Laparoscopic, Percutaneous and Transcervical Techniques for Uterine Fibroids Myolysis - CAM 40119

Description:
Various minimally invasive treatments for uterine fibroids have been proposed as alternatives to surgery. Among these approaches are laparoscopic ,percutaneous, and transcervical techniques to induce myolysis, which includes radiofrequency ablation (RFA), laser and bipolar needles, cryomyolysis, and magnetic resonance imaging-guided laser ablation.

Background
Uterine Fibroids
Uterine fibroids, also known as leiomyomas, are among the most common conditions affecting women in their reproductive years; symptoms include menorrhagia, pelvic pressure, or pain. It is estimated that uterine fibroids occur in up to 70% of women by menopause, with approximately 25% of these being clinically significant and requiring intervention.¹ The prevalence rate of uterine fibroids is 2 – 3 times higher among Black women compared with White women, and there are higher rates of hysterectomy and myomectomy compared with non-surgical therapy, potentially demonstrating a disparity in access to uterine-sparing interventions.^2,3

Treatment
Surgery, including hysterectomy and various myomectomy procedures, is considered the criterion standard for symptom resolution. However, there is the potential for surgical complications and, in the case of a hysterectomy, the uterus is not preserved. In addition, multiple myomectomies may be associated with longer operating time, postoperative febrile morbidity, and development of pelvic adhesions. There has been long-standing research interest in developing minimally invasive alternatives for treating uterine fibroids, including procedures that retain the uterus and permit future childbearing. Treatment options include uterine artery embolization and transcutaneous magnetic resonance imaging-guided focused ultrasound therapy (see evidence review 7.01.109). Various techniques to induce myolysis have also been studied including Nd:YAG lasers, bipolar electrodes, cryomyolysis, and radiofrequency ablation. With these techniques, an energy source is used to create areas of necrosis within uterine fibroids, reducing their volume and thus relieving symptoms. Early methods involved multiple insertions of probes into the fibroid, performed without imaging guidance. There were concerns about serosal injury and abdominopelvic adhesions with these techniques, possibly due to the multiple passes through the serosa needed to treat a single fibroid.⁴ Newer systems using radiofrequency energy do not require repetitive insertions of needle electrodes. Ultrasonography is used laparoscopically or transcervically to determine the size and location of fibroids, to guide the probe, and to ensure the probe is in the correct location so that optimal energy is applied to the fibroid. Percutaneous approaches using magnetic resonance imaging guidance have also been reported.

Regulatory Status
In 2012, the Acessa™ System (Acessa Health, formerly Halt Medical) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for percutaneous laparoscopic coagulation and ablation of soft tissue and treatment of symptomatic uterine fibroids under laparoscopic ultrasound guidance (K121858). The technology was previously approved in 2010, at which time it was called the Halt 2000GI™ Electrosurgical Radiofrequency Ablation System. In 2014, the ultrasound guidance system received marketing clearance from the FDA (K132744). FDA product code: GEI. In 2018, the third-generation Acessa™ ProVu System^® was cleared for marketing by the FDA through the 510(k) process for use in percutaneous, laparoscopic coagulation and ablation of soft tissue, including treatment of symptomatic uterine fibroids under laparoscopic ultrasound guidance. (K181124). Hologic acquired Accessa Health in 2020. FDA product code: HFG.

In 2018, the Sonata^® Sonography-Guided Transcervical Fibroid Ablation System (Gynesonics) was cleared for marketing by the FDA through the 510(k) process for diagnostic intrauterine imaging and transcervical radiofrequency ablation as treatment of symptomatic uterine fibroids (K173703). The Sonata System 2.1 received marketing clearance in 2020 (K193516) and the Sonata System 2.2 received marketing clearance in 2021 (K211535). The Sonata system was previously known as Vizablate. FDA product codes: KNF, ITX, and IYO.

Cryoablation is a surgical procedure that uses previously approved and available cryoablation systems; and as a surgical procedure, it is not subject to regulation by the FDA. Other products addressed in this review (e.g., Nd:YAG lasers, bipolar electrodes) have long-standing FDA approval, and there are no products specifically approved for the treatment of uterine fibroids.

Related Policies:
701109 MRI-Guided Focused Ultrasound (MRqFUS)

Policy:
Laparoscopic or transcervical radiofrequency ablation (RFA) as a treatment of symptomatic uterine fibroids is considered MEDICALLY NECESSARY in women 18 years and older when ALL of the following conditions are met:

Evidence of uterine fibroids via ultrasound that are less than 10 cm in diameter for laparoscopic RFA with Acessa or 7 cm for transcervical RFA with Sonata; AND
Patient desires a uterine-sparing treatment approach or is ineligible for hysterectomy or other uterine-sparing alternatives to RFA (e.g., laparoscopic myomectomy, uterine artery embolization [UAE]) (see Policy Guidelines); AND
Patient has experienced at least 1 of the following symptoms that are a direct result of the fibroid(s):
- Menorrhagia or other abnormal uterine bleeding that interferes with daily activities or causes anemia (see Policy Guidelines);
- Pelvic pain or pressure;
- Urinary symptoms (e.g., urinary frequency, urgency) related to bulk compression of the bladder;
- Gastrointestinal symptoms related to bulk compression of the bowel (e.g., constipation, bloating);
- Dyspareunia (painful or difficult sexual relations).

Other laparoscopic, transcervical, or percutaneous techniques for myolysis of uterine fibroids, including use of laser or bipolar needles, cryomyolysis, and magnetic resonance imaging-guided laser ablation, are investigational/unproven therefore considered NOT MEDCIALLY NECESSARY.

Uterine power or mechanical morcellation in LAPAROSCOPIC HYSTERECTOMY OR LAPAROSCOPIC MYOMECTOMY for the treatment of fibroids are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY. Use of a morcellator should be filed if it was utilized.

Policy Guidelines
Eligibility Considerations
Abnormal uterine bleeding refers to uterine bleeding of abnormal frequency, duration, and volume that interferes with a patient’s quality of life. Patients with abnormal uterine bleeding with an inadequate response to appropriately selected medical therapy may be considered for alternate uterine-sparing interventions. In patients > 45 years of age with menorrhagia or other abnormal bleeding, endometrial biopsy is recommended prior to treatment to rule out endometrial malignancy and/or additional assessment to rule out a risk for uterine leiomyosarcoma.

Clinical trial experience with radiofrequency ablation (RFA) has been limited to patients with overall uterine size ≤ 16 gestational weeks size based on pelvic examination. In patients where fibroids cannot be distinguished from adenomyosis on ultrasound, advanced imaging (e.g., magnetic resonance imaging [MRI]) may be required. For patients with pelvic pain, alternative causes such as endometritis and active pelvic inflammatory disease should be excluded prior to treatment with RFA.

