Fibroid Treatment
Number: 0304
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
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Aetna considers radiofrequency ablation (open, laparoscopic (e.g., the Acessa System), or transcervical (e.g., the Sonata System)) or transcatheter uterine artery embolization (UAE, e.g., by means of tris-acryl gelatin microspheres (Embospheres Microspheres)) medically necessary as an alternative to hysterectomy or myomectomy for the treatment of uterine fibroids when the member has persistence of one or more symptoms directly attributed to uterine fibroids (i.e., excessive menstrual bleeding (menorrhagia), bulk-related pelvic pain, pressure or discomfort, urinary symptoms referable to compression of the ureter or bladder, and/or dyspareunia).
Aetna considers other uses of transcatheter UAE experimental and investigational because its effectiveness for indications other than the one listed above has not been established.
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Aetna considers myomectomy or hysterectomy using power morcellation experimental and investigational for the removal of uterine fibroids because its safety and effectiveness has not been established. An exception to this policy, fibroid removal with power morcellation is considered medically necessary for the following indications in women without known or strongly suspected uterine cancer:
- premenopausal women who wish to maintain fertility and who have no risk factors for uterine sarcoma (e.g., history of 2 or more years of tamoxifen therapy, history of pelvic irradiation, history of childhood retinoblastoma, Lynch syndrome, or personal history of hereditary leiomyomatosis and renal cell carcinoma syndrome);
- premenopausal women who have clinical indications for hysterectomy and who have no risk factors for uterine sarcoma, where a vaginal hysterectomy is technically difficult due to the large size of the uterus; or
- women with co-morbidities (e.g., cardiovascular, renal, hepatic, pulmonary, endocrine, or morbid obesity) where surgical alternatives to fibroid removal with power morcellation (hysterectomy without power morcellation, radiofrequency ablation, uterine artery embolization) pose an unacceptable risk.
In all cases, the member must be informed of alternative procedures for fibroids and the risks of power morcellation in spreading unsuspected cancerous tissue beyond the uterus.
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Aetna considers the following treatments for uterine fibroids experimental and investigational because their safety and effectiveness have not been established:
- Acupuncture
- Cryomyolysis
- Cryotherapy
- Electrical ablation
- Interstitial thermotherapy
- Laparoscopic uterine artery occlusion
- Lasers
- Ultrasound (focused ultrasound) ablation, with or without magnetic resonance imaging (MRI) guidance.
Background
Uterine fibroids (i.e., leiomyomas or myomas) are noncancerous growths that develop from the smooth muscular tissue of the uterus (also known as myometrium) usually during childbearing years. The size and growth pattern of uterine fibroids varies and may be found as subserosal, intramural, submucosal or pedunculated masses. They may also be located in the cervix or broad ligament. Although the cause is unknown, hormones seem to be a related factor.
Uterine fibroids represent the most common gynecological tumor in women of reproductive age and are responsible for over 200,000 hysterectomies per year. Most fibroids, even large ones, do not produce symptoms. However, they can cause a variety of symptoms including menometrorrhagia, dysmenorrhea, pelvic pain, reproductive failure, and compression of adjacent pelvic viscera, or be totally asymptomatic. A large array of treatment options exist for this disorder. Surgical treatments include hysterectomy, abdominal myomectomy, laparoscopic myomectomy, myolysis, and more recently magnetic resonance imaging (MRI)-guided ultrasound ablation. Non-surgical treatments include medical therapy (e.g., gonadotropin-releasing hormone agonist) and uterine artery embolization (UAE).
Uterine Artery Embolization
For the last 20 years, therapeutic embolization has been successfully performed on various parts of the body. In more recent years, this technology has been applied to uterine fibroids in an effort to eliminate the nagging symptoms associated with uterine fibroids and offer women an alternative to hysterectomy and myomectomy. This outpatient procedure, which may require an over-night admission for pain control, uses angiographic techniques and fluoroscopic guidance to embolize the uterine arteries, similar to the methods used to control post-operative and post-partum hemorrhage. The embolization, consisting of tiny particles of polyvinyl alcohol (500 to 700 micron size), occludes the blood supply to the fibroids, which results in their ischemic infarction and subsequent degeneration over a period of weeks and months. Average fibroid volume reduction is approximately 50 % in 3 months and 65 % at 1 year. Uterine volume decreases by approximately 40 % in 3 months. The reduction in the fibroid's size leads to a decrease or resolution in the symptoms they cause. The procedure takes approximately 1 to 2 hours and it is anticipated that most women can return to work 7 days after the procedure.
The initial studies that have been published to date suggest that both menorrhagia and symptoms caused by the bulk of these fibroids will be significantly improved or will resolve in 80 to 90 % of patients on short-term follow-up. The patients in these series have tolerated the procedure well and patient satisfaction is high, but they all require careful post-procedural pain management. While severe ischemic injury to the uterus has been feared, the literature suggests that this occurs in only 1 to 2 % of patients. Unlike myomectomy, all fibroids can be treated simultaneously, regardless of their location or size in the uterus. Unlike Lupron, the literature indicates that premature menopause is rarely induced. It has been shown that if the procedure is not successful and surgery is needed, this surgery is rendered easier, with a likelihood of less bleeding.
However, long-term follow-up on a larger number of cases will be required before any definitive statement can be made about the ultimate role of embolization in the treatment of uterine fibroids as compared to the other available therapies. The long-term outcome is not known, in that recanalization of the arteries could occur or collateral vessels could be recruited which might allow re-growth of the fibroids. Post-procedure fertility and the ability to carry a pregnancy to term are not presently known since most patients in published series have not sought to become pregnant. The effect on ovarian function has been a question, given the sporadic reports of amenorrhea after treatment. It is not known whether ovarian infarction occasionally occurs to affect function or whether merely decreasing uterine flow is sufficient to affect ovarian function. Further, it is not clear whether ovarian function is affected in only a few patients or whether it is more common and just not apparent clinically.
In a review on percutaneous UAE for the treatment of symptomatic fibroids, Lupattelli et al (2005) stated that although randomized trials are still underway, UAE appears a good option for those patients who whish to conserve their fertility or when surgery is contra-indicated. However, to assess the long-term effects of UAE longer follow-up is needed. This is in agreement with the observation of Bachmann (2006) who noted that treatment options for women with symptomatic uterine leiomyomas have been expanded to include radiological interventions with UAE and focused ultrasound surgery despite the lack of long-term efficacy data.
Despite the unknowns, it is clear that the initial experience with UAE suggests that this procedure is effective and safe in the short term and represents a promising new therapy for this very common medical condition.
A report by the American College of Obstetricians and Gynecologists (2004) stated that "UAE for the treatment of symptomatic fibroids, when performed by experienced physicians, appears to provide good short-term relief among appropriate candidates." ACOG strongly recommends that women who wish to undergo UAE have a thorough evaluation with an obstetrician/gynecologist to help facilitate optimal collaboration with interventional radiologists and ensure that the procedure is appropriate. There is insufficient data at this time to ensure that UAE is safe for women who may wish to become pregnant in the future, the report notes. Moreover, few studies have assessed the effect of embolization on pregnancy-related outcomes. For these reasons, ACOG considers the procedure investigational or relatively contraindicated in such women. Also, the report warns that UAE is rarely, if ever, indicated in post-menopausal women.
Uterine artery embolization is contraindicated in women with any of the following conditions:
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Post-menopausal women with fibroid growth or rapid growth at any time (may indicate development of sarcoma); or
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Women who have evidence of current genito-urinary infection and/or malignancy; or
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Women who may wish to become pregnant in the future; or
- Women with a history of prior pelvic X-ray treatments, pelvic malignancy, chronic infections or severe endometriosis.
A report on the management of uterine fibroids prepared for the Agency for Healthcare Research and Quality (Viswanathan et al, 2007) stated that women who undergo UAE have shorter recoveries and spend less time in the hospital than women who have hysterectomies.
Han and colleagues (2021) stated that data are limited regarding comparison between non-spherical polyvinyl alcohol (PVA) particles and tris-acryl gelatin microspheres (TAGM; Embosphere Microsphere) in UAE. Ina RCT, these researchers compared pain after UAE with PVA versus TAGM for treatment of symptomatic fibroids. Subjects were randomly assigned to be administered non-spherical PVA (355 to 550 μm) or TAGM (500 to 700 μm). Both groups were administered fentanyl-based intravenous patient-controlled analgesia (PCA) during the first 24 hours following UAE and rescue analgesics. Neutrophil-to-lymphocyte ratio was measured to evaluate inflammatory response. Contrast-enhanced MRI 1 day after UAE was used to examine dominant fibroid necrosis and ischemia of normal myometrium. Symptom severity score and health-related QOL score were examined before and 3 months after UAE. Variables measured over time were analyzed by using the generalized estimating equation method. A total of 54 subjects (mean age of 44 years ± 4 [standard deviation]) were evaluated (27 subjects in each group). Although pain scores and fentanyl dose were not different during the first 24 hours, use of rescue analgesics was higher in the PVA group (33 % versus 11 %; p = 0.049). After embolization, symptom severity score and health-related QOL score were not different between groups (symptom severity score: 16 (inter-quartile range [IQR] of 6 to 22 for PVA versus 19 (IQR of 9 to 34) for TAGM, p = 0.45); health-related QOL score of 93 (IQR of 80 to 97 for PVA) versus 89 (IQR of 84 to 96 for TAGM, p = 0.41). Changes in neutrophil-to-lymphocyte ratio from before to 24 hours after UAE were greater in the PVA group (3.9 [IQR of 2.7 to 6.8] for PVA and 2.5 [IQR of 1.5 to 4.6] for TAGM; p = 0.02). Rates of complete dominant fibroid necrosis were not different between groups, but transient global uterine ischemia of normal myometrium was more frequent in the PVA group (44 % versus 15 %; p = 0.04). The authors concluded that when used in UAE, polyvinyl alcohol particles and tris-acryl gelatin microspheres resulted in similar pain scores and fentanyl dose. Polyvinyl alcohol resulted in a greater inflammatory response, higher rates of rescue analgesic use, and more frequent transient global uterine ischemia.
MRI-Guided Focused Ultrasound
High intensity focused ultrasound with the imaging guidance of magnetic resonance imaging (MRI) known as magnetic resonance guided focused ultrasound sonication (MRgFUS) is now available. Currently, there is very little information regarding the effectiveness of MRI-guided ultrasound ablation for the treatment of uterine leiomyomata. In a review on the surgical and non-surgical management of uterine leiomyomata, Myers et al (2002) concluded that available evidence on the management of uterine leiomyomata is of poor quality. This is in agreement with the observation of Olive (2000) who stated that existing studies are generally small and of poor quality. There is a strong need for appropriately designed and analyzed randomized clinical trials, and surgical trials should preferably be multi-center/multi-surgeon.
Studies by Tempany et al (2003) as well as Stewart et al (2003) suggested that MRI-guided focused ultrasound surgery appeared to be safe and effective for the treatment of uterine leiomyomas. However, both studies were authored by the same group of investigators and addressed only the safety and feasibility of this approach in treating uterine fibroids. These studies had small number of patients – 9 in the study by Tempany et al (2003), and 55 in the study by Stewart et al (2003). They only demonstrated the safety and feasibility of MRI-guided focused ultrasound ablation for the treatment of uterine fibroids; however, its clinical value has not been established.
The first FDA-approved MRI-guided focused ultrasound system for the treatment of women with symptomatic uterine fibroids is the ExAblate 2000 System (InSightec, Ltd.). The U.S. pivotal trial included 192 women who had symptomatic uterine fibroids and were randomized to a hysterectomy (n = 83) or the ExAblate procedure (n = 109). At 6 months, 70.6 % of the ExAblate patients experienced a greater than 10-point reduction in the Uterine Fibroid Symptoms and Quality of Life Questionnaire score. The mean reduction in fibroid volume at 6 months was 13.5 %, but non-enhancing volume remained within the treated fibroid at 6 months. The hysterectomy patients performed better at 6 months than the ExAblate patients on several quality-of-life measurements, including role physical, body pain, general health, vitality, and mental health. The hysterectomy patients had a much higher rate of having at least 1 significant complication than the ExAblate patients (46 % versus 12 %). The ExAblate patients missed less work than the hysterectomy patients (1.2 versus 19.2 working days) during the first 30 days post-surgery (FDA Summary of Safety and Effectiveness Results).
The FDA required InSightec to conduct a 3-year post-market study to better assess the long-term safety and effectiveness of the ExAblate 2000 System. The study includes additional numbers of African-American women, because, as a group, these women have a greater incidence of uterine fibroids but were under-represented in the original study.
Further studies are needed to elucidate the exact role of MRI-guided focused ultrasound ablation in the management of uterine fibroids, especially studies that examine the correlation of treatment effect with changes in symptoms as well as comparisons of this new technology with other treatment methods such as UAE.
An assessment by the Canadian Coordinating Office of Health Technology Assessment on MRI-guided focused ultrasound for the treatment of uterine fibroids (Chen, 2005) concluded that "[l]ong-term studies of larger patient groups are needed to provide further reliable evidence on the safety of this procedure, as well as its clinical and cost-effectiveness".
