fennessy et al (17). Because the summary of those reports herein is limited, it is recommended that the interested reader review each report in detail. The trials to date have been initial phase I and phase II trials in which all patients underwent MR-guided focused ultrasound and then hysterectomy. Thus, pathologic correlation was available in all cases. The first trial provided important data on safety and feasibility of focused ultrasound with direct pathologic correlation. The subsequent trials were performed with a group of patients who underwent only MR-guided focused ultrasound and a control group of women who underwent hysterectomy. These trials were designed similarly, with all patients screened by using standardized quality-of-life and fibroid-specific questions and MR imaging to determine eligibility. The questionnaires established the baseline symptom severity and were repeated at several points after treatment began to allow objective measurement of the effects of treatment. The trials were limited to perimenopausal women who were thought to be "family complete."
The treatment protocol was established in consultation with the Food and Drug Administration. The initial guidelines required that the treatment be limited to no more than 3 hours of sonication delivery and that the tissue volume to be ablated be 100–150 cm3. In most cases, the time constraint was the primary reason that treatment was stopped. The distance from the sonications to the outer border of the uterus was no less than 15 mm.
The results of the clinical trials have shown that the treatment is safe; is effective at 6, 12, and now 24 months afterward; and is highly acceptable to patients. The treatment response was measured by improvements in the symptom severity score. The initial reports showed that 70% of patients had score changes of over 10 points, which is consistently higher than expected. This outcome is particularly impressive when placed in the context of the relatively small volume treated. In many cases, only one-third of the target fibroid was ablated, and yet the symptom improvement was over 20 points. More recent publications have shown even greater improvement with the new guidelines, which are less restrictive than before (18). Also, it is now clear that the nonperfused tissue volume should be as high as possible (greater than 60%), as there is a close relationship between nonperfused tissue volume and outcomes. It is also important to note that there are several predictors of success (19), namely low signal intensity on T2-weighted images before treatment and nonperfused tissue volume over at least 20%.
Other clinical applications of MR-guided focused ultrasound are currently in trials, including ablation of bone metastases for palliation and pain relief, brain tumors for volume reduction, and liver metastases for reduction in tumor burden. Prostate cancer will also be treated by using MR-guided focused ultrasound in the future (18).
In conclusion, the potential of this method of ablation is truly remarkable and, when fully realized, will likely cause a sea change in current clinical surgical care. The applications of MR-guided focused ultrasound extend beyond tumor ablation into drug delivery and alteration of the blood-brain barrier (20–24). This unique ability to cause local thermal ablation with such precision and control is unparalleled.
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