48

Uterine leiomyomas, commonly referred to as fibroidsor myomas, are a significant source of morbidity for re-productive-aged women.1 Black women are both morelikely to have leiomyomas and more likely to have severedisease.2,3 Because these benign smooth muscle cell tu-mors of the uterus are cured by hysterectomy, their eco-nomic impact has been examined chiefly in relationshipto the costs of hysterectomy. Current estimates of cost inthe United States alone exceed $1.2 billion annually.4,5

But, this figure significantly underestimates cost, given the

wide variety of alternatives to hysterectomy that are usedcurrently and the number of women who choose no treat-ment on the basis of the invasiveness of current options.

Women increasingly are seeking minimally invasive al-ternatives to hysterectomy, motivated by the trend towardlater childbearing and the desire to minimize recoverytime. Laparoscopic and hysteroscopic myomectomy anduterine artery embolization (UAE) are widely used forthese tumors.1,6,7 Although these options are less invasivethan hysterectomy, some options are restricted to womenwith myomas in particular locations, and other optionsinvolve significant morbidity.

Surgically guided thermoablative techniques (such asmyolysis and cryomyolysis) have been studied for thetreatment of myomas, yet seem to have considerable vari-ability in response.8-10 The introduction of image guid-ance with the use of magnetic resonance has producedmore consistent results but still requires an invasive ap-proach for the placement of probes directly into the fi-broid tissue.11-13

Focused ultrasound surgery (FUS) is a novel noninva-sive technique that is capable of producing coagulativenecrosis at a precise focal point within the body. The lo-cation and extent of treatment can be monitored accu-rately with real-time magnetic resonance imaging (MRI)and MRI thermal mapping.14,15 The feasibility of MRI-guided FUS for the ablative treatment of benign breast fi-

From the Departments of Obstetrics, Gynecology and Reproductive Biol-ogy,a Radiology,b and Pathology,cBrigham and Women’s Hospital and Harvard Medical School, the De-partments of Obstetrics and Gynecology,d Radiology,e and Pathology,f StMary’s Hospital, the Departments of Obstetrics and Gynecologyg and Ra-diology,h Sheba Medical Center, the Departments of Radiologyi and Gy-necology,j Charité Medical Center and Humboldt University, and theDepartments of Obstetrics and Gynecologyk and Radiology,l HadassahMedical Center.Supported by Insightec, Ltd (Haifa, Israel) and by National Institutes ofHealth grants No. P01 CA 67165-06 and CA 46627 (Bethesda, Md).Received for publication September 30, 2002; revised December 20,2002; accepted February 13, 2003.Reprint requests: Elizabeth A. Stewart, MD, Center for Uterine Fibroids,Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115USA. E-mail: eastewart@partners.org© 2003, Mosby, Inc. All rights reserved.0002-9378/2003 $30.00 + 0doi:10.1067/mob.2003.345

Focused ultrasound treatment of uterine fibroid tumors: Safetyand feasibility of a noninvasive thermoablative technique

Elizabeth A. Stewart, MD,a Wladyslaw M. W. Gedroyc, MD,e Clare M. C. Tempany, MD,b

Bradley J. Quade, MD, PhD,c Yael Inbar, MD,h Tilman Ehrenstein, MD,i Asher Shushan, MD,k

Jonathan T. Hindley, MD,d Robert D. Goldin, MD,f Matthias David, MD,j Miri Sklair, MD,l andJaron Rabinovici, MDg

Boston, Mass, London, United Kingdom, Tel-Hashomer and Jerusalem, Israel, and Berlin, Germany

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of focused ultrasoundsurgery with magnetic resonance imaging guidance for the noninvasive treatment of uterine leiomyomas.STUDY DESIGN: Fifty-five women with clinically significant uterine leiomyomas were treated. Pain and com-plications were assessed prospectively, and posttreatment magnetic resonance imaging was used to mea-sure the treatment effects. Patients in three of the five centers underwent planned hysterectomy aftertreatment, which provided pathologic correlation of treatment.RESULTS: Seventy-six percent of the enrolled patients completed the full treatment session. All treatmentswere conducted in an outpatient setting with minimal discomfort for subjects and no major complications.Pathologic examination of the uterus confirmed that magnetic resonance imaging guidance provides the safeand accurate delivery of effective levels of thermal energy with a 3-fold increase in volume of histologicallydocumented necrosis, compared with treatment volume (6.6 ± 0.8 vs 18.4 ± 3.9 mL, P < .005).CONCLUSION: Magnetic resonance imaging–guided focused ultrasound surgery appears to be a well-toler-ated treatment for uterine leiomyomas. (Am J Obstet Gynecol 2003;189:48-54.)