An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2005) concluded that MRI-guided focused ultrasound for uterine fibroids did not meet the TEC criteria: "The evidence is insufficient to determine whether the use of MR-guided, focused ultrasound improves net health outcome or whether it is as beneficial as any established alternatives." The TEC assessment stated that limitations in quality of the existing evidence include significant loss to follow-up at longer follow-up intervals, lack of adequate well-controlled comparison studies, and lack of comparability between treatment groups in the available nonrandomized comparisons. The TEC assessment considered both published evidence on MRI-guided focused ultrasound and unpublished evidence from the InSightec study that was submitted to the FDA to support a PMA. The TEC assessment noted that the few available comparisons suggest that MRI-guided focused ultrasound may not be as effective as available alternatives. The TEC assessment reported that patient satisfaction from the procedure is higher with hysterectomy, as is the degree of symptom relief. The TEC assessment found no direct comparisons of MRI-guided ultrasound to either UAE or myomectomy available in the literature, but that this did not preclude TEC to reach some general and preliminary comparisons. The TEC assessment noted that durability of MRI-guided ultrasound is a major concern; a substantially greater proportion of women undergo other (or repeat) procedures after MRI-guided ultrasound compared to either UAE or myomectomy. The TEC assessment also found that available data suggest that fibroid volume reduction with MRI-guided ultrasound is much lower than with comparison procedures. Uterine artery embolization appears to produce a more profound improvement in symptom severity scores than MRI-guided ultrasound. For fertility preservation, myomectomy is the treatment of choice (TEC, 2005). The TEC assessment stated that neither UAE nor MRI-guided ultrasound is recommended if the woman desires to preserve fertility. The TEC assessment concluded that further study of the procedure and its durability, especially in light of other available treatments, is needed.
The National Institute for Health and Clinical Excellence (NICE, 2007) released interventional procedures guidance that concluded that "[c]urrent evidence on the safety and efficacy of magnetic resonance image (MRI)-guided focused ultrasound for uterine fibroids does not appear adequate" and that "further research on the procedure and publication of long-term outcomes would be useful." NICE reviewed the evidence on the safety and efficacy of the procedure, which comes from three uncontrolled case series. Most of the papers excluded from the analysis were earlier reports on some of the same women. The NICE assessment noted that a majority of published data have been reported by one study group. The NICE advisors observed that the primary endpoint in these case series was change in symptom severity rather than fibroid shrinkage, and that there is limited reduction in fibroid volume following the procedure (NICE, 2007). The assessment stated that there is no evidence on the effects of this procedure on fertility.
A related NICE interventional procedure consultation document (NICE, 2006) stated that the maximum follow-up reported across all the studies was 19.5 months, and that most of the studies report on outcomes at 6 months. A significant proportion of women included in these studies were lost to follow-up. In addition, a significant proportion of women sought alternative treatments following the procedure, such as hysterectomy. The NICE assessment listed skin burns as a potential complication from the procedure, occurring in 5 % of subjects in 1 case series (NICE, 2007). Another potential complication was reversible neural damage; 2 studies reported on cases of pain in the distribution of the sciatic nerve which resolved in both cases within 1 year of the procedure. The NICE advisors also commented that thermal damage to adjoining structures was a theoretical concern.
The Agency for Healthcare Research and Quality's report on management of uterine fibroids (Viswanathan et al, 2007) concluded that research is lacking for the long-term symptom relief of MRI-guided-ultrasound ablation.
An assessment of the evidence on treatment of uterine fibroids by BMJ Clinical Evidence concluded that the effectiveness of MRI-guided focused ultrasound is unknown (Lethaby and Vollenhoven, 2006).
The American College of Radiology’s clinical guideline on "Radiologic management of uterine leiomyomas" (Burke et al, 2012) rendered MRI-guided high-frequency focused ultrasound ablation a "2" rating for a woman with multiple uterine fibroids resulting in a 20-week-sized uterus on physical examination and menorrhagia; a "3" rating for a woman with multiple submucosal and intramural fibroids presenting with menorrhagia and pelvic pain; a "4’ rating for a woman with menometrorrhagia who presents with 3 dominant leiomyomas, ranging in size from 6 to 8 cm and intramural in location; a "3" rating for a woman with menorrhagia with a single 3 cm intramural fibroid and diffuse adenomyosis; a "3" rating for a woman with pelvic discomfort and 8 cm pedunculated subserosal fibroid; and a "3" rating for a woman with constipation and a 12 cm subserosal leiomyoma compressing the rectum (Rating scale: 1,2,3 denotes usually not appropriate; 4,5,6 denotes may be appropriate). Furthermore, the guideline stated that "To date, there is little long-term information on the efficacy of this technology".
An UpToDate review on "Overview of treatment of uterine leiomyomas (fibroids)" (Stewart, 2013) states that "Magnetic resonance guided focused ultrasound surgery (MRgFUS) (e.g., ExAblate 2000) is a more recent option for the treatment of uterine leiomyomas in premenopausal women who have completed childbearing. This noninvasive thermoablative technique converges multiple waves of ultrasound energy on a small volume of tissue, which leads to its thermal destruction, and can be performed as an outpatient procedure. The maximum size of a leiomyoma for this procedure is uncertain. It is not typically size alone that limits treatment, but size, vascularity, access and other factors. This system is not indicated for leiomyomas which are resectable with a hysteroscope, heavily calcified, or when intervening bowel of bladder could be damaged by treatment. While desire for future pregnancy was originally a contraindication for this therapy, labeling for the device now allows treatment in women considering future pregnancy following counseling …. Studies are needed to determine long-term outcome and optimal candidates for this procedure; comparative studies are also needed".
The Australasian CREI Consensus Expert Panel on Trial evidence (ACCEPT) group’s consensus statement on "Fibroids in infertility" (Kroon et al, 2011) stated that "Newer treatments such as uterine artery embolisation, radiofrequency ablation, bilateral uterine artery ligation, magnetic resonance-guided focussed ultrasound surgery and fibroid myolysis require further investigation prior to their establishment in the routine management of fibroid-associated infertility". Furthermore, the updated French College of Gynecology and Obstetrics’ guideline on "Therapeutic management of uterine fibroid tumors" (Marret et al, 2012) stated that "Myolysis is under assessment, and research on its use is recommended".
In a multi-center, clinical study, Stewart et al (2006) evaluated outcomes at 6 and 12 months after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for symptomatic uterine leiomyomas. Pre-menopausal women with symptomatic uterine leiomyomas and no plans for future pregnancy (n = 109 at 6 months and n = 82 at 12 months) received a single treatment session of MRgFUS for uterine fibroids. Main outcome measures were reduction in fibroid symptoms as measured by the symptom severity score (SSS) of the Uterine Fibroid Quality-of-Life Instrument (UFS-QOL), the only validated measure of leiomyoma symptomatology. A 10-point reduction in the SSS was selected as the targeted improvement. A total of 71 % of women undergoing MRgFUS reached the targeted symptom reduction at 6 months, and 51 % reached this at 12 months. The magnitude of improvement in SSS was greater than predicted, with subjects having a mean decrease of 39 % and 36 % at 6 and 12 months, respectively. This paralleled the improvement seen using the short form-36 instrument. A modest volume reduction similar in magnitude to the treated volume was seen. The incidence of adverse events was low. These researchers concluded that MRgFUS treatment results in short-term symptom reduction for women with symptomatic uterine leiomyomas with an excellent safety profile.
Sharp (2006) stated that new technologies for the treatment of uterine leiomyomata include UAE, MRI-guided focused ultrasonography, laparoscopic uterine artery occlusion, and cryomyolysis. There is sound evidence for shorter hospital stay, quicker return to work, and a similar major complication rate compared with hysterectomy. Uterine artery embolization appears to be effective for up to 5 years in reducing bulk symptoms and menorrhagia associated with leiomyomata. The chance of re-operation for leiomyoma-related symptoms within 5 years is 20 to 29 %. Women who wish to become pregnant should be cautioned about potential complications during pregnancy. There is insufficient evidence to recommend UAE in post-menopausal women. With regard to MRI-guided focused ultrasonography, fibroid cryomyolysis (freezing), and laparoscopic uterine artery occlusion, Sharp (2006) commented that although the initial symptom reduction outcomes have been reported as favorable, more data are needed to better understand the durability of these results.
In a review of treatment of uterine fibroids, Van Voorhis (2009) stated that although early outcomes of up to 1 year are encouraging, long-term effectiveness and comparative studies are needed before focused ultrasound can be recommended for the treatment of uterine fibroids.
Mindjuk et al (2015) reported on the 12-month technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success. A total of 252 women (mean age, 42.1 ± 6.9 years) with uterine fibroids underwent MRgFUS. All patients underwent MRI before treatment. Results were evaluated with respect to post-treatment nonperfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data. NPV ratio was significantly higher in fibroids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MR images and in fibroids distant from the spine (>3 cm). NPV ratio was lower in fibroids with septations, with subserosal component and in skin-distant fibroids (p < 0.001). NPV ratio was highly correlated with clinical success: NPV of more than 80 % resulted in clinical success in more than 80 % of patients. Reintervention rate was 12.7 % (mean follow-up time, 19.4 ± 8 months; range, 3-38). Expulsion of fibroids (21 %) was significantly correlated with a high clinical success rate. No severe adverse events were reported.
Gorny et al (2014) assessed the mid-term outcomes of magnetic resonance (MR)-guided focused ultrasound (US) treatments of uterine fibroids. Investigators conducted a retrospective follow-up of 138 patients treated at a single institution between March 2005 and November 2011. The patients were not part of a clinical study and were followed through retrospective review of their medical records and telephone interviews to assess additional treatments for fibroid-related symptoms. Survival methods, including Cox proportional hazards models, were used to assess the association between incidence of additional treatments and patient data obtained during screening before treatment. The average length of follow-up was 2.8 years (range of 1 to 7.2 years). The cumulative incidence of additional treatments at 36 months and 48 months after MR-guided focused US was 19% and 23%, respectively. Women who did not need additional treatment were older than women who did (46.3 ± 5.6 years versus 43.0 ± 5.8 years; p = 0.006; hazard ratio [HR], 0.855; 95 % confidence interval [CI]: 0.789 to 0.925). Additionally, women with heterogeneous or bright fibroids on T2-weighted MR imaging were more likely to require additional treatment compared with women with homogeneously dark fibroids (HR, 5.185 or 5.937, respectively; 95 % CI: 1.845 to 14.569 or 1.401 to 25.166, respectively). Physician predictions of treatment success, recorded during the screening process, had significant predictive value (P = .018). An accompanying editorial (Matsumoto, 2014) noted that this study was limited by lack of symptom and quality-of-life assessments, a skewed patient population (90% white), absence of imaging follow-up, and the need to treat approximately 48% of patients (66 of 138) twice with MR-guided focused US. The mean non-perfused volume (NPV) of fibroids reported by Gorny, et al. was only 45.5%. After uterine artery embolization (UAE) for fibroids, the NPV is typically 4 90%and often 100%, with a positive correlation noted between the percent of fibroid infarction and long-term clinical outcomes. The editorialist noted that, given the limitations of the technology, only 20% of patients who present with symptoms related to fibroids are likely to be good candidates for MR-guided focused US therapy. In the German experience, only 16% of the patients screened were candidates (citing Mindjik et al). The editorialist stated that the hope is that the FIRSTT (Fibroid Interventions: Reducing Symptoms Today and Tomorrow) trial, which will compare focused US versus UAE therapy for uterine fibroids, will demonstrate that outcomes with MR-guided focused US are at least equivalent to UAE so that we can incorporate "Sound" technology into reimbursable therapies for women in the United States with uterine fibroids.
Dobotwir et al (2012) described and evaluated treatment of uterine fibroids using MRgFUS during its first 24 months of use at The Royal Women's Hospital Melbourne. The investigators reported that 100 Victorian women were treated with MRgFUS using the ExAblate 2000 system. Treatment outcomes based on fibroid volume shrinkage measured at 4 and 12 months post-treatment and symptom severity score assessment (Symptom Severity Score Quality of Life - SSS-QOL) pre- and post- (4-6 weeks, 4, 6 and 12 months) treatment. Mean non-perfused volume of the treated fibroids were 67% ± 25% (n =100) immediately post-treatment. At 4 months post-treatment, the treated fibroids demonstrated an average volume reduction of 29% ± 32% (n = 74) and at 12 months 38% ± 45% (n = 32). Mean symptom severity scores (SSS-QOL) improved by 51% from 59 ± 21 (n = 97) at baseline to 29 ± 17 (n = 36) by 12 months.
Desai et al (2012) reported on the results of MRgFUS treatment carried out on Indian patients in one hospital. The investigators treated 50 Indian women (mean age = 36.2 ± 8.3 years) for fibroids as outpatients using the ExAblate MRgFUS system (InSightec). Non-perfused volumes (NPVs) were measured immediately after treatment to calculate the treatment outcomes. A validated symptom-specific questionnaire to record their symptoms prior to treatment and six months following treatment was completed by patients. The size of the fibroids was measured on the day of the treatment and during the 6-month checkup to calculate shrinkage. Adverse events during and following treatment were recorded and monitored. The average NPV ratio measured after the treatment was 88% ± 6%, indicative of high ablated fibroid tissue. Prior to treatment, the mean Symptoms Severity Score was 56.9 ± 4.8 (n = 50), which is indicative of highly symptomatic patients. Six months following treatment, there was an average fibroid shrinkage of 30% ± 11%, and a significant decrease in the mean score to 28.6 ± 6.0 (n = 50) (P < 0.001). There were no reports of serious or unexpected adverse events at any point during treatment or during the follow-up period from any of the 50 women treated in the current study.
