National Medical Policy

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1 National Medical Policy Subject: Policy Number: MRI Guided Ultrasound Ablation of Uterine Fibroids NMP313 Effective Date*: January 2007 Updated: November 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State's Medicaid manual(s), publication(s), citations(s) and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation X Local Coverage Determination (LCD)* Article (Local)* Other None Ablative Therapy: Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 1

2 outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net Inc. considers MRI-guided ultrasound ablation of uterine fibroids investigational due to the lack of large, randomized, controlled clinical trials with adequate follow-up in the medical literature to demonstrate the long-term safety and efficacy of this treatment. Definitions MRI Magnetic resonance imaging HIFU High-intensity-focused ultrasound USgHIFU Ultrasound-guided high intensity focused ultrasound NPV Non-perfused volume DCE Dynamic contrast material-enhanced SSS Symptom severity score Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes Uterine leiomyoma ICD-10 Codes D25.Ø-D25.9 CPT Codes 0071T 0072T Leiomyoma of uterus Focused ultrasound ablation of uterine leiomyomata, including MR guidance; total leiomyomata volume of less than 200 cc of tissue Focused ultrasound ablation of uterine leiomyomata, including MR guidance; total leiomyomata volume greater or equal to 200 cc of tissue HCPCS Codes N/A Scientific Rationale Update November 2015 MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 2

3 According to an ACOG practice bulletin on alternatives to hysterectomy in the management of leiomyomas, regarding Magnetic Resonance Imaging-Guided Focused Ultrasound Surgery, the bulletin states, Whereas short-term studies show safety and efficacy, long-term studies are needed to discern whether the minimally invasive advantage of MRI-guided focused ultrasound surgery will lead to durable results beyond 24 months. Protocols for treating larger leiomyoma volumes are being studied. (reaffirmed in 2014) Ferrari et al (2015) evaluated the treatment efficacy of uterine adenomyosis using magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) as a miniinvasive therapy. Twenty-three patients affected by symptomatic uterine adenomyosis (11 focal and 7 diffuse forms), diagnosed using MRI, were included in this study. Eighteen out of 23 were submitted to MRgFUS. All junctional zone more than 12 mm in width were considered to be adenomyosis. Study evaluates the pretreatment target volume measured prior to the treatment on the CE T1-weighted sequence and the MRgFUS-treated volume (MRgFUS-TV), represented by the volume of the lesion ablated, measured directly by means of the MRgFUS. The treated volume on the CE T1-weighted sequence (CE MRI-TV) was measured immediately after treatment. After 1 year, the junctional zone thickness was measured in order to compare pre- and post-treatment values. The therapeutic plan consisted of a highenergy-grid sonication. Symptomatology was assessed through the UFS-QOL. The pre-treatment target volume mean value was of 59.7 cc; the MRgFUS-TV had a mean value of 44.9 cc, and the mean value of CE MRI-TV, measured immediately after treatment, was of 52.8 cc, with an increase of 13.7 %. The 86.5 % of the lesion was treated. After 1 year from the treatment, 15/18 (83 %) patients showed thickness of the junctional zone <12 mm; 3/18 (17 %) had a junctional zone >12 mm. The authors concluded MRgFUS is an encouraging mini-invasive treatment for adenomyosis that permits to maintain the integrity of the uterus in a pathology with limited therapeutic possibility. Mindjuk et al (2015) assessed the 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. The authors concluded adequate patient selection and correct treatment techniques, based on the learning curve of this technology, combined with technical advances of the system, lead to higher clinical success rates with low complications rate, comparable to other uterine-sparing treatment options. Quinn et al (2014) examined the safety and re-intervention rates following MRgFUS for uterine fibroids at 5 years to assess how the non-perfused volume (NPV), fibroid signal intensity and use of gonadotrophin-releasing hormone analogues (GnRHa) affect the re-intervention rates. This cohort study included women undergoing MRgFUS for treatment of their uterine fibroids between 2003 and Of 280 MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 3

4 women undergoing MRgFUS the rate of minor complications was 3.9% and there were 3 serious complications (1.1%) including one skin burn, a fibroid expulsion and one case of persistent neuropathy. The NPVs achieved following MRgFUS have increased as the experience with this treatment has grown. In a 5-year follow-up study of 162 women, the overall re-intervention rate was 58.64%, but in those treatments with greater than 50% NPV the re-intervention rate was 50%. The authors concluded MRgFUS treatment of uterine fibroids is a safe treatment for uterine fibroids. The re-intervention rate at 5 years is high, but the improvements in NPVs achieved may further improve the long term results. Scientific Rationale Update November 2014 Ikink et al (2014) compared the effectiveness of magnetic resonance-guided highintensity focused ultrasound (MR-HIFU) with that of uterine artery embolisation (UAE) for treatment of uterine fibroids. Between January 2010 and January 2013, 51 women with symptomatic uterine fibroids underwent MR-HIFU. Follow-up and MR imaging were compared to 68 women treated with UAE, who fulfilled eligibility criteria for MR-HIFU - e.g., size ( 12 cm) and number ( 5) of fibroids. We compared median symptom severity (tsss), total health-related quality of life (HRQoL) scores, and reintervention rates. The adjusted effect on symptom relief and HRQoL improvement was calculated using multivariable linear regression. Cox regression was applied to calculate the adjusted risk of reintervention between both treatments. Median tsss improved significantly from baseline to three-month follow-up (P < 0.001) for both MR-HIFU (53.1 (IQR [ ]) to 34.4 (IQR [ ]) and UAE (65.3 (IQR [ ]) to 21.9 (IQR [ ]). In addition, significantly better HRQoL scores were observed after three months (P < 0.001). However, in multivariate analysis, UAE had a stronger effect on symptom relief and HRQoL improvement than MR-HIFU (P < 0.001). Patients treated with MR-HIFU had a 7.1 (95 % CI [ ]; P = 0.002) times higher risk of reintervention within 12 months (18/51 vs. 3/68). The investigators concluded both MR-HIFU and UAE result in significant symptom relief related to uterine fibroids. However, MR-HIFU is associated with a higher risk of reintervention. Gorney et al (2014) assessed long-term outcomes of MR-HIFU treatments of uterine fibroids in a retrospective follow-up of 138 patients treated at a single institution between March 2005 and November 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, y). 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 y ± 5.6 vs 43.0 y ± 5.8; P =.006; hazard ratio, 0.855; 95% confidence interval, ). 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 (hazard ratio, or 5.937, respectively; 95% confidence interval, or , respectively). Physician predictions of treatment success, recorded during the screening process, had significant predictive value (P =.018). The reviewers concluded the long-term rates of additional interventions after MR-HIFU of symptomatic uterine fibroids were found to be comparable with other uterine-sparing procedures, such as uterine artery embolization or myomectomy. Older patient age and homogeneously dark fibroids MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 4

