MRI-guided Focused Ultrasound Surgery of Uterine Leiomyomas 1

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1 MRI-guided Focused Ultrasound Surgery of Uterine Leiomyomas 1 Fiona M. Fennessy, Clare M. Tempany Uterine fibroids are the most common pelvic tumors in women and are a significant cause of morbidity for women of reproductive age. Today, there are a variety of less invasive alternatives available to hysterectomy, such as myomectomy, hormonal therapy, uterine artery embolization, and more recently magnetic resonance-guided focused ultrasound surgery (MRgFUS). With this technique, ultrasound waves are focused through intact skin of the anterior abdominal wall resulting in localized thermal tissue ablation, monitored by online MR temperature control. By using an effective combination of image guidance and energy delivery, MRgFUS therefore allows for preservation of uterine function while obviating the need for a minimally invasive procedure or surgery. Key Words. Leiomyoma; fibroid; MRI; MRgFUS; focused ultrasound. AUR, 2005 The growing field of image-guided intervention and therapy has seen tremendous growth in recent years. One of the reasons for this is the availability of improved imaging techniques that allow rapid real-time imaging and treatment monitoring. Focused ultrasound surgery (FUS), a form of thermal tissue ablation, is a noninvasive technique first used in 1942 (1). However, its acceptance was limited because of a lack of precise target definition and difficulty in controlling the focal spot position and beam dosimetry. This technique can now be performed with magnetic resonance (MR) guidance, allowing for precise target definition and monitoring of treatment temperature deposition. MR-guided FUS (MRgFUS) is a new noninvasive treatment choice for selected uterine leiomyoma. This Acad Radiol 2005; 12: From the Section of Abdominal Imaging and Intervention, Department of Radiology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA Received December 22, 2004; revised May 16, 2005; accepted May 25. Supported by Insightec Inc, Haifa, Israel, and National Institutes of Health 5R25 CA , R01 CA046627, and P01 CA Address correspondence to: F.F.M. ffennessy@partners.org AUR, 2005 doi: /j.acra article reviews the emerging role of MRgFUS in the treatment of uterine leiomyomas. It reviews the MR findings of uterine leiomyomas, explains the principles of thermal ablation with MRgFUS, and describes the results of clinical trials to date of MRgFUS in the treatment of uterine leiomyomas. LEIOMYOMAS A uterine leiomyoma is a gonadal-steroid dependent benign smooth-muscle tumor. It is the most common female pelvic tumor, occurring in up to 25% of women. Although the majority are asymptomatic, approximately 25% are associated with pelvic pain, menorrhagia, dysmenorrhagia, dyspareunia, pressure-related symptoms such as pelvic fullness and urinary frequency, and infertility. Larger leiomyomas are more likely to be symptomatic. It is thought that a reduction in leiomyoma size is associated with an improvement in symptoms (2,3). Leiomyomas shrink in size after menopause and are therefore responsive to gonadotrophin-releasing hormone analogues. Anatomically, the most common organ of origin of leiomyomas is the uterus, although they can also arise from 1158

2 Academic Radiology, Vol 12, No 9, September 2005 MRI-GUIDED FOCUSED ULTRASOUND SURGERY Table 1 Magnetic Resonance Sequences Obtained for Evaluation and Characterization of Uterine Leiomyomas Using a 1.5-T Magnet and Either a Body Coil or Phased Array Multicoil Plane Sagittal locator Axial T2 Sagittal T2 Coronal T2 Axial T1 Sagittal/axial/coronal T1 Pulse sequence SSFSE FSE FSE FSE FSPGR FSPGR Comment Include kidneys Stacks to include kidneys Pre- and post-gadolinium FSE sequences: TR/TE 4,000/102; field of view to fit; slice thickness, 4 5 mm with 1 2 mm gap; matrix, ; 1 2 signal averages. FSE, fast spin echo; FSPGR, fast spoiled-gradient echo; SSFSE, Single Shot Fast Spin Echo; TR, repeat time; TE, echo time. the fallopian tubes, broad ligament, cervix. and ovary. The most common location within the uterus is an intramural location. They can be subserosal, which may give rise to a pedunculated exophytic mass (usually in the fundus), or they can be in a submucosal location. This is the least common location, but the most likely to produce symptoms, such as menorrhagia and infertility. Histologically, leiomyomas are mesenchymal smooth muscle tumors. They are nonencapsulated but usually remain sharply demarcated from surrounding myometrium