MRI-guided high intensity ultrasound ablation of uterine fibroids does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This treatment is currently being studied in a clinical trial.

 

For contracts without primary coverage criteria, MRI-guided high intensity ultrasound ablation of uterine fibroids is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

There is minimal published data regarding MRI guided high intensity focused ultrasound ablation of uterine fibroids.  Stewart and colleagues reported the results of a case series of 55 women with symptomatic uterine fibroids who either underwent high intensity focused ultrasound treatment or who underwent a planned hysterectomy within one month after the ultrasound treatment.   In this latter group, hysterectomy specimens provided pathologic correlation of treatment.  Typically only one fibroid was targeted for treatment and no attempt was made to target the fibroid that was the most likely to cause symptoms.  Additionally, fibroids that would require the ultrasound beam to pass through bowel or bladder were excluded from treatment.  While the procedure was well tolerated, there was no attempt to assess mid or long term outcomes.  High intensity focused ultrasound has also been investigated as a treatment of breast fibroadenomas, prostate cancer and renal cancer.

 

In a review article Sharp commented :  “Outcomes of patients undergoing magnetic resonance-guided focused ultrasonography at 6 months and 12 months were reported from the FDA trial.  They followed 109 patients at 6 months and 82 patients at 12 months.  Although only modest volume reductions were noted, 13.5% at 6 months and 9.4% at 12 months using intention to treat analysis.  71% reached their target symptom reduction at 6 months and 51% at 12 months.  At 12 months 21% of women needed an alternative surgical therapy for leiomyomata...Long-term studies are needed to discern whether the minimally invasive advantage of this approach will lead to durable results.”  Other authors also indicated the need for longer-term follow-up.

 

A search of the MEDLINE database was performed for the period of August 2006 through September 2007. A technology assessment from the Agency for Healthcare Research and Quality (AHRQ) on the management of uterine fibroids was published.  Their literature search was completed in August 2006 and evaluated the same studies reviewed above. The AHRQ report concluded that the strength of the evidence about MRgFUS is weak, and that the one carefully conducted prospective case series ranks as poor for informing clinical decision making.

 

Two new publications from the MRgFUS study group were identified. One of the reports compared results from patients treated with the original (33% of fibroid volume with a maximum treatment time of 120 min, n = 96) and modified (50% treatment volume, 180 min maximum treatment time, and a second treatment if within a 14-day period, n = 64) protocols.  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%). Interpretation of these results is 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. The second publication reported 24-month follow-up from three Phase 3 trials and one post-marketing study (total of 416 patients).  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%. Less 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. In addition, the studies lack concurrent control groups; randomized controlled trials are needed to compare the efficacy and durability of MRgFUS with alternative treatments.

 

 

In 2009, Taran and colleagues reported outcomes for the hysterectomy group (Taran, 2009).  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; safety data were also reported. A significantly higher proportion of women in the hysterectomy group reported at least one adverse event compared to women in the MRgFUS group. 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 in the MRgFUS group and 8 of 83 in the hysterectomy group. At 6 months, there were significantly higher scores in the hysterectomy group on 2 out of 8 sub-scales on the SF-36; scores on the remaining subscales did not differ significantly between groups. The SF-36 scores are 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 is not clear why the original primary outcome, the SSS, was not reported.

 

There are several prospective case series reports from Japan on the efficacy and safety of MRgFUS for treating uterine fibroids. A series from Tokyo published in 2008 included 48 women, over 18 years of age, who were candidates for surgical intervention due to symptomatic fibroids (Morita, 2008).  During the 12-month follow-up period, 2 patients required surgical interventions, and 2 patients required additional drug treatment for fibroids. The average reduction in fibroid volume determined by MR imaging at 6 months after treatment was 33%. This volume reduction is correlated with the fibroid's treated volume (range: 35-115mm). No serious complications were recorded during the treatments or follow-up period. The patients were asked about subjective relief of symptoms and if they sought additional treatments. The authors concluded that MRgFUS can safely be used to noninvasively treat symptomatic uterine fibroids and avoid the need for surgical intervention in the short term.

 

A case series by Funaki and colleagues included 91 women (141 uterine fibroids) from a single center in Kobe, Japan; like the other Japanese case series, the study included women who were candidates for conventional surgery due to symptomatic fibroids (Funaki, 2009).  Outcomes were assessed at 6, 12 and 24 months after MRgFUS treatment. Fibroids were classified into 3 types based on the signal intensity of pre-treatment T2-weighted MRI images. Type 3 had the highest signal intensity (equal to or higher than that of the myometrium); the center no longer treats these types of fibroids with MRgFUS due to poor outcomes, and the 11 women with type 3 myomas were excluded from some analyses. The Symptom Severity Score of 72 patients with type 1 and 2 leiomyomas was a mean of 35.1 (standard deviation=21) before treatment and decreased significantly starting at 3 months follow-up; this decrease was maintained for up to 24 months. The mean volume change ratio for types 1 and 2 leiomyomas decreased a mean of 36.5% six months post-treatment and decreased a mean of 39.5% at 24 months. Type 3 fibroids did not show a reduction in size 6 months after treatment. Twelve of the 80 type 1 and 2 patients had additional interventions after a median of 34 months (range 6-64 months) due to unsuccessful outcomes. Five women had repeat MRgFUS treatments, 3 had a hysterectomy or myomectomy and 3 had transcervical resections.

