Uterine leiomyomas are highly prevalent and, when symptomatic, may be treated with a variety of options such as hormonal manipulation, uterine artery embolization, myomectomy, or definitive hysterectomy.1 Medical management has largely focused on treatment of leiomyoma symptoms and not the underlying problem. Even with recent advances, medical treatment requires continued hormonal manipulation with resulting side effects until menopause to maintain the effect. Symptomatic women with leiomyomas wish to avoid invasive surgery, and one fourth delay treatment for up to 5 years.2 All alternatives to hysterectomy may result in a need for surgical reintervention, and lower rates are desirable from the patient and health system perspective. Hirst et al3 reported a 23% cumulative probability of undergoing hysterectomy within 4.6 years of uterine artery embolization.
In response to a perceived need for additional, less invasive treatment options, a significant literature base has emerged demonstrating the efficacy of radiofrequency and other hyperthermal ablation methods in the management of uterine leiomyomas and other solid tumors.4–14 The Sonata System (previously called VizAblate) provides transcervical radiofrequency ablation and has been shown, through the results of the FAST-EU Trial, to reduce leiomyoma volume, decrease heavy menstrual bleeding, and improve health utility scores in women with symptomatic leiomyomas.15–17
This article describes results through 12 months of the Sonography Guided Transcervical Ablation of Uterine Fibroids pivotal trial. The aims of this trial were to assess the treatment efficacy, including freedom from surgical reintervention, and safety of the Sonata System in a cohort of patients with heavy menstrual bleeding and uterine leiomyomas.
ROLE OF THE FUNDING SOURCE
Gynesonics, Inc funded this study and participated in the study design, research, analysis, interpretation of data, review and approval of the publication.
Sonography Guided Transcervical Ablation of Uterine Fibroids is a prospective, interventional, multicenter, single-arm trial involving patients with symptomatic uterine leiomyomas who elected transcervical leiomyoma ablation as treatment. The Sonography Guided Transcervical Ablation of Uterine Fibroids trial was performed under an investigational device exemption from the U.S. Food and Drug Administration (FDA). The investigational device exemption application (IDE G140114) received FDA approval without conditions on October 3, 2014. Study enrollment began in April 2015 and ended in October 2016. The coprimary endpoints, both assessed at 12 months postablation, consisted of 1) reduction in menstrual blood loss as assessed by pictorial blood loss assessment chart and 2) the rate of surgical reintervention for heavy menstrual bleeding resulting from treatment failure. The pictorial blood loss assessment chart is a validated assessment tool to estimate menstrual blood loss using icons representing various degrees of saturation of sanitary products.18 Scores 100 or less have been reported to represent eumenorrhea.18–20 Secondary endpoints included safety, reduction in total and perfused leiomyoma volume as measured by contrast-enhanced magnetic resonance imaging, change in the symptom severity score and health-related quality-of-life subscales of the Uterine Fibroid Symptom and Quality-of-Life Questionnaire, overall patient treatment outcome using the Overall Treatment Effect Scale, time to return to normal activity, satisfaction, change in general health outcome as determined by the EuroQoL questionnaire, pain and tolerance of the procedure, length of stay, and occurrence of pregnancy with pregnancy outcome. Self-reported scores on the Euro-QoL questionnaire are translated to health utility scores ranging from values of less than 0, representing health states worse than “death,” to a maximum score of 1.0, representing “perfect health.” An increase of 0.04 is considered by health economists to represent a minimally important difference.21 Enrolled patients were followed at 10 days, 30 days, 3 months, 6 months, and at 12 months, with longer term follow-up planned for 24 and 36 months.
Premenopausal women between the ages of 25 and 50 years were enrolled if they met specific inclusion criteria. These included the presence of up to 10 leiomyomas of International Federation of Gynecology and Obstetrics types 1, 2, 3, 4, 2–5 (transmural), or all of these with diameters between 1.0 and 5.0 cm (Fig. 1). Patients were also required to have at least one leiomyoma that indented or impinged on the endometrial cavity (eg, International Federation of Gynecology and Obstetrics type 1, type 2, type 3, or type 2–5). A minimum pictorial blood loss assessment chart score 150 or greater and 500 or less was required at baseline along with consistent menstrual cycles that were within normal limits. Exclusion criteria included a desire for future pregnancy, the presence of type 0 myomata 1.0 cm or greater, endometrial polyps 1.5 cm or greater or multiple polyps, bulk symptoms attributable to subserous leiomyomas, prior endometrial ablation or uterine artery embolization or uterine artery occlusion or hyperthermic ablation of leiomyomas, uterine volume 1,000 cm3 or greater, the presence of tubal implants for sterilization, and clinically significant adenomyosis. Although from a technical perspective, transcervical leiomyoma ablation could be used to treat type 0 myomata, considering the relative availability and ease of treatment of type 0 leiomyomas through existing modalities, patients with such leiomyomas were excluded. Washout periods were required for medicated intrauterine systems, long-acting progestins, and medical therapy for heavy menstrual bleeding. Women taking hormonal contraceptive pills were required to remain on their current regimen without interruption or brand change for 6 months before enrollment through 12 months of follow-up and the introduction of medical therapy for heavy menstrual bleeding during the 12-month posttreatment period was not permitted.