Himabidu et al (2014) reported on a prospective study of 32 consecutive Indian women with clinically symptomatic uterine fibroids who were treated with MRgFUS from February 2011 to October 2011. Pre and post treatment symptom severity scores (SSS) were assessed at the time of enrolment and at one, three and six months follow up using a validated uterine fibroid symptom - quality of life questionnaire (UFS-QOL). Pre and post treatment fibroid volumes were compared immediately after treatment and at six months follow up using contrast enhanced MRI scan. Non-perfused volume (NPV) ratios were calculated and correlated with fibroid volume reductions immediately after the treatment and at the end of six months follow up. The investigators reported that the procedure was well tolerated by the patients and procedure related adverse effects were non-significant. Significant reductions in SSS were seen at one, three and six month intervals after the treatment (P<0.01). Significant reductions were noticed in fibroid volumes at six months follow up compared to pretreatment fibroid volumes (P<0.01). Significant positive correlations were observed between NPV ratios and reduction in fibroid volumes at six months follow-up (r=0.659, P<0.01).
Clark et al (2014) stated that the role of MRgFUS in the treatment of fibroids has been evolving since its introduction in 2004. Several new devices and techniques including location-specific treatment, volumetric therapy, and vessel-targeted therapy have been introduced over the last few years. Several case series reported uncomplicated pregnancy following MRgFUS; however, results of the ongoing studies will further elucidate the utility of MRgFUS in patients planning future fertility. These investigators performed a systematic review of the literature and studies that reported quality of life at baseline and after 6 months were included in a meta-analysis. The authors concluded that MRgFUS represents a minimally invasive treatment for uterine fibroids that is able to improve the quality of life and fibroid size with durability. They stated that it is possible that MRgFUS could be the treatment of choice for patients desiring future fertility; however, further investigation is needed.
Pron (2015) evaluated patients' eligibility for magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) treatment of symptomatic uterine fibroids and the technical success, safety, effectiveness, and durability of this treatment. This review also compared the safety and effectiveness of MRgHIFU with other minimally invasive uterine-preserving treatments and surgeries for uterine fibroids. A literature search was performed on March 27, 2014, using Ovid Medline, Ovid Medline In-Process and Other Non-Indexed Citations, Ovid Embase, Ebsco Cumulative Index to Nursing & Allied Health Literature (CINAHL), and EBM Reviews, for studies published from January 1, 2000 to March 27, 2014. The evidence review identified 2 systematic reviews, 2 randomized controlled trials (RCTs), 45 cohort study reports, and 19 case reports involving HIFU treatment of symptomatic uterine fibroids. Eligibility for MRgHIFU treatment was variable, ranging from 14 % to 74 %. In clinical cohort studies involving 1,594 patients, 26 major complications (1.6 %) were reported. Magnetic resonance-guided HIFU resulted in statistically and clinically significant reductions in fibroid-related symptoms in studies conducted in 10 countries, although few involved follow-up longer than 1 year. Re-treatment rates following MRgHIFU were higher in early clinical studies involving regulated restrictions in the extent of fibroid ablation than in later reports involving near-complete ablation. Emergent interventions, however, were rare. Although a desire for fertility was an exclusion criterion for treatment, spontaneous term pregnancies did occur following HIFU. There were no randomized trials comparing MRgHIFU and other guidance methods, other minimally invasive treatments, or surgeries for symptomatic uterine fibroids. Limitations with MRgHIFU included restricted eligibility, requirement for a dedicated MR device to guide the treatment, lengthy procedure time, and loss of MR opportunity time. The authors concluded that for women failing medical therapy and seeking alternatives to hysterectomy for symptomatic uterine fibroids, MRgHIFU provided a safe and effective, non-invasive, uterine-preserving treatment from which they rapidly recover. The treatment advantages of MRgHIFU are potentially offset by restrictive eligibility, lengthy procedure time, and dependence on availability of an MR device. They stated that the lack of comparative evidence between MRgHIFU and other, more established uterine-preserving treatments limits informed decision-making among therapeutic options.
The Ontario Health Technology Advisory Committee’s recommendation regarding “Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) for treatment of symptomatic uterine fibroids” (OHTAC, 2015) stated the following:
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Multiple clinical and technical factors resulted in highly variable eligibility rates for MRgHIFU, ranging from 14 % to 74 %. In clinical cohort studies involving 1,594 patients, 26 major complications (1.6 %) were reported, MRgHIFU treatment resulted in statistically and clinically significant reductions in fibroid-related symptoms in clinical cohort studies from sites in 9 countries. However, few studies involved follow-up of longer than a year. Re-treatment rates following MRgHIFU were higher in the earlier clinical studies involving regulatory required restricted fibroid ablation, than in the later studies, which involved more complete ablation; emergent interventions, however, were rare. Although a desire for fertility was a study exclusion criterion, full-term pregnancies did occur following HIFU suggesting that HIFU may also have a role in fertility preservation. There were no randomized trials comparing MRgHIFU with other methods of imaging guidance, other minimally invasive treatments, or surgeries for symptomatic uterine fibroids.
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There are several limitations with MRgHIFU technology. These include restricted eligibility criteria and the need for an MR scanner that is compatible with the specific brand of HIFU equipment being used. This may mean the purchase of a dedicated scanner for MRgHIFU, or, if an existing scanner is used, loss of MR opportunity time for other patients due to the lengthy procedure time for MRgHIFU. In Ontario, there is also limited access as few centers have: interventional radiologists with technical competence in the procedure, multi-disciplinary team approaches to fibroid management, or organized referral patterns for this condition. There is also a lack of comparative evidence on MRgHIFU versus other uterine-preserving treatments such as UAE and myomectomy, limiting the ability to make informed decisions between these therapeutic options. The main deciding factor between these interventions may well depend on patient factors, given the restrictive criteria for MRgHIFU.
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Based on the current available evidence, OHTAC recommends that magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) be considered as one option in the treatment of symptomatic uterine fibroids in women who are unresponsive to medical therapy.
While the 2015 Ontario Health Technology Advisory Committee recommended that MRgHIFU be considered as one option in the treatment of symptomatic uterine fibroids in women who are unresponsive to medical therapy, the “grade of recommendation” and “level of evidence” were not provided. Studies published after the OHTAC recommendation did not furnish strong support for the OHTAC recommendation.
In a pilot, randomized, placebo-controlled trial, Jacoby et al (2016) evaluated the feasibility of a full-scale placebo-controlled trial of (MRgFUS and obtained estimates of safety and effectiveness. Pre-menopausal women with symptomatic uterine fibroids were randomized in a 2:1 ratio to receive MRgFUS or placebo procedure. Primary outcome was change in fibroid symptoms from baseline to 4 and 12 weeks after treatment assessed by the Uterine Fibroid Symptom Quality of Life Questionnaire (UFS-QOL); secondary outcome was incidence of surgery or procedures for recurrent symptoms at 12 and 24 months. A total of 20 women with a mean age of 44 years (± standard deviation 5.4 years) were enrolled, and 13 were randomly assigned to MRgFUS and 7 to placebo. Four weeks after treatment, all participants reported improvement in the UFS-QOL: a mean of 10 points in the MRgFUS group and 9 points in the placebo group (for difference in change between groups). By 12 weeks, the MRgFUS group had improved more than the placebo group (mean of 31 points and 13 points, respectively). The mean fibroid volume decreased 18% in the MRgFUS group with no decrease in the placebo group at 12 weeks. Two years after MRgFUS, 4 of 12 women who had a follow-up evaluation (30 %) had undergone another fibroid surgery or procedure. The authors concluded that women with fibroids were willing to enroll in a randomized, placebo-controlled trial of MRgFUS; and a placebo effect may explain some of the improvement in fibroid-related symptoms observed in the first 12 weeks after MRgFUS.
An UpToDate review on "Overview of treatment of uterine leiomyomas (fibroids)" (Stewart, 2016) states that "Magnetic resonance guided focused ultrasound surgery (MRgFUS) (e.g., ExAblate 2000) is a more recent option for the treatment of uterine leiomyomas in premenopausal women who have completed childbearing …. Studies are needed to determine long-term outcome and optimal candidates for this procedure; comparative studies are also needed".
In a multi-center prospective, single-arm pilot study, Parsons and colleagues (2017) evaluated the safety and acute tissue ablation efficacy of a trans-abdominal HIFU prototype device that uses ultrasound imaging guidance for rapid non-invasive ablation of uterine fibroids. The secondary objective was to assess preliminary fibroid-related symptom improvement and fibroid volume reduction at 3 to 6 months post-treatment in subsets of patients. Women with a diagnosis of symptomatic uterine fibroids planning to undergo hysterectomy were considered for this pilot study; 73 subjects underwent trans-abdominal ultrasound-guided HIFU treatment using a volumetric ablation technique referred to as "shell ablation", in which the HIFU energy was deposited in patterns that partially encapsulate the peripheral region of the targeted fibroid(s). Patients were divided into 2 sequential cohorts:- the Development Cohort (the first 37 patients treated), and
- the Validation Cohort (the final 36 patients treated).
Development Cohort treatments were performed for dose-ranging purposes to identify the optimum HIFU treatment parameters, while the Validation Cohort treatments were performed to validate these final settings; 65 patients (89.0 %) received only prophylactic oral, sublingual, or intra-muscular (IM) analgesia before treatment, sometimes with oral anxiolytics. The remaining 8 patients (11.0 %) were anesthetized prior to treatment; 67 patients (91.8 %) then had scheduled hysterectomies between 0 to 179 days after treatment completion. Adverse events (AEs) were monitored until study exit, which ranged from 10 to 191 days post-treatment. The primary efficacy end-point measured in all 73 patients was the non-perfused volume (NPV) of tissue produced, which was assessed between 0 to 7 days post-treatment either by tissue sectioning following hysterectomy or by gadolinium-enhanced MRI. The following secondary efficacy end-points were also measured in subsets of patients who were prospectively scheduled for delayed hysterectomies: changes in menstrual blood loss (MBL), symptom severity (SS), and quality of life (QOL) scores were assessed using validated techniques at 3 months post-treatment in 10 patients, and changes in treated fibroid volume were assessed using MRI at 3 to 6 months post-treatment in 14 patients. In all 73 patients, there were no reports of any serious adverse device effects, including no damage to any extra-uterine collateral tissues or the abdominal skin. In the Development Cohort, a mean NPV of 17.9 ± 24.9 cm3 (range of 0 to 123.0) was produced in a mean total treatment time of 4.9 ± 2.4 minutes (range of 1.1 to 11.3 minutes). These metrics improved in the Validation Cohort, where a mean NPV of 44.9 ± 58.5 cm3 (range of 0 to 284.7) was produced in a mean total treatment time of 3.6 ± 2.1 minutes (range of 1.5 to 9.5). In the subsets of patients with data available, there was a significant improvement in QOL score (median of 16.5 point increase, p = 0.011), an improving trend in SS score (median of 13.5 point decrease, p = 0.254), and a significant improvement in treated fibroid volume (mean of 24.0 % decrease, p = 0.013). In 8 patients who had above-average MBL scores at baseline and regular menstrual cycle lengths during follow-up, there was also a significant improvement in MBL score (median of 40.8 % decrease, p = 0.035). The authors concluded that ultrasound-guided HIFU ablation with the prototype device demonstrated an excellent safety profile and produced clinically relevant NPVs in a mean total treatment time of under 4 minutes using the final validated treatment settings. They stated that short-term clinical efficacy metrics assessed in subsets of patients were encouraging, and larger studies should be conducted to confirm these results.
Saino and associates (2018) stated that MRgHIFU is not feasible in all patients with uterine fibroids because of limiting anatomical factors such as scar tissue, bowel loops or other obstacles in the sonication path. These may prevent the treatment or limit the treatment window, and therefore, also the volume where HIFU therapy can be delivered. Bowel loops present a particular problem because of bowel gas bubbles and hard particles which may cause reflection or absorption of US energy, potentially leading to thermal damage and even bowel perforation. Most commonly used techniques for bowel re-positioning are bladder and/or rectum filling but these are not always sufficient to re-position the bowel loops. With more efficient bowel re-positioning technique, the number of eligible patients for MRgHIFU could be increased, and therapy efficacy be improved in cases where bowel loops limit the treatment window. A wedged exterior gel pad was used in 2 patients presented with in total of 4 symptomatic fibroids undergoing MRgHIFU when bladder and/or rectum filling was insufficient to re-position the bowel loops. No severe adverse effects were observed in these cases. The non-perfused volume ratios (NPVs) immediately after treatment were 86 % and 39 % for the 1st patient, and 3 % for the 2nd patient. The authors concluded that these preliminary findings suggested that the use of a wedged gel pad during MRgHIFU could be an effective tool to manipulate the bowels in cases where the bladder and/or rectum filling is insufficient to re-position the bowel loops. These researchers also noted that a wedged gel pad could also be used in other situations to achieve better treatment coverage to the uterine fibroid. The drawbacks of this study included the small number of patients (n = 2) and the lack of Funaki type III fibroids, although these type of lesions were typically not well-suitable for HIFU therapy.
