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ORIGINAL RESEARCH |
From the Academic Department of Obstetrics and Gynaecology, Department of Radiology, Imperial College London at St. Mary’s Hospital, London, United Kingdom.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We report a prospective study of women with leiomyomata in excess of 10 cm in diameter who received GnRH agonist before magnetic-resonance–guided focused ultrasound treatment. Eligible participants were recruited from the gynecology outpatient clinics. Entry criteria were a minimal leiomyoma symptom severity score and confirmation of uterine dimensions based on screening magnetic resonance imaging. These women received a 3-month course of GnRH agonists followed by magnetic-resonance–guided focused ultrasound treatment. The primary outcome measurement was reported change in symptom severity score as judged by the Uterine Fibroid Symptom and Quality of Life questionnaire. Comparison was made at enrollment, treatment, and at 3, 6, and 12 months posttreatment. A secondary outcome was the measured change in target leiomyoma volume.
RESULTS: Forty-nine women were enrolled in the study. There was a 45% reduction in median symptom severity score at 6 months and 48% at 12 months posttreatment, with 83% of women achieving at least a 10-point reduction in symptom scoring at 6 months and 89% at 12 months (P < .001). There was an average reduction in target leiomyoma volume of 21% overall at 6 months (P < .001) and 37% at 12 months (P < .001). No serious infective complications or emergency operative interventions were recorded.
CONCLUSION: The use of GnRH agonist therapy before magnetic-resonance–guided focused ultrasound improves the thermoablative treatment effect.
LEVEL OF EVIDENCE: II-3
More than 1,000 women with leiomyomata have been treated worldwide, and the results of phase III clinical trials have been published. Early work established that this technique, delivered in the outpatient setting, is technically feasible,8 reproducible, and causes a significant symptom reduction in more than 75% of women treated9 with leiomyomata smaller than 10 cm in diameter. Furthermore, patients treated with magnetic-resonance–guided focused ultrasound return to work, on average, within 48 hours compared with 19 days in those treated with conventional surgical techniques.10
To date magnetic-resonance–guided focused ultrasound treatment has been restricted to women with leiomyomata of 10 cm diameter or less, because the time required to perform the procedure is volume dependant. This limitation has important clinical implications because leiomyomata may be asymptomatic until this size threshold has been crossed, particularly among black women, in whom presentation at a younger age with larger leiomyomata is common.11 We postulated that by administering GnRH agonists to effect a temporary shrinkage in leiomyoma volume before carrying out magnetic-resonance–guided focused ultrasound we could extend this innovative treatment to a much wider patient group. The aim of this study was to prospectively evaluate the clinical outcome of magnetic-resonance–guided focused ultrasound in terms of Uterine Fibroid Symptom and Quality of Life scores and leiomyoma volume in 50 patients with uterine leiomyoma diameter greater than 10 cm.
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MATERIALS AND METHODS |
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All potential study participants underwent initial MR imaging of the pelvis in a 0.5T scanner (GE Medical Systems, Milwaukee, WI) (Fig. 1A). These images were reviewed by the same consultant Radiologist (WG) to confirm the diagnosis of uterine leiomyomata, exclude any other pelvic pathology and determine the presence of a suitable acoustic window to carry out magnetic-resonance–guided focused ultrasound treatment. An absolute contraindication to treatment was the finding of loops of bowel or abdominal wall scars in the projected ultrasound beam pathway. Three patients were excluded from entering into the study on imaging criteria as described above who would otherwise have been suitable on clinical criteria alone. Screening measurements were based on the largest diameter of the target leiomyoma being a minimum of 10cm. Further volumetric calculations were then carried out using standard DICOM imaging software (Image Viewer, ComMedica Ltd., Surrey, UK). This was utilized to calculate the area of the uterus and target leiomyoma on each individual MR slice, these values are summated and multiplied by slice thickness to give a value for target leiomyoma total volume using the Cavalieri principle.13
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Gonadotrophin-releasing hormone agonist, Goserelin 3.6 mg (Zoladex, AstraZeneca, London, UK), was administered as a course of three subcutaneous injections at 28-day intervals commencing on day 1 or 2 of the menstrual cycle. Magnetic-resonance–guided focused ultrasound was carried out 14–21 days after the third injection. On the day of treatment all patients were requested to shave their abdomen from the level of the umbilicus to the pubic symphysis. Previous studies have identified that there is an increased risk of minor skin burns in areas of hair growth, presumed to be secondary to air trapping in these regions.10 An intravenous cannula and urinary catheter were inserted and a pregnancy test performed.