Baseline investigations included transvaginal ultrasonography, contrast-enhanced magnetic resonance imaging (for subsequent volume and perfusion calculations as well as to exclude significant adenomyosis and hypercalcified leiomyomas), sexually transmitted infection screening along with the pictorial blood loss assessment chart, Uterine Fibroid Symptom and Quality-of-Life, and EuroQoL assessments. Patients were required to have had standard cervical cancer screening per national guidelines along with negative endometrial sampling within the previous 12 months and a negative pregnancy test before the procedure. Additional imaging of the endometrial cavity such as diagnostic hysteroscopy or saline infusion ultrasonography was at the discretion of the investigator. Treated patients also underwent a second contrast-enhanced magnetic resonance study at 12 months postablation; this enabled the measurements of changes in total and perfused leiomyoma volume (using voxel volume determination) and total uterine volume. All baseline and 12-month magnetic resonance studies were submitted to an independent core imaging laboratory to ensure quality control and consistency regarding measurements and determination of eligibility. The core imaging laboratory also credentialed magnetic resonance facilities used by each clinical site and provided protocol training to each site's associated magnetic resonance technologists. For each patient at 12 months, the treatable leiomyoma with the greatest percentage reduction in total leiomyoma volume from baseline was identified on magnetic resonance imaging. This was used to calculate mean maximal total and perfused leiomyoma volume reductions per patient at 12 months.
Each patient provided her informed consent to participate in the trial, and every clinical site obtained local institutional review board or ethics committee approval before commencing patient enrollment. The FDA and the Federal Commission for Protection against Health Risks in Mexico approved the Sonography Guided Transcervical Ablation of Uterine Fibroids trial. All studies and records had protected health information removed to deidentify each patient’s data in the clinical database. All magnetic resonance studies were similarly anonymized before being sent to the core imaging laboratory.
Treatment was provided using the Sonata System, which integrates intrauterine ultrasound imaging with a radiofrequency treatment device to provide a uterus-conserving, transcervical incisionless treatment for a range of leiomyoma types and sizes (Figs. 2 and 3). Sonata has received clearance by the FDA and has CE marking in the European Union. Transcervical radiofrequency ablation with the Sonata System has been described previously.15,16,22 Gynecologist training entails didactic instruction and practice on physical uterine models with various leiomyoma configurations. This training is supervised and guided by industry-provided clinical specialists, experienced users of Sonata, or both.
A leiomyoma may require a single ablation but could also require more than one, depending on its size, location, and geometry. A treating physician can visualize the formation and distribution of hyperechoic water vapor (outgassing) within the leiomyoma that is associated with the thermal necrosis generated by radiofrequency energy within the targeted leiomyoma. This is normally visible both during and for several minutes after ablation. This guides individual physician judgment regarding any need for additional ablation within a given targeted leiomyoma.
Device insertion required cervical dilatation to 27 Fr (9 mm), and this could be accomplished with mechanical, osmotic, or pharmacologic dilators. The use of prophylactic antibiotics was at physician discretion.
Objective performance criteria were set for both coprimary endpoints. For the menstrual bleeding reduction coprimary endpoint, success required both a 50% or greater reduction in pictorial blood loss assessment chart score that was also 250 or less with a 95% lower confidence limit 45% or greater of patients (ie, at least 45% of patients must have achieved both a pictorial blood loss assessment chart reduction of at least 50% and a score 250 or less). Success for the surgical reintervention endpoint was defined as the proportion of patients who did not require surgical reintervention for heavy menstrual bleeding with the 95% lower confidence limit of the percentage of patient success 75% or greater. Trial success required achieving or surpassing the objective performance criteria of both coprimary endpoints.
