Ultrasound-guided high intensity focused ultrasound for the treatment of gynaecological diseases: A review of safety and efficacy

Abstract

As a non-surgical treatment, high intensity focused ultrasound (HIFU) has received increasing interest for the treatment of gynaecological diseases over the last 10 years. Many studies have shown that HIFU is safe and effective in treating patients with uterine fibroids, adenomyosis, cervicitis or vulvar diseases. Both magnetic resonance imaging-guided HIFU (MRgHIFU) and ultrasound-guided HIFU (USgHIFU) can offer gynaecologists non-invasive techniques to treat patients with uterine benign diseases. Focused ultrasound therapy can also be used effectively to treat cervicitis and vulvar diseases. As gynaecologists gain more experience with this technology, the rate of severe adverse effects has been lowered with the development of this non-invasive technique. In this paper we review the literature available regarding the utilisation of magnetic resonance imaging-guided focused ultrasound/MRgHIFU or USgHIFU and new findings from our group in the treatment of gynaecological diseases: uterine fibroids, adenomyosis, cervicitis, vulvar diseases, caesarean scar pregnancies, and abdominal wall endometriosis.

• Adenomyosis
• adverse effects
• complications
• high intensity focused ultrasound (HIFU)
• uterine fibroids

Introduction

Uterine fibroids and adenomyosis are very common benign uterine diseases. Approximately 50% of patients present symptoms and require treatment. Depending on the size and location, the fibroids or adenomyotic lesions may lead to dysmenorrhea, menorrhagia, frequency of urination, and reduction of pregnancy rate for women. High intensity focused ultrasound (HIFU) or focused ultrasound surgery (FUS) is a non-surgical therapeutic treatment that has been used in treating solid tumours by focusing high intensity ultrasound in the target [1]. In 2002, Wang et al. reported their preliminary results and showed that ultrasound-guided HIFU (USgHIFU) is safe and effective in treating uterine fibroids [2]. In 2004, magnetic resonance-guided FUS (MRgFUS) received USA Food and Drug Administration approval for treatment of uterine fibroids. Over the last few years, this non-invasive technique has also been used in treating adenomyosis [3,4]. With the development of imaging monitoring technology and this therapeutic technique, HIFU has been accepted as a routine treatment for uterine fibroids and adenomyosis in many clinical centres in China [5,6]. This article reviews the gynaecological treatments using this innovative and potentially revolutionary technology.

Advantages of HIFU with different monitoring technologies

Currently, magnetic resonance imaging (MRI) or ultrasound is used for guidance. MRI has excellent anatomical resolution and MRI-based thermal mapping offers real-time temperature monitoring during HIFU treatment; thus, it may enhance safety and efficacy during HIFU treatment.

Ultrasonography was the first diagnostic imaging technique that was introduced in monitoring HIFU treatment. Compared to MRgFUS/MRgHIFU, USgHIFU is less costly; ultrasound offers real-time anatomical monitoring imaging. Greyscale change during treatment is a reliable indicator in monitoring the response to HIFU [7]. In addition, USgHIFU is quiet, and does not require the patient to be enclosed in a confined space. To help reduce the risk of skin burn, the ultrasound beam is coupled to the abdominal wall through cold degassed water. During treatment, the patient is positioned prone on the HIFU table and a nurse and a physician sit close to the patient. The patient experiences a friendly environment and can comfortably communicate with the nurse or the physician.