Treatment Approach Considerations for Radiofrequency Ablation
Uterine fibroids are categorized according to the International Federation of Gynaecology and Obstetrics (FIGO) leiomyoma subclassification system (see Table PG1). Choice of laparoscopic versus transcervical RFA treatment is dependent on fibroid number, size, type and location, and patient preferences. For example, predominantly lower uterine segment or cervical leiomyomata, or those with a predominant submucosal location or intramural FIGO type 2 or 3 fibroids, may suggest a transcervical approach, whereas fibroids with largely fundal or extramural components may suggest a laparoscopic approach. Patients aiming to avoid future deliveries via obligate cesarean section may prefer a transcervical approach. Select women with numerous fibroids may benefit from combined laparoscopic RFA and laparoscopic myomectomy. Patients with intramural fibroids, intra-abdominal adhesions, or medical contraindications may not be candidates for alternative uterine-sparing interventions.

Table PG1. FIGO Leiomyoma Subclassification System

Group	Type	Description
Submucosal	0	Pedunculated intracavitary
	1	< 50% intramural (≥50% submucosal)
	2	≥ 50% intramural (<50% submucosal)
Other	3	100% intramural, contacting endometrium
	4	100% intramural, no endometrial or subserosal contact
	5	Subserosal, ≥ 50% intramural
	6	Subserosal, < 50% intramural
	7	Pedunculated subserosal
	8	Non-myometrial location (e.g., cervical, broad ligament, parasitic)
Hybrid	X-X	Both submucosal and subserosal components. Submucosal component designated by first number and subserosal component designated by second number.

FIGO: International Federation of Gynaecology and Obstetrics.
Table adapted from Gomez et al. (2021). MRI-based pictorial review of the FIGO classification system for uterine fibroids. Abdom Radiol. 46(5): 2146-2155. PMID: 33385249.

Reinterventions
Reintervention with RFA may be considered for patients meeting policy criteria with documentation of new or recurrent fibroid development following a partial response with the initial procedure. However, data on reinterventions for new or recurrent fibroids is limited and documentation procedures for repeat anatomic mapping of fibroids are not standardized.

Coding
See the Codes table for details.

In November 2014, the U.S. Food and Drug Administration published a safety communication on laparoscopic power morcellators used for myomectomy and hysterectomy in most women. (Morcellators are not otherwise addressed herein). The Administration recommended that manufacturers of these devices include in their product labels a boxed safety warning and wording on contraindications (see https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM424123.pdf).

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Some of the lysis procedures are specialized and not widely disseminated; therefore, requests for out-of-network referral may occur.

Rationale
This evidence review was created in July 2004 and has been updated regularly with searches of the PubMed database until it was archived in December 2009. In July 2013, the review returned to active status. The most recent literature update was performed through Jan. 3, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Radiofrequency Ablation
Clinical Context and Therapy Purpose
The purpose of radiofrequency ablation (RFA) in women who have uterine fibroids is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in women with uterine fibroids?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is women with symptomatic uterine fibroids.

Interventions
The therapy being considered is laparoscopic or transcervical RFA of fibroids under ultrasonic guidance.

Comparators
The following therapies are currently being used to manage symptomatic uterine fibroids: medical management, uterine artery embolization (UAE), myomectomy, and hysterectomy. Surgery, including hysterectomy and myomectomy, is considered the criterion standard for symptom resolution. However, there is the need to recover from surgery, and in the case of a hysterectomy, the uterus is not preserved. UAE is associated with poor pregnancy outcomes and is not advised in patients who desire to become pregnant.

A retrospective cohort from claims data of over 35,000 women found that of the less invasive procedures, myomectomy had the lowest 12-month reintervention rate (4.2%), followed by UAE (7.0%), and endometrial ablation (12.4%).⁵

Outcomes
The outcomes of interest are complications, postoperative pain and recovery time, symptom resolution, fibroid regrowth or recurrence and need for reintervention at 3 to 5 years, and health-related quality of life. The symptom severity score (SSS) is a 0 to 100 scale where higher SSSs indicate more severe symptoms. The EuroQol 5-Dimension (EQ-5D) is a 0 to 100 scale where lower scores indicate worse quality of life. Reinterventions may involve retreatment with RFA or other uterine-sparing techniques or definitive treatment with hysterectomy.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
Studies identify the relevant commercially available technology.

Review of Evidence
Systematic Reviews
A systematic review and meta-analysis by Sandberg et al. (2018) evaluated the risk of reintervention and quality of life after uterine-sparing interventions for fibroids (see Tables 1 and 2).⁶Reintervention was defined as any additional treatment required at ≥ 1 year after initial treatment owing to symptomatic recurrence of fibroids. Reinterventions directly related to procedure complications and studies enrolling women with a prior history of fibroid interventions were excluded. Risk of reintervention at 12 months was 0.3% for laparoscopic RFA compared with 3.6% for UAE and 1.1% for myomectomy. Symptom severity and quality of life scores were similar for the 3 treatments. Only 1 RFA study was identified on reintervention risk at 36 months (10.4%)which was comparable to UAE (7.4%; 95% Confidence Interval [CI], 0.9 to 10.7%); no RFA studies were identified on reintervention risk at 60 months. At 36 months, the reintervention risk for hysterectomy varied from 0.6% (95% CI, 0 to 2.3%; I2 = 60.2%; 4 studies) for myomectomy to 8.1% for laparoscopic RFA (1 study). A systematic review by Havryliuk et al. (2017) that did not separate outcomes by the length of follow-up found a reintervention rate of 5.2% after RFA (4 studies, 12 to 36 mo follow-up) compared to 4.2% after myomectomy (6 studies, 12 to 52 mo follow-up).⁷ There was no significant difference in complication rates between RFA (6.3%) and myomectomy (7.9%). The length of stay after myomectomy was 2 days (range 0.5 to 6.0). No data were provided on the length of stay after RFA.

Lin et al. (2019) conducted a meta-analysis of improvement in symptom severity, quality of life, and reintervention after RFA.⁸ The review included 1 RCT (interim analysis only with high loss to follow-up) and 7 non-comparative trials. The reintervention risk at a weighted mean follow-up of 24.65 months (range, 3 to 36 months) was 4.4% (95% CI, 1.6 to 8.45%; I2 = 65.0%; 7 studies). Improvements in symptoms and quality of life were maintained out to 24 months in 3 studies and out to 36 months in 1 study. No studies were identified that had follow-up longer than 36 months.

Bradley et al. (2019) conducted a systematic review of 32 prospective studies on laparoscopic, transvaginal, or transcervical RFA.⁹ Most were conducted outside of the U.S. with devices that are not cleared or approved by the U.S. Food and Drug Administration. The overall reintervention risk was 4.2% at 12 months, 8.2% at 24 months, and 11.5% at 36 months. Reintervention rates at 12 months did not differ significantly for the laparoscopic, transvaginal, or transcervical RFA procedures. Because many of the devices are not available in the U.S., relevance for the current review is limited.