The leiomyoma ultrasound machine used in this study (ExAblate 2000, Insightec, Haifa, Israel) integrates fully with a 1.5-Tesla MR scanner (GE Medical Systems), and the ultrasound transducer lies within a bath of degassed water in the midsection of the table. The patient is placed prone on this modified gantry, allowing a direct acoustic pathway into the target leiomyoma,, and initial rapid gradient echo localizer images assist accurate positioning of the patient’s uterus. Baseline T2 images are then obtained in the coronal, axial, and sagittal planes, and these are transferred to the leiomyoma ultrasound workstation for treatment planning.
A detailed description of the technique of magnetic-resonance–guided focused ultrasound has been published previously.9 Briefly, treatment consists of a series of high-intensity sound wave pulses, each one focused to a precise target point within the leiomyoma to cause localized thermocoagulation. The volume of ablation after an individual sonication pulse is small (approximately 6 mm x 25 mm), and multiple consecutive lesions are required to produce a larger coalescent treatment area. The aim of this study was to achieve the maximal area of coagulative necrosis in the target leiomyoma within the allocated study time.
During treatment, real-time thermal maps were created using phase-shift imaging, providing accurate feedback on the temperatures achieved.14 This allows the operator to modify sonication parameters and overcome the substantial biovariability within individual leiomyomata. Thermal mapping also reassures the operator that the thermal lesions do not extend beyond the boundary of the leiomyoma into normal myometrium or extrauterine structures.
Directly after completion of treatment, contrast-enhanced (Omniscan, Nycomed, Amersham, Buckinghamshire, UK), fat-saturated, T1-weighted, gradient echo images are obtained in sagittal, coronal, and axial planes (Fig. 1B). This enables visualization of the area of thermocoagulation within the leiomyoma, which is seen as nonenhancing on the postcontrast films. From these images it is possible to calculate the final volume of ablated tissue using volume analysis software as described previously.13
The primary clinical outcome was measured by change in the transformed symptom severity score of the Uterine Fibroid Symptom and Quality of Life questionnaire. The Uterine Fibroid Symptom and Quality of Life questionnaire is a validated, symptom and health-related quality-of-life questionnaire specific to uterine leiomyomata.12 This tool calculates a score between 0 and 100 for symptom severity, where a higher score indicates more severe symptoms related to bleeding, uterine bulk, or both. Patients completed this questionnaire before treatment with GnRH agonist, on the day of magnetic-resonance–guided focused ultrasound, and at the 3-, 6-, and 12-month follow-up visits. In addition, at the final visit, patients were asked for a subjective assessment of their satisfaction with the overall treatment.
Follow-up MR imaging with contrast enhancement was performed at 6 and 12 months by the same radiologist who performed the baseline examination. Volumetric analysis was carried out to calculate change in size of the uterus, target leiomyoma, and nonperfused volume (Fig. 1C).
Summary descriptive statistics were used for demographic data, Quality of Life scores and volume measurements. Wilcoxon signed rank tests were used for comparison of symptom severity score and measured volumes before and after treatment. Null hypotheses were rejected at a P level of less than .05. All statistical analyses were conducted using SPSS version 13.0 (SPSS Inc., Chicago, IL). A Freidman test was also used to examine whether a significant change in Quality of Life scores had occurred over the whole course of the study.
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RESULTS |
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Low transverse abdominal scars were present in seven women. Of these, three were due to previous open myomectomy, three after Caesarean delivery, and one as a result of ovarian cystectomy. One woman had been diagnosed with mild endometriosis, but the remaining subjects had no history of additional gynecologic pathology. No patients had other previous leiomyoma interventions such as uterine artery embolization.