by a pseudocapsule of light areolar tissue or compressed myometrial tissue. They are subject to a wide variety of degenerative phenomena. Hyaline fibrosis, edema, hemorrhage, and cystic and carneous degeneration can occur. Sarcomatous degeneration is rare, occurring in less than 1% of all leiomyomas. Ultrasound is usually the first imaging modality of choice for the detection and diagnosis of leiomyoma. It usually demonstrates a well-defined, usually hypoechoic uterine lesion, which may demonstrate shadowing if the leiomyoma contains calcium. With computed tomography, an enlarged uterus is again seen, as are any focal calcifications, but the individual leiomyoma are usually less well defined. MR imaging is the optimal imaging modality, because it can define, diagnose, and characterize all leiomyomas. Its role is not limited to detection and diagnosis, because it is important in therapy planning and treatment monitoring. A combination of T1- and T2-weighted images is usually sufficient in diagnosis of uterine leiomyomas. The addition of intravenous gadolinium is helpful in the characterization of these benign tumors, which may effect treatment decisions, because homogenous enhancement or internal necrosis can be determined. A suggested MRI protocol for imaging and characterization of leiomyomas is outlined in Table 1. Imaging Appearance of Leiomyomas The typical features of a leiomyoma on a T2-weighted image is that of a well-defined uterine mass with homogenously low signal intensity, similar to that of muscle (Fig 1). If there is central hemorrhagic degeneration, there may be high foci of T1 signal intensity, consistent with blood. Degenerated leiomyomas may demonstrate heterogeneous signal with foci of high T2 signal interspersed within the mass. As degeneration progresses, the areas of high signal intensity on T2-weighted images become more confluent. Areas of calcification will be seen as areas of very low signal intensity, clustered or rimlike. Another subgroup of leiomyomas have a high T2-weighted signal and a heterogeneous architecture, not from degeneration. The high T2-weighted signal is thought to be due to edematous tissue, characteristic of cellular leiomyomas. Gadolinium has been shown to be helpful in differentiating these cellular lesions from degenerative lesions: cellular lesions show diffuse early enhancement on dynamic imaging, whereas hyperintense degenerative lesions show irregular delayed enhancement or no enhancement. Treatment Options for Symptomatic Leiomyomas There are multiple treatment choices for those who seek therapy for symptomatic leiomyomas. Treatments range from medical management with gonadotrophinreleasing hormone analogues to myomectomy to total abdominal hysterectomy. Before receiving treatment, it is important that the entire pelvis is imaged to confirm the presence of uterine leiomyomas, and exclude other potential etiologies for pelvic pain such as endometriosis or adenomyosis. Although hysterectomy is the most definitive treatment, removing the cause of pain along with any possibility of recurrence, many women are reluctant to be this aggressive and are becoming much more interested in less invasive options. Treatments that would preserve fertility and reduce recovery time are more readily available to patients today. This trend has been clearly demonstrated by the significant growth and interest in uterine artery embolization (UAE). First introduced in1995 (4), it has rapidly spread and has become widely available 1159

3 FENNESSY AND TEMPANY Academic Radiology, Vol 12, No 9, September 2005 Figure 1. Coronal T2-weighted image depicting the typical features of a leiomyoma on magnetic resonance. There is a well-defined low signal intensity intramural uterine mass, similar to signal intensity of that of muscle. This is surrounded by intermediate signal intensity myometrium. A Foley catheter is noted within the bladder, inferior to the uterus. Sagittal T2-weighted image demonstrating multiple uterine leiomyomas; *: posterior intramural uterine leiomyoma with a submucosal component present; **: anterior subserosal leiomyoma. across the world. Imaging plays an important role in the selection of patients for treatments such as UAE. This minimally invasive procedure results in ischemia of the uterus and all uterine leiomyomas, with resultant decrease in volume. It requires an overnight hospital stay and a short recovery period, the average number of days before returning to normal activity reported as 8 (5). Other image-guided techniques such as laser myolysis