The sample size for this study was 125 or greater treated patients to achieve 90% power with an α level equal to 0.05 and an assumed success rate of 60%. Including a conservative estimate for “lost to follow-up” of 15%, the number of patients needed to treat was calculated to be 147. Patient success was calculated separately for the two coprimary endpoints such that it was possible for a patient to have experienced treatment success for one coprimary endpoint and not for the other. Study success was achieved if both coprimary endpoint success criteria were met. All statistical analyses were performed with SAS 9.3. Changes from baseline were analyzed with the Wilcoxon signed-rank test. Values were considered significant at the level of α=0.05. The rate of surgical reintervention during 12 months, along with 95% CI, was determined using the life-table methods.
One hundred forty-seven patients were enrolled and treated at 22 investigational centers located in the United States (21) and Mexico (one). The median age was 43 years (range 31–50 years), and median body mass index (calculated as weight (kg)/[height (m)]2) was 28 (range 18–50). Table 1 summarizes menstrual bleeding and leiomyoma characteristics at baseline.
All 147 patients were treated in an outpatient setting, including hospital-based operating rooms, ambulatory care centers, and procedure rooms within physician offices. Of these settings, 87 patients (59.2%) received treatment in a hospital-based operating room, 37 (25.2%) in an ambulatory care center, and 23 (15.6%) in a physician office. Seventy-four patients (50.3%) received general anesthesia, and 73 (49.7%) were treated under conscious sedation, both deep and mild sedation. Paracervical blockade was coadministered as an ancillary local anesthetic modality in 48.3% of patients. Mean length of stay (measured from procedure start to discharge, including procedure time) was 2.5±1.2 hours with 109 of 147 patients (74.1%) having a length of stay 3 hours or less. Discretionary use of prophylactic antibiotics was provided for 57 (38.8%) patients.
Four patients were excluded from the full analysis set population as a result of having reached menopause with a resultant inability to provide a pictorial blood loss assessment chart diary at their 12-month visits. Thus, the full analysis set consists of 143 patients. For the menstrual bleeding reduction endpoint evaluation in the full analysis set population, 142 of the 143 patients were included in this analysis, because the one patient who underwent surgical reintervention before her 12-month visit was excluded from the analysis of this endpoint per the prespecified study statistical analysis plan. Of these 142 patients, 135 provided a pictorial blood loss assessment chart questionnaire at their 12-month visits; the 12-month pictorial blood loss assessment chart was missing for the remaining seven patients: three patients completed the 12-month visit but did not provide a pictorial blood loss assessment chart diary, three patients were withdrawn before the 12-month visit, and one patient missed her 12-month visit. Missing pictorial blood loss assessment chart values for these seven patients were imputed using the last observation carried forward.
Detailed menstrual bleeding reduction results are provided in Table 2. The mean pictorial blood loss assessment chart score decreased by 38.9%, 48.4%, and 51.1% at 3, 6, and 12 months, respectively (P<.001), and 95.1% of patients experienced reduced menstrual bleeding at 12 months. At 12 months postablation, 99.3% of patients (95% CI 95.1–99.9%) did not undergo surgical reintervention for heavy menstrual bleeding (coprimary endpoint). One patient underwent elective hysterectomy for bleeding just before her 12-month visit.
Transcervical radiofrequency ablation of uterine leiomyomas with the Sonata System resulted in significant improvements in patient-reported outcomes, beginning with the 3-month visit (the first posttreatment visit that included these questionnaires). Detailed Uterine Fibroid Symptom and Quality-of-Life results are summarized in Tables 3 and 4. Regarding the Overall Treatment Effect Scale questionnaire, 96.3% of patients (130/135) at 12 months noted improvement in their leiomyoma symptoms, 3.0% (4/135) reported no change in symptoms, and 0.7% (1/135) noted a worsening of symptoms.
Patients reported significantly improved health status on the Euro-QoL questionnaire at 12 months postprocedure. At baseline, patients in the Sonography Guided Transcervical Ablation of Uterine Fibroids trial had a mean overall score of 0.72 (N=143). At 12 months (n=133), their mean health utility scores rose 0.17 points to 0.89 (P<.001).
Most patients (97%) at 12 months reported satisfaction with the treatment and the same percentage (97%) would also recommend Sonata to a friend or family member. Specifically, 70.4% of reporting patients (n=135) indicated that they were “very satisfied” with treatment, 17.8% were “moderately satisfied,” 8.9% were “somewhat satisfied,” 2.2% were “somewhat dissatisfied,” and 0.7% were “moderately dissatisfied” at 12 months. Similarly, 81.5% would “definitely recommend” treatment with Sonata, 15.6% would “probably recommend” it, and 3.0% would “probably not recommend” treatment with Sonata at 12 months. No patient indicated dissatisfaction with the treatment or that she would “definitely not recommend” the treatment.