Mohr-Sasson et al (2018) stated that fibroid tumors are the most common benign tumors in women of reproductive age. Treatment is usually indicated for those who are symptomatic, with different techniques being used. In a single-center, cohort study, these researchers compared the long-term outcome of laparoscopic myomectomy with magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of symptomatic uterine fibroid tumors. This trial was carried out on all patients with symptomatic uterine fibroid tumors who were admitted to a single tertiary care center and treated operatively with laparoscopic myomectomy or treated conservatively with MRgFUS from January 2012 until January 2017. Assessment for further interventions and sustained fibroid-associated symptoms was performed, with the use of the Uterine Fibroid Symptom and Quality of Life symptom severity score. A total of 154 women met the inclusion criteria. Complete follow-up evaluation was achieved for 64 women who underwent laparoscopic myomectomy and for 68 women who were treated by MRgFUS. Follow-up time was similar for the 2 groups (median of 31 months [inter- quartile range (IQR), 17 to 51 months] versus 36 months [IQR, 24 to 41]; p = 0.95). The rate of additional interventions was 5 (7.8 %) and 9 (13.2 %), respectively (p = 0.312). Similarly, the Uterine Fibroid Symptom and Quality of Life symptom severity score questionnaire score at follow-up interviews revealed comparable median scores of 17 (IQR, 12 to 21) versus 17 (IQR, 13 to 22) for laparoscopic myomectomy and MRgFUS, respectively (p = 0.439). Analysis of each of the symptoms separately (bleeding, changes in menstruation, abdominal pain, bladder activity, nocturia, fatigue) did not change these findings, nor did a multi-variate analysis. The authors concluded that satisfaction with long-term outcome and rate of reinterventions after MRgFUS treatment or laparoscopic myomectomy for uterine fibroid tumors was comparable. Moreover, these researchers stated that further larger randomized trials are needed to confirm these findings.
The authors stated laparoscopic myomectomy is the treatment of choice offered to patients at their center unless there is contraindications because of an enlarged uterus that require laparotomy, highly suspicious malignancy, contraindication for surgery because of severe medical conditions, or patient preference for other therapeutic options. Despite the difficulties, future randomized trials should still be encouraged to overcome some of the selection biases. Another drawback of the study was that data concerning future (??) intervention were based on patient reports and was liable to recall bias. Furthermore, fertility success rate after both treatments was an important outcome measure to be evaluated; but was considered to be beyond the scope of this study.
In a systematic review and meta-analysis, Verpalen and associates (2019) re-examined the effectiveness of magnetic resonance-HIFU (MR-HIFU) therapy for uterine fibroids by excluding studies with restrictive treatment protocols that are no longer used. The National Guideline Clearinghouse, Cochrane Library, TRIP, Medline, Embase and WHO International Clinical Trials Registry Platform (ICTRP) databases were searched from inception until the June 22, 2018. Keywords included "MR-HIFU", "MRgFUS", and "Leiomyoma". Only studies about MR-HIFU treatment of uterine fibroids with at least 3 months of clinical follow-up were evaluated for inclusion. Treatments with US-guided HIFU devices or protocols not aiming for complete ablation were eliminated. The primary outcome was the improvement in fibroid-related symptoms. Technical outcomes included screening and treatment failures, treatment time, application of bowel-interference mitigation strategies and the non-perfused volume (NPV) percentage. Other secondary outcomes were the QOL, fibroid shrinkage, safety, re-interventions, reproductive outcomes, and costs. Meta-analysis was performed using a random-effects model (DerSimonian and Laird). A total of 18 articles (1,323 treated patients) met the inclusion criteria. All selected studies were case-series except for 1 cross-over study. Overall, the quality of the evidence was poor-to-moderate. The mean NPV% directly post-treatment was 68.1 %. The use of bowel-interference mitigation strategies may lead to increased NPV%. The mean symptom reduction at 12-months was 59.9 % and fibroid shrinkage was 37.7 %. The number of AEs was low (8.7 %), stratification showed a difference between HIFU systems. The re-intervention percentage at 3 to 33.6 months follow-up ranged from 0 to 21 %. Longer follow-up was associated with a higher risk at re-interventions. Reproductive outcomes and costs couldn't be analyzed. The authors concluded that controlled trials should define the role of MR-HIFU in the management of uterine fibroids.
Browne et al (2021) examined the impact of technology improvements on the outcomes of MRgFUS treatments of symptomatic uterine leiomyomas (uterine fibroids). The study compared ablation volumes and incidence of adverse events (AEs) in patient groups treated with 2 generations of MRgFUS systems from a single vendor. These investigators described the findings of a retrospective, single-center, comparative study of 2 groups of women with symptomatic uterine leiomyomas who were clinically treated with MRgFUS. Group 1 (n = 130) was treated using the 1st-generation system between March 2005 and December 2009; group 2 (n = 71) was treated using the 2nd-generation between December 2013 and September 2019. The 2nd-generation MRgFUS system resulted in significantly improved non-perfused volume ratios in both dark and bright T2 fibroid categories compared with the 1st-generation system (dark -- 80 % versus 46 %, p = 0.00002 and bright -- 46 % versus 32 %, p = 0.001). There were no recorded hospital admissions, no skins burn, and no reported major AEs since the introduction of this 2nd-generation ExAblate 2100 system with advanced safety and treatment planning features. The authors concluded that this study has demonstrated that improvements to current MRgFUS technology resulted in significantly increased efficacy and patient safety of clinical treatments of patients with symptomatic uterine leiomyomas.
The authors stated that this study had 2 main drawbacks. First, this was a retrospective, single-center, single-vendor study. Second, these researchers only presented the immediate results observed after the procedure; symptom relief was not part of their analysis. They noted that given the importance of examining the long-term impact of the MRgFUS treatment on symptom relief, they are currently conducting a follow-up study of all subjects using the Uterine Fibroid Symptom and Quality of Life questionnaire.
Wang et al (2021) noted that uterine fibroids are common benign tumors among pre-menopausal women. High- intensity focused ultrasound (HIFU) is an emerging non-invasive intervention that uses the high-intensity US waves from US probes to focus on the targeted fibroids. However, the efficacy of HIFU in comparison with that of other common treatment types in clinical procedure remains unclear. In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of HIFU with other techniques that have been widely used in clinical settings. They searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, Cumulative Index to Nursing & Allied Health Literature, Web of Science, ProQuest Nursing & Allied Health Database, and t3 Chinese academic databases, including randomized controlled trials (RCTs), non-RCTs, and cohort studies. The primary outcome was the rate of re-intervention, and the GRADE approach was used to interpret the findings. About 18 studies met the inclusion criteria. HIFU was associated with an increased risk of re-intervention rate in comparison with myomectomy (MYO) [pooled odds ratio (OR): 4.05, 95 % confidence interval (CI): 1.82 to 8.9]. The results favored HIFU in comparison with hysterectomy (HYS) on the change of follicle-stimulating hormone [FSH; pooled mean difference (MD): -7.95, 95 % CI: -8.92 to 6.98), luteinizing hormone (LH; MD: -4.38, 95 % CI: -5.17 to 3.59), and estradiol (E2; pooled MD: 43.82, 95 % CI: 36.92 to 50.72)]. HIFU had a shorter duration of hospital stay in comparison with MYO (pooled MD: -4.70, 95 % CI: -7.46 to 1.94, p < 0.01). It had a lower incidence of fever (pooled OR: 0.15, 95 % CI: 0.06 to 0.39, p < 0.01) and a lower incidence of major AEs (pooled OR: 0.04, 95 % CI: 0.00 to 0.30, p < 0.01) in comparison with HYS. The authors concluded that HIFU may help maintain femininity and shorten the duration of hospital stay. Moreover, these researchers stated that high-quality clinical studies with a large sample size, a long-term follow-up, and the newest HIFU treatment protocol for evaluating the re-intervention rate are suggested to be carried out. Clinical decision should be based on the specific situation of the patients and individual values.
Tsai et al (2021) stated that HIFU is a new non-invasive treatment creating no surgical wound. In a systematic review and meta-analysis, these researchers examined the safety and effectiveness of HIFU treatment compared with conventional surgery for patients with uterine myomas. They searched PubMed, Embase, and the Cochrane Library for studies published before January 2021. Studies comparing the outcome of HIFU and conventional surgery (myomectomy and hysterectomy) for patients with uterine myomas were included. These investigators carried out meta-analyses by using a random effects model. Uterine myoma symptom score and QOL score were analyzed using the MD; the recovery time and frequency of major AEs were also evaluated. A total of 10 studies were included. HIFU relieved uterine myoma symptoms significantly when compared with conventional surgery at 6 months (MD -1.61; 95 % CI: -2.88 to -0.33) and 12 months (MD -2.44; 95 % CI: -3.68 to -1.20) following treatment. Similarly, HIFU group improved the QOL score significantly at 6 months (MD 2.14; 95 % CI: 0.86 to 3.42) and 12 months (MD 2.34; 95 % CI: 0.82 to 3.86) following treatment when compared with the surgery group. The authors concluded that HIFU could be a safe and effective therapeutic option for patients with uterine myomas; however, one of its side effects, skin burns, requires further research and discussion. These researchers stated that additional studies involving more RCTs are needed.
Anneveldt et al (2021) noted that myomectomy is currently the gold standard for the treatment of uterine fibroids in women who desire pregnancy; however, this approach has a long convalescence. Promising alternatives may be non-invasive HIFU under either MR-HIFU or ultrasound guidance (USgHIFU). In a systematic review, these investigators provided an overview of reproductive outcomes following these 2 relatively new ablation techniques. They carried out a systematic literature search to identify studies reporting reproductive outcomes following HIFU treatment of fibroids. Only peer-reviewed, full studies were included. Outcomes included pregnancy rate, live-birth rate, miscarriage rate as well as caesarian section rate, time to conceive, reported complications, and possible prognostic factors. A total of 21 studies were included; 14 studies reported 124 pregnancies after MR-HIFU. Two placenta previas and no uterus ruptures were reported. Pregnancy rate was collected retrospectively and ranged between 7 % and 36 %. Miscarriage rate in the oldest and largest prospective registry was 39 %. After USgHIFU, 366 pregnancies were reported with 1 fetal intra-uterine death, 6 placenta previas and no uterus ruptures. The only prospective study reported a pregnancy rate of 47 % and a miscarriage rate of 11 %. Possible prognostic factors like age were unavailable in most studies. The authors concluded that based on the heterogeneous data currently available, reproductive outcomes following HIFU appeared non-inferior to outcomes after the current standard of care (SOC). However, a RCT comparing reproductive outcomes after HIFU and SOC is needed to provide sufficient evidence on the preferred fibroid treatment for women with a pregnancy wish.
Furthermore, an UpToDate review on “Uterine fibroids (leiomyomas): Treatment overview” (Stewart, 2022) states that “Focused ultrasound surgery utilizes high intensity ultrasound energy to induce coagulative necrosis of fibroids. The treatment can be guided by ultrasound, most widely used in China and typically called high intensity focused ultrasound (HIFU), or by magnetic resonance imaging (MRI), termed MRgFUS in the rest of the world … It appears that MRgFUS results in a reduction in myoma volume of approximately 37 to 40 % … Review by the United Kingdom's National Institute for Health and Care Excellence suggests the data are adequate to support clinical use of MRgFUS and limited data support use of HIFU in special circumstances”. However, “MRgFUS is not listed in the “Summary and Recommendations” section of this UTD review.
Laparoscopic Uterine Artery Occlusion
Hald et al (2007) compared clinical outcome 6 months after treatment with bilateral laparoscopic occlusion of the uterine artery versus uterine leiomyoma embolization. A total of 66 pre-menopausal women with symptomatic uterine leiomyomata were randomized to treatment with either laparoscopic occlusion of uterine arteries or uterine leiomyoma embolization. The primary outcome was reduction of blood loss from pre-treatment to 6 months post-operatively, measured by a Pictorial Bleeding Assessment Chart. Secondary outcomes included patients' own assessment of symptom reduction, post-operative pain assessed using visual analog scales, ketobemidone used post-operatively, complications, secondary interventions, and failures. Fifty-eight women were included; 6-month follow-up data were available for 28 participants in each group. The percentage reduction in Pictorial Bleeding Assessment Chart scores did not differ between the treatment groups (52 % after uterine leiomyoma embolization and 53 % after laparoscopy, p = 0.96). The study had 52 % power to detect a 20 % difference on the Pictorial Bleeding Assessment Chart. Fewer participants in the group treated with uterine leiomyoma embolization complained of heavy bleeding after 6 months (4 % compared with 21 %, p = 0.044). The post-operative use of ketobemidone was higher after uterine leiomyoma embolization (46 mg compared with 12 mg, p < 0.001). The authors concluded that both laparoscopic occlusion of uterine vessels and embolization of uterine leiomyoma improved clinical symptoms in the majority of patients. Participants with the laparoscopic procedure had less post-operative pain but heavier menstrual bleeding 6 months after treatment. They noted that a larger study and longer follow-up is necessary before a definite conclusion can be made regarding the most effective treatment.