and cryotherapy have been tested and applied, but do require the invasive placement of probes. Most recently, a new and attractive totally noninvasive therapy has recently been added to the list of options: MRgFUS. This technique, approved by the US Food and Drug Administration (FDA) in October 2004, uses an effective combination of image guidance and thermal energy delivery. FUNDAMENTALS OF MRgFUS FUS is a thermal ablation method that uses sound waves created in tissue as a source of thermal injury. The tissues within the focal point at which the ultrasonic energy is delivered are heated to a critical level ( 55 C) that results in tissue necrosis and apoptosis or cell death. The local tissue structure and content, through which the beam passes, has a considerable effect on the ultimate tissue temperatures achieved, because blood vessels are great conductors of heat and can move heat away from the point of delivery, thereby acting as an inherent cooling system. Lynn et al first investigated the potential surgical application of FUS more than five decades ago (1). Since then, ultrasound has been extensively tested for trackless surgery of brain both in animals (6,7) and in humans (8). During the past decade and half, new clinical trials using focused ultrasound for noninvasive surgery of the prostate, kidney, liver, bladder (9 12), and eye (13) have demonstrated the clinical potential of this method. Although the use of FUS for the ablation of malignant tumors has been repeatedly shown to be promising (14), its widespread acceptance as a soft-tissue ablation method has been limited because of the difficulty of controlling 1160

4 Academic Radiology, Vol 12, No 9, September 2005 MRI-GUIDED FOCUSED ULTRASOUND SURGERY the focal spot position, precise target definition, and beam dosimetry. Fortunately, MR imaging can satisfy the key requirements for an image-guided focused ultrasound procedure, with true interactive treatment monitoring using thermal imaging. The fundamental principle of image-guided therapy is that of maximal therapy to a target tissue, with little or no damage to surrounding tissues (15 17). MR has excellent anatomic resolution for targeting, high sensitivity for localizing tumors, and temperature sensitivity for detecting temperature elevations. The area of interest can be imaged, the target identified and characterized, and the location of the target assessed for therapy. The adjacent anatomy and relationship of normal anatomical structures to the defined target can be evaluated. Quantitative MRI-based temperature mapping allows relatively small temperature elevations to be detected before any irreversible tissue damage is induced (18). This technique is based on the temperature dependence of the water proton resonant frequency shift (19), which has been extensively tested for monitoring thermal ablation therapies. Phase imaging is used to estimate the temperature-dependent proton resonant-frequency shift using a fast spoiled gradient-recalled-echo sequence. Temperature elevations across the focal plane can be monitored before, during and after each sonication. Using this technique, focal temperature elevations and effective thermal doses may be estimated (20,21). Thus the location of the focus can be detected at relatively low powers and the accuracy of targeting can be verified. The effect of treatment can be evaluated using intravenous gadolinium to demonstrate the amount of tissue necrosis as depicted by nonenhancing tissue. Therefore, MR and its guidance can provide the key elements in an imageguided procedure: imaging-based preplanning before the procedure, imaging-based lesion targeting before and on the day of the procedure, imaging-guided therapy delivery and monitoring during and after the procedure, and imaging-based assessment of therapy results at time points after the procedure. EQUIPMENT The equipment used for MRgFUS described in this manuscript and being used in clinical trials is an ExAblate 2000 (InSightec, Haifa, Israel), which is built into a table that docks with a compatible 1.5 T MR scanner (GE Figure 2. Magnetic resonance-guided focused ultrasound surgery equipment: the piezoelectric multielement phased array transducer is built into a table that docks with a compatible magnetic resonance scanner. Signa, General Electric Health Care, Milwaukee, WI). The ultrasound transducer is a piezoelectric multielementphased array. It has a 120-mm diameter and operating frequency between 0.5 and 1.5 MHz. It is located within the ExAblate table, surrounded by a water tank (Fig 2, Fig 3). A thin plastic membrane covers the water tank and allows the ultrasound beam to propagate into the tissue within the pelvis. The patient lies in a prone position in the magnet. The anterior pelvic/abdominal wall is positioned over the water tank (Fig 3). Acoustic coupling between the pelvis and the water tank is achieved by placing a gel pad under the pelvis, which contours around the anterior pelvic wall under the weight of the patient. The transducer array electronically controls the location of the focal spot and controls the volume of coagulation necrosis. Motion of the transducer along three axes is achieved with a mechanical positioning device. Ultrasound waves are focused through the intact skin of the anterior abdominal wall, causing high-temperature deposition at the focal point in the tissue for a few seconds, resulting in thermal tissue ablation. MRgFUS PROCEDURE Patient Selection Eligibility criteria for patient enrollment, as defined by the FDA for clinical trials reported here, required that candidate be greater than 18 years of age, in a premenopausal status with no desire for future pregnancies. A uterine size of less than 20 weeks was a necessary criterion, with no dominant leiomyoma greater than 10 cm in diameter. Women who had other pelvic disease or uncon- 1161

5 FENNESSY AND TEMPANY Academic Radiology, Vol 12, No 9, September 2005 Figure 3. Diagrammatic representation (a), and Sagittal T2-weighted image (b), depicting the patient lying in the prone position. The transducer is surrounded by a water tank, located within the Ex-Ablate table. A plastic membrane covers the water tank, and acoustic coupling is achieved by a gel pad positioned between the anterior abdominal/pelvic wall and the water tank. The patient s leiomyoma is positioned so that it overlies the ultrasound transducer. The location of the leiomyoma relative to all pelvic structures is delineated. The beam path is then planned in three orthogonal planes. trolled systemic disease were excluded. Those that were unsuitable candidates for MRI, such as women with cardiac pacemakers, were also excluded. A negative pregnancy test before screening was a necessity (which was repeated the day of treatment for confirmation). Those with extensive scarring along the anterior lower abdominal wall were excluded, as scar tissue in the path of the ultrasound beam may lead to thermal skin damage at the skin surface. Optimization of the selection criteria, however, is ongoing and will be better defined over time. As part of the selection process, patients have a screening standardized MR using a standard protocol (Table 1) on a 1.5-T GE Signa magnet. The patient is scanned lying in a prone position, however, in contrast to standard positioning. This protocol allows for confirmation of the diagnosis of the leiomyoma, location of the target lesion, determination of size and volume, and the absence or presence of enhancement. Patient Preparation for Treatment On arrival in our department, consent for intravenous conscious sedation is obtained. Intravenous conscious sedation using intravenous versed and fentanyl is used to minimize motion and patient discomfort during the procedure, while allowing the patient to remain awake to provide continuous feedback about any sensation or pain she may feel during the procedure. The patient is asked to arrive to the department fasting from the night before, and a Foley catheter is placed to drain the urinary bladder and to keep it empty during the procedure. Before beginning the procedure the patient s lower abdominal wall skin is examined and must hair free (the night before the procedure the patient is instructed to shave all hair from her lower abdomen to the pubic symphysis). Pretreatment Image Analysis Immediately before treatment, the patient has an MR imaging study to identify and confirm the leiomyoma(s) chosen for FUS on the screening study using T2-weighted fast spin echo images in three orthogonal planes. These images are used to plan the beam path to the targeted lesion. The location of the leiomyoma relative to all adjacent structures is delineated. All local bowel loops are assessed and must not be in the potential beam path. The anterior abdominal wall and any skin scars or areas of irregularity such as keloids, are 1162