Uterine fibroids: MRgHIFU/MRgFUS versus USgHIFU

Based on the results of a multiple-centre clinical trial, MRgFUS was approved by the USA Food and Drug Administration for clinical treatments of uterine fibroids. From earlier studies, results have shown that MRgFUS for uterine fibroids is feasible and safe [8,9]. Although the ablation volume was only around 30% of the targeted fibroids, patients reported either significant or partial improvement in symptoms. Treated fibroids decreased in volume by 12% and 15% at 1 and 6 months, respectively [10]. Later, Stewart et al. [11] reported that patients undergoing MRgFUS for smaller fibroid volume ablation had sustained symptom relief. However, Froeling et al. [12] reported that the re-intervention was significantly lower and the improvement of symptoms was significantly better after uterine artery embolization (UAE) compared to MRgHIFU. Ikink [13] performed another study to compare the symptom improvement and re-intervention rates after UAE and MRgFUS. Their results showed that both MRgHIFU and UAE result in significant symptom relief, but MRgHIFU is associated with a higher risk of re-intervention [13]. These results can be explained by the low non-perfused volume (NPV) ratio achieved by MRgFUS/MRgHIFU. Many studies have also demonstrated that subjects with a higher NPV ratio have significantly greater improvement, with lower probability of re-intervention (Table 1) [14–17]. Therefore, large NPV ratio achievement of treated fibroids is important for long-term symptom relief. Recently, two centres in China have completed a study using MRgHIFU to treat 104 patients with uterine fibroids. The average NPV ratio was 79.3 ± 15.8%, and an NPV ratio higher than 70% was observed in 76.7% of the treated fibroids. In this study, 18 patients reported pain or discomfort in the treated region, sciatic/buttock pain, and/or vaginal discharge after HIFU treatment; five patients had skin blisters or burns. Based on the Society of Interventional Radiology’s adverse effects classification, these adverse effects were classified as either class A or B and often subsided in 3 to 7 days. In earlier studies, to avoid bowel injury, many patients were excluded from MRgFUS because of bowel presence in the acoustic pathway [18]. Later, the Chongqing group showed that MRgHIFU is safe and feasible in ablating uterine fibroids in patients with the bowel lying anterior to the uterus if the patients have specific bowel preparation combined with the use of a degassed water balloon to compress or push the bowel away from the acoustic pathway [19].

Table 1. Relationship between non-perfused volume ratio and reintervention.

NPV ratio (%)	Re-intervention (%)	Nationality	References
16.6	37	USA	Fennessy et al. (2007) [14]
25.8	28	USA	Fennessy et al. (2007) [14]
45.4	6.2	Canada	Gorny et al. (2011) [15]
46.6	8.3	Japan	Okada et al. (2009) [16]
55	10	USA	LeBlang et al. (2010) [17]

NPV, non-perfused volume.

In 1999, USgHIFU was first used to treat malignant tumours in China [20]. Three years later, Wang et al. [2] reported their preliminary results of uterine fibroids treated with USgHIFU. Later, in 2004, Wu et al. reported their results from 85 patients with symptomatic uterine fibroids treated with USgHIFU between 1997 and 2001 at several centres in China [20]. From July 2001 to January 2003, 23 patients with symptomatic uterine fibroids who did not wish to have hysterectomy were enrolled in another study. After HIFU treatment, the volume of menstruation reduced and uterine volume decreased throughout the follow-up period. Unfortunately, temporary numbness on the lower limbs was observed in four patients because of a sciatic nerve injury, which has now been avoided by changing the treatment protocol in 2006 [21]. Since then, many results have shown that patients with uterine fibroids have benefited from USgHIFU [5,22].

Currently, this technique has been clinically considered as an alternative treatment for patients with uterine fibroids in China. Recently, the cases that were treated in 10 centres in China between 2006 and 2013 were retrospectively evaluated. Among them, 6545 out of 7439, or approximately 88%, of patients had a solitary fibroid, and multiple fibroids were seen in 818 of 7439, which corresponded to approximately 11% of the patients. The median volume of the dominant fibroid tumour was 67.5 cm³ (interquartile range, 38.1–134.5 cm³). The incidence of the types of dominant fibroid tumour was classified as follows: 893 of them (12%) were submucosal fibroids, 5059 (68%) intramural fibroids, and 1478 (20%) subserosal fibroids. The location distributions of the dominant fibroids were as follows: approximately 47% of the fibroids were located in the anterior wall (3496 cases), 31% in the posterior wall (2306 cases), 6% in the lateral wall (447 cases), and 16% in the fundus (1190 cases).

Table 2 shows that the average treatment time (defined as the time from the first sonication to the last sonication) was 84.2 ± 38.8 min (range 30–240 min) for uterine fibroids. The sonication time was 1243.8 ± 725.2 (range 506–2658) s. We considered a NPV ratio of over 25% as a technical success. Based on this criterion, 98.4% (7319/7439) of the uterine fibroids had successful ablation with an average of 83.1 ± 15.6% (range 25–100%) of NPV ratio. The NPV ratio was greater than 70% in more than 80% of the treated fibroids. On the basis of these NPV ratios achieved, the re-intervention rate was less than 10% after 24-month follow-up.