5 were associated with fewer additional treatments. Physician assessment of treatment success was found to be a valuable tool in patient screening. Froeling et al (2013) compared the long-term outcome after UAE versus MR-HIFU for symptomatic uterine fibroids. Seventy-seven women (median age, 39.3 years; range, years) with symptomatic uterine fibroids, equally eligible for UAE and MR- HIFU based on our exclusion criteria underwent treatment (UAE, N = 41; MR-g HIFU, N = 36) from 2002 to 2009 at our institution. Symptom severity (SS) and total health-related quality of life (Total HRQoL) scores were assessed by the uterine fibroid symptom and quality of life (UFS-QoL) questionnaire before treatment and at long-term follow-up after UAE (median 61.9 months) and after MR-HIFU (median: 60.7 months). Re-intervention rates were assessed for each therapy and compared. Re-intervention was significantly lower after UAE (12.2%) than after MR- HIFU (66.7%) at long-term follow-up (p<0.001). After UAE changes in SS (50 pretreatment vs. 6.3 post-treatment) and Total HRQoL (57.8 pre-treatment vs. 100 post-treatment) were significantly better than changes in SS (42.2 pre-treatment vs post-treatment) and Total HRQoL score (66.4 pre-treatment vs posttreatment) after MR- HIFU (p = and respectively). The investigators concluded improvement of SS and Total HRQoL scores was significantly better after UAE resulting in a significant lower re-intervention rate compared to MR-HIFU. Trumm et al (2013) assessed the impact of the advanced technology of the new ExAblate 2100 system (Insightec Ltd, Haifa, Israel) for MRI-guided focused ultrasound surgery on treatment outcomes in patients with symptomatic uterine fibroids, as measured by the nonperfused volume ratio in a retrospective analysis of 115 women (mean age, 42 years; range, years) with symptomatic fibroids who consecutively underwent MRI-guided focused ultrasound treatment in a single center with the new generation ExAblate 2100 system from November 2010 to June Mean ± SD total volume and number of treated fibroids (per patient) were 89 ± 94 cm and 2.2 ± 1.7, respectively. Patient baseline characteristics were analyzed regarding their impact on the resulting nonperfused volume ratio. Magnetic resonance imaging-guided focused ultrasound treatment was technically successful in 115 of 123 patients (93.5%). In 8 patients, treatment was not possible because of bowel loops in the beam pathway that could not be mitigated (n = 6), patient movement (n = 1), and system malfunction (n = 1). Mean nonperfused volume ratio was 88% ± 15% (range, 38%-100%). Mean applied energy level was 5400 ± 1200 J, and mean number of sonications was 74 ± 27. No major complications occurred. Two cases of first-degree skin burn resolved within 1 week after the intervention. Of the baseline characteristics analyzed, only the planned treatment volume had a statistically significant impact on nonperfused volume ratio. Reviewers concluded with technological advancement, the outcome of MRI-guided focused ultrasound treatment in terms of the nonperfused volume ratio can be enhanced with a high safety profile, markedly exceeding results reported in previous clinical trials. Scientific Rationale Update November 2012 Venkatesan et al (2012) et al described the preliminary safety and accuracy of a magnetic resonance (MR) imaging-guided high-intensity-focused ultrasound (HIFU) system employing new technical developments, including ablation control via volumetric thermal feedback, for the treatment of uterine leiomyomata with histopathologic correlation. In this phase I clinical trial, 11 women underwent MRguided HIFU ablation (Sonalleve 1.5T; Philips Medical Systems, Vantaa, Finland), followed by hysterectomy within 30 days. Adverse events, imaging findings, and pathologic confirmation of ablation were assessed. The relationship between MR MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 5

6 imaging findings, thermal dose estimates, and pathology and HIFU spatial accuracy were assessed using Bland-Altman analyses and intraclass correlations. There were 12 leiomyomata treated. No serious adverse events were observed. Two subjects decided against having hysterectomy and withdrew from the study before surgery. Of 11 women, 9 underwent hysterectomy; all leiomyomata demonstrated treatment in the expected location. A mean ablation volume of 6.92 cm(3) ± 10.7 was observed at histopathologic examination. No significant differences between MR imaging nonperfused volumes, thermal dose estimates, and histopathology ablation volumes were observed (P >.05). Mean misregistration values perpendicular to the ultrasound beam axis were 0.8 mm ± 1.2 in feet-head direction and 0.1 mm ± 1.0 in and left-right direction and -0.7 mm ± 3.1 along the axis. Zhao et al (2012) retrospectively investigated whether uterine fibroids with hyperintense on pretreatment T2-weighted MRI could be treated with ultrasoundguided high intensity focused ultrasound (USgHIFU). 282 patients with 282 symptomatic uterine fibroids who underwent USgHIFU treatment were retrospectively analyzed. Based on the signal intensity of T2-weighted MRI, uterine fibroids were classified as hypointense, isointense and hyperintense. Hyperintense fibroids were subjectively further subdivided into heterogeneous hyperintense, slightly homogeneous hyperintense and markedly homogeneous hyperintense based on the signal intensity of fibroid relative to myometrium and endometrium on T2- weighted MRI. Enhanced MRI was performed within one month after HIFU treatment. Non-perfused volume (NPV, indicative of successful ablation) ratio, treatment time, treatment efficiency, energy effect ratio and adverse events were recorded. The median volume of uterine fibroids was 70.3cm(3) (interquartile range, cm(3)). The average NPV ratio, defined as non-perfused volume divided by the fibroid volume after HIFU treatment, was 76.8±19.0% (range, 0-100%) in the 282 patients. It was 86.3±11.9% (range, %) in the group with hypointense fibroids, 77.1±16.5% (range, %) in isointense fibroids, and 67.6±23.9% (range, %) in hyperintense fibroids. The lowest NPV ratio, lowest treatment efficiency, more treatment time, more sonication energy and pain scores were observed in the slightly homogeneous hyperintense fibroids, and the NPV ratio was 55.8±26.7% (range, %) in this subgroup. Investigators concluded based on their results, the heterogeneous and markedly homogeneous hyperintense fibroids were suitable for USgHIFU, and only the slightly homogeneous hyperintense fibroids should be excluded. Kim et al (2012) evaluated initial clinical outcomes of volumetric MR-guided HIFU ablation by using a one-layer strategy to treat large (>10 cm in diameter) uterine fibroids, with investigation of the correlation between effectiveness of the one-layer strategy and dynamic contrast material-enhanced (DCE) MR parameters. Twentyseven women (mean age, 44.5 years) with 27 large uterine fibroids (mean diameter, 11.3 cm ± 1.4 [standard deviation] [range, cm]; fibroid volume, ml ± [range, ml]) underwent volumetric MR-guided HIFU ablation with a one-layer strategy. (All treatment cells were placed in one coronal plane at a depth of half to anterior two-thirds of the anteroposterior dimension of fibroids.) Treatment time, immediate nonperfused volume (NPV), and effectiveness of a onelayer strategy (ratio of immediate NPV to total volume of treatment cells planned) correlating with baseline DCE MR parameters (volume transfer constant [K(trans)], fractional extravascular extracellular space, and fractional blood plasma volume [Pearson correlation test]), complications, 3-month follow-up volumes, and symptom severity score (SSS) changes (paired t test) were assessed retrospectively. All treatments showed technical success in one session (mean treatment time, MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 6