6 Academic Radiology, Vol 12, No 9, September 2005 MRI-GUIDED FOCUSED ULTRASOUND SURGERY Figure 4. Sagittal (a) and coronal (b) temperature-sensitive, phase-difference, fast-spoiled gradient-recalled-echo magnetic resonance images, acquired at peak temperature increase during two sonications. Sagittal view (a) was acquired parallel to the direction of the ultrasound beam, and coronal (b) was acquired was acquired perpendicular to the direction of the beam. evaluated, in combination with the clinical history of any prior pelvic surgery. The skin surface must be as flat as possible to allow good coupling of the ultrasound transducer and prevent any local decoupling during treatment, which can lead to skin injury. The entire pelvis is examined for any other possible abnormalities. Treatment Volume Selection The outlined volume of the leiomyoma to be treated is selected, on the basis of pretreatment T2-weighted MR images, using system software. Treatment methods as defined by the FDA for the clinical trials reported here required that a subvolume of the target be delineated for treatment. The outlined volume to be treated is then visualized in two orthogonal planes, usually coronal and sagittal planes. Software in the system allows display of the ultrasound beam and its pathway to the leiomyoma is overlaid on all tissues through which it will pass. Using these images, care is taken to ensure direct pathway of the beam to the desired treatment volume without traversing bowel or bladder. Using the treatment volume outlined, a sonication plan is derived by the physicist and physician. Focal sonications are placed such that the entire target volume is covered, to ensure full coverage and tissue coagulation in the selected volume. These planned sonications can be modified interactively during the treatment to obtain complete MR thermometry derived thermal dose and complete coverage of target volume, and resultant nonenhancement of the selected volume in posttreatment images. Sonications The positioning of the sonication beam is such that induced tissue coagulation covers the selected portion of the leiomyoma. Before commencing the therapeutic sonications, an initial low-energy test pulse is aimed within the target volume. During each sonication, multiple (two to five) sets of MR thermometry images are obtained. This temperature-sensitive, phase-difference based MR imaging monitors focus localization and tissue temperature changes with a fast spoiled gradientrecalled-echo sequence. At the initial stage, they are used to confirm correct location of the sonication and to ensure that the thermal change is visualized. The location of the focus is clearly seen on the temperature-sensitive images (Fig 4) and the temperature change can be measured. After the thermal low-power sonications are confirmed, therapeutic sonications begin. Each sonication lasts seconds, followed by seconds of cooling time. The peak temperature 1163

7 FENNESSY AND TEMPANY Academic Radiology, Vol 12, No 9, September 2005 Figure 5. Coronal T1-weighted images after administration of intravenous gadolinium. (a) Obtained at screening, before treatment. (b) Obtained immediately after treatment. Although the screening image demonstrates homogenous enhancement pattern of the uterine leiomyoma, there is a large new area of nonperfused volume immediately after treatment. and thermal dose derived from the MR images is used as a guide to ensure that adequate power is delivered to coagulate the target tissue. Because continual feedback occurs from the thermal images, the correct thermal dose to achieve necrosis is assured. The exact paths of the sonications are monitored online and are changed if necessary during the treatment (eg, should motion occur). This process continues until all planned sonications have been delivered. Posttreatment Image Analysis After treatment has finished, the patient remains in the same position for posttreatment imaging before and after administration of intravenous gadolinium, to determine the area of nonperfusion (necrotic) volume (Fig 5). The skin of the anterior abdominal wall is examined to ensure no skin injury is evident. The patient is observed for a short period while recovering from the conscious sedation and is then discharged home with an escort. For the purposes of the clinical trials, the patient returned for clinical follow-up within a week of treatment, and present for MR imaging 6 months, 1 year (Fig 6), and 2 years after treatment. CLINICAL TRIALS OF MRgFUS IN THE TREATMENT OF UTERINE LEIOMYOMAS: RESULTS The FDA approved MRgFUS in October 2004 for the treatment of uterine leiomyomas. This form of therapy was investigated in centers across the globe (Brigham and Women s Hospital, Boston, MA; Johns Hopkins University, Baltimore, MD; Mayo