Overall, 98% (144/147) of patients found the transcervical ablation treatment to have been tolerable: 64.6% (n=95) of patients reported the procedure to have been “very tolerable,” 30.6% (n=45) found the procedure “moderately tolerable,” 2.7% (n=4) characterized it as “minimally tolerable,” and 2% (n=3) said it was “intolerable.” Overall mean pain scores (0–10 scale) were 0.2±1.0 (range 0.0–7.0) during the procedure and 2.6±2.8 (range 0.0–10.0) during recovery (reported for the time between procedure completion and discharge and recorded before discharge). Mean procedural pain scores were 0.01±0.1 for procedures under general anesthesia and 0.5±1.3 for procedures under conscious sedation. Mean recovery pain scores were 3.4±2.9 for patients receiving general anesthesia and 1.9±2.4 for those who were treated under conscious sedation. During recovery, 49 patients (33.3%) were managed with nonsteroidal antiinflammatory drugs and 39 patients (26.5%) received narcotics.
On average, patients reported returning to normal daily activities in 2.2±2.2 days, with more than half of the patients returning to normal activity within 1 day of the procedure. Employed patients returned to work in a mean 3.6±2.6 days postprocedure. Patients resumed a normal diet at 0.8±1.3 days, normal sleep at 0.7±1.6 days, and normal urinary and bowel functions at 0.2±0.8 days and 1.4±1.9 days, respectively.
Table 5 summarizes characteristics of ablated leiomyomas. Although patients were excluded for having one or more leiomyomas with diameters greater than 5.0 cm on transvaginal ultrasonogram, intrauterine ultrasonography from the Sonata System was used to provide the data in Table 5 regarding baseline leiomyoma size (for consistency, magnetic resonance measurements by the independent core imaging laboratory at baseline and 12 months were used to provide final comparative data regarding leiomyoma size and volume). On average, leiomyomas received 1.1±0.4 ablations; 64 leiomyomas (14.5%) were treated with two or more ablations. Most (80.8%) ablated leiomyomas ranged from 1 to 4 cm in diameter.
Among the patients whose qualifying leiomyoma(ta) indented the endometrial cavity (types 1, 2, or 2–5), the success rates for achieving 50% or greater reduction in pictorial blood loss assessment chart at 12 months were similar (64.3%, 68.0%, 61.9%; P=.94). For the 25.4% (36/142) of patients included in the analysis of the bleeding reduction coprimary endpoint whose only qualifying leiomyoma was a type 3 myoma, 63.9% (23/36) realized at least a 50% reduction in pictorial blood loss assessment chart score at 12 months. There were no significant differences in study success for either coprimary endpoint regarding the inclusion qualifying leiomyoma type, including patients whose sole qualifying leiomyoma was a type 3 myoma.
At 12 months postprocedure, the mean reduction in total uterine volume was 12.9% (n=133), from 267.3 cm3 at baseline to 232.6 cm3 at 12 months (P<.001). The mean maximal reductions in total and perfused leiomyoma volumes per patient from baseline to 12 months was 62.4% (n=129) and 63.9% (n=128), respectively (P<.001 for both).
There were no occurrences of device-related adverse events, serious or otherwise. There were two procedure-related serious adverse events reported in two patients (1.4%). One involved a deep venous lower extremity thrombus diagnosed 15 days postprocedure, managed as an outpatient without sequelae. The other event involved a patient who had received prophylactic antibiotics at the time of her treatment, but presented with a chief complaint of leukorrhea, pelvic pain, and unconfirmed low-grade fever 28 days postprocedure and was managed with overnight admission and broad-spectrum antibiotics. An independent medical advisory committee concluded that the event was related to leiomyoma sloughing and leukorrhea with no evidence of infection.
Nonserious procedure-related adverse events were reported in 74 patients (50.3%). These included leiomyoma sloughing (30.6%), cramping or pain (7.5%), leukorrhea (6.1%), uncomplicated genitourinary infections (4.8%), nonspecific (constitutional) symptoms (3.4%), expelled leiomyoma (1.4%), flu-like symptoms (1.4%), nausea or vomiting (0.7%), and other nongynecologic events (constipation, sore throat, atelectasis, high blood pressure; 5.4%).