7 minutes ± 38.9). NPV was ml ± 119.1, which was 64.2% ± 19.9 (<50%, n = 4; 50%, n = 23) of fibroid volume. Ratio of immediate NPV to total volume of treatment cells (1.79 ± 0.61) negatively correlated with DCE MR imaging K(trans) values (r = , P =.017). Minor complications occurred in five patients (18.5% [thermal injury of abdominal wall, n = 3; 30-day leg numbness, n = 1; cystitis, n = 1]). At 3-month follow-up (n = 18), mean SSS had decreased from 37.4 at baseline to 24.0 (P <.001), and volume reduction ratio was 0.64 ± 0.15 (P <.001). Investigators concluded volumetric MR-guided HIFU ablation with a one-layer strategy is safe and effective for treatment of large uterine fibroids. Effectiveness of this strategy showed a significant negative correlation with K(trans) values at baseline DCE MR imaging. Voogt et al (2012) assessed the safety and technical feasibility of volumetric MR- HIFU ablation for treatment of patients with symptomatic uterine fibroids in a prospective multicenter study. Thirty-three patients with 36 fibroids were treated with volumetric MR-HIFU ablation. Treatment capability and technical feasibility were assessed by comparison of the NPVs with MR thermal dose predicted treatment volumes. Safety was determined by evaluation of complications or adverse events and unintended lesions. Secondary endpoints were pain and discomfort scores, recovery time and length of hospital stay. The mean NPV calculated as a percentage of the total fibroid volume was 21.7%. Correlation between the predicted treatment volumes and NPVs was found to be very strong, with a correlation coefficient r of All patients tolerated the treatment well and were treated on an outpatient basis. No serious adverse events were reported and recovery time to normal activities was 2.3±1.8 days. Investigators concluded that volumetric MR-HIFU is safe and technically feasible for the treatment of symptomatic uterine fibroids. Scientific Rationale Update November 2011 Kim et al. (2011) completed a study in which a total of 10 symptomatic uterine fibroids (diameter: mean, 8.9 cm; range, cm) in 10 female patients (mean age, 42.2 years) were treated with MRI guided ultrasound therapy using the volumetric ablation technique. MRI and conventional contrast-enhanced MRI were obtained as a baseline and as an immediate follow-up study, respectively. After regions of interest of each treatment cell were properly registered to both MRI studies, dynamic contrast-enhanced (DCE) MRI parameters (K, ve, vp) and operatorcontrollable therapy parameters (power, treatment cell size, sonication depth) were investigated on a cell-by-cell basis to reflect tissue inhomogeneity. Two types of ablation efficacy indices (volume of 240 equivalent minutes at 43 C/treatment-cell volume, nonperfused volume/treatment-cell volume) were then correlated with those parameters using multiple linear regression analysis to determine which factors were significant predictors for ablation efficacy. The author used 293 treatment cells (4 mm, n = 12; 8 mm, n = 115; 12 mm, n = 149; 16 mm, n = 17), and all of them were analyzable. Ablation efficacies were 1.06 ± 0.58 and 0.67 ± K (B = , P < and B = , P < 0.001, respectively) among DCE-MRI parameters and acoustic power (B = 0.008, P < 0.001; B = 0.010, P < 0.001, respectively) among therapy parameters were revealed to be independently significant predictors for both types of ablation efficacy. A higher K value at baseline DCE-MRI suggested a poor ablation efficacy of MRI guided ultrasound therapy for symptomatic uterine fibroids. Additional studies or clinical trials are necessary to determine the long-term efficacy and safety. The Agency for Healthcare Research and Quality (AHRQ, 2007) notes The strength of evidence about MRI-guided ultrasound ablation of fibroids is weak, although we MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 7

8 identified one carefully conducted prospective case series. Overall, the study suggested reasonable tolerance (16 percent of women reported severe pain at some point during the treatment and 8 percent reported severe to moderate pain after the procedure), improvement in quality of life (71 percent improved), and modest change in fibroid size (13 percent decrease). During more than a year of follow-up, 11 percent of women experienced worsened symptoms; 28 percent elected further treatment including myomectomy and hysterectomy. There have been a number of Clinical Trials on MRI Guided Ultrasound Ablation of Uterine Fibroids. Some have recently been completed with no study results posted. A Phase III Clinical Trial on Therapeutic MRI Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids (HIFU) is currently recruiting members. The ClinicalTrials.gov Identifier is NCT The purpose of this study is to collect supplementary safety and technical effectiveness data of MRI guided ultrasound in ablating uterine tissue associated with symptomatic fibroids in a 3T MRI scanner. The importance of this therapy is that it offers a non-invasive, uterine sparing procedure for the treatment of uterine fibroids in pre and perimenopausal women. MRI guided ultrasound is used to heat and thermally ablate fibroid tissue. The MRI system identifies the ultrasound path and monitors heat rise in the fibroid tissue. The goal of the study is to collect supplementary 3T treatment safety and technical effectiveness data in a 1 month follow-up study. MR guided HIFU will be performed in patients who pass inclusion/exclusion criteria. Safety, quality of life, and imaging endpoints will be evaluated in all study patients. The study was verified on March Scientific Rationale Update February 2011 Magnetic resonance imaging-guided focused ultrasound surgery has been investigated as a noninvasive treatment for symptomatic uterine myomas. Results of studies suggest that the procedure provides short- and mid-term benefits for most patients who have uterine fibroids; however, the long-term efficacy of this procedure is unknown. Taran et al (2009) compared women undergoing magnetic resonance-guided focused ultrasound (MRgFUS) to a group of contemporaneously recruited women undergoing total abdominal hysterectomy. Patient demographics, safety parameters, quality of life outcomes and disability measures are reported. One hundred and nine women were recruited in seven centers for MRgFUS treatment and 83 women who underwent abdominal hysterectomy were recruited in seven separate centers to provide contemporaneous assessment of safety. The adverse-event profile and disability parameters were prospectively assessed. Patients were also screened at baseline and at 1, 3 and 6 months using the SF-36 health survey questionnaire. There were no life-threatening adverse events in either group. Overall, the number of significant clinical complications and adverse events was lower in women in the MRgFUS group compared to women undergoing hysterectomy. MRgFUS was associated with significantly faster recovery, including resumption of usual activities. At 6 months of follow-up, there were four (4%) treatment failures in the MRgFUS arm. Regarding SF-36 subscale scores, at 6 months there was improvement in all SF-36 subscales for both treatment groups. However, most of the SF-36 subscale scores were significantly better at this stage in the hysterectomy group than in the MRgFUS group. Women undergoing MRgFUS had steady improvement in all parameters throughout the 6-month follow-up period, despite the fact that they continued to have myomatous uteri and menstruation, which at baseline had given them significant symptomatology. The investigators concluded results of this study show that MRgFUS treatment of uterine leiomyomas leads to clinical improvement MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 8