Transcervical RFA was evaluated in a qualitative systematic review by Arnreiter and Oppelt (2021).¹⁰ They included 10 studies that reported on myoma volume, patient-reported outcomes, surgical reinterventions, side effects, or safety during pregnancy and delivery. No RCTs were available to perform a meta-analysis. Single-arm studies (n = 7, 5 prospective) and case reports (n = 3) were evaluated with quality assessment tools; all the single-arm studies were considered to be of fair quality with a high risk of selection bias. Four studies reported on myoma volume, patient-reported symptoms, and reinterventions, 3 studies investigated the effect on surrounding tissue, and 3 articles were case reports on pregnancies after treatment with the transcervical system. Myoma volume, measured by contrast-enhanced magnetic resonance imaging (MRI), was reduced by an average 63.2% in total volume (n = 157) and 64.5% (n = 156) in perfused volume at 12 months. The symptom severity score was reduced by 55% at 12 months and similar improvement was maintained at 24 and 64 months. Health-related quality of life improved from 38.8 points before treatment to 83.3 points at 12 months (n = 183). Reported re-intervention rates ranged from 0.7% to 8% at 12 months, 5.2% at 24 months, and 11.8% at 64 months after ablation, but loss to follow-up was high limiting confidence in these results. Reporting of adverse events was incomplete; of 227 patients, 47.6% of patients experienced adverse events. Although most adverse events were mild, 4 patients required inpatient treatment. There was no reported evidence of wall thinning or scars, no significant change in uterine wall thickness, and no intrauterine adhesions (n = 19 to 34). The authors identified case reports of 3 pregnancies after transcervical RFA with no complications. This systematic review is limited by the lack of available RCTs and high risk of bias in the published literature.

Table 1. Characteristics of Systematic Reviews on RFA

Study	Dates	Trials	Participants	N	Design	Duration
Sandberg et al. (2018)⁶	2006 – 2016	45	Women with symptomatic uterine fibroids undergoing myomectomy, UAE, or laparoscopic RFA	17,789	Studies evaluating any reintervention and quality of life with consecutive enrollment and follow-up of ≥ 12 mo	11.2 – 34.7 mo
Lin et al. (2019)⁸	2000 – 2018	8	Women with symptomatic uterine fibroids undergoing myomectomy, UAE, or laparoscopic RFA	581	Studies evaluating symptoms and quality of life	> 12 mo
Bradley et al. (2019)⁹	2005 – 2019	32	Women with symptomatic uterine fibroids undergoing laparoscopic, transvaginal, or transcervical RFA	1283	Prospective studies for treatment of uterine fibroids with RFA (variety of devices)	12 – 36 mo
Arnreiter and Oppelt (2021)¹⁰	2011 – 2019	10	Women with symptomatic uterine fibroids undergoing transcervical RFA with the SONATA system	Range, 1 – 147	Studies that reported on myoma volume, patient-reported outcomes, surgical reinterventions, side effects, and safety during pregnancy and delivery.	1 week – 64.4 mo

RFA: radiofrequency ablation; UAE: uterine artery embolization; SONATA: sonography-guided transcervical ablation of uterine fibroids

Table 2. Results of Systematic Reviews on RFA

Study	Reintervention Risk (95% CI), %			Change in Symptom Severity Score (95% CI)			Change in QOL (95% CI)
	At 12 Months	At 36 Months	At 60 Months	At 12 Months	At 24 Months	At 36 Months	At 12 Months	At 24 Months
Sandberg et al. (2018)⁶
Total studies	40	8	27	18			11
Myomectomy	1.1 (0.0 to 3.7)	1.2 (0.0 to 5.2)	12.2 (5.2 to 21.2)	-37.6 (-43.8 to -31.4)			39.9 (33.0 to 46.8)
UAE	3.6 (2.4 to 4.9)	7.4 (0.9 to 10.7)	14.4 (9.8 to 19.6)	-35.8 (-40.6 to -30.9)			38.9 (35.8 to 41.9)
Laparoscopic RFA	0.3 (0.0 to 1.6)	10.4 (1 study)	Unknown	-37.0 (-44.6 to -29.4)			35.1 (28.7 to 41.6)
Lin et al. (2019)⁸		Range, 3 to 36 mo
Total Studies		7		6	3	1	3	1
Laparoscopic RFA		4.39 (1.60 − 8.45)		-39.37 (-34.70 to -44.04)	-33.51 (-22.24 to -44.78)	-32.60 (-27.75 to -37.45)	29.21 (12.44 to 45.98)	38.60 (33.60 to 39.79)
P Value				< 0.001	< 0.001	< 0.001	p < 0.001	p < 0.001
Bradley et al. (2019)⁹
Total Studies
RFA (various)	4.2	11.5			-40		+39
					< 0.001		< 0.001
Arnreiter and Oppelt (2021)¹⁰
Transcervical RFA				-55.1 (SD, 41.0)			277%

CI: confidence interval; QOL: quality of life; RFA: radiofrequency volumetric thermal ablation; SD: standard deviation; UAE: uterine artery embolization.

Randomized Controlled Trials of Laparoscopic Radiofrequency Ablation
Studies of laparoscopic RFA include RCTs.

One RCT evaluating laparoscopic RFA (Brucker et al., 2014)¹¹ was included in the Sandberg et al. (2018) systematic review;⁶ Tables 3 and 4 describe key RCT trial characteristics and results.

The Treatment Results of Uterine Sparing Technologies (TRUST) Canada post-market RCT compared laparoscopic RFA with laparoscopic myomectomy for the treatment of symptomatic fibroids. A 2018 publication by Rattray et al. of TRUST included 45 patients (23 RFA, 22 myomectomy) and reported primarily on short-term resource utilization and return to work.¹² RFA was found to be noninferior to laparoscopic myomectomy in the length of stay. Clinical outcomes at 3 months were improved by a similar percentage in both groups (-44.8%) and women treated with RFA required less time to return to work (11.1 vs 18.5 days, p = .019). A post-market, prospective, single-arm analysis of the ongoing TRUST study reported by Yu et al. (2020) surveyed 26 surgeons who performed 105 procedures with 100 per-protocol patients to capture surgical experiences and safety outcomes.¹³ Surgeons received proctored training during study run-in and provided self-assessments after performing ≥ 2 procedures at 4 to 8 weeks follow-up. No acute serious adverse events (≤ 48 hours) were reported compared with 2 (1.46%) in the premarket study. Both studies reported 1 (< 1%) serious adverse event within 30 days of the procedure. No efficacy outcomes were reported.