In a pilot randomized clinical trial, Cunningham and colleagues (2008) compared peri-operative pain and institutional use for women undergoing transcatheter UAE and transcatheter uterine artery occlusion (UAO) for the treatment of heavy uterine bleeding associated with uterine leiomyomas. Pre-menopausal women with heavy uterine bleeding related to uterine leiomyomas were enrolled. Either a standard UAE with microspheres or UAO using vascular coils was used. The main outcome measures were analgesic use, institutional stay, and post-procedural numeric pain scales. A total of 16 women were enrolled and 14 underwent study procedures (UAE n = 8, UAO n = 6). Baseline Aberdeen Menorrhagia Severity Scale scores, also known as the Ruta scores, were similar in each group (UAE = 54, UAO = 53). Median pre-procedural uterine volume was similar for each group (UAE = 557 ml, UAO = 612 ml). The median post-procedural pain scale was less for UAO than UAE (UAO 1, UAE 5; p < 0.05). Six patients with UAE and no patients with UAO required parenteral narcotic analgesia in the recovery room (p < 0.05). Patients with UAE used 6 hospital nights and patients with UAO used 1 hospital night (p = 0.09). Three-month Aberdeen Menorrhagia Severity Scale scores were reduced to a similar degree in each group (UAE = 58 %, UAO = 63 %). The authors concluded that transcatheter UAO is a promising alternative transcatheter technique for the treatment of symptoms related to uterine leiomyomas, with less post-procedural pain, reduced requirements for analgesics, and shorter hospital stays than transcatheter UAE. They stated that although the results of the study are promising, larger-scale trials with longer follow-up are needed to both confirm these results and evaluate the long-term efficacy of transcatheter UAO.
In a review of treatment of fibroids by means of UAO, Brill (2009) discussed the putative mechanism of action and clinical application of Doppler-guided UAO; and noted that this approach is a new investigational treatment modality for uterine fibroids.
Panagiotopoulou et al (2014) evaluated the effectiveness of uterine-sparing interventions for women with symptomatic uterine fibroids who wish to preserve their uterus. MEDLINE, EMBASE, CENTRAL, conference proceedings, trial registers and reference lists were searched up to October 2013 for RCTs. Outcome measures were patient satisfaction, re-intervention and complications rates, reproductive outcomes, and hospitalization and recovery times. A total of 5 trials, involving 436 women were included; 2 compared UAE with myomectomy and 3 compared UAE with laparoscopic UAO. Indirect treatment comparison showed that myomectomy and UAE resulted in higher rates of patient satisfaction (odds ratio [OR] 2.56, 95 % CI: 0.56 to 11.75 and 2.7, 95 % CI: 1.1 to 7.14, respectively) and lower rates of clinical failure (OR 0.29, 95 % CI: 0.06 to 1.46 and 0.37, 95 % CI: 0.13 to 0.93, respectively) than laparoscopic UAO. Myomectomy resulted in lower re-intervention rate than UAE (OR 0.08, 95 % CI: 0.02 to 0.27) and laparoscopic UAO (OR 0.08, 95 % CI: 0.01 to 0.37) even though the latter techniques had an advantage over myomectomy because of shorter hospitalization and quicker recovery. There was no evidence of difference between the three techniques in ovarian failure and complications rates. The evidence for reproductive outcomes is poor. The authors concluded that these findings suggested that laparoscopic UAO is less effective than UAE and myomectomy in treatment of symptomatic fibroids. The choice between UAE and myomectomy should be based on individuals' expectations and fully informed discussion.
In a systematic review and meta-analysis, Sanders and colleagues (2019) examined evidence on surgical outcomes following UAO at myomectomy. A total of 26 studies involving 2,871 patients located via database searches of Medline, Embase, Web of Science, PubMed, clinicaltrials.gov, and cited references were included in this study. Participants included intervention groups undergoing UAO at laparoscopic or abdominal myomectomy (UAO+M) (1,569 patients), and control groups undergoing myomectomy alone (1,302 patients). Primary outcome of surgical blood loss (estimated blood loss [EBL], transfusion rate, and change in hemoglobin (Hb) values), and secondary outcomes including operative time, length of stay (LOS), conversion and complications rates, fibroid recurrence, and changes in fibroid-related symptoms. Patients undergoing UAO+M had a statistically significant reduction in EBL (mean difference [MD] -103.7 ml; 95 % CI: -126.5 to -80.8), blood transfusion (RR 0.24; 95 % CI: 0.15 to 0.39), and change in Hb values (MD -0.60 g/dL; 95 % CI: -0.79 to -0.40) compared with controls. Using UAO+M prolonged operative times (MD 10.9 mins; 95 % CI: 3.5 to 18.2) but shortened the LOS (MD -0.37 days; 95 % CI: -0.62 to 0.11). Using UAO+M lowered the complication rates (RR 0.73; 95 % CI: 0.52 to 1.00) to the threshold of statistical significance and reduced the risk of fibroid recurrence (RR 0.36; 95 % CI: 0.16 to 0.83) compared with controls. The authors concluded that UAO at myomectomy was associated with decreased surgical blood loss and transfusion rate compared with control patients. Moreover, these investigators stated that further research is needed on reproductive outcomes and the effect on ovarian reserve before routine use can be recommended in women desiring future fertility.
In a meta-analysis, Tranoulis and associates (2019) examined the safety and efficacy of laparoscopic UAO (LUAO) during laparoscopic myomectomy (LM) on intra- and post-operative morbidity and evaluated its impact on leiomyoma recurrence rates. Medline, Scopus, Web of Science, and Cochrane Database were searched for relevant references from inception until December 2018, in line with PRISMA guidelines. Two authors screened for study eligibility and extracted data; RCTs and observational studies (OSs) comparing short- and long-term morbidity of LM with or without LUAO were included. The modified Jadad score and the methodologic index for non-randomized studies were used to evaluate the quality of RCTs and OSs, respectively. A total of 12 studies encompassing 750 LM and 873 LUAO-LM cases were included in the meta-analysis. The studies were of moderate quality. LUAO-LM appeared to significantly decrease intra-operative blood loss, post-operative Hb drop, and blood transfusion rate. A trend toward shorter hospital LOS was demonstrated, whereas no significant difference in operation duration was observed. The combined procedure seemingly contributed to lower recurrence rate. No LUAO-related complications were reported. Moderate-to-high heterogeneity was observed for few outcomes. The authors concluded that this was the 1st meta-analysis to-date to provide a convincing overview of safety and efficacy of LUAO-LM. These researchers stated that although a medium risk of bias warranted some caution with interpretation of the results, LUAO-LM seemingly improved intra- and post-operative outcomes in women with symptomatic leiomyomas.
Herbal Therapies
In a Cochrane review, Liu and colleagues (2009) evaluated the risks and benefits of herbal preparations for uterine fibroids. These investigators searched following electronic databases: the Trials Registers of the Cochrane Menstrual Disorders and Subfertility Group and the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, the Chinese Biomedical Database, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), AMED, and LILACS. The searches ended on 31st December 2008. Randomized controlled trials comparing herbal preparations with no intervention, placebo, medical treatment or surgical procedures in women with uterine fibroids were selected. Trials of herbal preparations with or without conventional therapy were also included. Two review authors collected data independently. They assessed trial risk of bias according to their methodological criteria; and presented dichotomous data as risk ratios (RR) and continuous outcomes as MD, both with 95 % CI. These investigators included 2 randomized trials (n = 150) with clear description of randomization methods. The methodological risk of bias of the trials varied. There were variations in the tested herbal preparations, and the treatment duration was 6 months. The outcomes available were not the primary outcomes selected for this review, such as symptom relief or the need for surgical treatment; trials mainly reported outcomes in terms of shrinkage of the fibroids. Compared with mifepristone, Huoxue Sanjie decoction showed no significant difference in the disappearance of uterine fibroids, number of patients with shrinking of uterine fibroids or average volume of uterine fibroids, but less effective than mifepristone on reducing average size of uterus (MD 23.23 cm(3), 95 % CI: 17.85 to 28.61). There was no significant difference between Nona Roguy herbal product and gonadotropin-releasing hormone agonist in average volume of uterine fibroids or size of uterus. No serious adverse effects from herbal preparations was reported. The authors concluded that current evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies of large sample and high quality. They stated that further high quality trials evaluating clinically relevant outcomes are needed.
Acupuncture
In a Cochrane review, Zhang and associates (2010) evaluated the benefits and harms of acupuncture in women with uterine fibroids. The following electronic databases were searched May 21, 2009: the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; AMED; the Menstrual Disorders and Subfertility Group's Specialised Register of Trials; Chinese Biomedical Literature Database (CBM); Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS); Chinese Medical Current Contents (CMCC) and China National Knowledge Infrastructure(CNKI). Citation lists, experts in the field and grey literature were also referred to. No restrictions such as language were applied. All RCTs comparing acupuncture management with placebo acupuncture, no management, Chinese medication, Western medication or other managements of uterine fibroids were considered for inclusion. Acupuncture management included either traditional acupuncture or contemporary acupuncture, regardless of the source of stimulation (e.g., body, electro, scalp, elongated, fire, hand, fine needle, moxibustion). Acupuncture management without needling was excluded. Two review authors assessed trial risk of bias according to our a priori criteria. No trials were included in this version of the review, therefore no data were collected. No randomized double-blind controlled trials met the inclusion criteria. The authors concluded that the effectiveness of acupuncture for the management of uterine fibroids remains uncertain. They stated that more evidence is needed to establish the safety and effectiveness of acupuncture for uterine fibroids. There is a continued need for well-designed RCTs with long-term follow-up.
Transversus Abdominis Pane (TAP) Block
Young et al (2012) stated that the transversus abdominis plane (TAP) block is a relatively new regional anesthesia technique that provides analgesia to the parietal peritoneum as well as the skin and muscles of the anterior abdominal wall. It has a high margin of safety and is technically simple to perform, especially under ultrasound guidance. A growing body of evidence supports the use of TAP blocks for a variety of abdominal procedures, yet, widespread adoption of this therapeutic adjunct has been slow. In part, this may be related to the limited sources for anesthesiologists to develop an appreciation for its sound anatomical basis and the versatility of its clinical application.
Abdallah et al (2012) noted that ultrasound guidance has led a surge of interest in TAP block for post-operative analgesia following abdominal surgery. Despite or because of the numerous descriptive applications and techniques that have recently populated the literature, results of comparative studies for TAP block have been inconsistent. This systematic review pragmatically addressed many unanswered questions, specifically the following: what are the effects of surgical procedure, block dose, block technique, and block timing on TAP block analgesia? A total of 18 intermediate- to good-quality randomized trials that included diverse surgical procedures were identified. Improved analgesia was noted in patients undergoing laparotomy for colorectal surgery, laparoscopic cholecystectomy, and open and laparoscopic appendectomy. There was a trend toward superior analgesic outcomes when 15 ml of local anesthetic or more was used per side compared with lesser volumes. All 5 trials investigating TAP block performed in the triangle of Petit and 7 of 12 trials performed along the mid-axillary line demonstrated some analgesic advantages. Eight of 9 trials using pre-incisional TAP block and 4 of 9 with post-incisional block revealed better analgesic outcomes. Although the majority of trials reviewed suggested superior early pain control, these researchers were unable to definitively identify the surgical procedures, dosing, techniques, and timing that provide optimal analgesia following TAP block. This review suggested that the understanding of the TAP block and its role in contemporary practice remains limited.
- the accuracy of placement of the needle and thus the local anesthetic in a 'blind' technique, and
- the potential for damage to adjacent structures.
Furthermore, there is a lack of evidence regarding the safety and effectiveness of the TAP block in the management of patients with uterine fibroids.
Laser Ablation
Law and associates (2000) reported that laser ablation of uterine fibroids using a percutaneous approach under local anesthetic in an open magnetic resonance scanner was performed in 12 symptomatic women awaiting hysterectomy. Accurate laser fiber placement was assisted by the use of a magnetic resonance needle tracking system, as well as laser heat dissipation monitored during treatment by a real-time imaging processor. This day case procedure was well-tolerated by all women, with 8 women subsequently declining their planned surgery. Follow-up measurements of treated fibroid volume by MRI demonstrated a mean decrease of 37.5 % at 3 months. The authors concluded that this novel minimally invasive approach offers an alternative to surgery for women with fibroids, but longer follow-up is needed to ascertain maximal fibroid shrinkage and to compare outcome with traditional surgery.
Cryoablation
Cowan et al (2002) developed a trans-abdominal interventional MRI-guided cryoablation procedure for the treatment of uterine fibroid tumors and reported this novel approach. This study represented the preliminary and first report of a prospective Institutional Review Board-approved protocol to study interventional MRI-guided cryoablation of uterine fibroid tumors. Women were selected on the basis of symptoms that were related to uterine fibroid tumors (bleeding, uterine pain, pelvic congestion, compression symptoms) and the absence of any desire for child bearing. A physical examination confirmed the presence of fibroid tumors, and MRI was performed before the procedure to measure the size and number of fibroid tumors. Patients returned to the interventional MRI and underwent placement of 3 to 5 probes (2 to 3 mm) under MRI-directed guidance. Follow-up MRI determined the size reduction of the lesion, and a clinical evaluation determined the change in symptoms. A total of 9 patients were treated and had substantial reduction in the uterine size (average, 66 % volume reduction), and their primary symptoms have either improved or resolved. The authors concluded that this was the first reported review of interventional MRI-directed cryotherapy of uterine fibroid tumors. These preliminary findings need to be confirmed by well-designed studies.
