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High-intensity focused ultrasound in the treatment of uterine fibroids


15 June, 2009  

Although more studies are needed to determine which fibroids are most effectively treated with HIFU, there is enough clinical and laboratory confirmation to conclude that it is a safe and effective method of treatment

Theodore Dubinsky, Associate Professor, Department of Radiology, University of Washington, USA

Women experiencing symptoms from fibroids now have a greater choice of therapies than ever before. Fibroids can be treated medically with partial and complete myomectomy, hysterectomy, uterine artery embolisation, and now with high-intensity focused ultrasound (HIFU). Myometrial resection can be hysteroscopic or laparoscopic, and hysterectomy can be performed using a vaginal approach or via an open laparotomy.

Each therapy has advantages and disadvantages with regard to indication, effectiveness, complications and treatment time. Less well described in the literature is the response of different types of fibroids to each of these therapies. In general, there is a trend away from simply performing hysterectomies in these women in favour of less invasive procedures, and the most recent and innovative of these is HIFU.

HIFU depends upon the use of focused ultrasound energy to ablate soft tissue and has been used to treat some primary tumours, as well as metastatic disease. Some form of imaging, either ultrasound or magnetic resonance, must be used to locate the lesion to be treated. HIFU is then performed, after which some method is used for follow-up to determine whether the treatment has been successful, and if not, whether more treatment is indicated and feasible. HIFU is completely non-invasive, and can be used to treat tumours that are deep within the uterus, provided the lesion to be treated is visible and has no bone or gas in front of it that would prevent the transmission of ultrasound energy to it. This article presents a review of HIFU specifically with regard to the treatment of fibroids.

Clinically viable technology
High-intensity focused ultrasound acts upon soft tissues predominantly by increasing the temperature of the tissue being treated, and by cavitation. Temperatures as high as 80°C can be achieved in soft tissues being treated with HIFU. High-intensity focused ultrasound is the only clinically viable technology that can be used to achieve a local temperature increase deep inside the human body in a non-invasive way, and, currently, magnetic resonance is the only imaging method that can display temperature within soft tissues during therapy.

Magnetic resonance imaging (MRI) guidance of the procedure allows in-situ target definition and identification of nearby healthy tissue to be spared. In addition, MRI can be used to provide continuous temperature mapping during HIFU for spatial and temporal control of the heating procedure and prediction of the final lesion based on the received thermal dose. The technique has been tested extensively in preclinical studies and is now accepted in the clinic for ablation of uterine fibroids. Gadolinium-based contrast agents, together with MRI and ultrasound, may be used for tumour localisation.[1]

Cavitation occurs when gas comes out of solution within the tissues and forms microbubbles that then oscillate in size as they are subjected to the alternating compression and rarefication of the ultrasound beam until they eventually rupture. This temperature change, as well as the cavitation, results in coagulative necrosis of the tissue. The treatment area can vary in size from an area of roughly 3 mm to perhaps 1 cm. Hence, for a large lesion, multiple areas must be heated until the lesion is covered entirely. Over time, the entire necrotic treatment area fills in with granulation tissue, and it eventually becomes fibrotic and starts to decrease in size.

Best response
In one study, HIFU was applied to skeletal muscle in rabbits and the histology was then examined over time. Initially, only subtle staining changes were identified within the lesions. In the chronic phase (days 51–100), the muscle was replaced or infiltrated by variable amounts of scar and fat similar to degenerative muscle disorders. Histologic changes were limited to the tissue within the intensity focus of the transducer and were not seen in intervening tissues. The authors concluded that these results in muscle tissue may provide the basis for understanding ultrasound effects in the treatment of uterine fibroids.[2]

Fibroids that are predominantly cellular will respond best to HIFU. Those that are already degenerating and centrally necrotic, as well as those that are already predominantly fibrotic, are not really good candidates for HIFU therapy. Lesions up to 5 cm in diameter can be treated practically, although larger lesions may take several treatment sessions. In general, it makes sense to treat myometrial and submucosal fibroids rather than subserosal or pedunculated ones, but this can depend on the woman’s symptoms, whether she is a good operative risk, and the need to preserve fertility.

