Transcervical fibroid ablation with the Sonata™ system for treatment of submucous and large uterine fibroids

Abstract Objective To examine the role and benefits of transcervical fibroid ablation (TFA) in the treatment of submucous and large uterine fibroids. Methods A subgroup of patients with submucous or large fibroids were analyzed from two prospective clinical trials (FAST‐EU and SONATA) of sonography‐guided TFA with the Sonata® system. Key outcomes were changes in menstrual blood loss, symptom severity and health‐related quality of life on the Uterine Fibroid Symptom and Quality‐of‐Life Questionnaire, health‐related quality of life on the EQ‐5D questionnaire, and surgical reinterventions for heavy menstrual bleeding. Results Among 197 women (534 treated fibroids), 86% of women with only submucous fibroids and 81% of women with large fibroids (>5 cm) experienced bleeding reduction within 3 months post‐ablation. Overall symptom severity and health‐related quality of life showed sustained, significant improvements over 12 months. Additional fibroid mapping of large fibroids with magnetic resonance imaging in the FAST‐EU trial showed an average volume reduction of 68%. Among women with only submucous fibroids, the rate of surgical reintervention through 1 year of follow up was 3.7% in FAST‐EU and 0.0% in SONATA. Conclusion With the Sonata system, TFA is an effective single‐stage treatment option for non‐pedunculated submucous myomata, and larger or deeper uterine fibroids (including fibroid clusters) for which hysteroscopic treatment is not suitable. ClinicalTrials.gov: FAST‐EU, NCT01226290; SONATA, NCT02228174.


| INTRODUC TI ON
Uterine fibroids are highly prevalent, being present in up to 80% or more of women in the USA over their reproductive lives (depending on ethnicity). 1 Several treatment options exist, but hysterectomy and myomectomy remain the most common interventions. Fibroid characteristics such as size, location, and number influence the choice and effectiveness of treatment. Using the FIGO (the International Federation of Gynecology & Obstetrics) classification, type 0-2 fibroids have submucous involvement, type 3 fibroids abut the endometrium but are completely intramural, type 4 fibroids are completely intramural, types 5 and 6 fibroids have serosal involvement, type 7 fibroids are pedunculated on the subserosal surface, and type 8 fibroids are identified in ectopic locations. 2 With regard to submucous fibroids and large-diameter fibroids, as there are several treatment options available, their optimal management may warrant further review.
Women with submucous fibroids (FIGO type 0, type 1, and type 2) are generally managed with operative hysteroscopy, including myomectomy and treatment with various morcellation devices.
Although it permits transcervical management of such fibroids, this approach has limitations. Because visualization is via hysteroscopy, fibroids that are not visible from the endometrial cavity (e.g., intramural and subserous fibroids) are not typically amenable to hysteroscopic treatment. Larger and/or deeper type 2 submucous fibroids treated via hysteroscopic resection/morcellation often require a multistage approach because only a partial resection can be safely performed at the first operation. Subsequent interval extrusion of the remaining fibroid into the endometrial cavity permits additional resection later under hysteroscopic guidance. [3][4][5] Emanuel et al. 6 reported on their experience with hysteroscopic myomectomy in a cohort of 272 women where 17% of patients required multiple procedures to achieve complete myomectomy.
In a retrospective cohort study of 153 women undergoing hysteroscopic myomectomy, de novo intrauterine adhesiogenesis was detected in 1.5% of women with a solitary myoma, but 78% of women with at least two apposing myomata had intrauterine adhesions. 7 Fluid overload, resulting in hyponatremia and the possibility of pulmonary and/or cerebral edema, is a potential complication for all operative hysteroscopy procedures, but is more common among patients undergoing operative hysteroscopy with monopolar electrosurgical systems. 8 Transcervical fibroid ablation (TFA) with the Sonata ® system offers a less invasive, incisionless, uterus-preserving, transcervical approach, with real-time visualization using intrauterine ultrasound guidance. The system has been demonstrated as safe and effective for the treatment of symptomatic uterine fibroids. 9 3 ). This can be sufficient to treat a 5-cm diameter myoma with a single ablation. Larger fibroids above 5 cm may require the application of multiple ablations. The Sonata system has been described in detail elsewhere. [12][13][14] The prospective multicenter controlled FAST-EU trial of TFA with the Sonata system required all patients to have at least one indenting fibroid (type 1, type 2 or type 2-5 [transmural] fibroids), and additional intramural fibroids were also treated if present. 9 The trial followed patients through 12 months and reported significant improvements in menstrual bleeding symptoms and quality of life scores, low surgical reintervention rate, and no device-related adverse events.
In the SONATA prospective multicenter controlled pivotal clinical trial of premenopausal women with symptomatic fibroids, women were required to have at least one indenting or abutting fibroid (type 1, type 2, type 2-5 [transmural], or type 3 [intramural] fibroids). 11 The trial followed patients through 36 months and reported significant improvements in menstrual bleeding symptoms and quality of life scores, a low (5.5%) cumulative surgical reintervention rate, and no device-related adverse events in the first 24 months. 10,11 In order to assess the clinical benefits of TFA when specifically used to treat patients with non-pedunculated submucous (type 1 and type 2) uterine fibroids and contrast its role in the transcervical armamentarium, the clinical outcomes of prospective controlled trials involving patients with only submucous fibroids, as well as those with large fibroids over 5.0 cm in maximum diameter, were evaluated. with at least one indenting fibroid (type 1, type 2, or type 2-5 [transmural] fibroids), and additional fibroid types were also treated if present. The trial followed patients over 12 months, with specific imaging and other assessments performed at 3, 6, and 12 months. SONATA was a multicenter, prospective, controlled trial of sonography-guided TFA with similar inclusion criteria and follow-up assessments, with patient long-term follow up for 3 years. Complete trial details have been previously reported for FAST-EU 9,13 and SONATA. 10,11,15 In this current subgroup analysis of individual participant data from both trials, we evaluated clinical outcomes in patients with submucous fibroids or large fibroids more than 5.0 cm in maximum diameter.