Sakuhara et al (2006) evaluated the feasibility and effectiveness of MRI-guided percutaneous cryoablation for uterine fibroids as a minimally invasive treatment alternative. From August 2001 to June 2002, MRI-guided percutaneous cryoablation was performed on 7 uterine fibroids in 6 patients who displayed clinical symptoms related to tumors. Using a horizontal-type open MR system, cryoablation probes were percutaneously placed in fibroids. Fibroids were ablated, and the site and size of ice balls were monitored on MR I. Post-operatively, patients completed a questionnaire to assess changes in presenting clinical symptoms, and MR images were obtained for all patients at follow-up. Changes in clinical symptoms and tumor volume were evaluated in each patient. All treated patients showed reductions in tumor size. Mean volume reduction rate was 40.3 % at 6 weeks post-operatively, and 79.4 % at 9 to 12 months. All patients reported fever after treatment. Surgical drainage was required for abscess in the probe channel in 1 patient, and transient liver damage occurred in another. Subjective symptoms improved in all patients except 1 who had multiple tumors, and no patient complained of new symptoms after cryoablation during follow-up. The authors concluded that MRI-guided percutaneous cryoablation represents a feasible and effective treatment for uterine fibroids. These findings need to be confirmed by well-designed studies with more patients and longer-term follow-up.
In a multi-center, pilot case-series study, Pansky and colleagues (2009) evaluated cryoablation of uterine fibroids using laparoscopically assisted placement of 17-gauge cryoablation needles. Patient satisfaction was documented with a validated Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire. Procedural efficacy was evaluated by assessing fibroid shrinkage. Treatment was followed by assessments at 3, 6, and 12 months. Median fibroid volume reduction was 43.3 % (19 patients) and 66.4 % (15 patients) at 6 and 12 months, respectively. Median UFS-QOL score improvement was 61.9 % and 66.7 % at 6 and 12 months, respectively. Additionally, patients experienced marked improvement of bleeding and fibroid bulk symptoms. The median Symptom Severity Score at baseline was 50, 25.0 (-59 %) at 6 months, and 12.5 (-66.7 %) at 12 months. The authors concluded that these pilot data indicated that uterine fibroid cryoablation is a safe and effective minimally invasive alternative to treat symptomatic uterine fibroids. These preliminary findings need to be validated by well-designed studies.
Radiofrequency Ablation
Bergamin et al (2005) evaluated the feasibility and effectiveness of laparoscopic radiofrequency ablation (RFA) of uterine fibroids. A total of 18 women with symptomatic intramural uterine myomas underwent RFA under laparoscopic guidance. Post-operative sonographic evaluations of the fibroids size were scheduled at 1, 3, 6 , 9, and 12 months. The impact of myoma-related symptoms on quality of life (QOL) was assessed using a validated questionnaire. The median number of myomas treated per patient was 1 (1 to 3). The median baseline volume of the dominant myoma was 67.2 cm 3 (14.8 to 332.8). No intra-operative or post-operative complications occurred. The median reductions in myomas volume were 41.5 %, 59 %, and 77 % at 1, 3, and 6-months, follow-up evaluation, respectively. No further change in fibroid size was observed at 9 months and 1 year. A significant improvement in the symptoms score and QOL score was observed at 3 and 6 months, follow-up. The authors concluded that in this pilot study, laparoscopic RFA successfully reduced fibroid symptoms and fibroid volume in short-term follow-up. Moreover, they stated that additional studies are needed before its safety and effectiveness can be confirmed.
Milic et al (2006) reported the findings of 4 patients (with symptomatic uterine fibroids measuring less than 6 cm) who underwent laparoscopic ultrasound-guided RFA using multi-probe array electrodes. Follow-up of the treated fibroids was performed with gadolinium-enhanced MRI and patients' symptoms were assessed by telephone interviews. The procedure was initially technically successful in 3 of the 4 patients and MRI studies at 1 month demonstrated complete fibroid ablation. Symptom improvement, including a decrease in menstrual bleeding and pain, was achieved in 2 patients at 3 months. At 7 months, 1 of these 2 patients experienced symptom worsening that correlated with recurrent fibroid on MRI. The third, initially technically successfully treated patient did not experience any symptom relief after the procedure and was ultimately diagnosed with adenomyosis. The authors concluded that these preliminary findings suggested that RFA is a technically feasible treatment for symptomatic uterine fibroids in appropriately selected patients.
Guido et al (2013) stated that although most myomas are asymptomatic, quality of life is compromised for many women with uterine fibroid disease. Twelve-month outcomes from the Halt Trial have been reported in the literature. These researchers analyzed the clinical success of radiofrequency volumetric thermal ablation (RFVTA) of symptomatic uterine fibroids at 2 years of follow-up. A prospective, multi-center, outpatient interventional clinical trial of fibroid treatment by RFVTA in 124 premenopausal women (mean age of 42.4 ± 4.4 years) with symptomatic uterine fibroids and objectively confirmed heavy menstrual bleeding (greater than or equal to 160 to less than or equal to 500 ml). Outcome measures included: subject responses to validated questionnaires, treatment-emergent adverse events, and surgical re-intervention for fibroids at 24 months post-procedure. Continuous and categorical variables were summarized using descriptive statistics and means and percentages. Comparisons between visits were based on t-tests using repeated measures models. P-values < 0.05, adjusted for multiplicity, were statistically significant. A total of 112 subjects were followed through 24 months. Change in symptom severity from baseline was -35.7 (95 % confidence interval [CI]: -40.1 to -31.4; p < 0.001). Change in health-related quality of life (HRQL) was 40.9 (95 % CI: 36.2 to 45.6; p < 0.001). HRQL sub-scores also improved significantly from baseline to 24 months in all categories (concern, activities, energy/mood, control, self-consciousness, and sexual function) [p < 0.001]. Six patients underwent surgical re-intervention for fibroid-related bleeding between 12 and 24 months providing a re-intervention rate of 4.8 % (6/124). The authors concluded that radiofrequency volumetric thermal ablation of myomas significantly reduces symptom severity and improves quality of life with low surgical re-intervention through 24 months of follow-up.
Robles et al (2013) confirmed the results of an earlier study assessing the safety and effectiveness of a laparoscopic RFVTA system among women with symptomatic myomas. In a prospective study at the Hospital of Francisco Marroquin University, Guatemala City, consecutive pre-menopausal women with symptomatic myomas seeking uterine-sparing treatment were enrolled between August 2008 and July 2011. The women were treated by RFVTA. Uterine fibroid symptom and health-related quality-of-life (UFS-QOL) questionnaires were completed at 0, 3, 6, and 12 months. Among 114 women screened, 36 were enrolled (ages 33 to 51 years), and 35 were followed for 12 months. Symptom severity scores reduced significantly (p < 0.05): baseline (63.3), 3 months (23.1), 6 months (15.4), 12 months (9.6). Health-related quality-of-life scores improved significantly (p < 0.05): baseline (37.3), 3 months (79.9), 6 months (85.1), and 12 months (87.7). The mean ± SD difference in uterine volume from baseline (215.2 ± 117.9 cm(3)) to 12 months (167.0 ± 120.8 cm(3)) was 48.2 cm(3) (95 % CI: -22.8 to 119.2; p = 0.192). Nine adverse events among 8 individuals were minor and unrelated to the procedure. The authors concluded that RFVTA of fibroids resulted in significantly improved symptom severity and quality-of-life scores and provides an outpatient uterine-sparing option for treatment of myomas.
Chudnoff et al (2013) examined the safety and effectiveness of laparoscopic ultrasound-guided RFVTA of uterine myomas in symptomatic women. A cohort of 135 pre-menopausal symptomatic women with uterine myomas, uteri 14 weeks of gestation-sized or less with no single myoma exceeding 7 cm, and objectively confirmed heavy menstrual bleeding participated in this prospective, international trial of outpatient laparoscopic ultrasound-guided RFVTA. Bleeding outcomes were measured by alkaline hematin analysis at baseline and again at 3, 6, and 12 months post-treatment. Validated QOL and patient satisfaction scales and objective measurements of uterine and myoma volume were conducted at 3, 6, and 12 months. The mean baseline menstrual blood loss of women in the full analysis set (n=127) was 272.7 ± 82.3 ml. At 3-, 6-, and 12-month follow-ups, mean alkaline hematin and associated menstrual blood loss decreased from baseline levels by 31.8 %, 40.7 %, and 38.3 %, respectively (p < 0.001, paired t test). Symptom severity decreased from a baseline mean transformed score of 61.1 to 26.6 at 12 months post-procedure (p < 0.001, paired t-test). Health-related QOL improved from a mean transformed score of 37.3 at baseline to 79.5 at 12 months (p < 0.001, paired t-test). At 12 months post-procedure, total mean myoma volume decreased from baseline by 45.1 % (measured by magnetic resonance imaging). There was 1 serious adverse event (1 of 135 [0.7 %]) requiring re-admission 5 weeks post-procedure and 1 surgical re-intervention for persistent bleeding; 94 % of the women reported satisfaction with the treatment. The authors concluded that RFVTA of myomas is well-tolerated and results in rapid recovery, high patient satisfaction, improved quality of life, and effective symptom relief.
Berman and colleagues (2014) found that radiofrequency volumetric thermal ablation of uterine fibroids resulted in sustained relief from fibroid symptoms and continued improvement in health-related quality of life through 36 months postablation. A total of 135 pre-menopausal women (mean age of 42.5 ± 4.6 years; mean BMI of 30.5 ± 6.1) with symptomatic uterine fibroids and objectively confirmed heavy menstrual bleeding (greater than or equal to 160 to less than ofr equal to 500 ml) were enrolled in the study of radiofrequency ablation of uterine fibroids. A totlal of 104 participants were followed prospectively through 36 months after fibroid treatment by RFVTA. For 104 evaluable subjects with 36-month data, change in symptom severity from baseline (60.2 ± 18.8) to 36 months was -32.6 (95 % CI: -37.5 to -27.8; p < 0.001). Health-related quality of life also improved from the baseline value of 39.2 ± 19.2 to 36 months by a change of 38.6 (95 % CI: 33.3 to 43.9; p < 0.001). Patient-reported UFS-QOL subscores showed statistically significant improvement from baseline to 36 months in all categories (concern, activities, energy/mood, control, self-consciousness, and sexual function) [p < 0.001]. For the 104 subjects with 36-month data, mean health state scores (EuroQol 5-Dimension [EQ-5D]) improved from a baseline value of 71.0 ± 19.3 to 86.2 ± 11.7 at 36 months. The cumulative re-intervention rate of 10.4 % (14/135) at 36 months was well below the possible 25 % maximum expected at the beginning of the trial. The investigators concluded that the low re-intervention data through 36 months is a positive outcome for patient well-being.
Brucker et al (2014) reported that radiofrequency volumetric thermal ablation resulted in the treatment of more fibroids, a significantly shorter hospital stay, and less intraoperative blood loss than laparoscopic myomectomy. The investigators reported on a prospective, randomized, single-center study of the outcomes of RFVTA versus laparoscopic myomectomy (LM) for symptomatic uterine fibroids in women who desired uterine conservation. The surgeons were blinded to the treatment until all fibroids had been mapped by laparoscopic ultrasound. The mean hospitalization times were 10.0 ± 5.5 (median of 7.8 [range of 4.2 to 25.5]) hours for the RFVTA group and 29.9 ± 14.2 (median of 22.6 [range of 16.1 to 68.1]) hours for the LM group (p < 0.001, Wilcoxon test). Intra-operative blood loss was 16 ± 9 (median of 20 [range of 0 to 30]) ml for the RFVTA procedures and 51 ± 57 (median of 35 [range of 10 to 300]) ml for the LM procedures. The percentage of fibroids imaged by laparoscopic ultrasound that were treated/excised was 98.6 % for RFVTA and 80.3 % for LM. Two complications were reported: vertigo (n = 1; RFVTA) and port site hematoma (n = 1; LM).
This study had 2 drawbacks. The racial makeup of the participants was homogeneous (100 % white); a more heterogeneous population might have resulted in decreased bias. However, all participants had symptomatic fibroids and their surgeons had extensive experience in LM but no experience with RFVTA prior to training for the study. The lack of long-term data, including pregnancy outcomes. The participants will be followed for 5 years and pregnancy outcomes, symptom improvement, and overall treatment satisfaction will be evaluated on the basis of the participants’ responses to validated questionnaires. It should also be noted that the study was sponsored by Halt Medical.
The Society of Obstetricians and Gynaecologists of Canada (SOGC)’s guideline on "Abnormal uterine bleeding in pre-menopausal women" (Singh et al, 2013) states that "Several non-hysteroscopic ablation techniques are currently available. Balloon, microwave, and radiofrequency ablation devices have a large reported clinical experience. One of the main advantages of these techniques is their successful implementation in a surgical suite or clinic setting, which avoids the use of operating room resources and general anaesthetic".
Bradley and co-workers (2019) carried out a systematic review of prospective studies for treatment of uterine fibroids with RFA. Main outcomes were procedure time, patient recovery metrics, change in fibroid volume, SSS, HR-QOL, and re-interventions. Data were analyzed with random effects meta-analysis and meta-regression. These researchers identified 32 articles of 1,283 unique patients (median age of 42 years) treated with laparoscopic RFA (19 articles), transvaginal RFA (8 articles), or TFA (5 articles). Mean procedure time was 49 mins, time-to-discharge was 8.2 hours, time-to-normal activities was 5.2 days, and time-to-return to work was 5.1 days. At 12 months follow-up, fibroid volume decreased by 66 %, HR-QOL increased by 39 points, and SSS decreased by 42 points (all p < 0.001 versus baseline). The annual cumulative rate of re-interventions due to fibroid-related symptoms was 4.2 %, 8.2 %, and 11.5 % through 3 years. The authors concluded that RFA of uterine fibroids significantly reduced fibroid volume, provided significant durable improvements in fibroid-related QOL, and was associated with favorable re-intervention rates.