Table 3. Summary of Key Randomized Controlled Trial Characteristics for Laparoscopic RFA

				Interventions
Study	Countries	Sites	Dates	Participants^a	Active	Comparator
Brucker et al. (2014)¹¹; Hahn et al. (2015)¹⁴; Kramer et al. (2016)^15,	Germany	1	2012 – 2013	≥ 18 y Menstruating Symptomatic uterine fibroids < 10 cm Uterine size ≤ 16 gestational wk Desire uterine conservation Not pregnant or lactating Race or ethnicity: 100% White	RFA = 26	LM = 25
Rattray et al. (2018)¹²(TRUST Canada) NCT015663783	Canada	Multiple	2012 – 2017	≥ 18 y Menstruating Symptomatic uterine fibroids < 10 cm Uterine size ≤ 16 gestational wk Desire uterine conservation Not pregnant or lactating Race or ethnicity: 76% White, 11% Black, 4% Asian, 2% Other, 0% Latino/Hispanic	RFA = 23	LM = 22

LM: laparoscopic myomectomy; RFA: radiofrequency volumetric thermal ablation.
^a Key eligibility criteria.

Table 4. Summary of Key Randomized Controlled Trial Outcomes for Laparoscopic RFA

Study	Primary Outcome	Secondary Outcomes
	Hospital LOS (SD), hours	Mean SSS		Mean HRQOL
		12 months	24 months	12 months	24 months
Brucker et al. (2014)¹¹; Hahn et al. (2015)¹⁴; Kramer et al. (2016)¹⁵	50	43^a	43	43	43
Laparoscopic RFA	10.0 (5.5)	24.7	16	87	89.4
Laparoscopic myomectomy	29.9 (14.2)	26	22.3	83	85.6
p	< .001^b	NS^c	NS	NS	NS
Rattray et al. (2018)¹²(TRUST Canada)
Laparoscopic RFA	6.7 (3.0)
Laparoscopic myomectomy	9.9 (10.7)
p	< .001

HRQOL: health-related quality of life; LOS: length of stay; NS: not significant; RFA: radiofrequency volumetric thermal ablation; SSS: Symptom Severity Score.
^a Analyses at 12 and 24 months were per protocol and included 84% of randomized participants.
^b Met criteria for noninferiority: hospital LOS after RFA no more than 10% longer than after laparoscopic myomectomy.
^c Exact between-group p values were not reported.

In the Brucker et al. (2014) trial,¹¹ all patients in the myomectomy group were hospitalized overnight; although not explicitly stated, this appeared to be the standard procedure at the study hospital. In the laparoscopic RFA (Acessa) group, there was an unplanned hospitalization due to unexplained vertigo and 4 hospitalizations as a standard procedure because the patients also underwent adhesiolysis. It is unclear whether these abdominal adhesions were due to prior surgical interventions for uterine fibroid myolysis; however, patients with significant intra-abdominal adhesions and known or suspected endometriosis or adenomyosis were excluded from the study.

Secondary outcomes of the RCT were reported by Hahn et al. (2015)14, (12-month outcomes) and by Kramer et al. (2016)15, (12-month and 24-month outcomes). In addition to summary symptom and quality of life measures, the publications reported on 11 symptoms: heavy menstrual bleeding, increased abdominal girth, dyspareunia, pelvic discomfort/pain, dysmenorrhea, urinary frequency, urinary retention, sleep disturbance, backache, localized pain, and "other symptoms" (not specified).

Limitations of the 12- and 24-month analyses, shown in Tables 5 and 6, included lack of intent-to-treat analysis and failure to describe secondary study hypotheses and statistical analyses clearly. The RCT had a small sample size and thus might have been underpowered to detect clinically meaningful differences in secondary outcomes, so these results do not rule out potential differences between treatments.

Table 5. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Brucker et al. (2014)¹¹; Hahn et al. (2015)¹⁴; Kramer et al. (2016)¹⁵	4. Enrolled populations do not reflect relevant diversity.				1. Insufficient to determine reintervention rates
Rattray et al. (2018)¹²(TRUST Canada)

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aPopulation key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4. Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^eFollow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 6. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Brucker et al. (2014)¹¹; Hahn et al. (2015)¹⁴; Kramer et al. (2016)¹⁵				6. Not intent-to-treat	1. Power for secondary outcomes unclear
Rattray et al. (2018)¹²(TRUST Canada)		1, 2, 3. No blinding

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Prospective Single Arm Studies of Laparoscopic Radiofrequency Ablation
Jacoby et al. (2020) surveyed gynecologist experience and health outcomes following adoption of laparoscopic RFA into clinical practice for 26 patients across 5 academic medical centers in California in the Uterine Leiomyoma Treatment with Radiofrequency Ablation (ULTRA) trial.¹⁶ Eligibility criteria included women ≥ 21 years of age seeking uterine-sparing surgical treatment of leiomyomas for heavy bleeding, pelvic pressure or discomfort, urinary or bowel symptoms, or dyspareunia. Women seeking future fertility were informed that there are insufficient data to determine the impact of treatment on fertility outcomes. No intraoperative complications or major adverse events were reported. Significant improvements in menstrual bleeding, sexual function, and quality of life were reported from baseline to 12 weeks, with a 47% decrease in the Leiomyoma Symptom Severity Score. Self-rated mean procedure difficulty score decreased from 6 to 4.25 following the fourth procedure among general gynecologists new to the technology. The authors concluded that laparoscopic RFA can be introduced into clinical practice with good clinical outcomes.

Prospective Single Arm Studies of Transcervical Radiofrequency Ablation
Studies of transcervical RFA are limited to prospective single-arm studies (see Tables 7 and 8).

The pivotal study for the Sonata transcervical RFA system (sonography-guided transcervical ablation of uterine fibroids [SONATA]) was a prospective single-arm study with 147 premenopausal women who had symptomatic uterine fibroids with heavy menstrual bleeding.¹⁷ Patients were excluded if they desired to become pregnant. There were 2 (1.4%) procedure-related adverse events during the first year of follow-up and no additional device-related adverse events between the 1- and 2- year follow-up. At the 24 month follow-up, patients reported significantly improved symptom severity scores, HRQL, and EQ-5D. The cumulative rate of surgical intervention for heavy menstrual bleeding was 5.2% (95% CI 2.5% to 10.6%). Follow-up at 3 years showed a reintervention rate of 8.2%.¹⁸ In patients who did not undergo reintervention, menopause, or withdrawal (not last observation-carried-forward), the gains observed at the 2-year follow-up were maintained at 3 years. In the 105 patients (71%) who remained in the trial, significant improvements in the SSS (P < .001), HR-QoL (P < .001), quality of life (P < .001) work absenteeism (P < .001), and impairment for work (P < .001) and physical activity (P < .001) were maintained. These results are limited by the loss to follow-up in the 3-year results.