 

A prospective registry of pregnancies after MRgFUS had been maintained by the manufacturer of the ExAblate device. A 2008 article reported that there were 54 known pregnancies a mean of 8 months after treatment (Rabinovici, 2008). 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 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.

 

Several ongoing randomized controlled trials were identified. Insightec is sponsoring a trial comparing MRgFUS to myomectomy, in women with uterine fibroids who desire pregnancy (NCT00730886). In addition, the Mayo clinic is sponsoring a trial comparing MRgFUS to uterine artery embolization; desire for pregnancy is not an inclusion or exclusion criteria but women who are pregnant or actively trying to become pregnant are ineligible (NCT00995878). As of April 2010, the Mayo clinic sponsored trial is actively recruiting participants.

 

A 2009 review article states that, in addition to the treatment of uterine fibroids, MRgFUS is being evaluated for several clinical conditions including the ablation of benign and malignant tumors, and palliative therapy of bone pain associated with metastases (Jolesz, 2009). The author, who has financial links to Insightec, concludes, “At an early stage of development, MRgFUS’s safety and efficacy to address specific diseases must be demonstrated through rigorous clinical trials that are scrutinized by regulatory agencies including the FDA.”

 

Limited data are available for the application of MRgFUS in the breast. Six reports of feasibility studies are available describing preliminary results of using MRgFUS in the breast, and the first case report using this technique for breast cancer was published in 2001. A total of 73 treated patients have published data; 9 were treated for benign tumors, 40 were treated for malignancy with subsequent resection for histopathologic analysis, and 24 non-surgical candidates/refused surgery patients were treated as adjuvant therapy to existing tamoxifen protocols. Fibroadenoma, ductal carcinomas, adenocarcinomas, and lobular carcinomas have been treated. The adverse effects profile includes a few second-degree skin burns, and protocols maintain a roughly 1-cm distance between the tumor margin and the skin or rib cage. Residual tumor in the treated area appears to be a problem, with authors recommending treatment of the entire tumor plus 1 cm of surrounding tissue, as is done in lumpectomy. No long-term outcome studies are available.

 

Investigators are working to overcome the major obstacle of MRgFUS treatment in brain cancer applications—the skull. The skull bone attenuates and distorts the ultrasound beam propagation such that FUS treatments published to date involve removal of the skull bone. Specialized equipment is under development, and study using phased array transducer ‘helmets’ that are adjusted to correct for ultrasound beam distortion. A phase I clinical trial is underway, but no data in humans are available (Jaaskelainen, 2003).  

 

There are several prospective Insightec-sponsored studies evaluating MRgFUS for the treatment of bone metastases. Gianfelice and colleagues treated 11 patients at one institution in Canada with painful bone metastases who had failed other available treatment options (Gianfelice, 2008). The mean visual analog scale (VAS) pain score was 6.0 (out of 10) at baseline; this decreased to 1.3 at 1 month and 0.5 at 3 months. All patients reported a decrease in the intake of analgesics; 7 patients stopped using pain medication for their bone metastases. Liberman and colleagues conducted a multicenter study, with sites in Canada, Israel and Germany. 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 (Liberman, 2009).  The mean VAS score decreased from 5.9 before treatment to 1.8 three months after treatment. Thirteen out 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. Independent verification of treatment effects with larger groups of patients is needed.

 

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 (AHRQ, 2007).

 

No guideline or position statement from the American College of Obstetrics and Gynecologists (ACOG) was identified on MRgFUS for treatment of uterine fibroids.

 

MRgFUS is only FDA-approved 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. Other than the lack of randomization, this study was limited in that data on the comparison group was not published until 5 years after data on the treatment group, the clinical significance of the primary outcome is unclear and there was only one-year follow-up. There is insufficient evidence on the long-term treatment effects, recurrence rates and impact on future fertility and pregnancy.

 

MRgFUS is being investigated for use in several applications that are not currently approved by the FDA. There are some preliminary reports of safety and efficacy in small number of patients. There is insufficient evidence on the impact on health outcomes for treatment of other benign and malignant tumors.

 

 

 

 

 

 

 

 

 

 

    

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Guidelines from the National Comprehensive Cancer Network on bone cancer (v. 2.2018), breast cancer (v. 1.2018), brain cancer (v. 1.2018), and prostate cancer (v. 2.2018) do not mention magnetic resonance-guided ultrasound as a treatment option (NCCN, 2018).