The authors stated that there were several drawbacks pertaining to the quality of the included studies that may influence conclusions. First, there was less precision in the RFA results following 12 months of follow-up since fewer studies reported longer term data. Second, the number of included studies was insufficient to perform statistical comparisons among RFA delivery approaches for several outcomes. In these cases where these investigators reported the results descriptively, it was plausible that clinically important differences in patient outcomes existed among RFA delivery approaches that were not detectable in this meta-analysis due to insufficient statistical power. More importantly, since the comparative RFA outcomes reported in this study were derived from different studies and analyzed through meta-regression, the post-hoc results should be considered hypothesis-generating only. Third, it was not possible to determine from this analysis whether RFA efficacy was influenced by fibroid type or volume due to concerns of aggregation bias whereby real associations observed at the patient level (e.g., fibroid volume in each patient) often did not agree with those observed at the study level (e.g., mean fibroid volume in each study). Finally, these researchers planned to report the frequency of complications in this meta-analysis; however, complication reporting was highly inconsistent and inadequate such that any attempts at reporting these data would have led to inaccurate and misleading results. For example, most studies provided no criteria or definitions regarding complication reporting. Furthermore, several studies simply reported that no complications occurred without any further commentary. Regardless, no serious procedural complications such as death or iatrogenic injury to the bowel, bladder, or ureter were reported in any study. These investigators stated that authors of future RFA studies are encouraged to provide detailed definitions of complications and a complete listing of reported complications during follow-up, with further specification of event seriousness and relationship to the RFA procedure.
Power Morcellation
Laparoscopic power morcellators are medical devices used during different types of minimally invasive surgeries (FDA, 2014). These can include certain procedures to treat uterine fibroids (e.g., hysterectomy and myomectomy). Morcellation refers to the division of tissue into smaller pieces or fragments and is often used during laparoscopic surgeries to facilitate the removal of tissue through small incision sites. Recent clinical information suggested that laparoscopic power morcellation poses a risk of spreading unsuspected cancerous tissue (e.g., uterine sarcomas) to travel beyond the uterus (FDA, 2014).
In April 2014, the U.S. Food and Drug Administration (FDA, 2014) issued a warning about laparoscopic power morcellators because of this risk of spreading cancer. The FDA estimates that 1 in 350 women undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma. The FDA discouraged the use of laparoscopic power morcellation of uterine fibroids since no reliable method exists to predict whether a woman’s uterine fibroid may have sarcoma and with the risk of spreading possible cancerous tissue within the abdomen and pelvis.
In July 2014, a morcellation device manufacturer (Ethicon, Inc.) instituted a recall on all its morcellation devices (including generators and disposables product codes MX0100, MX0200, MX0100R, MX0200R, DV0015, DV0025, MD0100, MD0200, MD0140, MD0120), citing uncertainty in the risk-benefit assessment associated with the use of power morcellators.
In November 2014, the FDA issued an updated warning on the use of laparoscopic power morcellators (FDA, 2014). The FDA warned against using laparoscopic power morcellators in the majority of women undergoing hysterectomy or myomectomy for uterine fibroids. The FDA stated: "Health care providers and patients should carefully consider available alternative treatment options for the removal of symptomatic uterine fibroids. Limiting the patients for whom laparoscopic morcellators are indicated, the strong warning on the risk of spreading unsuspected cancer, and the recommendation that doctors share this information directly with their patients, are part of FDA guidance to manufacturers of morcellators. The guidance strongly urges these manufacturers to include this new information in their product labels".
The FDA (2014) concluded that laparoscopic power morcellation is contraindicated in women who are peri- or post-menopausal; women who are candidates for alternative surgical procedures that would allow en bloc tissue removal of uterine tissue such as through the vagina route or through mini-laparotomy incision; and women with known or suspected uterine malignancy. The FDA suggests that morcellation may continue to be an acceptable therapeutic option for a small group of women, which might include some younger women not yet peri-menopausal who wish to keep their uterus and maintain their fertility after being informed of the risks.
Some investigators have suggested that the use of an intraperitoneal bag during morcellation may be helpful in reducing intraperitoneal tissue dissemination. However, power morcellation within a bag is not well studied and has several limitations that potentially increase the risk of the procedure (ACOG, 2014).
An UpToDate review on "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas" (Stewart, 2015) states: "Surgical techniques that disrupt the uterine specimen (scalpel or power morcellation, supracervical hysterectomy) should NOT be performed in women with known or suspected uterine or other gynecologic cancer. We recommend NOT using power morcellation of uterine tissue for women who have significant risk factors for uterine sarcoma (e.g., postmenopausal status, history of ≥2 years of tamoxifen therapy, history of pelvic irradiation, history of childhood retinoblastoma, or personal history of hereditary leiomyomatosis and renal cell carcinoma [HLRCC] syndrome). For premenopausal women with uterine fibroids and no significant uterine sarcoma risk factors, based upon appropriate counseling regarding risks and benefits of morcellation versus laparotomy, the patient can then make an informed choice regarding the surgical approach".
Bogani and colleagues (2015) reviewed the current evidence on the effects of intra-abdominal morcellation on survival outcomes of patients affected by unexpected uterine leiomyosarcoma (ULMS) and estimated the risk of recurrence in those patients. PubMed (MEDLINE), Scopus, Embase, Web of Science databases as well as ClinicalTrails.gov, were searched for data evaluating the effects of intra-abdominal morcellation on survival outcomes of patients with undiagnosed ULMS. Studies were evaluated per the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) and the ACOG guidelines. A total of 60 manuscripts were screened, 11 (18 %) were selected and 4 (7 %) were included. Overall, 202 patients were included: 75 (37 %) patients had morcellation of ULMS, while 127 (63 %) patients had not. A meta-analysis of these studies showed that morcellation increased the overall (62 % versus 39 %; odds ration [OR]: 3.16 (95% CI: 1.38 to 7.26)) and intra-abdominal (39 % versus 9 %; OR: 4.11 (95 % CI: 1.92 to 8.81)) recurrence rates as well as death rate (48 % versus 29 %; OR: 2.42 (95 % CI: 1.19 to 4.92)). No between-group difference in cumulative extra-abdominal recurrence (OR: 0.34 (95 % CI: 0.07 to 1.59)) rate was observed. The authors concluded that these findings support a significant correlation between uterine morcellation and an increased risk of intra-abdominal recurrence in patients affected by unexpected ULMS. However, they stated that the limited data on this issue and the absence of high level of evidence suggest the need of further studies designed to estimate the risk to benefit ratio of morcellation in patients with uterine fibroids and undiagnosed ULMS.
In December 2017, the FDA confirmed that power morcellation used for laparoscopic myomectomy or hysterectomy for uterine fibroids is associated with increased risk for spreading cancer. The review was the first undertaken since its 2014 safety communication warning of the risk. In an analysis of 23 recent studies, the prevalence of undiagnosed uterine sarcoma during myomectomy or hysterectomy for presumed fibroids was 1 in 225 to 1 in 580, and that of leiomyosarcoma was 1 in 495 to 1 in 1,100. These figures were similar to the FDA's 2014 estimates. The prevalence increases with age – occult sarcoma prevalence reached 2 % to 3 % for women over age 60. In addition, overall survival (OS) and disease-free survival (DFS) were lower with morcellator use. The report concluded that "While minimally invasive surgery conveys several significant advantages over open surgery for women with fibroids, the use of laparoscopic power morcellators during these surgeries poses a risk due to the potential presence of unsuspected sarcoma in this population. FDA continues to caution against the use of LPMs in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids".
The American College of Obstetricians and Gynecologists’ Committee Opinion on “Uterine Morcellation for Presumed Leiomyomas” (ACOG, 2021) stated that morcellation is a surgical technique employed to decrease the size of the uterus or myomas by creating smaller pieces to allow the tissue to be removed via small incisions or with laparoscopic instruments. Open (uncontained) morcellation of the uterus and myomas has been scrutinized because of the possible spread of an unsuspected leiomyosarcoma while using a power morcellator during a hysterectomy or myomectomy for presumed symptomatic uterine leiomyomas. Prior to considering morcellation of the uterus, a woman should be examined to determine if she is at increased risk of malignancy of the uterine corpus. Morcellation of a malignancy is contraindicated and women should be evaluated pre-operatively to identify malignancy. However, leiomyosarcoma cannot be reliably diagnosed pre-operatively; therefore, there is a risk that a woman with a presumed leiomyoma may have a malignancy that may be spread via morcellation, leading to a potentially worsened prognosis. The Committee noted that although an abdominal hysterectomy or myomectomy may reduce the chance of spreading cancer cells in women with undiagnosed leiomyosarcoma, it is associated with increased morbidity when compared with minimally invasive approaches. The obstetrician-gynecologist and patient should engage in shared decision-making, including informed consent, explaining the risks and benefits of each approach to surgery for presumed leiomyomas, the risks and benefits of morcellation, and alternatives to morcellation.
Ultrasound-Guided Trans-Cervical Ablation
In a prospective, multi-center, single-arm, interventional trial, Chudnoff and colleagues (2019) examined the 12-month safety and effectiveness of transcervical ablation for the treatment of symptomatic uterine leiomyomas. Transcervical ablation was performed on 1 to 10 leiomyomas per patient with leiomyoma diameters ranging from 1 to 5 cm. Treated leiomyomas included all non-pedunculated types. Co-primary end-points assessed at 12 months were reduction in menstrual blood loss and absence of surgical re-intervention. Additional assessments included symptom severity, quality of life (QOL), patient satisfaction, reductions in uterine and leiomyoma volumes, and safety. A total of 147 patients were enrolled and treated in the U.S. and Mexico. The study met its co-primary end-points at 12 months (n = 143; full analysis set), because 64.8 % of patients (95 % confidence interval [CI]: 56.3 to 72.6 %) experienced 50 % or greater reduction in menstrual bleeding and 99.3 % of patients (95 % CI: 95.1 to 99.9 %) were free from surgical re-intervention. 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 < 0.001), and 95.1 % of patients experienced a reduction in menstrual bleeding at 12 months. There were significant mean improvements in symptom severity and health-related QOL (HR-QOL) of 32.1 points and 43.7 points, respectively, at 12 months (all p < 0.001). Mean maximal leiomyoma volume reduction per patient was 62.4 % (p < 0.001). More than 50 % of patients returned to normal activity within 1 day, 96.3 % of patients reported symptom improvement at 12 months, and 97 % expressed satisfaction with the treatment at 12 months. There were no device-related adverse events (AEs). The authors concluded that transcervical ablation was associated with a significant reduction in leiomyoma symptoms with no device-related AEs and a low surgical re-intervention rate through 12 months, demonstrating its potential to safely and effectively treat all non-pedunculated leiomyoma types through a uterus-conserving, incisionless approach.
The authors stated that drawbacks of this study included a non-randomized design, a limit of 5 cm, and the exclusion of patients who desired fertility. Although not randomized, this study was a multi-center, interventional trial with prospectively defined end-points having set objective performance criteria. Well-designed interventional trials can provide compelling evidence for the effectiveness of a treatment. This 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 re-intervention and bleeding primary end-points. Maximum leiomyoma diameter was limited to 5 cm in this trial. 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 this trial, 64 leiomyomas (14.5 %) were treated with at least 2 ablations. Patients who desired fertility were excluded as a result of ethical reasons because this trial was a pivotal safety and effectiveness study. This enriched the eligible population for older patients and minimized the ability to track perinatal and post-partum outcomes. However, the study included 3-year follow-up of patients and the reporting of any pregnancy outcomes should they occur. In addition, a world-wide clinical registry characterizing the long-term outcomes with transcervical leiomyoma ablation out to 5 years is ongoing.
In a retrospective, single-arm, long-term data-collection study, Garza-Leal (2019) examined the long-term (greater than 5 years) clinical outcomes of transcervical radiofrequency ablation of uterine fibroids. A total of 23 women with heavy menstrual bleeding secondary to fibroids were treated with transcervical radiofrequency ablation guided by integrated intra-uterine sonography (using the Sonata System, Gynesonics, Redwood City, CA). This study was within the 12-month Fibroid Ablation Study-EU clinical trial in Mexico. Symptoms were assessed using the Uterine Fibroid Symptom and QOL’s Symptom Severity Score (SSS) and HR-QOL subscales. Patients were queried regarding pregnancy and surgical re-interventions. A total of 17 women (73.9 %) provided long-term follow-up information, with a mean of 64.4 months ± 4.5 months (range of 57 to 73 months). From baseline, mean SSS decreased significantly from 64.9 ± 16.9 to 27.6 ± 36.1, and mean HR-QOL improved significantly from 27.2 ± 22.4 to 76.0 ± 32.6 (p = 0.002, and p = 0.0001, respectively). There were no surgical re-interventions through the first 3.5 years post-treatment. There was an 11.8 % incidence of surgical re-interventions over 5.4 years of average follow-up, with 2 hysterectomies occurring after 3.5 and 4 years post-ablation, respectively (event rate: 2.2 % per year; 95 % CI: 0.3 % to 7.9 %). Freedom from surgical re-intervention at 1, 2, and 3 years was 100 %, and, at 4 and 5 years, was 88.2 % ± 7.8 %. There was a single pregnancy occurring within the 1st year of treatment leading to a normal-term delivery by elective repeat cesarean section. The authors concluded that transcervical radiofrequency ablation with the Sonata System produced substantial durable clinical benefits beyond 5 years with a low re-intervention rate. This was a retrospective study with small sample size (only 17 out of 23 provided long-term data).