The Fibroid Ablation Study EU (FAST-EU) was a prospective single-arm trial with the previously named VizAblate transcervical RFA.¹⁹ Fifty women who had heavy menstrual bleeding were included in the study. Patients were excluded if they desired to become pregnant. The primary outcome measure, that at least 50% of patients with > 30% reduction in perfused fibroid volume, was achieved at the 3-month follow-up. Twelve-month follow-up was not in the original study design, and only 28 (58.3%) of participants agreed to return for an MRI at this time point. Symptom Severity Scores were obtained in all patients except for 1 patient due to pregnancy. A clinically significant minimum 10 point reduction in the SSS was obtained in 82% of patients at 3 months, 86% at 6 months, and 78% at 12 months. There were 34 adverse events deemed possibly, probably, or definitely related to the procedure. Four patients (8%) underwent surgical reintervention between 6 and 12 months post-ablation.

Shifrin et al. (2021) conducted a subgroup analysis of patients with submucous (type 1, 2, or 2-5) or large fibroids (> 5 cm) from patients in the FAST-EU and SONATA clinical trials.20, In total, 72.5% of the 534 treated fibroids were not amenable to hysteroscopic resection because they were intramural, transmural, or subserous. At 3 month follow-up, 86% of women with only submucous fibroids and 81% of women with large fibroids experienced bleeding reduction. At 12 month follow-up, a reduction in menstrual bleeding was found in 92% to 96% of women with submucous fibroids and 86% to 100% of women with large fibroids (although fibroids > 5 cm was an exclusion in SONATA, 2.5% (n = 11) of patients were in this category). Improvement in the SSS, HR-QoL, and EQ-5D were also noted in these subgroups. Rates of surgical reintervention for women with submucous fibroids was less than 3.7%.

The Transcervical Radiofrequency Ablation of Uterine Fibroids Global Registry (SAGE) will enroll 500 patients treated with transcervical RFA at up to 50 sites in Europe (NCT03118037). Participation in the registry requires willingness to return for follow-up visits through 5 years, with no restrictions for participation based on patient age (> 18), fibroid type and size, prior surgical history, or desire for future fertility. Characteristics and adverse events from the first 160 women in the registry were reported by Christoffel et al. (2021).²¹ A total of 241 fibroids were treated with another 271 identified by sonography but not ablated. Patients will be followed for 5 years.

Table 7. Summary of Single-Arm Study Characteristics for Transcervical RFA

Study	Study Location	Participants	Treatment Delivery¹	Follow-Up
Brolmann et al. (2016) ¹⁹(FAST-EU)	7 community or academic gynecologists in EU and Mexico	50 women > 28 years of age with heavy menstrual bleeding for at least 3 months and no desire to become pregnant	VizAblate transcervical RFA	12 mo
Miller et al. (2020)^17,¹⁸(SONATA)	24 community or academic gynecologists from 21 centers in the US and Mexico	147 premenopausal women 25 – 50 years of age with symptomatic uterine fibroids (1 – 5 cm) with heavy menstrual bleeding and no desire to become pregnant	Sonata transcervical RFA	3 years
Christoffel et al. (2021)²¹(SAGE)	Registry from 50 sites in Europe	First 160 of 500 women > 18 years of age who select transcervical RFA for symptomatic uterine fibroids and agree to follow-up	Sonata transcervical RFA	5.3 mo (range 0.1 to 25.0)

FAST-EU: Fibroid Ablation Study EU; RFA: radiofrequency ablation; SAGE: Transcervical Radiofrequency Ablation of Uterine Fibroids Global Registry; SONATA: sonography-guided transcervical ablation of uterine fibroids

Table 8. Summary of Single Arm Study Results for Transcervical RFA

Study	Baseline	3 mo	12 mo	24 mo	36 mo
Brolmann et al. (2016) ¹⁹FAST-EU
n (%)	50	50	48
Percentage change in perfused fibroid volume (SD)	18.3 (20.6)	5.8 (9.6)	6.6 (11.3) n = 28
Symptom Severity Score (SD)	61.7 (16.9)	31.7 (20.1)	26.6 (24.0)
HRQL	34.3 (19.0)	76.4 (22.2)	80.7 (24.7)
Surgical reintervention			4 (8%)
Miller et al. (2020)^17,¹⁸(SONATA)
n (%)	147			125 (85%)	105 (71%)
Symptom Severity Score (SD)	55 (19)	27 (19) P < .001		24 (18) P < .001	22 (21) P < .001
HRQL (SD)	40 (21)	78 (22) P < .001		83 (19) P < .001	83 (23)
EQ-5D (SD)	0.72 (0.21)	0.87 (0.13) P < .001		0.89 (0.14) P < 0.001	0.88 (0.16)
Surgical reintervention				5.5%	8.2%

EQ-5D Euroqol 5-dimension; HRQL: Health-related quality of life; FAST-EU: Fibroid Ablation Study EU; RFA: radiofrequency ablation; SAGE: TransScervical Radiofrequency Ablation of Uterine Fibroids Global Registry; SD: standard deviation; SONATA: sonography-guided transcervical ablation of uterine fibroids

Pregnancy Outcomes After Radiofrequency Ablation
Keltz et al. (2017) published a systematic review of published literature on pregnancy outcomes after thermal ablation of uterine fibroids.²² For laparoscopic RFA, reviewers identified 20 pregnancies reported in 4 case series; the denominator (i.e., the number of patients treated in these series) was not reported. Of the 20 pregnancies, 7 were undesired and were electively terminated. For the remaining 13 pregnancies, there was 1 spontaneous abortion and 12 full-term births. Nine of the 12 live births were delivered by cesarean section.

Berman et al. (2020) conducted a retrospective review of pregnancy delivery and safety after laparoscopic RFA of uterine fibroids.²³ The review included results from 2 RCTs, 6 cohort studies, and commercial cases (total N = 28) that evaluated rates of spontaneous abortion, preterm delivery, postpartum hemorrhage, placental abnormalities, intrauterine growth restriction, and rates of cesarean delivery. Thirty pregnancies resulted in 26 full-term births (86.7%), with an equal distribution of vaginal and cesarean deliveries, and the spontaneous abortion rate (13.3%) was within the range for the general population. There were no cases of preterm delivery, uterine rupture, placental abruption, placenta accreta, or intrauterine growth restriction. One patient experienced severe postpartum hemorrhage. While these retrospective results did not identify any safety signals for pregnancy, ongoing prospective studies that are evaluating pregnancy outcomes will provide more confidence in pregnancy outcomes after laparoscopic RFA.

Section Summary: Radiofrequency Ablation
Prospective case series, systematic reviews, and RCTs comparing RFA with laparoscopic myomectomy have been published. The meta-analyses found low rates of reintervention with RFA and quality of life outcomes that were similar to myomectomy and UAE at 12 months. Data on reintervention rates is limited, including reinterventions for hysterectomy. Two RCTs found that RFA was noninferior to laparoscopic myomectomy on the primary outcome (length of hospitalization). A number of secondary outcomes of 1 RCT were reported at 12 and 24 months, including symptoms and quality of life outcomes; none differed significantly between groups. The RCT only had 43 patients in subgroup analyses at 12 and 24 months, and may have had insufficient power for the secondary outcomes. The procedure is associated with a reduction in symptoms and improvement in quality of life in the short-term. The reintervention rate at longer follow-up is unknown. Because most trials excluded women who desired to become pregnant, the impact of RFA on pregnancy outcomes is uncertain. Additional well-designed comparative trials with longer follow-up are needed to determine the effect of RFA on health outcomes compared with other treatment options, including myomectomy.