| MATERIAL S AND ME THODS
The sonography-guided TFA procedure (Sonata system, Gynesonics, Inc., Redwood City, CA, USA) consists of an integrated intrauterine sonography probe and radiofrequency (RF) ablation handpiece that allows the gynecologist to identify, target, and ablate uterine fibroids. The integration of real-time ultrasound imaging enables the physician to visualize, target, and ablate a greater range of fibroids than could be approached via operative hysteroscopy. 13 A graphical interface is displayed on the live ultrasound image that identifies the target ablation area and the extent of thermal heating.
The gynecologist uses this information to confirm that the ablation is within the fibroid while confining the thermal safety border to within the uterine serosa.

| RE SULTS
In the FAST-EU clinical trial, 50 women received TFA for the treatment of 92 fibroids. Of these 50 women, 42 had at least one submucous myoma and 10 women had at least one fibroid larger than 5 cm, with the largest measuring 6.9 cm in maximum diameter (Table 1).
Additional fibroid mapping with magnetic resonance imaging in this trial showed an average volume reduction of 68.3% in fibroids larger than 5 cm. In the SONATA clinical trial, 147 women underwent a TFA procedure involving 442 fibroids; which 63 women had at least one submucous myoma and 9 women had at least one fibroid larger than 5 cm, with the largest measuring 6.5 cm in maximum diameter.
In total, 72.5% of the 534 treated fibroids in both trials were not amenable to hysteroscopic resection because they were either intramural (45.9%), transmural (18.5%), or subserous (8.1%). 10 Among all treated patients, TFA was highly effective in reducing menstrual bleeding. The percentages of patients with a reduction in menstrual bleeding at 3, 6, and 12 months were 88%, 92%, and 89%, respectively, in the FAST-EU trial and 86%, 89%, and 95%, respectively, in the SONATA trial. The analysis in the report demonstrates similar trends in patients with only submucous fibroids and those with large

| DISCUSS ION
Transcervical fibroid ablation with the Sonata system offers a less invasive, incisionless fibroid treatment using intrauterine ultrasound guidance for visualization. It should not be thought of as the antiquated procedure known as "myolysis". In myolysis, RF energy was used to create focal small ablations via multiple punctures through the uterine serosa without image guidance but with the potential for intra-abdominal adhesiogenesis. 17 The ability to perform multiple ablations in a targeted fibroid enables the Sonata system to create a larger aggregated treatment volume. There are no specified limits to fibroid size or to the number of treatable fibroids with the Sonata system. In the SONATA clinical trial, as many as nine fibroids were ablated in a single patient; in some cases, a single ablation was used to treat one or more clusters of adjacent fibroids. Because of the orientation, proximity, and high resolution of the intrauterine ultrasound probe integrated within the treatment device, "single fibroids" visualized via transvaginal sonography may be seen to consist in actuality of clusters of two or more individual fibroids using intrauterine sonography. In such cases, it can be feasible to treat several clustered fibroids with a single ablation. Hence, the number and size of fibroids to be ablated is always up to a physician's clinical judgment.   with large fibroids, however, is admittedly small. That reflects the reality that most fibroids in the population are no larger than 5 cm.
Wegienka et al. 24 evaluated 596 women with fibroids and found that 81.5% had fibroids of 5 cm or less in diameter; only 11.5% had large fibroids. Additional studies will likely reinforce the conclusions reached in this report.
In conclusion, data from prospective controlled clinical trials showed that TFA with the Sonata system is an effective singlestage treatment option for non-pedunculated submucous and large myomata. The number and size of fibroids to be treated are at the physician's discretion as there are no limits on the number or size of treatable fibroids with the Sonata system. Considering the disadvantages of hysteroscopic resection and morcellation of submucous fibroids, such as the need for staged procedures, a higher reintervention rate, and potential for intrauterine adhesiogenesis, TFA is a compelling option for the transcervical management of any non-pedunculated, including submucous, myomata as well as larger, clustered, or deeper non-pedunculated uterine fibroids for which hysteroscopic treatment is not suitable.

ACK N OWLED G M ENTS
We acknowledge David B. Toub, Taraneh G. Farazi, and Larry Miller for editorial assistance, and ABOND CRO Inc. for providing data management and statistical support.

CO N FLI C T S O F I NTE R E S T
The authors have no conflicts of interest.

AUTH O R CO NTR I B UTI O N S
GS, ME, PG, and GP contributed to the design, planning and conduct of the study and to writing the manuscript. Data analysis was performed by ABOND CRO, who was mentioned in the