Surgery Section - MRI-Guided Focused  Ultrasound (MRgFUS) for the Treatment of Uterine Fibroids and Other Tumors

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Uterine fibroids are one of the most common conditions affecting women in the reproductive years; symptoms include menorrhagia, pelvic pressure, or pain. There are several approaches that are currently available to treat symptomatic uterine fibroids: hysterectomy; abdominal myomectomy; laparoscopic and hysteroscopic myomectomy; hormone therapy; uterine artery embolization; and watchful waiting. Hysterectomy and various myomectomy procedures are considered the gold standard treatment. However, there has been longstanding research interest in developing minimally invasive alternatives including endometrial ablation, various laparoscopic ablative procedures using differing energy sources (i.e., laser, radiofrequency ablation, or cryotherapy) and uterine artery embolization. Most recently, there has been interest in using high intensity focused ultrasound (HIFU) treatment that is guided by magnetic resonance imaging (MRgFUS) 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. The ultrasound waves from each sonication can be focused into a maximum tissue volume of 4.3 cm3, causing a rapid rise in temperature, sufficient to cause tissue ablation at the focal point. Initial protocols allowed treatment of only up to 33% volume of each fibroid, although this has been expanded to permit treatment of up to 50% volume of each fibroid.  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.  The ultrasound equipment is all specially designed to be compatible with MRI magnets.

On October 22, 2004, the U.S. Food and Drug Administration (FDA) approved via the Premarket Application (PMA) process, the ExAblate™ 2000 System (InSightec, Inc., Dallas, TX) for “ablation of uterine fibroid tissue in pre- or peri- menopausal women with symptomatic uterine fibroids who desire a uterine sparing procedure.” The FDA approval letter states that patients must have a uterine gestational size of less than 24 weeks and those patients must have completed childbearing.

MRI-guided high-intensity focused ultrasound ablation of other tumors, including breast, prostate, renal tumors, and brain tumors and for the treatment of tumors metastatic to bone for the palliation of pain, is also being studied. However, the FDA approved device for MRI-guided ultrasound ablation is only for uterine fibroids.

Policy/Criteria

MRI-guided high intensity focused ultrasound ablation (MRgFUS) is considered investigational for all indications including but not limited to the following:

1. Uterine fibroids
2. Breast tumors
3. Brain tumors
4. Prostate cancer
5. Renal cancer

Scientific Background

Uterine Fibroids

This policy was originally created in July 2004, prior to FDA approval of the ExAblate 2000 system, and subsequently updated with a 2005 TEC Assessment on Magnetic Resonance-Guided Focused Ultrasound Therapy For Symptomatic Uterine Leiomyomata. (2) At that time there were minimal published data regarding MRI-guided high-intensity focused ultrasound ablation of uterine fibroids.

he 2005 TEC Assessment compared magnetic resonance-guided focused ultrasound (MRgFUS) to conventional therapies including hysterectomy, myomectomy, and uterine artery embolization.

The primary health outcomes of interest included fibroid-related symptoms, treatment-related morbidity and mortality, and quality of life. To assess fibroid-related symptoms, the Uterine Fibroid Symptom Quality of Life (UFS-QOL) Score, which is a validated tool that was designed to assist in comparing studies and procedures by standardizing symptom improvement, was used. The symptom severity score (SSS) is 1 of 2 scores measured in the UFS-QOL. Symptom severity is measured by eight questions relevant to bulk and bleeding symptoms. It is a 0–100 scale with 0 representing no symptoms and 100 representing the maximum severity of all symptoms queried.

The Assessment concluded that the available evidence on MRgFUS is insufficient to permit conclusions regarding the effect on health outcomes. One multi-center study including 109 subjects treated with MRgFUS, the “pivotal” study (designed for FDA approval of the ExAblate® 2000 device), was a comparative trial including 83 subjects treated with hysterectomy. However, comparative data on the hysterectomy group was largely missing in the reporting of results. (3) It is unclear what represents a clinically meaningful change in the primary outcome measure for the FDA study (SSS). A threshold of greater than 10 points was selected for the analysis, but this is somewhat arbitrary and not substantiated by other research.

Results of the “pivotal” study by Hindley and colleagues found, at 6 months’ follow-up, 70.6% of the MRgFUS group achieved a 10-point or greater reduction in SSS, but this decreased to 38.5% at 12 months; intention to treat analysis was included. SSS results for the hysterectomy group were not reported, but presumably they would be normal. The proportions of women in the MRgFUS group at 6 months that were satisfied with their therapy or felt that they had an adequate treatment effect were 76% or 72%, respectively, but these values were not reported for the hysterectomy group, nor were they reported for either group at 12 months. In addition, 21% of those treated by MRgFUS needed additional surgical treatment, and 4% underwent a repeat MRgFUS by 12 months.

In 2005, Stewart and colleagues published similar 6-month follow-up results of the original pivotal study as well as 12-month follow-up results of only 82 patients. (4)  They reported 71% percent of patients reached the targeted symptom reduction of a 10-point reduction in SSS at 6 months and 51% reached target at 12 months, no intention to treat analysis was provided. The proportion of women in the MRgFUS group that were satisfied with their therapy or felt that they had an adequate treatment effect at 12 months was not reported.

InSightec submitted its semi-annual report (unpublished material shared with permission of InSightec) to the FDA. (5) While not yet peer reviewed, some data are relevant to the evidence in support of MRgFUS. The report includes 24-month follow-up of the original pivotal trial study population. Sixty-two patients continued on from the 12-month follow-up. By 24 months, a total of 40 (of the original 109) patients underwent an alternative treatment or repeat procedure (36.5%). For the 40 patients not already considered treatment failures or lost to follow-up at 24 months, the symptom severity score efficacy measure is essentially unchanged at 24 months from the 6- and 12-month scores.