Safe method
Fibroids in rats were studied at the University of Washington. Thirty-five tumours in 27 Eker rats that had spontaneous in-situ uterine fibroids were randomly assigned into two groups receiving HIFU (n = 29) or sham (n = 6) treatments. High-intensity focused ultrasound was applied intraoperatively directly to the fibroids at 3.5 MHz in 10-second bursts to produce coagulative necrosis lesions (3 mm by 10 mm), spaced 5 mm apart. Sham treatments consisted of exposing the tumours and handling them similarly to those in the HIFU treatment group, but HIFU was not applied. Tumour volume was measured every week transabdominally using B-mode ultrasound imaging. Gross examination and histological analysis were performed after euthanasia. More than half of the tumours in the HIFU treatment group showed significant tumour volume reduction. The average tumour volume in the sham treatment group increased 40-fold. Gross and histological analysis showed coagulative necrosis of tumour cells in the HIFU treatment group. The authors concluded that HIFU may provide an effective and safe method of treating uterine fibroid tumours.[3] One publication compared the use of contrast- enhanced ultrasound (CEUS) to monitor HIFU therapy with contrast-enhanced MR. On CEUS, residual unablated tumours were found in three of 64 uterine fibroids (4.7%) and failed treatment was found in eight of 64 uterine fibroids (12.5%). Of the 58 ablated fibroids without residual tumours after HIFU ablation, the volumes of all the fibroids decreased by varying degrees during one-year follow-up. The authors concluded that CEUS was potentially useful for evaluating the therapeutic effect of percutaneous HIFU ablation for uterine fibroids.[4]

Effective treatment
Ren et al ablated 187 fibroids in 119 women. No severe complications were observed in any of them after HIFU ablation. Histologic specimens obtained at needle biopsy resulted in 51 (82.3%) of 62 biopsy specimens showing obvious signs of necrosis under light microscopy, and more subtle changes in cellular structure that indicated  nonviability could be found in 60 specimens (96.8%) under electron microscopy. However, viable cells still could be found in 16 specimens (25.8%). Follow- up imaging, which included CT, ultrasound and MR, showed absence or reduction of blood supply in the lesions after HIFU ablation. Median reductions in tumour size as a percentage of initial tumour volume at one, three, six and 12 months after HIFU treatment were 21.2%, 29.6%, 44.8% and 48.7%, respectively. The authors concluded that the imaging and histopathologic evidence of their study directly validated HIFU ablation as an effective treatment of uterine fibroids[5].

Another study appears to validate the use of HIFU. In 12 patients scheduled to have abdominal hysterectomy, 5–60 impulses of HIFU were applied through the intact skin upon uterine tissues directly prior to the surgical procedure. Tissue intensities lay between 3,200 and 6,300 W/cm2, and a fixed pulse length of 4 s was used. No side-effects were encountered other than one first-degree skin burn, and the treatment was well tolerated. Histology showed clearly demarcated coagulative necrosis in the targeted tissues.
Treatment was concluded in less than 45 minutes for each patient. The authors concluded that focused ultrasound was an effective method to selectively destroy tissue within the uterus, and the transabdominal access route was very feasible.[6]

Conclusion
Clearly, there is enough clinical and laboratory confirmation to conclude that HIFU is a safe and effective method for treating fibroids. However, more studies will be necessary to determine which fibroids are most effectively treated. It probably makes sense to try medical therapy on most women first before undertaking more invasive therapy. If the uterus is too large or has too many fibroids, they are probably not good candidates for HIFU. No data exist for comparing uterine artery embolisation with HIFU, and outcome studies in randomly paired groups will be necessary to determine whether one is more cost-effective than the other. What is also not clear at this time is what reduction in volume is needed to make the patient symptomatic. One inherent advantage of HIFU, however, is that it is easy to perform a repeat treatment if necessary, whereas all of the other therapies, which are more
invasive, cannot be easily repeated.

References
1. Moonen CT. Spatio-temporal control of gene expression and cancer treatment using magnetic resonance imaging-guided focused ultrasound. Clin Cancer Res 2007;13(12):3482-9.
2. Solomon SB, et al. Histologic evolution of high-intensity focused ultrasound in rabbit muscle. Invest Radiol 2003;38(5):293-301.
3. Keshavarzi A, et al. Treatment of uterine fibroid tumors in an in situ rat model using high-intensity focused ultrasound. Fertil Steril 2003; 80 Suppl 2:761-7.
4. Zhou XD, et al. Therapeutic response assessment of high-intensity focused ultrasound therapy for uterine fibroid: utility of contrast-enhanced ultrasonography. Eur J Radiol 2007;62(2):289-94.
5. Ren XL, et al. Extracorporeal ablation of uterine fibroids with high-intensity focused ultrasound: imaging and histopathologic evaluation. J Ultrasound Med 2007;26(2):201-12.
6. Fruehauf JH, et al. High-intensity focused ultrasound for the targeted destruction of uterine tissues: experiences from a pilot study using a mobile HIFU unit. Arch Gynecol Obstet 2008;277(2):143-50.