In June 2005, Blue Cross Blue Shield Association (BCBSA) published a Technology Evaluation Center (TEC) Assessment on magnetic resonance imaging-guided high intensity focused ultrasound (MRgFUS) therapy for symptomatic uterine leiomyomata; this assessment found insufficient evidence of efficacy compared to the conventional therapies. (1) The following is a summary of the literature through June 2012.
No randomized controlled trials (RCTs) have been published using MRgFUS. There is one published non-randomized study comparing MRgFUS to another treatment for uterine fibroids; this is the “pivotal” study designed for FDA approval of the ExAblate® 2000 device. (2,3) The study included 109 women treated with MRgFUS and 83 women treated with abdominal hysterectomy. The primary outcome was change in the symptom severity score (SSS) that is part of the validated Uterine Fibroid Symptom Quality of Life. Symptom severity is measured by 8 questions relevant to bulk and bleeding symptoms; it is a 0–100 scale, with the higher number representing greater severity of symptoms. Outcome data were initially reported for the MRgFUS group only. At 6 months’ follow-up, 71% of the MRgFUS group achieved a 10-point or greater reduction in SSS, but this decreased to 51% at 12 months. It is unclear what represents a clinically meaningful change in SSS, the primary outcome measure. A threshold of greater than 10 points was selected for the analysis, but this is somewhat arbitrary and not substantiated by other research. Twenty-one percent of those treated by MRgFUS needed additional surgical treatment, and 4% underwent a repeat MRgFUS by 12 months.
In 2009, Taran and colleagues reported outcomes for the hysterectomy group. (4) The Taran article did not include the original primary outcome measure, SSS scores, and instead reported findings on a different quality of life measure, the SF-36; also reported were safety data. A significantly higher proportion of women in the hysterectomy group (82 of 83, 99%) reported at least one adverse event compared to women in the MRgFUS group (88 of 109, 81%). Pain or discomfort, adverse events associated with the gastrointestinal tract, dermatological system, nervous system, and cardiovascular system were significantly more common in the hysterectomy group. However, a similar proportion reported a serious adverse event, 9 of 109 (8%) in the MRgFUS group and 8 of 83 (10%) in the hysterectomy group. At 6 months, there were significantly higher scores in the hysterectomy group on 2 of 8 subscales on the SF-36; scores on the remaining subscales did not differ significantly between groups. The SF-36 scores were subject to a multiple comparison bias; a large number of statistical comparisons were done for secondary outcomes and p-values were not adjusted. Moreover, it was not clear why the original primary outcome, the SSS, was not reported.
Another non-randomized comparative study compared two variations on the MRgFUS procedure. (5) Patients were either treated with the original protocol (33% of fibroid volume with a maximum treatment time of 120 min, n=96) or modified protocol (50% treatment volume, 180 min maximum treatment time, and a second treatment if within a 14-day period, n=64). In the original group, the nonperfused (effectively treated) area was calculated at 17% of fibroid volume compared with 26% of fibroid volume with the modified protocol. Overall, symptom severity was reported to have decreased from a score of 62 at baseline to 33 at 12 months, with fewer patients in the modified group choosing alternative treatment (28% vs. 37%, respectively). Interpretation of these results was limited by 49% loss to follow-up; 55 patients (57%) from the original treatment protocol completed follow-up. Only 21 patients (33%) from the modified protocol group were evaluable at 12-month follow-up.
A 2007 publication reported 24-month follow-up from three Phase 3 trials and 1 postmarketing study (total of 416 patients). (6) The study found a relationship between the nonperfused volume ratio and the probability of undergoing additional leiomyoma treatment. For nonperfused volume ratios of 20% to 50%, there was a 25% probability of additional treatment. Patients with a nonperfused volume ratio of less than 20% of fibroid volume had a 40% probability of additional treatment. No shrinkage (and a trend toward growth) was seen with nonperfused volume ratios of 10% or less. Most women were found to have had limited treatments, with 57% of the patients having a nonperfused volume of 20% or less and 34% of the patients having a nonperfused volume between 30% and 70%. Fewer than 3% of women had a nonperfused volume ratio of 70% or greater. These results raise questions about the amount of nonperfusion achieved with current treatment protocols.
Several case series have reported on the efficacy and safety of MRgFUS for treating uterine fibroids. For example, a 2011 case series included 40 women who were treated with MRgFUS for symptomatic uterine fibroids at one center in the U.S. (7) The primary study endpoints were change from baseline in quality of life (QOL) and symptom severity. (Higher scores on the quality of life measure and lower scores on the symptom severity measure indicated improvement). Twenty-nine of the 40 (73%) patients completed the three-year follow-up. The mean symptom severity score was 64.8 at baseline and 17.0 at 3 years; this represents a mean reduction of 47.8 points. The mean baseline QOL score was 44.1 and the mean QOL at the 3-year follow-up was 83.9, a mean increase of 39.8 points. The improvement from baseline to 3 years was statistically significant for both outcome variables; however, there is no control group with which to compare results. Another 2011 single-center case series reported 12-month outcome data on 130 women treated with MRgFUS. (8) Eight women had additional procedures to relieve symptoms within one-year of MRgFUS treatment; 7 underwent hysterectomy and 1 underwent endometrial ablation. Data on symptom relief at 12 months were available for 70 of 130 (54%) of patients. Fifty-one of the 70 (73%) reported excellent symptom relief. Conclusions about efficacy of MRgFUS cannot be drawn due to the lack of a comparison group and the large amount of missing data.