Laser or Bipolar Needles
Clinical Context and Therapy Purpose
The purpose of therapy with laser or bipolar needles in patients who have uterine fibroids is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of laser or bipolar needles improve the net health outcome in women with uterine fibroids?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is women with symptomatic uterine fibroids.

Interventions
The therapy being considered is laser or bipolar needles.

Comparators
The following therapies are currently being used to manage symptomatic uterine fibroids: medical management, UAE , myomectomy, and hysterectomy. Surgery, including hysterectomy and myomectomy, is considered the criterion standard for symptom resolution. However, there is the need to recover from surgery, and in the case of a hysterectomy, the uterus is not preserved. UAE is associated with poor pregnancy outcomes and is not advised in patients who desire to become pregnant.

Outcomes
The outcomes of interest are complications, postoperative pain and recovery time, symptom resolution, need for reintervention, and health-related quality of life. The immediate follow-up would be a week for postoperative pain and recovery, and 3 to 5 years of follow-up would be needed to monitor for fibroid recurrence and retreatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Series
Several case series were identified, most published in the 1990s. For example, Goldfarb (1995) reported on outcomes for 300 women with symptomatic fibroids no larger than 10 cm who underwent myolysis using either Nd:YAG or bipolar needles.²⁴The author reported that the coagulating effect of the bipolar needle devascularized the fibroids, and the resulting shrinkage was comparable to that produced by Nd:YAG laser. An earlier study by Goldfarb (1992), included 75 patients who presented with symptomatic fibroids 5 to 10 cm in diameter.²⁵ Symptoms included pelvic pain, pressure, dyspareunia, and recurrent menorrhagia. The Nd:YAG laser was inserted into the fibroid multiple times (e.g., 75 to 100 punctures to coagulate a 5-cm fibroid). Based on an assessment by endovaginal ultrasound, the fibroids regressed in size and, after 6 to 14 months of follow-up, the size remained stable. No patient experienced significant complications. Nisolle et al. (1993) reported on a case series of 48 women offered myolysis instead of myomectomy if they had completed childbearing.²⁶ The authors reported that maximal decrease in fibroid size had occurred by 6 months, however, as reported, it is unclear among the 28 of 48 patients with more than 2 fibroids whether all fibroids were treated in each patient, and, if not, how treated fibroids were selected. Additionally, no associated patient symptoms were reported.

Several authors have reported pelvic adhesions as a complication of the Nd:YAG laser procedure, presumably due to thermal damage to the serosal surface. In addition, the Nd:YAG laser produces a significant amount of smoke, which can obscure visibility.^27,28

Section Summary: Laser or Bipolar Needles
The evidence base on the use of lasers or bipolar needles only includes case series, small in size, and published in the 1990s. RCTs comparing laser and bipolar needles with alternative treatments for uterine fibroids and reporting health outcomes are needed.

Cryomyolysis
Clinical Context and Therapy Purpose
The purpose of cryomyolysis in patients who have uterine fibroids is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does cryomyolysis improve the net health outcome in women with uterine fibroids?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is women with symptomatic uterine fibroids.

Interventions
The therapy being considered is cryomyolysis. Cryomyolysis entails inserting a -180°C cryoprobe into the center of a fibroid, which creates an "iceball" within the fibroid. Several freeze-thaw cycles are typically used, and the process may not be standardized.

Comparators
The following therapies are currently being used to manage symptomatic uterine fibroids: medical management, UAE , myomectomy, and hysterectomy. Surgery, including hysterectomy and myomectomy,is considered the criterion standard for symptom resolution. However, there is the need to recover from surgery, and in the case of a hysterectomy, the uterus is not preserved. UAE is associated with poor pregnancy outcomes and is not advised in patients who desire to become pregnant.

Outcomes
The outcomes of interest are, complications, postoperative pain and recovery time, symptom resolution, need for reintervention, and health-related quality of life. The immediate follow-up would be a week for postoperative pain and recovery, and 3 to 5 years of follow-up would be needed to monitor for fibroid recurrence and retreatment.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Series
No controlled studies evaluating cryomyolysis were identified.

Two case series have been identified. Zreik et al. (1998)²⁹ published a prospective pilot study with 14 patients, and Zupi et al. (2004)30, presented their experience with 20 patients.^29,30 In both case series, the authors reported that patients had symptom resolution. In the Zreik et al. (1998) series, cryomyolysis maintained or slightly reduced the myoma volume by 6%. In the Zupi et al. (2004) study, cryomyolysis was associated with a 25% reduction in fibroid size. Zupi et al. (2005) reported on the 1-year follow-up of these patients.³¹ Mean shrinkage in fibroid size continued until 9 months after surgery, to a mean volume reduction of 60%. In the Sandberg et al. (2018) systematic review (discussed above), the risk of reintervention was 15%.⁶ Interpretation of these studies is limited due to their small sample sizes and lack of comparison groups.

Section Summary: Cryomyolysis
The literature on cryomyolysis includes small case series, with no literature identified in the last decade. Controlled studies comparing cryomyolysis with alternative treatments for uterine fibroids and differentiating between outcomes related to fibroid treatment and outcomes related to the treatment of abnormal bleeding are needed.

Magnetic Resonance Imaging-Guided Laser Ablation
Clinical Context and Therapy Purpose
The purpose of MRI-guided laser ablation in patients who have uterine fibroids is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does MRI-guided laser ablation improve the net health outcome in women with uterine fibroids?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is women with symptomatic uterine fibroids.

Interventions
The therapy being considered is MRI-guided laser ablation.

Comparators
The following therapies are currently being used to manage symptomatic uterine fibroids: medical management, UAE , myomectomy, and hysterectomy. Surgery, including hysterectomy and myomectomy, is considered the criterion standard for symptom resolution. However, there is the need to recover from surgery, and in the case of a hysterectomy, the uterus is not preserved. UAE is associated with poor pregnancy outcomes and is not advised in patients who desire to become pregnant.

Outcomes
The outcomes of interest are, complications, postoperative pain and recovery time, resolution of symptoms, need for reintervention, and health-related quality of life. The immediate follow-up would be a week for postoperative pain and recovery, and 3 to 5 years of follow-up would be needed to monitor for fibroid recurrence and retreatment

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Nonrandomized Studies
No RCTs evaluating MRI-guided laser ablation were identified. A nonrandomized study by Hindley et al. (2002) was identified (see Tables 9 and 10).³² Results from the women treated with MRI-guided laser ablation were compared with a historical control group of 43 women who underwent a hysterectomy. Compared with the historical control group, the total score on the Menorrhagia Outcomes Questionnaire was significantly lower (i.e., worse outcomes) in those undergoing percutaneous myolysis. The quality of life subscores did not differ statistically.