9 with fewer significant clinical complications and adverse events compared to hysterectomy at 6 months' follow-up. Furnaki et al (2009) assessed the volume reduction ratio, symptom improvement and reintervention rate following magnetic resonance-guided focused ultrasound surgery (MRgFUS) for uterine myomas. A total of 91 Japanese women with symptomatic myomas underwent MRgFUS between June 2004 and June 2008 using the ExAblate 2000 system. The volume change ratio was calculated at 6, 12 and 24 months following MRgFUS based on T2-weighted magnetic resonance images. The symptom severity score (SSS) was examined before and after the treatment (at 3, 6, 12 and 24 months). Additional post-mrgfus treatments, such as hysterectomy, myomectomy, uterine artery embolization or repeat MRgFUS, were recorded and the reinterventional treatment rates were compared according to the signal intensity of pretreatment T2-weighted magnetic resonance images of the myomas. The mean volume change ratios of low- and intermediate-intensity (Type 1/2) myomas were % 6 months post-procedure and -39.5% 24 months post-procedure. The mean +/- SD SSS value for patients with Type 1/2 myomas before MRgFUS was /- 21.0, and the values diminished significantly during the 24-month follow-up period to a mean value of around High-intensity (Type 3) myomas were not observed to have decreased in size 6 months after MRgFUS. Of the 45 Type 1/2 myoma patients with complete follow-up, seven required reinterventional treatment within 24 months. The reintervention rates were 14.0% for Type 1/2 patients and 21.6% for Type 3 patients at 24 months post-treatment. The investigators concluded moderate volume reductions of Type 1/2 myomas were noted following MRgFUS, and the reduction in SSS values and the relatively low reintervention rates observed are encouraging. We found MRgFUS to be an appropriate treatment method for Type 1/2 uterine myomas. Clinical trials are ongoing. In 2010, the American Congress of Obstetricians and Gynecologists reaffirmed their practice guideline on alternatives to hysterectomy in the management of leiomyomas (Aug. 2008). Regarding MRI-guided focused ultrasound surgery the guideline states: Whereas short-term studies show safety and efficacy, long-term studies are needed to discern whether the minimally invasive advantage of MRI-guided focused ultrasound surgery will lead to durable results beyond 24 months. Protocols for treating larger leiomyoma volumes are being studied. Scientific Rationale Update February 2010 LeBlang et al (2009) assessed the degree of leiomyoma ablation and shrinkage after MRI-guided focused ultrasound treatment in 147 symptomatic leiomyomas in 80 women. The average volume of treated fibroids was 175+/-201 (SD) cm3. Before treatment, T2-weighted MR images in three planes were obtained to measure leiomyoma volume. Immediately after treatment, T1-weighted contrast-enhanced fat-suppressed MR images in three planes were used to measure nonperfused volume ratio. Similar images obtained 6 months after treatment were used to determine leiomyoma shrinkage. Qualitative and quantitative relations between fibroid volume, nonperfused volume ratio at treatment, and 6-month shrinkage were measured. The authors reported that the average nonperfused volume ratio was 55%+/-25% immediately after treatment. Six months after treatment, the average volume of treated fibroids had decreased to 112+/-141 cm3 (n=81) with an average volume reduction of 31%+/-28%. A linear regression model showed highly significant correlation between posttreatment nonperfused volume ratio and MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 9

10 shrinkage at 6 months. The author concluded that MRI-guided focused ultrasound therapy for leiomyoma can result in nonperfused volume ratio and shrinkage that exceed those in previous clinical trials because the treatment guidelines have been relaxed to allow a greater amount of tissue ablation. The results suggest that a larger nonperfused volume ratio can be achieved, resulting in greater shrinkage and improved relief of symptoms. Morita et al (2009) investigated the safety of magnetic resonance-guided focused ultrasound surgery (MRgFUS) treatments regardless of the distance between the treatment region and the uterine serosa. 83 pre-menopausal women with symptomatic uterine fibroids were treated with MRgFUS in 88 treatments. Treatment data was analyzed, measuring the distance between the treatment spots (sonications) and the serosa. Patients were followed up for 1 year and adverse events were collected. 79% and 37% of the sonications were less than 15 mm and 10 mm from the serosa, respectively. Treatment was always confined to the fibroid capsule. There were no unexpected or serious adverse events. The author concluded that reducing the margin between the fibroid treatment area and the uterine serosa, when possible, enables MRgFUS treatment of greater fibroid volume, while maintaining a high safety profile. Special attention should be paid when the uterus lies adjacent to other sensitive organs to avoid unintentional heating of these organs, using the planning and real-time MR images. According to a practice guideline from the American Congress of Obstetricians and Gynecologists on alternatives to hysterectomy in the management of leiomyomas (Aug. 2008), regarding MRI-guided focused ultrasound surgery: Whereas short-term studies show safety and efficacy, long-term studies are needed to discern whether the minimally invasive advantage of MRI-guided focused ultrasound surgery will lead to durable results beyond 24 months. Protocols for treating larger leiomyoma volumes are being studied. At this time, studies are needed to needed to determine the optimal candidates for this procedure and the optimal fibroid size threshold for MRgFUS. Comparative studies wilth long-term outcome data is also necessary. Several clinical trials are ongoing, and some are actively recruiting for participants, including a study that compares magnetic resonance imaging-guided ultrasound surgery (MRgFUS) to uterine artery embolization (UAE). Scientific Rationale Update January 2008 (NICE, 2007) The National Institute for Health and Clinical Excellence released an interventional procedures consultation that concluded that "current evidence on the safety and efficacy of 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 one study group has reported a majority of published data. 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. MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 10