Key words: Uterine leiomyomas, magnetic resonance imaging

Volume 189, Number 1 Stewart et al 49Am J Obstet Gynecol

broadenomas has been demonstrated already.16 Testingin an animal model has shown FUS to be a potential treat-ment strategy for uterine fibroids in humans.17

The hypothesis of the current study is that FUS can beused safely to produce coagulative necrosis in uterine fi-broids with real-time thermal monitoring with MRI guid-ance. This would be the first noninvasive ablativetechnique used for the treatment of uterine fibroids.

Material and methods

Fifty-five premenopausal or perimenopausal womenwith symptomatic uterine fibroids were recruited at fivesites: Brigham and Women’s Hospital (Boston) CharitéHospital (Berlin), Hadassah Medical Center (Jerusalem),St Mary’s Hospital (London), and Sheba Medical Center(Tel-Hashomer). Local institutional review boards ap-proved the study at each institution; the studies resultedin significant changes from the original protocol in twosites. At three sites (Brigham and Women’s Hospital,Charité Hospital, and St Mary’s Hospital) women whowere planning hysterectomy were recruited, and the hys-terectomy specimens of treated subjects were examined.Technical details of nine of these treated patients havebeen reported previously.18 This group will be termed thehysterectomy protocol. At the remaining sites (HadassahMedical Center and Sheba Medical Center) at the stipu-lation of the local institutional review board, women whowere eligible for hysterectomy were treated expectantlyafter treatment and not compelled to undergo hysterec-tomy, which was termed the observation protocol.

Typically one myoma was targeted for treatment. My-omas that were located where the FUS treatment beamwould pass through bowel or bladder were excluded.Complete coagulation of the entire myoma was not thegoal of the current study; rather, treatment was to inducecoagulative necrosis safely within an operator-definedportion of the targeted tumor. The ease of treatment de-termined the fibroid that was chosen, and no attempt wasmade to target the fibroid that was most likely to causesymptoms. Because most women had multiple leiomy-omas, a relatively small percentage of uterine tissue wastreated in each case.

All women were at least 18 years old and did not intendfuture childbearing. Women with uteri >20-week gesta-tional size or a dominant myoma >10 cm in diameterwere excluded, as were women with a hematocrit level of<25%, a positive pregnancy test, major medical disease,or contraindication to MRI (such as a pacemaker).

Patients were seen first by a gynecologist who obtainedinformed consent, completed an initial examination, andperformed a hematocrit and pregnancy test. Women whomet the eligibility criteria then underwent a screeningMRI to confirm that myomas were present and were fea-sible to treat and that no other disease process (such asan ovarian tumor) was present to preclude treatment.

The high intensity FUS system (ExAblate 2000; In-Sightec, Haifa, Israel) is fully integrated with a 1.5-TeslaMRI system (GE Medical Systems, Milwaukee, Wis). TheFUS system generates an ultrasound beam in the fre-quency range commonly used for therapeutic ultrasoundscanning (approximately 1-1.5 MHz) and brings it to afocal volume at which thermal energy is delivered to tar-geted tissue. The treatment volume is defined directly onthe magnetic resonance images that are acquired at thetime of the treatment. The FUS system uses this informa-tion to compute the optimal sonication grid to fully coag-ulate this targeted volume.

During sonication, the FUS system performs real-timethermal mapping of the treatment area based on mea-surements of proton resonance frequency shift that isgenerated by tissue heating. Treatment parameters canbe adjusted between sonications on the basis of immedi-ate imaging feedback. The goal was a target temperatureof 60°C to 70°C to induce coagulative necrosis. Beforetherapeutic sonication begins, a test sonication at lowpower (typically 10-50 W) is used to confirm targeting ac-curacy. This level of power is selected so that the inducedtemperature elevation does not create tissue damage.