Brooks et al (2020) noted that the INSPIRE study compared peri-operative and 12-month health economic and clinical outcomes associated with hysterectomy, myomectomy, and sonography-guided transcervical fibroid ablation (TFA) using the Sonata system. Cost and health care resource utilization (HCRU) data for TFA were obtained from a prospective, multi-center, single-arm clinical trial. Data for hysterectomy and myomectomy arms were derived from the Truven Health MarketScan commercial payer claims data-base. The Truven data was used to determine health economic outcomes and costs for the hysterectomy and myomectomy arms. For each arm, payer perspective costs were estimated from the available charge and HCRU data. TFA with Sonata had significantly lower mean length of stay (LOS) of 5 hours versus hysterectomy (73 hours) or myomectomy (79 hours; all p < 0.001). The average payer cost for TFA treatment, including the associated post-operative HCRU was $8,941. This was significantly lower compared to hysterectomy ($24,156) and myomectomy ($22,784; all p < 0.001). In the TFA arm, there were no device- or procedure-related costs associated with complications during the peri- or post-operative time frame. TFA subjects had significantly lower costs associated with complications, prescription medications, and radiology. The authors concluded that compared to hysterectomy and myomectomy, TFA treatment with the Sonata system was associated with significantly lower index procedure cost, complication cost, and LOS, contributing to a lower total payer cost through 12 months. These researchers stated that this study had several drawbacks. Because Sonata payment data were obtained from a subset of sites that participated in the clinical trial, the sample size was small. Also, as described previously, several assumptions had to be made about payments.
Lukes and Green (2020) reported on 3-year clinical outcomes of the SONATA pivotal trial of TFA in women with symptomatic uterine myomata. This prospective, controlled, multi-center, interventional trial enrolled 147 pre-menopausal women with symptomatic uterine fibroids who underwent uterus-preserving, US-guided TFA with the Sonata System. Clinical outcomes were examined over 3 years and included surgical re-interventions, SSS, and HR-QOL subscales of the Uterine Fibroid Symptom and QOL Questionnaire, EQ-5D questionnaire, overall treatment effect, treatment satisfaction, physical activity, work impairment, pregnancy outcomes, and AEs. The 3-year rates of surgical re-intervention for heavy menstrual bleeding calculated by the binomial and Kaplan–Meier methods were 9.2 % and 8.2 %, respectively. Compared to baseline, mean SSS decreased from 55 ± 19 to 22 ± 21, HR-QOL increased from 40 ± 21 to 83 ± 23, and EQ-5D increased from 0.72 ± 0.21 to 0.88 ± 0.16 (all p < 0.001). Treatment benefit on the SSS, HR-QOL, and EQ-5Q exceeded the minimal clinically important difference at every follow-up visit over 3 years. At 3 years, 94 % of the subjects reported treatment satisfaction, 88 % reported reduced fibroid symptoms, work absenteeism due to fibroid symptoms decreased from 2.9 % to 1.4 %, and impairment due to fibroids decreased from 51 % to 12 % for work, and 58 % to 14 % for physical activity (all p < 0.001); and no late complications occurred. The authors concluded that women treated with US-guided TFA in the SONATA pivotal trial experienced significant and durable reduction of fibroid-related symptoms, with low surgical re-intervention rates over 3 years of follow-up. Moreover, these researchers stated that additional long-term data with the Sonata System will be available from the SAGE registry (ClinicalTrials.gov Identifier: NCT03118037), a worldwide observational post-market study trial with goal of characterizing long-term (5 years) outcomes after treatment of uterine fibroids with the Sonata System in real-world clinical practice settings.
Roy et al (2021) reported on the quality-adjusted life years (QALYs) over 3 years after transcervical fibroid ablation (TFA) with the Sonata System in subjects included in the SONATA trial. Change in generic health status was assessed with the EuroQol 5-Dimension questionnaire (0–1 scale). Fibroid-specific quality of life (QOL) was measured on a 0 to 100 scale with the health-related quality of life subscale of the Uterine Fibroid Symptom and Quality-of-Life (UFS-QOL). The number of QALYs gained relative to baseline and cumulative QALYs were calculated using the area under the curve at each follow-up visit over 3 years. Among 147 women receiving TFA, fibroid-specific QOL increased from 40 – 21 at baseline to 84 – 19 at 1 year and 83 – 23 at 3 years ( p < 0.001). Generic QOL increased from 0.72 – 0.21 at baseline to 0.89 – 0.12 at 1 year and 0.88 – 0.16 at 3 years ( p < 0.001). Over 3 years, TFA resulted in 1.24 – 0.64 QALYs gained when using fibroid-specific health utility scores and 0.49 – 0.61 QALYs gained when using generic health utility scores. Cumulative QALYs experienced at 3 years as a percentage of perfect health were 82% with fibroid-specific scores and 88% with generic health scores. The investigatord concluded that women treated by TFA with the Sonata System for symptomatic uterine fibroids reported durable improvements in generic and fibroid-specific QOL, as well as clinically meaningful increases in QALYs over 3 years.
Piriyev and colleagues (2022) stated that fibroids are the most common benign uterine tumors. Transcervical RFA with the Sonata System offers a minimally invasive, incision-free, organ-preserving therapy, with intra-operative visualization of fibroids using intra-uterine US guidance. In a retrospective analysis, these researchers examined the effectiveness of transcervical RFA of fibroids that are 5 cm or larger using the Sonata System. A total of 151 patients have been treated with this method in the authors’ department up to the time of this analysis. Only patients with at least 1 fibroid of greater than or equal to 5 cm and with bleeding symptoms, who were treated with the Sonata System were included in this trial. A total of 50 patients were included in the study. A total of 57 fibroids were detected and treated; however, International Federation of Gynecology and Obstetrics (FIGO) 1 and 2 fibroids (a total 3 fibroids) were excluded. The smallest fibroid was 4 cm; and the largest fibroid was 12 cm. A single ablation was carried out in 18 cases, 2 ablation steps in 16 cases, 3 ablation steps in 13 cases, and more than 3 ablation steps in 3 cases. Depending on ablation steps, the shortest ablation time was 3 mins and 15 secs; and the longest ablation time was 25 mins and 6 secs, with an average time of 9 mins and 12 secs; 86 % of patients reported an improvement of symptoms. The authors concluded that the Sonata System is a simple, minimally invasive, rapid and successful method that showed significant improvement of symptoms even in large myomas from 5 cm or larger. This was a retrospective study with a relatively small sample size (n = 50 patients), and it did not furnish any data regarding the durability of transcervical RFA in providing meaningful relief from uterine fibroid symptoms. These preliminary findings need to be validated by well-designed studies.
Arnreiter and Oppelt (2021) conducted a systematic evidence review to evaluate the treatment success, possible side effects, and safety of radiofrequency ablation with the Sonata System. An electronic literature search in the PubMed and Medline databases was carried out from inception to August 2020. The review was performed in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Keywords such as "Sonata," "transcervical ablation," and "uterine myoma" were used to identify all relevant articles independently by both authors. Full-text articles in English that reported at least 1 of the following outcomes were included in the study: reduction in perfused/total myoma volume, effect of treatment on bleeding intensity and myoma-related symptoms, number of surgical reinterventions, adverse events, return to activities of daily life, effects on surrounding tissue, and safety during pregnancy. Ten studies matching the inclusion criteria were identified and used for further analysis. A reduction in total and perfused myoma volume of 63.2% and 64.5% was achieved. One of the studies showed a 53.8 ± 50.5% (n = 48) reduction in Menstrual Pictogram Score, and another study showed a 51.1 ± 40.9% (n = 142) reduction in Pictorial Blood Loss Assessment Chart at 12 months. 87.2% (n = 190) of the patients reported a clinically meaningful reduction in menstrual blood loss after 12 months. While Symptom Severity Scores dropped by 28.8 ± 19.3, 23.3 ± 23.7, and 23.7 ± 19.4 points at 3, 6, and 12 months, respectively, Health-Related Quality of Life Scores increased to 77.5 ± 22.0, 82.8 ± 19.0, and 83.3 ± 20.5 points. One study had an 8% reintervention rate after 12 months, and another study showed a 0.7% and 5.2% rate after 12 and 24 months. After an average of 64 months after ablation, the reintervention rate was 11.8%. Time to return to activities of daily life was 2.9 ± 2.5 days. No related complications during pregnancy and delivery were reported. The authors concluded that radiofrequency ablation with the Sonata System represents a minimally invasive, organ-preserving treatment option in patients with symptomatic uterine myomas, associated with clinically meaningful improvement of myoma-related symptoms.
Christoffel, et al. (2021) described the SAGE registry, which characterizes the long-term (5-year) outcomes of TFA when used to treat symptomatic uterine fibroids in real-world usage. The authors explained that SAGE is an ongoing postmarket global registry involving up to 50 sites and up to 500 women who select TFA with the Sonata system for treatment of symptomatic uterine fibroids. Patients are followed for 5 years. Main outcomes include symptom severity score and health-related quality of life subscales of the UFS-QoL, general health status on the EQ-5D, perceived treatment benefit, treatment satisfaction, work and activity patterns, overall patient treatment outcome, adverse events, pregnancy incidence and outcomes, and surgical reinterventions for heavy menstrual bleeding. The authors said that the SAGE registry represents the largest known study of TFA for uterine fibroids and will generate up to 2500 patient-years of outcome data. Preliminary results from the first 160 treated women suggest broad applicability of TFA to a wide range of fibroid types and sizes and an excellent safety profile, with a device-related adverse event rate of 0.6% and a serious procedure-related adverse event rate of 0.6%. Of the 241 fibroids treated, 10% were submucous, 52% transmural, 28% intramural, and 10% subserous. Ablated fibroid diameters ranged from <1 cm to >10 cm, with 27% of fibroids having maximum diameters >5 cm. The authors said that the real-world experience from SAGE will strengthen the existing evidence on the durability of TFA in providing meaningful relief from uterine fibroid symptoms and will have important clinical and economic implications for patients, physicians, and healthcare payers.
Lindner, et al. (2022) reported on updated evidence related to transcervical fibroid ablation (TFA) with the Sonata System. An additional 27 papers representing over 400 women and more than 800 treated fibroids have been published. Lindner, et al. stated that these demonstrate consistent, positive results, representing multiple prospective clinical trials, subgroup analyses, health economic analyses, case series, and systematic reviews of TFA. These include a 147-patient prospective clinical trial of TFA (the SONATA Clinical Trial) that demonstrated sustained symptom relief and an 8.2% cumulative reintervention rate through 3 years, a long-term study (VITALITY) confirming durable symptom relief with an 11.8% reintervention rate over > 5 years of mean follow-up, a clinical trial (OPEN) suggesting minimal potential for intrauterine adhesiogenesis post-TFA, preliminary results of a global registry (SAGE), and two subgroup analyses of TFA reporting favorable and safe outcomes in women with large fibroids > 5 cm in diameter. Three comparative health economic studies demonstrate favorable economic outcomes against both myomectomy and hysterectomy. A recent ACOG Practice Bulletin also noted equivalent outcomes for transcervical, laparoscopic, and transvaginal fibroid ablation. The authors concluded that accumulated clinical evidence, including systematic reviews and longitudinal prospective clinical trials, continues to confirm the safety and efficacy of TFA in women with symptomatic fibroids, including myomata > 5 cm. As a transcervical treatment modality that can safely address all nonpedunculated uterine fibroid types, the continued evidence base confirms TFA as an innovative and useful treatment option that meets a significant unmet clinical need, including among underserved populations, delivering significant durable reductions in fibroid symptoms.
A Decision Support Document from the Ludwig Boltzmann Institut for Health Technology Assessment (Lambert & Strohmaier, 2020) concluded: "No comparative studies were identified in the course of the search strategy. The study pool for the evaluation of evidence consisted of three prospective single-arm studies (234 patients), which were published in seven publications. The quality of the evidence regarding efficacy and safety was rated as low or very low for all relevant endpoints. . . . Due to the low quality of the evidence, comparative studies of TFA in symptomatic myomas are necessary in order to make a reliable statement regarding clinical efficacy and safety."
Guidelines on uterine leiomyomas from the American College of Obstetricians and Gynecologists (ACOG, 2021) states: "Radiofrequency ablation (RFA) can be delivered by a laparoscopic, transvaginal, or transcervical approach, using ultrasound guidance to induce coagulative necrosis in targeted uterine leiomyomas. All of the approaches are similarly effective in reducing uterine leiomyoma volume and in improving quality of life metrics, but the laparoscopic approach has been studied the most rigorously." The guideline's Summary of Recommendations states: "Laparoscopic radiofrequency ablation can be considered as a minimally invasive treatment option for the management of symptomatic leiomyomas in patients who desire uterine preservation and are counseled about the limited available data on reproductive outcomes" (emphasis added).
Guidance from the National Institute for Health and Care Excellence (NICE, 2021) concluded: "Evidence on the safety of transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids raises no major safety concerns. However, evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research."
A companion NICE Medtech Innovation Briefing on the Sonata System (NICE, 2021) reported: "Key uncertainties around the evidence or technology are that there is no long-term clinical outcomes data directly comparing the technology with standard care. Also, the efficacy of the technology in people who want to have children in the future is uncertain."
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Laparoscopic Power Morcellation
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