Thirty-eight of the 49 women completed magnetic-resonance–guided focused ultrasound treatment in one session, and 11 subjects required a second visit to complete therapy. Mean time between first and second treatment for this subgroup was 2.5 weeks. Mean treatment time was 183 minutes (± 24, range 150–240 minutes) for the first treatment and 178 minutes (± 27, range 135–210 minutes) for the second session with an average of 50 (± 20) sonications being delivered per patient. Total analgesic requirement during the procedure averaged 70 mg of meperidine (range 0–100 mg) and 7 mg of diazepam (range 0–10 mg). All patients remained fully conscious and communicative throughout treatment.
Table 1 summarizes pain experienced by patients at various points during magnetic-resonance–guided focused ultrasound after first treatment. They were asked to score pain on a scale between 0 and 4, where a score of 0 indicates no pain and a score of 4 indicates severe pain. This was recorded before, during, and immediately after treatment. Of note is the finding that although the majority of patients described moderate pain during treatment, this had disappeared, in all but one case, by the time the patients reached the recovery area.
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The results of the objective assessment of change in symptoms, based on the Uterine Fibroid Symptom and Quality of Life questionnaire, are shown in the box plot in Figure 2. At enrollment median symptom severity score was 63. This was reassessed on the day of treatment and found to have decreased by almost two thirds (symptom severity score = 22.44). This is explained by the 3 months pretreatment with GnRH agonist, which usually renders the patient amenorrheic and reduces leiomyoma volume, thereby alleviating the majority of leiomyoma-related symptoms. Despite a small rise in symptom score, as would be expected after the return of menses, the median symptom severity score at 6 and 12 months was still significantly reduced to 45% lower than at enrolment at 6 months and 48% lower at 12 months.
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Of the 49 women enrolled at 6 months, only 36 patients could be assessed at 12 months. Two patients were completely lost to follow up, four patients refused to participate in further QOL assessments, and six patients sought alternative therapy between 6- and 12-month assessments (one hysterectomy, one laser thermal ablation, three myomectomies, and one uterine artery embolization). One patient suffered a skin burn close to a scar and also left the study.
Figure 2 shows the median and quartile changes in QOL scores up to 12 months posttreatment. This box plot shows a substantial initial fall as described above, followed by a continued symptom score reduction after leiomyoma ultrasound treatment and after cessation of GNRH treatment, indicating prolonged improvement over this time. The Freidman test indicated that the fall in quality-of-life scores over the study was highly significant (P < .001), and the Wilcoxon signed-rank test showed that the change in quality-of-life value at each point of 3, 6, 12 months after therapy was significantly different from baseline (P < .001).
Previous studies of leiomyoma-focused ultrasonography in uterine leiomyomata have used a 10-point reduction in symptom severity score to signify a significant symptomatic improvement. In our cohort the number of patients achieving a 10-point or greater reduction in symptom severity score between baseline and 6 months was 83% (n = 35) (P < .001) and 89% at 12 months (P < .001). Only one patient described a significant deterioration in symptoms of more than 10 points, with the remainder (n = 6) describing no change over the course of the study.
Mean uterine volume at baseline was 1,217 cm3 (± 601 cm3). After three doses of GnRH agonists, this had reduced to 724 cm3 (± 369 cm3). This equates to an average volume reduction of 38.5% before treatment. After magnetic-resonance–guided focused ultrasound patients underwent a follow-up MRI scan with an average interval of 6 months and 5 days (± 12 days). No evidence of edema or soft tissue damage outside of the target leiomyoma was seen on follow-up imaging. Contrast-enhanced T1-weighted images demonstrated a mean nonperfused volume of 144 cm3 (± 127 cm3) created within the target leiomyoma.
There was a significant reduction in volume of the target leiomyoma of 21% at 6 months (P < .01) and 37% (P < .001) at 12 months over the duration of the study (mean = 105 mL; P < .01) in comparison with the pre-GNRH leiomyoma volumes.
Adverse events were monitored and reviewed at each study visit (treatment, 1 week, 3 months, 6 months, and 12 months). Two patients described lower back pain immediately after treatment, which persisted beyond 1 week but had resolved by 6 months. Small superficial skin burns (< 2 cm in diameter) occurred in two patients and healed with minimal scarring. The only serious adverse event was a 5-cm full-thickness skin burn in a patient with a previous low transverse laparotomy scar.15 This patient did not report any pain during the procedure due to a region of localized anesthesia adjacent to the scar. Excision and direct closure of the area was carried out with a good cosmetic result at 6 months. Other adverse events documented were fainting during treatment (n = 1), urticarial reaction to IV meperidine (n = 1), and a report of sensory loss to a small area of skin in the right groin, which persisted beyond 6 months (n = 1) but had resolved by 12 months.