A prospective registry of pregnancies after MRgFUS had been maintained by the manufacturer of the ExAblate device. A 2010 article reported that there were 54 known pregnancies a mean of 8 months after treatment. (9) They included 8 pregnancies from clinical trials designed for women who did not desire pregnancy, 26 pregnancies after commercial treatment, and 20 pregnancies in 17 patients from an ongoing study of MRgFUS in women trying to conceive. Twenty-two of the 54 pregnancies (42%) resulted in deliveries, 11 were ongoing beyond 20 weeks at the time the article was written. There were 14 miscarriages (26%) and 7 elective terminations (13%). Among the 22 live births, the mean birth weight of live births was 3.3 kg, and the vaginal delivery rate was 64%. The article provides initial information on the impact of MRgFUS for uterine fibroids on pregnancy; findings suggest that fertility may be maintained but that the number of cases is too small to draw definitive conclusions. Moreover, the study does not address the possible impact of MRgFUS treatment on the ability to become pregnant.
A 2011 review article on MRgFUS as an oncologic treatment stated, “Although the potential applications of MRgFUS in oncology are very promising, further studies of feasibility and tolerability are needed for different anatomical districts. Phase III studies are needed as soon as possible in order to make direct comparisons of MRgFUS with surgery and radiotherapy.” (10)
No controlled studies evaluating MRgFUS for treating breast cancer have been published. The published literature is limited to small case series (i.e., including fewer than 20 patients each). (11-14)
One article reported on initial findings in 3 patients. (15) The authors report that it was possible to focus an ultrasound beam into the brain transcranially, and they believe that thermal ablation without overheating the brain is possible; however, substantial technical barriers to using MRgFUS for treating brain tumors remain.
Palliative Treatment of Bone Metastases
No controlled studies evaluating MRgFUS for palliative treatment of bone metastases have been published. One RCT comparing MRgFUS to sham treatment is underway (see section on ongoing clinical trials, below). Several manufacturer-sponsored case series have been published. In 2009, Liberman and colleagues published findings of a multicenter prospective study conducted in Canada, Israel, and Germany. (16) The study included 31 patients who had painful bone metastases who had failed or refused other treatment options; 25 patients (81%) were available for 3-month follow-up. (18) The mean VAS score decreased from 5.9 before treatment to 1.8 three months after treatment. Thirteen of 25 patients who used non-opioid analgesics and 6 of 10 who used opioids decreased medication use after treatment. Neither series reported any treatment-related adverse effects.
Ongoing clinical trials
The FIRSST: Comparing MRgFUS (MR guided Focused Ultrasound) versus UAE (Uterine Artery Embolization) (NCT00995878) (17): This is a randomized controlled trial comparing MRgFUS to UAE in pre-menopausal women at least 25 years of age who have symptomatic uterine fibroids. The study is sponsored by the Mayo Clinic.
ExAblate (Magnetic Resonance-guided Focused Ultrasound Surgery) Treatment of Metastatic Bone Tumors for the Palliation of Pain (NCT00656305) (18): This randomized controlled trial is comparing Exablate treatment to sham treatment. It includes patients with symptomatic bone metastases or multiple myeloma bone lesions who are not candidates for radiation therapy. December 2011 was listed as the final data collection date for the primary outcome measure.
Practice Guidelines and Position Statements
Agency for Healthcare Research and Quality (AHRQ): A 2007 technology assessment on the management of uterine fibroids concluded that the strength of the evidence about MRgFUS is weak. (19)
A search of the National Guideline Clearinghouse database did not identify any practice guidelines that included recommendations on MRgFUS for treating uterine fibroids or other conditions.
MRIgFUS treatment is FDA-approved only for the treatment of uterine fibroids. To date, there are no randomized controlled trials and only one non-randomized study comparing MRgFUS to a different treatment. Limitations of the published comparative study include lack of randomization, data on the comparison group were not published until 5 years after data on the treatment group, the clinical significance of the primary outcome was unclear, and there were no follow-up data beyond 1 year. There is insufficient evidence on the long-term treatment effects, recurrence rates, and impact on future fertility and pregnancy. Thus, MRgFUS is considered experimental, investigational and unproven for treatment of uterine fibroids.
MRgFUS is being investigated for use in several applications that are not currently approved by the FDA. There are some small published case series but no comparative studies have been published. One RCT comparing MRgFUS to sham treatment as palliative therapy in patients with symptomatic bone metastases is underway. Due to a lack of regulatory approval and insufficient evidence of the impact on health outcomes, MRgFUS is considered experimental, investigational and unproven for treatment of other benign and malignant tumors.
Disclaimer for coding information on Medical Policies
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.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.