11 Results of the available studies suggest that the ExAblate procedure provides shortand mid-term benefits for most patients who have uterine fibroids; however, the long-term efficacy of this procedure is unknown. Although the largest available study found that more extensive fibroid ablation was associated with statistically significant reductions in symptom severity, a gradual worsening of symptoms was observed between 6 and 24 months of follow-up, regardless of the extent of ablation. The investigators did not report whether this worsening trend was statistically significant. Further evidence of the lack of long-term efficacy of the ExAblate procedure was obtained in a smaller study, which reported that, in spite of ablation of 56% of the mean volume of fibroids, 39% of treated fibroids began to regrow within 12 months after treatment. The lack of durability of ExAblate treatment may also be reflected in the frequency with which patients seek additional or alternate fibroid treatments after the ExAblate procedure. At 12-month follow-up in one arm of the largest available study, 28% of patients had sought additional or alternate fibroid treatment despite undergoing the more aggressive of two ExAblate treatment protocols. Further studies are needed to determine the long-term efficacy of the ExAblate procedure, to assess whether modifications to this procedure improve its long-term efficacy, and to evaluate the efficacy and safety of the ExAblate procedure relative to other treatments for uterine fibroids. Scientific Rationale Initial Uterine leiomyomata or fibroids are benign tumors of the uterus made up of groups of muscle cells and the extracellular matrix proteins collagen and elastin. Uterine fibroids are most common among women in the reproductive years but can occur at any age. There is a higher incidence of uterine fibroids in black women than white women. Although most women with uterine fibroids are asymptomatic, in some women fibroids can cause significant problems due to their size, number, and location. Symptoms may include abnormal uterine bleeding, anemia, dysmenorrhea, and noncyclic pelvic pain. Fibroids can also contribute to symptoms related to an enlarging pelvic mass such as urinary frequency or constipation. Symptoms associated with fibroids can have a significant impact on quality of life. Traditional therapies in the treatment of uterine fibroids have included medical and surgical options. Surgery is the mainstay of therapy for uterine fibroids. Hysterectomy and various myomectomy procedures are considered the gold standard treatment. Gonadotropin-releasing hormone (GnRH) agonists are the most effective medical therapy for uterine fibroids, however, they are primarily utilized pre-operatively in an effort to increase the hematocrit, decrease uterine size and reduce procedure related blood loss. GnRH agonists work by initially increasing the release of gonadotropins, followed by desensitization and downregulation to a hypogonadotropic, hypogonadal state clinically resembling menopause. Amenorrhea, improvement in hematologic parameters, and a significant reduction in uterine size usually occurs within three months of initiating therapy but there is rapid resumption of menses and pretreatment uterine volume after discontinuation of the medication. In addition, significant symptoms often accompany administration of GnRH agonists, such as bone loss, as a result from the severe hypoestrogenism. Add-back therapy with an estrogen-progestin after the initial phase of downregulation may minimize the side effects of long-term GnRH-analog administration. In rare cases, GnRHagonists may be used in women close to menopause or with acute medical contraindications to surgery. MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 11

12 There has been longstanding research interest in developing minimally invasive alternatives including endometrial ablation, various laparoscopic ablation procedures using differing energy sources (i.e., laser, radiofrequency ablation, or cryotherapy) and uterine artery embolization. Recently there has been interest in using high intensity focused ultrasound treatment that is guided by magnetic resonance imaging (MRI) as a totally noninvasive approach to the ablation of uterine fibroids. The ultrasound beam penetrates through the soft tissues and, using MRI for guidance and monitoring, the beam can be focused on targeted sites. The ultrasound causes a local increase in temperature in the target tissue, resulting in coagulation necrosis while sparing the surrounding normal structures. In addition to providing guidance, the associated MRI imaging can provide on-line thermometric imaging that provides a temperature "map" that can further confirm the therapeutic effect of the ablation treatment and allow for real time adjustment of the treatment parameters. In October 2004, the U.S. Food and Drug Administration (FDA) approved via the Premarket Application (PMA) process, the ExAblate 2000 for the treatment of symptomatic uterine fibroids in women who have completed childbearing and desire a uterine sparing treatment. Per the FDA, women should be pre- or peri-menopausal and have a uterine volume of less than 24 weeks. The noninvasive surgical technique, using the ExAblate 2000 combines a focused ultrasound beam that heats and destroys the uterine fibroid tissue using high-frequency, high-energy sound waves along with MRI and thermal mapping system to visualize patient anatomy, map the volume of fibroid tissue to be treated, and monitor the temperature of the uterine tissue after heating. Per the FDA, the ExAblate system is contraindicated in women metallic implants, or sensitivity to MRI contrast agents; obstructions in the treatment beam path, such as a scar, skin fold or irregularity, bowel, pubic bone, IUD (intrauterine device), surgical slips, or any hard implants; and fibroids that are close to sensitive organs such as the bowel or bladder, or are outside the image area. At this time, there is no other MRI-focused ultrasound technologies approved by the FDA. The FDA is requiring 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 will include additional numbers of African-American women, because, as a group, these women have a greater incidence of uterine fibroids but were underrepresented in the original study. There is minimal published data regarding MRI-guided high-intensity focused ultrasound ablation of uterine fibroids. The pivotal trial included 192 women who had symptomatic uterine fibroids and were randomized to a hysterectomy (83) or the ExAblate procedure (109). The study was initially designed to provide follow-up at 3 and 6 months post-treatment. A longer follow-up period with visits at 12, 24, and 36 months was subsequently added. 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, but this dereased to 38.5% at 12 months. Within 1 year, 21% required an alternative treatment for fibroids. A Tec assessment by Blue Cross Blue Shield (October 2005) found that 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. At least 1-2 years of follow-up data are needed to understand the durability of any early treatment effect. The Canadian Coordinating Office for Health Technology Assessment (COHTA) concluded in a tech assessment (July 2005) that early results from small sample MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 12