Table 9. Summary of Key Nonrandomized Trial Characteristics

Study	Type	Country	Participants	Treatment	Comparator	FU, y
Hindley et al. (2002)³²	Cohort with historical controls	U.K.	109 women with symptomatic fibroids seeking to avoid surgery	66 to MRI-guided laser ablation	43 to hysterectomy	1

FU: follow-up; MRI: magnetic resonance imaging.

Table 10. Summary of Key Nonrandomized Trial Results

Study	Mean Fibroid Volume Reduction (Range), %		MOQ Total	MOQ QOL/Satisfaction
	At 3 Months	At 1 Year
Hindley et al. (2002)³²
n/N (%)	47/66 (71)	24/66 (36)	34/66	33/66
MRI-guided laser ablation	-31 (21 to -76)	-41 (13 to -78)	51.5	51.5
Hysterectomy	NR	NR	48.7	49.0
p			0.02	0.06

MRI: magnetic resonance imaging; MOQ: Menorrhagia Outcomes Questionnaire; NR: not reported; QOL: Quality of Life.

The purpose of the limitations tables (see Tables 11 and 12) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 11. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Hindley et al. (2002)³²					Not sufficient duration to assess reintervention

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 12. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Hindley et al. (2002)³²	1 – 4. Not randomized, inadequate control for selection bias	1 – 3. Not blinded		1.High loss to follow-up

Section Summary: MRI-Guided Laser Ablation
A single nonrandomized study with historical controls was identified. Data reporting was incomplete, and self-reported outcomes were worse compared with a historical control group of women undergoing a hysterectomy. RCTs comparing MRI-guided laser ablation with alternative treatments for uterine fibroids and reporting health outcomes are needed.

Summary of Evidence
For individuals who have symptomatic uterine fibroids who receive RFA, the evidence includes prospective cohorts, RCTs, and systematic reviews. Relevant outcomes are symptoms, quality of life, and treatment-related morbidity. The meta-analysis found low rates of reintervention with RFA and quality of life outcomes that were similar to uterine artery embolization and myomectomy at 12 months. Data on reintervention rates at 36 months were limited to 1 RCT and 1 cohort study with high loss to follow-up. No studies reported reintervention rates at 60 months. Two RCTs found that RFA was noninferior to laparoscopic myomectomy on the primary outcome: length of hospitalization. A number of secondary outcomes were reported at 12 and 24 months in 1 RCT, including symptoms and quality of life. None of the secondary outcomes demonstrated significant between-group differences in a subgroup analysis of 43 patients. The procedure has faster recovery than myomectomy, and provides a reduction in symptoms and improvement in quality of life in the short term. Recurrence and reintervention rates at longer follow-up are unknown. Well-designed comparative trials with longer follow-up are needed to determine the effect of RFA on health outcomes compared with other treatment options such as myomectomy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have symptomatic uterine fibroids who receive laser or bipolar needles, the evidence includes case series. Relevant outcomes are symptoms, quality of life, and treatment-related morbidity. The case series were published in the 1990s, and the procedures used then may not reflect current practice. RCTs comparing laser or bipolar needles with alternative treatments for uterine fibroids are needed to evaluate the safety and efficacy of this technology adequately. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have symptomatic uterine fibroids who receive cryomyolysis, the evidence includes case series. Relevant outcomes are symptoms, quality of life, and treatment-related morbidity. Among the few case series, sample sizes were small (≤ 20 patients). RCTs comparing cryomyolysis with alternative treatments for uterine fibroids are needed to evaluate the safety and efficacy of this technology adequately. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have symptomatic uterine fibroids who receive magnetic resonance imaging-guided laser ablation, the evidence includes a study with historical controls. Relevant outcomes are symptoms, quality of life, and treatment-related morbidity. A single study with historical controls is not sufficiently robust to evaluate this technology. RCTs comparing magnetic resonance imaging-guided laser ablation with alternative treatments for uterine fibroids are needed to evaluate safety and efficacy adequately. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2021 Input
Clinical input was sought to help determine whether the use of laparoscopic or transcervical radiofrequency ablation (RFA) for individuals with symptomatic uterine fibroids would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input on the use of RFA was received from 3 respondents, including: 1 society-level response including input from physicians affiliated with academic medical centers and 2 physician-level responses with academic affiliations.

For individuals with symptomatic uterine fibroids, clinical input provides consistent support that the use of laparoscopic or transcervical RFA provides a clinically meaningful improvement in the net health outcome and is consistent with generally accepted medical practice.

Based on the evidence and independent clinical input, the clinical input supports that the following indication provides a clinically meaningful improvement in the net health outcome and is consistent with generally accepted medical practice.

Women 18 and older when ALL of the following conditions are met:

Evidence of uterine fibroids via ultrasound that are less than 10 cm in diameter for laparoscopic RFA with Acessa or 7 cm for transcervical RFA with Sonata; AND
Patient desires a uterine-sparing treatment approach or is contraindicated for hysterectomy or other uterine-sparing alternatives to RFA (e.g., laparoscopic myomectomy, uterine artery embolization [UAE]); AND
Patient has experienced at least 1 of the following symptoms that are a direct result of the fibroid(s):
- Menorrhagia or other abnormal uterine bleeding that interferes with daily activities or causes anemia;
- Pelvic pain or pressure;
- Urinary symptoms (e.g., urinary frequency, urgency) related to bulk compression of the bladder;
- Gastrointestinal symptoms related to bulk compression of the bowel (e.g., constipation, bloating);
- Dyspareunia (painful or difficult sexual relations).

Respondents noted that choice of laparoscopic versus transcervical RFA treatment is dependent on fibroid number, type and location, and patient preferences. For example, predominantly lower uterine segment or cervical leiomyomata, or those with a predominant submucosal location or intramural International Federation of Gynecology and Obstetrics (FIGO) type 2 or 3 fibroids (see Table PG1), may suggest a transcervical approach, whereas fibroids with largely fundal or extramural components may suggest a laparoscopic approach.

Further details from clinical input are included in the Appendix.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Obstetricians and Gynecologists
In 2021, the American College of Obstetricians and Gynecologists updated its practice bulletin on the management of symptomatic leiomyomas.¹Recommendations based on a review of evidence included the following:

Radiofrequency ablation can be considered as a minimally invasive treatment option in patients who desire to retain their uterus, provided they are counseled about the limited data on reproductive outcomes. Laparoscopic, transvaginal, or transcervical approaches using ultrasound guidance are considered similarly effective.
Focused ultrasound is associated with a reduction in leiomyoma and uterine size, but is associated with less improvement in symptoms and quality of life and a higher risk of reintervention compared with uterine artery embolization.
Myomectomy was recommended as an option in patients who desire uterine preservation or future pregnancy and are counseled about the risk of recurrence. The laparoscopic approach is associated with shorter hospitalization, less postoperative pain, faster return to work, and earlier return to normal activities.
Hysterectomy is recommended as a definitive surgical management option in patients who do not desire future childbearing or do not wish to retain their uterus.