Studies are also reporting the combined use of GnRH agonists along with MRgFUS in patients with larger fibroids.(6,7) and exploring methods for improving ablative techniques.(8,9)

The available evidence is limited, which raises concerns about the reliability and validity of the reported findings. A relatively small number of subjects have been included in the published outcomes studies considering the prevalence of fibroids. Also, the length of reported follow-up is insufficient because of the potential for regrowth of treated fibroids. Long term follow-up results are necessary to understand the durability of any early treatment effect. If complete infarction/ablation of the fibroid is required to prevent regrowth, then it is of concern that the current treatment protocol for MRgFUS, which allows treatment of only up to 50% of the fibroid, might not provide durable symptom relief. Limitations in quality of the existing evidence include significant loss to follow-up at longer follow-up intervals, lack of adequate well-controlled comparison studies, and lack of comparability between treatment groups in the available nonrandomized comparisons. (10)

Breast Applications

Limited data are available for the application of MRgFUS in the breast. Six reports of feasibility studies are available describing preliminary results of using MR-guided focused ultrasound in the breast (11-16) 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.

Brain Cancer Applications

Currently, investigators are working to overcome the skull as a major obstacle of MRgFUS treatment in brain cancer and other brain lesion applications. 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. (17)

Renal Cancer, Prostate Cancer and Other Applications

MRgFUS, non-guided high-intensity ultrasound (HiFU) and MR elastography-guided HiFU therapy have been investigated for other indications including but not limited to benign and malignant prostate lesions and renal cancer. (18-20) Current published clinical trials consist of small, short-term, uncontrolled, nonrandomized studies focused primarily on feasibility.

The paucity of data from well-designed controlled clinical trials does not permit scientific conclusions to be reached related to the health outcomes of high-intensity ultrasound ablation of uterine fibroids and other tumors. An updated search of the MEDLINE database through November 2008 failed to return any published data that alter the conclusions reached above.

References

1. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy No. 7.01.109
2. BlueCross and BlueShield Association Technology Evaluation Center TEC Assessment. Magnetic Resonance-Guided Focused Ultrasound Therapy for Symptomatic Uterine Leiomyomata (PDF), 2005; Vol 20, No. 10
3. 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):1713-9
4. 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):22-9
5. ExAblate 2000 device for the treatment of uterine fibroids. PMA # P040003, InSightec 2005 Semi Annual Report. InSightec, Inc.; Dallas, TX
6. Smart OC, Hindley JT, Regan L et al. Magnetic resonance guided focused ultrasound surgery of uterine fibroids—the tissue effects of GnRH agonist pre-treatment. Eur J Radiol.2006;59(2):163-7
7. Smart OC, Hindley JT, Regan L et al. Gonadotrophin-releasing hormone and magnetic-resonance-guided ultrasound surgery for uterine leiomyomata. Obstet Gynecol 2006;108(1):49-54
8. McDannold N, Tempany CM, Fenessy FM et al. Uterine leiomyomas:  MR imaging-based thermometry and thermal dosimetry during focused ultrasound thermal ablation. Radiology 2006;240(1):263-72
9. Fennessy FM, Tempany CM, McDannold Uterine leiomyomas: MR imaging-guided focused ultrasound surgery--results of different treatment protocols. Radiology 2007;243(3):885-93
10. Morita Y, Ito N, Hikida H et al. Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids - early experience. Eur J Obstet Gynecol Reprod Biol 2008;139(2):199-203
11. Hynynen K, Pomeroy O, Smith DN et al. MR imaging-guided focused ultrasound surgery of fibroadenomas in the breast: a feasibility study. Radiology 2001;219(1):176-85
12. Zippel DB, Papa MZ. The use of MR imaging guided focused ultrasound in breast cancer patients; a preliminary phase one study and review. Breast Cancer 2005;12(1):32-8
13. Huber PE, Jenne JW, Rastert R et al. A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery. Cancer Res 2001;61(23):8441-7
14. Gianfelice D, Khiat A, Amara M et al. MR imaging-guided focused US ablation of breast cancer: histopathologic assessment of effectiveness – initial experience. Radiology 2003;227(3):849-55
15. Gianfelice D, Khiat A, Amara M et al. MR imaging-guided focused ultrasound surgery of breast cancer: correlation of dynamic contrast-enhanced MRI with histopathologic findings. Breast Cancer Res Treat 2003;82(2):93-101
16. Gianfelice D, Khiat A, Boulanger Y et al. Feasibility of magnetic resonance imaging-guided focused ultrasound surgery as an adjunct to tamoxifen therapy in high-risk surgical patients with breast carcinoma. J Vasc Interv Radiol 2003;14(10):1275-82
17. Jaaskelainen J. Non-invasive transcranial high intensity focused ultrasound (HIFUS) under MRI thermometry and guidance in the treatment of brain lesions. Acta Neurochir Suppl 2003;88:57-60
18. Gelet A, Chapelon JY, Bouvier R et al. Local control of prostate cancer by transrectal high intensity focused ultrasound therapy: preliminary results. J Urol 1999;161(1):156-62
19. Kohrmann KU, Michel MS, Gaa J et al. High intensity focused ultrasound as noninvasive therapy for multilocal renal cell carcinoma: case study and review of the literature. J Urol 2002;167(6):2397-403
20. Diederich CJ, Nau WH, Ross AB et al. Catheter-based ultrasound applications for selective thermal ablation: progress towards MRI-guided applications in prostate. Int J Hyperthermia 2004;20(7):739-56

Cross References

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