The range of acoustic input power levels varied withthe tissue depth of the treated uterine fibroid and othertissue-related parameters (such as vascularization and tis-sue inhomogeneities). Average values were 100 to 200 Wat the skin line, which generated power densities at thefocal point in the range of 500 to 700 W/cm2.

Patients were treated in the MRI suite as outpatientswith a combination of narcotics, nonsteroidal anti-in-flammatory drugs (NSAIDs), and/or benzodiazepins forpain relief. Medications that were used in each centerwere not standardized because of differences in formu-lary medications.

Treatment time was planned to be ≤2 hours. Womenwere placed in the prone position, with the abdomenresting over the FUS treatment apparatus. Vital signswere monitored continuously, and the women were in di-rect voice contact with investigators at all times. Subjectswere discharged to home after approximately 1 hour ofobservation.

Patients were asked to rate their pain and discomforton a scale of 0 to 3 immediately before the treatment,during the treatment, and immediately before discharge.No specific assessment of previous pain experiences wasprovided for comparison.

Subjects in the hysterectomy protocol were seen ap-proximately 72 hours after treatment for a physical ex-amination and post-FUS MRI. Gadolinium-enhancedimages were used to measure the volume of absent perfu-sion that resulted from the treatment. Women then un-derwent hysterectomy within 1 month of the FUStreatment. Treatment images were correlated with thepathologic specimen, and careful sampling of the treated

50 Stewart et al July 2003Am J Obstet Gynecol

Table I. Demographics of women who were treated with focused ultrasound treatment

Menopause Body mass Treatment limitations Patient Age (y) Race status index (kg/m2) and adverse events

Hysterectomy protocolBrigham and Women’s Hospital

1 38 Black Pre 29 Abdominal scar, limited treatment2 40 Black Pre 29 First-degree skin burn3 39 Black Pre 21 Bowel in FUS beam, no

treatment, nausea and vaginal bleeding after treatment

4 48 White Pre 29 Equipment difficulties, limited treatment

5 42 White Pre 34 Test pulse not visible, notherapeutic treatment

6 42 Asian Pre 22 None7 41 Black Pre 37 None8 45 Black Pre 30 None9 51 White Pre 41 First-degree skin burn10 45 White Pre 23 None11 52 White Pre 27 Extension of sonication to myometrium

St Mary’s Hospital1 50 Asian Pre 27 Equipment difficulties, no treatment2 36 White Pre 29 Abdominal fat and scar, limited treatment3 40 Asian Pre 28 Abdominal fat and scar, limited treatment4 51 White Peri 25 None5 46 Black Pre 26 None6 46 Black Pre 30 None

Charité Hospital1 45 White Pre 29 None2 39 White Pre 35 None3 45 White Pre 24 None4 50 White Pre 26 None5 53 White Pre 26 Test pulse not visible, no therapeutic treatment6 57 White Peri 29 None7 53 White Peri 27 None8 38 White Pre 25 None9 49 White Peri 25 Abdominal scar, no therapeutic treatment10 49 White Pre 22 None11 48 White Peri 24 None

Observation protocolSheba Medical Center

1 48 White Peri 22 None2 51 White Peri 24 Inadequate analgesia, limited treatment3 33 White Pre 22 None4 50 White Peri 25 Inadequate analgesia, limited treatment5 51 White Pre 31 Inadequate analgesia, limited treatment6 47 White Pre 29 None7 48 White Peri 27 None8 45 White Pre 25 None9 52 White Pre 28 None10 44 White Pre 19 None11 41 White Pre 23 None12 42 White Pre 24 None13 50 White Pre 20 None14 51 White Pre 20 None15 46 White Pre 21 None

Hadassah Medical Center1 38 White Pre 22.2 None2 46 White Pre 23.6 None3 51 White Pre 25.2 Bowel in FUS beam, no treatment4 46 White Pre 20.9 None5 50 White Pre 20.5 Limited treatment, probable tissue aberration6 43 White Pre 25.7 None7 51 White Pre 19.8 None8 51 White Pre 27.9 None9 55 White Pre 25.7 None10 41 White Pre 24.11 None11 42 White Pre 30.44 None12 55 White Pre Not available None

Volume 189, Number 1 Stewart et al 51Am J Obstet Gynecol

fibroid and adjacent myometrium were carried out. Ser-ial sections were examined at 0.5-cm intervals, andtreated volume was calculated by the summation of theareas of necrosis based on the formula for the volume ofa prolate ellipsoid. Coagulative necrosis and interstitialhemorrhage were confirmed histologically with hema-toxylin and eosin staining.