13 studies indicate that magnetic resonance imaging guided focused ultrasound (MRgFUS) may provide short-term symptom relief with shorter recovery time and few reported major adverse effects but that long-term studies with larger patient groups are needed to provide further reliable evidence on the safety and clinical effectiveness. Stewart et al. (2006) assessed 109 women at 6 months and 82 women at 12 months following magnetic resonance-guided focused ultrasound surgery (MRgFUS) for symptomatic uterine leiomyomas. The investigators reported good short-term results with 71 percent decrease in fibroid-related symptoms at six months and 51 percent decrease at 12 months. In an earlier study by Stewart et al. (2003) 55 women were treated MRgFUS for symptomatic uterine leiomyomas. Pain and complications were assessed prospectively, and post-treatment magnetic resonance imaging was used to measure the treatment effects. Patients in three of the five centers underwent planned hysterectomy after treatment, which provided pathologic correlation of treatment. Seventy-six percent of the enrolled patients completed the full treatment session. Pathologic examination of the uterus confirmed that magnetic resonance imaging guidance provides the safe and accurate delivery of effective levels of thermal energy with a 3-fold increase in volume of histologically documented necrosis, compared with treatment volume. Smart et al. (2006) investigated the ablative effect of magnetic resonance guided focused ultrasound (MRgFUS) on fibroid tissue following the administration of gonadotrophin releasing hormone (GnRH) agonist. Fifty women with clinically symptomatic uterine fibroids with uterine diameter of 10 cm or greater were given 3 months pre-treatment with GnRH agonists. Twenty-seven patients were given GnRH agonist therapy prior to MRgFUS while 23 women underwent MRgFUS without pretreatment. In the patients who received GnRH agonists, the volume of ablation was significantly larger than that in the control group (0.06 cm3 versus 0.03 cm3) leading the investigator to conclude that the use of GnRH agonists potentiates the thermal effects of MRgFUS in women undergoing treatment of uterine fibroids. At this time, neither the American College of Obstetricians and Gynecologists (ACOG) nor the Society of Interventional Radiology has issued any statement or position on the use of MRgFUS. While MRI guided ultrasound ablation of uterine fibroids appears to be well tolerated, there is no long-term efficacy data published in the peer review literature. The literature does not adequately address the potential for regrowth of treated fibroids over time. Follow up with large long-term studies are needed to provide reliable evidence on the safety and efficacy as well as determining optimal candidates for this procedure. Large, well-controlled comparative studies to established effective treatments are also needed. At this time, InSightec is also conducting studies to evaluate the safety and effectiveness of MRgFUS for the palliation of pain due to bone metastases, treatment of liver malignancies, early breast tumors and brain lesions. Review History January 2007 Medical Advisory Council, initial approval January 2008 Update No revisions MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 13

14 February 2009 Update no revisions February 2010 Update no revisions February 2011 Update no revisions November 2011 Update. Added Revised Medicare Table. No revisions. November 2012 Update no revisions November 2013 Update no revisions. Codes updated. November 2014 Update no revisions November 2015 Update no revisions This policy is based on the following evidence-based guidelines: 1. Hayes Alert Technology Assessment Brief. ExAblate 2000 System for Ablation of Uterine Fibroids. Volume VIII. Number 5. May U.S. Food and Drug Administration. ExAblate 2000 System. American College of Obstetricians and Gynecologists (ACOG). Surgical alternatives to hysterectomy in the management of leiomyomas. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2000 May. 10 p. (ACOG practice bulletin; no. 16). 3. MRI-guided focused ultrasound for treatment of uterine fibroids. The Canadian Coordinating Office for Health Technology Assessment (CCOHTA). July Blue Cross Blue Shield Technology Evaluation Center. Magnetic Resonance- Guided Focused Ultrasound Therapy for Symptomatic Uterine Fibroids. Volume 20. Number 10. October National Institute for Health and Clinical Excellence (NICE). Magnetic resonance image-guided focused ultrasound for uterine fibroids. Interventional Procedures Consultation Document. London, UK: NICE; February American College of Obstetricians and Gynecologists (ACOG). Alternatives to hysterectomy in the management of leiomyomas. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2008 Aug. 14 p. (ACOG practice bulletin; no. 96). Reaffirmed Reaffirmed Reaffirmed Agency for Healthcare Research and Quality (AHRQ). Management of Uterine Fibroids: An Update of the Evidence. Evidence Report/Technology Assessment. Number 154. AHRQ Publication No. 07-E011. July National Institute for Health and Clinical Excellence (NICE). Magnetic resonance image-guided transcutaneous focused ultrasound for uterine fibroids. Nov Available at: 9. Hayes Health Technology Brief. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) Therapy (ExAblate; InSightec Ltd.) for Ablation of Uterine Fibroids. Mar Update Mar 2015 References Update November Ferrari F, Arrigoni F, Miccoli A, et al. Effectiveness of Magnetic Resonanceguided Focused Ultrasound Surgery (MRgFUS) in the uterine adenomyosis treatment: technical approach and MRI evaluation. Radiol Med Sep Gorny KR, Borah BJ, Brown DL, et al. Incidence of additional treatments in women treated with MR-guided focused US for symptomatic uterine fibroids: review of 138 patients with an average follow-up of 2.8 years. J Vasc Interv Radiol Oct;25(10): Ikink ME, Nijenhuis RJ, Verkooijen HM, et al. Volumetric MR-guided highintensity focused ultrasound versus uterine artery embolisation for treatment of symptomatic uterine fibroids: comparison of symptom improvement and reintervention rates. Eur Radiol Oct;24(10): Kim YS, Kim BG, Rhim H, et al. Uterine fibroids: semiquantitative perfusion MR imaging parameters associated with the intraprocedural and immediate MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 14

15 postprocedural treatment efficiencies of MR imaging-guided high-intensity focused ultrasound ablation. Radiology Nov;273(2): Leung JH, Yu SC, Cheung EC, et al. Safety and efficacy of sonographically guided high-intensity focused ultrasound for symptomatic uterine fibroids: preliminary study of a modified protocol. J Ultrasound Med Oct;33(10): Mindjuk I, Trumm CG, Herzog P, et al. MRI predictors of clinical success in MRguided focused ultrasound (MRgFUS) treatments of uterine fibroids: results from a single centre. Eur Radiol May;25(5): Orsi F, Monfardini L, Bonomo G, et al. Ultrasound guided high intensity focused ultrasound (USgHIFU) ablation for uterine fibroids: Do we need the microbubbles? Int J Hyperthermia May;31(3): Quinn SD, Vedelago J, Gedroyc W, Regan L. Safety and five-year reintervention following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids. Eur J Obstet Gynecol Reprod Biol Nov;182: Ren D, Wang W, Wang Y, et al. Ultrasound-guided focused ultrasound ablation of intramural, submucosal and subserosal uterine fibroids: 12-month follow-up results Nan Fang Yi Ke Da Xue Xue Bao Jun;34(7): Savic LJ, Lin MD, Duran R, et al. Three-Dimensional Quantitative Assessment of Lesion Response to MR-guided High-Intensity Focused Ultrasound Treatment of Uterine Fibroids. Acad Radiol Sep;22(9): Thiburce AC, Frulio N, Hocquelet A, et al. Magnetic resonance-guided highintensity focused ultrasound for uterine fibroids: Mid-term outcomes of 36 patients treated with the Sonalleve system. Int J Hyperthermia Nov;31(7): Zhang L, Zhang W, Orsi F, et al. Ultrasound-guided high intensity focused ultrasound for the treatment of gynaecological diseases: A review of safety and efficacy. Int J Hyperthermia May;31(3): Zhao WP, Han ZY, Zhang J, Liang P. A retrospective comparison of microwave ablation and high intensity focused ultrasound for treating symptomatic uterine fibroids. Eur J Radiol Mar;84(3): References Update November Froeling V, Meckelburg K, Schreiter NF, et al. Outcome of uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for uterine fibroids: long-term results. Eur J Radiol Dec;82(12): Froeling V, Meckelburg K, Scheurig-Muenkler C, et al. Midterm results after uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for symptomatic uterine fibroids. Cardiovasc Intervent Radiol Dec;36(6): Gorny KR, Borah BJ, Brown DL, et al. Incidence of Additional Treatments in Women Treated with MR-Guided Focused US for Symptomatic Uterine Fibroids: Review of 138 Patients with an Average Follow-up of 2.8 Years. J Vasc Interv Radiol Oct;25(10): Ikink ME, Nijenhuis RJ, Verkooijen HM, et al. Volumetric MR-guided highintensity focused ultrasound versus uterine artery embolisation for treatment of symptomatic uterine fibroids: comparison of symptom improvement and reintervention rates. Eur Radiol Oct;24(10): Ikink ME, Voogt MJ, Verkooijen HM, et al. Mid-term clinical efficacy of a volumetric magnetic resonance-guided high-intensity focused ultrasound technique for treatment of symptomatic uterine fibroids. Eur Radiol Nov;23(11): MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 15