Several studies have advocated for more effective and better tolerated leiomyoma management, because women with uterine leiomyomas often delay or avoid treatment as a result of a lack of acceptable options.2,23 The transcervical route may provide benefits to women with symptomatic leiomyomas compared with open or laparoscopic treatment options, including avoidance of the peritoneal cavity and no requirement for general anesthesia except when necessary on clinical grounds (eg, morbid obesity) or based on anesthesiologist or patient preference.
The leiomyoma ablation system described here could expand access to transcervical leiomyoma treatment beyond the smaller intracavitary or indenting leiomyomas treatable with operative hysteroscopy. In the Sonography Guided Transcervical Ablation of Uterine Fibroids trial, 79% of treated leiomyomas were intramural (types 3 and 4), transmural (type 2–5), and subserosal (types 5 and 6) myomata.
It is noteworthy that the trial included women with heavy menstrual bleeding who had type 3 myomata without leiomyomas that indented the endometrial cavity. At 12 months, these patients had treatment effectiveness similar to that of the overall study population. This suggests a possible association of type 3 leiomyomas with heavy menstrual bleeding. Previous work indicates that type 4 leiomyomas may also be associated with heavy menstrual bleeding.24
There were 24 treating investigators at 22 sites, including academic centers, community hospitals, and several private physician offices. This represents a wide variety of practicing obstetrician–gynecologists, none of whom had prior experience with transcervical leiomyoma ablation. Each investigator received the same training and support, consisting of didactic training followed by procedure simulation with a phantom model of a leiomyoma uterus. The Sonography Guided Transcervical Ablation of Uterine Fibroids trial results suggest that with appropriate training and support, transcervical radiofrequency ablation may be safely and effectively provided by obstetrician–gynecologists.
Limitations of the Sonography Guided Transcervical Ablation of Uterine Fibroids trial include a nonrandomized design, a limit of 5 cm, and the exclusion of patients who desired fertility. Although not randomized, Sonography Guided Transcervical Ablation of Uterine Fibroids is a multicenter interventional trial with prospectively defined endpoints having set objective performance criteria. Well-designed interventional trials can provide compelling evidence for the effectiveness of a treatment.25,26 The Sonography Guided Transcervical Ablation of Uterine Fibroids trial included a robust patient selection process to minimize confounding factors, excluding patients with other etiologies of abnormal uterine bleeding such as anovulation, adenomyosis, and bleeding disorders. Furthermore, the study included a mix of patient-reported outcomes to complement the objective reintervention and bleeding primary endpoints.
Maximum leiomyoma diameter was limited to 5 cm in Sonography Guided Transcervical Ablation of Uterine Fibroids. For purposes of this pivotal trial, leiomyomas were selected that could normally be treated with a single ablation. However, larger leiomyomas could be treated with multiple ablations. In the Sonography Guided Transcervical Ablation of Uterine Fibroids trial, 64 leiomyomas (14.5%) were treated with at least two ablations.
Patients who desired fertility were excluded as a result of ethical reasons because Sonography Guided Transcervical Ablation of Uterine Fibroids was a pivotal safety and effectiveness study. This enriched the eligible population for older patients and minimized the ability to track perinatal and postpartum outcomes. However, the study includes 3-year follow-up of patients and the reporting of any pregnancy outcomes should they occur. In addition, a worldwide clinical registry characterizing the long-term outcomes with transcervical leiomyoma ablation out to 5 years is ongoing (SAGE Global Registry, NCT # 03118037).
The 12-month results from the Sonography Guided Transcervical Ablation of Uterine Fibroids trial compare favorably with other nonextirpative leiomyoma treatments such as uterine artery embolization and laparoscopic radiofrequency ablation. Twelve-month surgical reintervention in the Sonography Guided Transcervical Ablation of Uterine Fibroids trial was 0.7% compared with 10% after uterine artery embolization in the REST trial and 0.7% after a single-arm prospective study of laparoscopic radiofrequency ablation with the Acessa System.27,28 The percentage of patients who met the FDA-required bleeding endpoint at 12 months was higher for the Sonography Guided Transcervical Ablation of Uterine Fibroids trial (64.8%) than that seen in the pivotal trial of the Acessa System (40.2%).28
As demonstrated in the Sonography Guided Transcervical Ablation of Uterine Fibroids trial, transcervical leiomyoma ablation was associated with a significant reduction in leiomyoma symptoms with no device-related adverse events and a low surgical reintervention rate through 12 months. General anesthesia was not required except on clinical or patient and physician grounds. The findings from this study demonstrate the potential of the Sonata System to safely and effectively treat a variety of nonpedunculated leiomyoma types through a uterus-conserving, incisionless approach.
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