Women in the observation protocol were treated ex-pectantly. Post-FUS MRI in this group occurred immedi-ately after FUS, and the women were not seen for a72-hour posttreatment visit.

Data are reported as the mean with the SEM as the re-ported measure of dispersion for normally distributed data.Before quantitative analysis, data sets were tested for nor-mality with the use of GraphPad Statistical software (SanDiego, Calif). For normally distributed data, differences in

means were assessed using t-tests for paired data. For non-parametric data, the Wilcoxon paired test was used instead.

Results

Fifty-five patients have been treated in the study todate, and the cases are typical of women with leiomyomas(Table I). Patients had a mean age of 46.3 ± 0.7 years anda high body mass index (26.0 ± 0.6 kg/m2). Black womenmade up 13% of the study population. The median treat-ment time was 1 hour 45 minute (range, 6-232 minutes),with total time in the scanner 3 hours (range, 56 min-utes–4 hours 55 minutes).

Seventy-six percent of patients who completed thescreening were able to undergo adequate FUS (Table I).Three patients (5%) received no sonication, because ofthe presence of bowel in the sonication pathway on the

Table II. Comparison of targeted treatment volume with radiographic and pathologically verified treatment results: hys-terectomy protocol

Treatment Nonperfused Pathologically verified PosthysterectomyPatient volume (mL) volume* necrotic volume complications

Brigham and Women’s Hospital

1† 2.1 0 0 Bleeding in incision, side opposite sonication

2 5.8 64.6 15.3 Postoperative fever3† 0.5 0.0 0.04† 4.9 1.5 1.2 Vaginal cuff cellulitis5‡ 0.0 0.0 0.06 9.3 6.3 22.1 Postoperative fever,

urinoma7 5.3 32.7 No surgery, lost

to follow-up8 6.6 19.9 38.49 4.9 21.2 13.710 12.5 5.3 4.911 7.2 8.3 2.1

St Mary’s Hospital1‡ 0.0 0.0 0.02† 4.5 0.0 0.0 Pelvic hematoma3 4.8 12.0 19.94 2.9 1.0 0.65 3.5 14.0 9.26 6.3 65.6 22.5

Charité Hospital1 13.2 31.8 41.22 3.7 21.0 5.23 2.8 2.8 2.04 8.9 12.3 11.45† 0.0 0.0 0.06 4.1 11.1 42.47 4.0 34.9 14.18 12.6 52.4 65.49† 0.0 0.0 0.010 9.9 24.3 11.511 2.3 10.1 8.2

*Nonperfused volume was performed by MRI at 72 hours.†Limited treatment, patients for whom only the test sonication was delivered are included as limited treatments.‡No sonication was delivered, patients for whom only the test sonication was delivered are included as limited treatments.

52 Stewart et al July 2003Am J Obstet Gynecol

day of treatment, which could not be remedied bychanges in positioning (2 patients), and because ofequipment failure (1 patient).

Less energy than prescribed in the treatment plan wasdelivered in 10 additional patients (18%, Table I). In mostcases, the inability to visualize the low energy test pulsecaused no therapeutic sonication to take place. Most casesappeared to be related to tissue aberration of the abdomi-nal wall, primarily the presence of surgical scars or inho-mogeneous fat and muscle deposition in the abdominalwall. Increasing experience with treatment planning madethis a less common occurrence as the study progressed.

Patients tolerated the procedure well. Pain and discom-fort were self-reported on a 4-point scale on the day oftreatment, with 0 representing no symptoms and 3 repre-senting severe symptoms. Subjects reported a modest in-crease in both pain (0.3 vs 1.1 points, P < .0001) and

discomfort (0.2 vs 0.8 points, P < .0001) during the treat-ment compared with levels immediately preceding treat-ment. The pain score immediately before discharge,however, was not significantly different from the score be-fore treatment (0.3 vs 0.5 points, P = not significant). Dis-comfort was modestly, but significantly, elevated at thetime of discharge (0.2 vs 0.5 points, P < .004) after treat-ment. Although 37% of patients received all three classesof intraoperative pain medication, 12% received NSAIDsalone and 8% benzodiazepines alone. In the UnitedStates, total doses that are administered during treatmentincluded fentanyl 50 to 300 µg and midazolam hydrochlo-ride 0.5 to 3.5 mg. Most international sites used diclofenacsodium 25 to 75 mg with meperidine 50 to 100 mg.