16 6. Kim YS, Kim BG, Rhim H, et al. Uterine Fibroids: Semiquantitative Perfusion MR Imaging Parameters Associated with the Intraprocedural and Immediate Postprocedural Treatment Efficiencies of MR Imaging-guided High-Intensity Focused Ultrasound Ablation. Radiology Jul 1: Park MJ, Kim YS, Rhim H, Lim HK. Safety and therapeutic efficacy of complete or near-complete ablation of symptomatic uterine fibroid tumors by MR imagingguided high-intensity focused US therapy. J Vasc Interv Radiol Feb;25(2): Rueff LE, Raman SS. Clinical and Technical Aspects of MR-Guided High Intensity Focused Ultrasound for Treatment of Symptomatic Uterine Fibroids. Semin Intervent Radiol Dec;30(4): Trumm CG, Stahl R, Clevert DA, et al. Magnetic resonance imaging-guided focused ultrasound treatment of symptomatic uterine fibroids: impact of technology advancement on ablation volumes in 115 patients. Invest Radiol Jun;48(6): Zucconi F, Colombo PE, Pasetto S, et al. Analysis and reduction of thermal dose errors in MRgFUS treatment. Phys Med Feb;30(1): References Update November Park MJ. Volumetric MR-guided high-intensity focused ultrasound ablation of uterine fibroids: treatment speed and factors influencing speed. Eur Radiol. 01 APR 2013; 23(4): Townsend: Sabiston Textbook of Surgery, 19th ed.2012 Saunders, An Imprint of Elsevier. Image-Guided Ablative Therapies. References Update November Dobrotwir A, Pun E..Clinical 24 month experience of the first MRgFUS unit for treatment of uterine fibroids in Australia. J Med Imaging Radiat Oncol Aug;56(4): Eckey T, Neumann A, Bohlmann MK, et al. Non-invasive thermoablation of symptomatic uterine fibroids with magnetic resonance-guided high-energy ultrasound. Radiologe Jul;51(7): Hesley GK, Gorny KR, Woodrum DA. MR-Guided Focused Ultrasound for the Treatment of Uterine Fibroids. Cardiovasc Intervent Radiol Mar Kim YS, Kim JH, Rhim H, et al. Volumetric MR-guided high-intensity focused ultrasound ablation with a one-layer strategy to treat large uterine fibroids: initial clinical outcomes. Radiology May;263(2): Venkatesan AM, Partanen A, Pulanic TK, et al. Magnetic resonance imagingguided volumetric ablation of symptomatic leiomyomata: correlation of imaging with histology. J Vasc Interv Radiol Jun;23(6): e4. 6. Voogt MJ, Trillaud H, Kim YS, et al. Volumetric feedback ablation of uterine fibroids using magnetic resonance-guided high intensity focused ultrasound therapy. Eur Radiol Feb;22(2): Voogt MJ, van Stralen M, Ikink ME, et al. Targeted vessel ablation for more efficient magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroids. Cardiovasc Intervent Radiol Oct;35(5): Zhao WP, Chen JY, Zhang L, et al. Feasibility of ultrasound-guided high intensity focused ultrasound ablating uterine fibroids with hyperintense on T2-weighted MR imaging. Eur J Radiol Sep 20. pii: S X(12)00407-X. References Update November 2011 MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 16

17 1. Clinicaltrials.gov. Therapeutic MRI Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids. ClinicalTrials.gov Identifier is NCT March 2, Available at: +Ablation+of+Uterine+Fibroids&rank=2 2. Goldman: Goldman's Cecil Medicine, 24th ed. Uterine Fibroids Saunders, An Imprint of Elsevier. 3. Gorny KR, Woodrum DA, Brown DL, et al. Magnetic resonance-guided focused ultrasound of uterine leiomyomas: review of a 12-month outcome of 130 clinical patients. J Vasc Interv Radiol Jun;22(6): Epub 2011 Apr Kim YS, Lim HK, Kim JH, et al. Dynamic contrast-enhanced magnetic resonance imaging predicts immediate therapeutic response of magnetic resonance-guided high-intensity focused ultrasound ablation of symptomatic uterine fibroids. Invest Radiol Oct; 46 (10): Stewart EA. Overview of treatment of uterine leiomyomas (fibroids). December 1, UpToDate. Updated July 19, Wang T, Wang W, Chen WZ, et al. Efficacy and safety of focused ultrasound ablation in treatment of submucosal uterine fibroids. Zhonghua Fu Chan Ke Za Zhi Jun;46(6): Zhang L, Chen WZ, Liu YJ, et al. Feasibility of magnetic resonance imagingguided high intensity focused ultrasound therapy for ablating uterine fibroids in patients with bowel lies anterior to uterus. Eur J Radiol Feb;73 (2): Epub 2008 Dec 23. References Update February Behera MA, Leong M, Johnson L, Brown H. Eligibility and accessibility of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of uterine leiomyomas. Fertil Steril Oct;94(5): Chen WZ, Tang LD, Yang WW, et al. Study on the efficacy and safety of ultrasound ablation in treatment of uterine fibroids. Zhonghua Fu Chan Ke Za Zhi Dec;45(12): Funaki K, Fukunishi H, Sawada K. Clinical outcomes of magnetic resonanceguided focused ultrasound surgery for uterine myomas: 24-month follow-up. Ultrasound Obstet Gynecol Nov;34(5): LeBlang SD, Hoctor K, Steinberg FL. Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: report of 80 patients. AJR Am J Roentgenol Jan;194(1): Taran FA, Tempany CM, Regan L, et al. Magnetic resonance-guided focused ultrasound (MRgFUS) compared with abdominal hysterectomy for treatment of uterine leiomyomas. Ultrasound Obstet Gynecol Nov;34(5): References Update February Clinical trials.gov. Uterine Fibroid Treatment: Magnetic Resonance Imagingguided Ultrasound Surgery (MRgFUS) Versus Uterine Artery Embolization (UAE). 2. de Melo FC, Diacoyannis L, Moll A, Tovar-Moll F. Reduction by 98% in uterine myoma volume associated with significant symptom relief after peripheral treatment with magnetic resonance imaging-guided focused ultrasound surgery. J Minim Invasive Gynecol Jul-Aug;16(4): Jolesz FA. MRI-guided focused ultrasound surgery. Annu Rev Med. 2009;60: LeBlang SD, Hoctor K, Steinberg FL. Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: report of 80 patients. AJR Am J Roentgenol Jan;194(1): MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 17