Clinic, Rochester, MN; St. Marys Hospital, London, UK; Sheba Medical Center, Tel- Hashomer, Israel; Hadassah Medical Center, Jerusalem, Israel; Charité Medical Center, Berlin, Germany). The results of the phase I and II trials were reported in 2003 (22,23). These began in 1999, enrolling eligible patients with symptomatic leiomyomas who were treated before hysterectomy. Before their hysterectomy, they underwent MRgFUS, and after hysterectomy, pathologic analysis of the uterus and leiomyoma was performed. The goal of this phase was not to attempt to treat the entire leiomyoma, but to induce a focal area of necrosis that could be documented at pathology. The average treatment sonication time was hours, and the average room time was 3 4 hours. Pathologic examination revealed hemor- 1164

8 Academic Radiology, Vol 12, No 9, September 2005 MRI-GUIDED FOCUSED ULTRASOUND SURGERY Figure 6. Axial (a,d), coronal (b,e), and sagittal (c,f) T2-weighted images through the pelvis. (a c) Obtained before treatment. (d f) Obtained 1 year after treatment. A reduction in fibroid size is apparent when comparison is made between the two time points. rhagic necrosis in the area of non-perfusion on the posttreatment MRI. The phase III clinical trial involved treatment of many more women with larger volumes within the leiomyomas, because these patients were not receiving any additional forms of therapy. The outcome being assessed in this phase of the clinical trial was change in patient symptomatology, as documented by the Uterine Fibroid Symptoms and Quality of Life Questionnaire score. This tool, which specifically evaluates leiomyoma-related symptoms (24), scores responses from 1 (not distressed) to 5 (distressed a great deal). A minimum score of 21 was required for inclusion in the study. Early results from this trial report a significant improvement in their uterine leiomyoma symptoms on follow-up questionnaires, with 79.3% of patients achieved a significant 10-point reduction in score. The mean reduction in score was in fact 27.3 points, mainly occurring in the first 3 months (25). The mean reduction in leiomyoma volume at 6 months was reported at 13.5%. It should be noted that for this phase of the clinical trial, the treatment time was limited to 180 minutes or to a maximal treatment of 100 ml leiomyoma volume, whichever came first. To date, more than 200 patients have been treated. No serious adverse events have occurred from MRgFUS. In phase I and II trials, two patients had first-degree skin blisters, both caused by scars, and both of which healed normally. The early report of the phase III trial show five 1165

9 FENNESSY AND TEMPANY Academic Radiology, Vol 12, No 9, September 2005 patients to have continued heavy menses after treatment, requiring blood transfusions, thought to be related to the underlying cause rather than the treatment. One patient reported pain and bleeding after treatment, thought to reflect a treatment failure rather than a device-related adverse event. An additional one patient was admitted overnight for nausea related to the treatment. One patient from the phase III trial reported leg and buttock pain immediately after treatment (25). The MR images showed the sciatic nerve to be in the far field of the sonication pathway. MR neurography and electromyography studies did not demonstrate nerve damage. This case did lead to changes in treatment protocol, with 4 centimeters now being the minimal allowed distance from the treatment spot to nerve bundles that are in close proximity to a bone surface. CONCLUSION MRgFUS is a novel, FDA-approved, noninvasive technique for treatment of uterine leiomyomas. Results of clinical trials to date have demonstrated this technique to be feasible and effective. It has yet to be determined which types of uterine leiomyomas would benefit the most from this form of treatment. The procedure has been well accepted by patients (23). Importantly, it allows a patient to return to normal everyday life 1 2 days after treatment. When compared with hysterectomy (which reports a 6- to 8-week return), or uterine artery embolization (8 days after which patients return to normal activity), the impact of this treatment on both patient morbidity and the cost to society may be quite significant. ACKNOWLEDGMENT Minna So, MD, Nathan McDannold, PhD, Kullervo Hynynen, PhD, and Elizabeth Stewart, MD. REFERENCES 1. Lynn JG, Zwemer RL, Chick AJ, et al. A new method for the generation and use of focused ultrasound in experimental biology. 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