The average volume that was treated was 12.1 mL(range, 0-61 mL); excluding limited treatments, this vol-ume increased to 14.1 mL (range, 2.3-61 mL; Tables II andIII). Posttreatment gadolinium-enhanced scans, however,suggested a significantly larger area of nonperfusion thanexpected, based on treatment volumes (Table II and Fig-ure). The nonenhancing volume increased modestly com-pared with treatment volume when assessed immediatelyafter treatment, as performed in the observation protocol(20.0 ± 3.2 mL vs 34.6 ± 6.2 mL, P < .004). A much moresubstantial increase was seen in the hysterectomy group,which underwent MRI 72 hours after the FUS procedure(6.5 ± 0.8 mL vs 22.6 ± 4.3 mL, P < .002). This extension ofeffective treatment volume was confirmed in the hysterec-tomy group with women who underwent hysterectomy amean of 8.6 days (range, 2-31 days) after FUS treatment(Figure). A 3-fold increase in volume of histologically doc-umented necrosis, compared with treatment volume (6.6± 0.8 mL vs 18.4 ± 3.9 mL, P < .005), was documented butwas confined to the margins of the treated myoma.

All patients who were able to undergo treatment weretreated as outpatients, and no patient required pro-longed observation before discharge or readmission afterdischarge. No patients were seen for complaints betweenthe time of treatment and the 72-hour visit. Only 10% ofthe women for whom 72-hour follow-up is available re-ported taking pain medication after treatment. One pa-tient reported taking oral narcotics, and the rest of thepatients used either acetaminophen or NSAIDs in equalnumbers. At 72 hours, the most frequently reportedsymptom was general discomfort in 25% of participants(mild, 75%; moderate, 17%; and severe, 8%). Pain andabdominal tenderness that was related to fibroid tumorswas reported by 14% of women, and only one patientrated each symptom as severe. Nausea and pain at thetreatment site were reported in 10% of subjects, and allsubjects rated both those symptoms as mild.

Two subjects were found by the physician at the time ofthe office follow-up to have 1-cm first-degree skin burnson the abdomen that the subjects themselves had notnoted previously. Two subjects, in whom the indication

Table III. Comparison of targeted treatment volumewith radiographic and pathologically verified treatmentresults: observation protocol

Nonperfused volumeTreatment by MRI immediately

Patient volume (mL) after treatment

Sheba Medical Center1 11 Not performed2* 4 Not performed

33 61 534* 14 165* 14 226 13 167 11 22

4 58 9 239 9 810 36 6211 18 1312 15 913 18 5314 60 4115 41 64

Hadassah Medical Center1 11 182 12 1423† 0 04 13 9

6 305* 22 06 16 167 21 578 46 939 17 30.610 16 3811 14 2612 6 11

*Limited treatment, patients for whom only the test sonicationwas delivered are included as limited treatments.

†No sonication was delivered, patients for whom only the testsonication was delivered are included as limited treatments.

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for hysterectomy was menorrhagia, had increased vaginalbleeding after the FUS procedure that was consistent withprevious bleeding.

The group of women who underwent hysterectomy didhave a significant incidence of adverse events after hys-terectomy, most of which were in patients who receivedeither no therapeutic sonication or minimal energy deliv-ery. Febrile morbidity was the most common complica-tion. Three Brigham and Women’s Hospital patients weretreated for presumed infection and received antibioticsand/or were readmitted after hysterectomy. After analysisof these cases, the protocol was modified to the use pro-phylactic antibiotics at the time of FUS treatment. No fur-ther febrile morbidity was seen.

Two patients had a posthysterectomy pelvic hematomathat required surgical drainage, and one patient had sig-nificant incisional bleeding on the opposite side of the in-cision from where the FUS sonication beam entered,which required surgical ligation of a single artery. One

patient withdrew from the study after treatment but be-fore hysterectomy for nonmedical reasons and has notrescheduled the surgery.