18 5. Morita Y, Takeuchi S, Hikida H, et al. Decreasing margins to the uterine serosa as a method for increasing the volume of fibroids ablated with magnetic resonance-guided focused ultrasound surgery. Eur J Obstet Gynecol Reprod Biol Sep;146(1): Zaher S, Gedroyc WM, Regan L. Patient suitability for magnetic resonance guided focused ultrasound surgery of uterine fibroids. Eur J Obstet Gynecol Reprod Biol Apr;143(2): References Update February Mikami K, Murakami T, Okada A, et al. Magnetic resonance imaging-guided focused ultrasound ablation of uterine fibroids: early clinical experience. Radiat Med May; 26(4): Fennessy FM, Tuncali K, Morrison PR, Tempany CM. MR imaging-guided interventions in the genitourinary tract: an evolving concept. Radiol Clin North Am Jan; 46(1): , vii. References Update January Fennessy FM, Tempany CM, McDannold Uterine leiomyomas: MR imaging-guided focused ultrasound surgery--results of different treatment protocols. Radiology 2007; 243(3): Ren XL, Zhou XD, Zhang J, et al. Extracorporeal ablation of uterine fibroids with high-intensity focused ultrasound: imaging and histopathologic evaluation. J Ultrasound Med. 2007; 26(2): InSightec. ExAblate Available at: 3&lang=EN&res=0. 4. Zhou XD, Ren XL, Zhang J, et al. Therapeutic response assessment of high intensity focused ultrasound therapy for uterine fibroid: utility of contrastenhanced ultrasonography. Eur J Radiol. 2007; 62(2): Funaki K, Fukunishi H, Funaki T, et al. Magnetic resonance-guided focused ultrasound surgery for uterine fibroids: relationship between the therapeutic effects and signal intensity of preexisting T2-weighted magnetic resonance images. Am J Obstet Gynecol. 2007; 196(2): 184.e1-184.e6. 6. Funaki K, Fukunishi H, Funaki T, Kawakami C. Mid-term outcome of magnetic resonance-guided focused ultrasound surgery for uterine myomas: from six to twelve months after volume reduction. J Minim Invasive Gynecol. 2007; 14(5): Stewart EA, Gostout B, Rabinovici J, et al. Sustained relief of leiomyoma symptoms by using focused ultrasound surgery. Obstet Gynecol. 2007; 110(2 Pt 1): Rabinovici J, Inbar Y, Revel A, et al. Clinical improvement and shrinkage of uterine fibroids after thermal ablation by magnetic resonance-guided focused ultrasound surgery. Ultrasound Obstet Gynecol. 2007; 30(5): American College of Radiology (ACR). ACR Practice Guideline for Performing and Interpreting Magnetic Resonance Imaging (MRI). Updated ClinicalTrials.gov [website]. MR Guided Focused Ultrasound Treatment of Uterine Fibroids With Enhanced Sonication. Updated July 17, Available at: O'Sullivan AK, Weinstein MC, and Thompson D, et al. OC29: Cost-effectiveness of magnetic resonance image-guided focused ultrasound (MRgFUS) for the treatment of uterine fibroids. Ultrasound Obstet Gynecol. 2007; 30(4): 376 References - Initial MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 18

19 1. Bachmann G. Expanding treatment options for women with symptomatic uterine leiomyomas: timely medical breakthroughs. Fertil Steril. 2006;85(1): Stewart EA, Rabinovici J, Tempany CM, et al. Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids Fertil Steril. 2006;85(1): Stewart, EA, Gedroyc, WM, Tempany, CM, et al. Focused ultrasound treatment of uterine fibroid tumors: Safety and feasibility of a noninvasive thermoablative technique. Am J Obstet Gynecol 2003; 189: Hindley J, Gedroyc WM, Regan L et al. MRI guidance of focused ultrasound therapy of uterine fibroids: early results. AJR Am J Roentgenol 2004; 183(6): Smart OC, Hindley JT, Regan L, Gedroyc WM. Magnetic resonance guided focused ultrasound surgery of uterine fibroids--the tissue effects of GnRH agonist pretreatment. Eur J Radiol Aug;59(2): McDannold N, Tempany CM, Fennessy FM, et al. Uterine leiomyomas: MR imaging-based thermometry and thermal dosimetry during focused ultrasound thermal ablation. Radiology Jul;240(1): InSightec. ExAblate 2000: Non-invasive surgery using MR guided Focused Ultrasound (MRgFUS) Available at: Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, prior notice or website posting is required before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 19

20 No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member s Contract Controls Coverage Determinations. Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize, modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary depending on individual need and the benefits covered under your contract. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member s contract shall govern. The Policies do not replace or amend the Member s contract. Policy Limitation: Legal and Regulatory Mandates and Requirements The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Reconstructive Surgery CA Health and Safety Code requires health care service plans to cover reconstructive surgery. Reconstructive surgery means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following: (1) To improve function or (2) To create a normal appearance, to the extent possible. Reconstructive surgery does not mean cosmetic surgery," which is surgery performed to alter or reshape normal structures of the body in order to improve appearance. Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by physicians specializing in reconstructive surgery. Reconstructive Surgery after Mastectomy California Health and Safety Code requires treatment for breast cancer to cover prosthetic devices or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy. Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for medically necessary reasons, as determined by a licensed physician and surgeon. Policy Limitations: Medicare and Medicaid Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation. MRI Guided Ultrasound Ablation of Uterine Fibroids (ExAblate) Nov 15 20