National Institute for Health and Care Excellence
In 2021, the National Institute for Health and Care Excellence (NICE) published an interventional procedures guidance on the use of transcervical ultrasound-guided radiofrequency ablation (RFA) for symptomatic uterine fibroids.³³ The NICE noted that while evidence on the safety of transcervical RFA raises no major safety concerns, evidence on the efficacy of the procedure is limited in quality. Therefore, the NICE recommends that the procedure should only be used with special arrangements for clinical governance, consent, and audit or research.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this evidence review are listed in Table 13.

Table 13. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01563783^a	The Trust (Treatment Results of Uterine Sparing Technologies) Study	260	Sep 2022
NCT03219385^a	Directed Ablation of Uterine Fibroids Using a Noninvasive Approach (DIANA)	180	Sep 2022
NCT03118037^a	Transcervical Radiofrequency Ablation of Uterine Fibroids Global Registry (SAGE)	100	Dec 2025
NCT02163525^a	Post Market TRUST - U.S.A. Study	114	Jun 2024
NCT02100904	Uterine Leiomyoma Treatment With Radiofrequency Ablation (ULTRA) Registry (ULTRA Registry)	800	Jan 2025
Unpublished
NCT02260752	Patient-Centered Results for Uterine Fibroids (COMPARE-UF)	3,094	Sep 2020

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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Rattray DD, Weins L, Regush LC, et al. Clinical outcomes and health care utilization pre- and post-laparoscopic radiofrequency ablation of symptomatic fibroids and laparoscopic myomectomy: a randomized trial of uterine-sparing techniques (TRUST) in Canada. Clinicoecon Outcomes Res. 2018; 10: 201-212. PMID 29670382
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Hahn M, Brucker S, Kraemer D, et al. Radiofrequency Volumetric Thermal Ablation of Fibroids and Laparoscopic Myomectomy: Long-Term Follow-up From a Randomized Trial. Geburtshilfe Frauenheilkd. May 2015; 75(5): 442-449. PMID 26097247
Kramer B, Hahn M, Taran FA, et al. Interim analysis of a randomized controlled trial comparing laparoscopic radiofrequency volumetric thermal ablation of uterine fibroids with laparoscopic myomectomy. Int J Gynaecol Obstet. May 2016; 133(2): 206-11. PMID 26892690
Jacoby VL, Parvataneni R, Oberman E, et al. Laparoscopic Radiofrequency Ablation of Uterine Leiomyomas: Clinical Outcomes during Early Adoption into Surgical Practice. J Minim Invasive Gynecol. May 2020; 27(4): 915-925. PMID 31376584
Miller CE, Osman KM. Transcervical Radiofrequency Ablation of Symptomatic Uterine Fibroids: 2-Year Results of the SONATA Pivotal Trial. J Gynecol Surg. Dec 01 2019; 35(6): 345-349. PMID 32226268
Lukes A, Green MA. Three-Year Results of the SONATA Pivotal Trial of Transcervical Fibroid Ablation for Symptomatic Uterine Myomata. J Gynecol Surg. Oct 01 2020; 36(5): 228-233. PMID 33061253
Brolmann H, Bongers M, Garza-Leal JG, et al. The FAST-EU trial: 12-month clinical outcomes of women after intrauterine sonography-guided transcervical radiofrequency ablation of uterine fibroids. Gynecol Surg. NA 2016; 13: 27-35. PMID 26918001
Shifrin G, Engelhardt M, Gee P, et al. Transcervical fibroid ablation with the Sonata system for treatment of submucous and large uterine fibroids. Int J Gynaecol Obstet. Oct 2021; 155(1): 79-85. PMID 33544889
Christoffel L, Romer T, Schiermeier S. Transcervical Radiofrequency Ablation of Uterine Fibroids Global Registry (SAGE): Study Protocol and Preliminary Results. Med Devices (Auckl). 2021; 14: 77-84. PMID 33688276
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Goldfarb HA. Bipolar laparoscopic needles for myoma coagulation. J Am Assoc Gynecol Laparosc. Feb 1995; 2(2): 175-9. PMID 9050553
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Zreik TG, Rutherford TJ, Palter SF, et al. Cryomyolysis, a new procedure for the conservative treatment of uterine fibroids. J Am Assoc Gynecol Laparosc. Feb 1998; 5(1): 33-8. PMID 9454874
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National Institute for Health and Care Excellence (NICE). Interventional procedures guidance: Transcervical ultrasound-guided radiofrequency ablation for symptomatic uterine fibroids [IPG689]. March 31, 2021; https://www.nice.org.uk/guidance/ipg689. Accessed on January 3, 2022.

Coding Section

Codes	Number	Description
CPT		See Policy Guidelines.
	58674 (effective 1/1/2017)	Laparoscopy, surgical, ablation of uterine fibroid(s) including intraoperative ultrasound guidance and monitoring, radiofrequency
ICD-10-CM		Investigational for all relevant diagnoses
	D25.0-D25.9	Leiomyoma of uterus, code range
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services.
	0U593ZZ, 0U594ZZ, 0U598ZZ, 0UB94ZZ	Surgical, female productive system, destruction, uterus, code range
Type of Service	Surgery
Place of Service	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2013 Forward

08/24/2022	Updating entire policy including an update to allow laparoscopic or transcervical RFA to treat uterine fibroids if medical necessity guidelines are met.
09/01/2021	Annual review, no change to policy intent. Updating description, rationale and references.
09/01/2020	Annual review, no change to policy intent. Updating rationale and references.
06/29/2020	Interim review, removing the word laparoscopic from the policy statement and adding Sonata to the policy statement. No other changes.
09/04/2019	Annual review, no change to policy intent. Updating background, regulatory status, guidelines and references.
09/05/2018	Annual review, no change to policy intent.
07/24/2017	Interim review to add clarifying language surrounding morcellation to indicate that morcellation in relation to a laparoscopic hysterectomy or laparoscopic myomectomy is investigational.
06/07/2017	Interim review updating morcellation language to include power and mechanical morcellation as investigational.
11/28/2016	Updating coding section with 2017 codes.
09/12/2016	Annual review. Updating Title, policy verbage, background, description, rationale, coding section and references.
09/01/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
09/15/2015	Annual reivew, no change to policy intent. Updated background, description, rationale and references. Added guidelines and regulatory status.
09/29/2014	Annual review. Updated title, rationale, description, references. Added language regarding morcellation being investigational. Added coding section.
01/14/2014	Annual review, updated rationale, references and description. Added related policies and benefit application. No change to policy intent.

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Laparoscopic, Percutaneous and Transcervical Techniques for Uterine Fibroids Myolysis - CAM 40119