In only one instance was thermal injury detected in thenormal surrounding myometrium. An analysis of serial im-ages that was obtained during the procedure showed thatthe energy deposition was originally within the plannedtreatment region, but the targeted tissue changed its posi-tion because of the filling of the bladder. There was no clin-ical sequela in this case.

Comment

MRI-guided FUS, the first noninvasive surgical therapyfor fibroid tumors, appears to provide targeted ablation ofuterine leiomyomas with an excellent safety profile. TheMRI-based thermal mapping not only enhances safety butalso appears to enhance efficacy because treatment para-meters can be adjusted to ensure that target temperaturesreach the point at which tissue necrosis is achieved.

Figure. Radiographic and pathologic confirmation of FUS in uterine leiomyomas. A, On pretreatment T1-weighted spinecho images, treated fibroid is visualized in center of image. Endometrial cavity is seen to the right, and a fibroid to whichdegeneration had occurred before treatment is seen below the endometrial cavity. The treatment plan was drawn so thattreatment occurred away from the endometrial cavity. B, At 72-hour posttreatment visit, gadolinium nonenhancing areain this T1-weighted spin echo image is seen occupying a large portion of this section of the myoma, where treatment wascarried out. C, Gross pathologic examination of hysterectomy specimens revealed well-circumscribed areas of hemor-rhagic necrosis that corresponded to treated volumes. D, Histologic examination demonstrated coagulative necrosisthroughout treated volume, with patches of interstitial hemorrhage scattered throughout necrotic tissue (which is visibleat periphery of illustrated field). Necrosis was complete typically within grossly abnormal area in cases in which optimalFUS energy had been delivered.

54 Stewart et al July 2003Am J Obstet Gynecol

For patients, the experience of FUS differs markedlyfrom earlier techniques. In contrast with UAE, after whichpostprocedure pain and fever are common, patients hadfew complaints after FUS; there were no cases of postem-bolization syndrome or significant pain after the proce-dure.6,7 This difference may be due to the targeted natureof the lesion with FUS compared with the global and morediffuse effect of blocking both uterine arteries. It is alsoplausible that the instant nature of thermally induced pro-tein denaturation and cell necrosis differs from the slowlydeveloping ischemic injury after UAE. In contrast withsurgical procedures, there was minimal risk from anesthe-sia and no incisional pain or morbidity.

The fact that the volume of necrotic tissue exceeds thetreated area is similar to experiments that involve genetransfection in leiomyomas.19 In this model, a small num-ber of cells that were transfected with a lethal constructproduced a large “bystander effect” that caused the deathof many more cells than predicted.19 The hypothesizedmechanism is that, with injury to a single cell, mediatorsof apoptosis are generated and can spread through gapjunctions to extend the area of tissue destruction.19,20 Al-ternatively, interruption of the vascular supply could havecaused local ischemia and thus additional treatment ef-fect. Further studies of the hysterectomy specimens thatwere obtained in this study will help elucidate this issue.

Future studies will need to define whether the necrosisthat is seen shortly after treatment translates into endpoints that are associated with a reduction in leiomyomasymptoms, chiefly volume reduction and resolution ofleiomyoma-related bleeding. Additionally, correlation ofboth treatment and patient parameters with the surro-gate endpoint of post-FUS MRI and, ultimately, symptomreduction will be necessary in future studies to optimizetherapy for individual women.

The following individuals also served as authors: YacovItzchak, MD, PhD (Department of Radiology, Sheba Med-ical Center); Nathan McDannold, PhD, Kullervo Hynynen,PhD, and Ferenc A. Jolesz, MD (Department of Radiology,Brigham and Women’s Hospital and Harvard MedicalSchool); Joerg W. Oestmann, MD (Department of Radiol-ogy, Charité Medical Center and Humboldt University);Simcha Yagel, MD, and Ariel Revel, MD (Department ofObstetrics and Gynecology, Hadassah Medical Center);Moshe Gomori, MD (Department of Radiology, HadassahMedical Center); andLesley Regan, MD (Department ofObstetrics and Gynecology, St Mary’s Hospital).

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