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DISCUSSION |
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This development will have significant implications for the clinical application of magnetic-resonance–guided focused ultrasound. Uterine leiomyomata are the most common benign tumor of the female genital tract. Estimates from randomly selected population samples show a cumulative incidence reaching 70% in white women and more than 80% in African-American women by the age of 50 years.16 Shifts in cultural attitudes and a rising maternal age have resulted in women becoming increasingly reluctant to undergo conventional surgical treatment for their uterine leiomyomata. The falling rates of hysterectomy in the last decade reflect this change in attitude, as does the increasing uptake of nonsurgical intervention such as the Mirena levonorgestrelintrauterine system (Schering Health, Burgess Hill, UK)17 and uterine artery embolization. This trend is particularly noticeable in women with larger leiomyomata who are at a much higher risk of postoperative complications and blood transfusion after surgery.18
The use of GnRH agonist pretreatment is well established and routinely used by many surgeons before open or endoscopic surgery for uterine leiomyomata. This regulatory neuropeptide, when administered in a continuous fashion, creates a temporary hypoestrogenic state. It has been observed that in this hormonal milieu a significant reduction in leiomyoma volume occurs.19 Because leiomyomata rapidly regrow to their original size within a few months of discontinuing GnRH agonists20 and longer-term administration is associated with significant morbidity, such as osteopenia,21 this type of drug cannot be used as a definite treatment for symptomatic leiomyomata. However, as a time-limited adjunctive therapy, it provides the technical advantages of smaller tumor size and also the additional benefit of reduction in vascular flow.22,23 When magnetic-resonance–guided focused ultrasound is performed in tissues that are relatively avascular, higher localized temperatures are created due to diminished heat conduction. This plays a key role in enhancing thermoablation and results in much larger areas of coagulative necrosis being achieved per joule of energy applied.
The average area of nonperfusion created during treatment, in this series of patients, was almost double that of the previously published efficacy study.9 Although in this cohort treatment times were on average 10% longer, this would be unlikely to account for the dramatic difference reported between the two groups. In our experience, the addition of GnRH agonist enables the creation of a thermal lesion that is 50% larger, per unit of treatment time. We believe that it is this potentiating effect that accounts for the excellent rates of symptom reduction achieved, despite the large leiomyoma volumes we were dealing with. It has been observed that there is a direct correlation between volume of thermal ablation at treatment and clinical outcome. Therefore, by first reducing the size of the uterus and subsequently ablating a large proportion of the tissue, we have, on average, been able to reduce a patient’s reported symptom scores by approximately 45% at 6 and 12 months posttreatment. Longer-term results will be available in due course. Our symptomatic improvement rates in this study for leiomyomata greater than 10 cm diameter have overall been almost identical to previous reports where recruitment was restricted to leiomyomata smaller than 10 cm.9
In conclusion, we report a simple medical treatment that can enhance the effects of thermoablation. Pretreatment of leiomyomata with GnRH agonists allows the use of magnetic-resonance–guided focused ultrasound to be extended to patients with larger tumors, without prolonging therapy times or reducing efficacy. Indeed, it would appear that the reduction in vascularity causes potentiation of the thermal energy deposited within the leiomyomata. Our findings increase the scope of magnetic-resonance–guided focused ultrasound for the treatment of uterine leiomyomata and also demonstrate the potential for using medical adjuvant therapies before thermoablation in other organs
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Footnotes |
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Supported by InSightec Ltd, Haifa, Israel who provided the ExAblate 2000 Magnetic resonance guided focused ultrasound machine used to carry out treatment, sponsored the salary of a Research Fellow (O. C. Smart) at Imperial College London plus sponsoring travel for O. C. Smart to present related work.
Corresponding author: Prof. W. Gedroyc, IMR unit, St. Mary’s Hospital, Praed Street, London W2 1NY, United Kingdom; e-mail: w.gedroyc{at}imperial.ac.uk.
doi:10.1097/01.AOG.0000222381.94325.4f
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