Table 2. Treatment results of patients with uterine fibroids or adenomyosis.

Technical parameters	Uterine fibroids	Adenomyosis
Technical success rate	98.4% (7319/7439)	94.6% (2411/2549)
Average treatment time	1243.8 ± 725.2 s (506–2658)	1169.7 ± 707.7 s (185–3600)
Median non-perfused volume	75.8 cm^3	48.7 cm^3
NPV ratio	83.1 ± 15.6% (25–100%)	73.2 ± 23.6$ (21–100%)

NPV, non-perfused volume.

In Spain, more than 300 patients with uterine fibroids were treated with USgHIFUin the Hospital Mútuade Terrassa, Barcelona, from January 2009 to December 2013. Using an average power of 370 W, the NPV covered more than 80% of the fibroid in most cases. The treatment time ranged from 1–5 h. No severe adverse effects occurred, and all patients returned to routine activities within 1 day after treatment. In early 2010 the first baby conceived after treating a fibroid with USgHIFU, a male infant, was born in the University Hospital Mútua de Terrassa. His weight was 3.23 kg. So far this year, around 20 babies have been born in this hospital after USgHIFU treatment. The Central Bank Medical Center, Moscow, Russia, as well as the Catholic University of Korea, have reported similar results. Therefore, USgHIFU has great potential in treating uterine fibroids.

Adenomyosis: MRgHIFU/MRgFUS versus USgHIFU

Treatment of adenomyosis is always a challenge for clinicians. Hysterectomy is still the only definitive treatment for this disease. However, this surgical operation is not suitable for women wishing to conceive. Since the adenomyotic lesion is ill-defined, myomectomy has proven to be less effective because of the high recurrence rate. Other treatments, including the levonorgestrel-releasing intrauterine device (IUD), the gonadotropin-releasing hormone analogues (GnRHa), non-steroidal anti-inflammatory drugs (NSAIDs), and oral contraceptives are also available for symptom relief. However, the effects of these non-surgical treatments are limited due to side effects, resulting in recurrence of symptoms after the therapy cessation [23]. As an ablative technique, HIFU can be used to destroy adenomyotic lesions. A few groups have begun to use MRgFUS/MRgHIFU to treat patients with adenomyosis. In 2006, Rabinovici et al. [24] first reported a case of a 36-year-old woman who had difficulty conceiving because of symptomatic focal adenomyosis. After treatment using MRgFUS, the patient experienced significant symptom relief and a remarkable reduction in the adenomyotic lesion size at 6 weeks, although only a part of the lesion was ablated. This patient conceived and gave birth at term to a healthy baby [24]. In 2008, Fukunishi et al. [25] reported their early results of 20 patients with adenomyosis treated with MRgFUS. A group from Chongqing also tested the feasibility of MRgHIFU ablation for adenomyosis [26]. These preliminary results demonstrated that MRgFUS is feasible and safe in treating symptomatic adenomyosis.

USgHIFU has also been used to treat adenomyosis. In 2009, Yang et al. [27] reported their results of using laparoscopic HIFU treatment for focal adenomyosis. This HIFU treatment was performed using a hand-held transducer during the surgical procedure followed by hysterectomy. The histological results showed that the treated adenomyotic lesion presented typical characteristics of coagulation necrosis with a clear margin between the treated and untreated region [27]. Recently a few studies have examined the application of USgHIFU in clinical settings for treating patients with symptomatic adenomyosis [4,6,28]. Zhou et al. [4] and Zhang et al. [6] demonstrated that USgHIFU treatment is safe and effective in ablating adenomyotic lesions and in alleviating its symptoms [6]. This treatment can be used effectively to treat both diffuse and focal adenomyosis.

Currently, more and more gynaecologists are considering this non-surgical treatment as an option for patients with adenomyosis. We retrospectively evaluated the safety and efficacy of USgHIFU for adenomyosis between 2006 and 2013. During this period, a total of 2549 patients with symptomatic adenomyosis were treated in 10 centres in China. We defined technical success for adenomyosis as an occurrence of non-perfused volume (NPV) of no less than 1 cm³ in the planned ablation area. In this study, 94.6% (2411/2549) of the patients underwent a successful ablation, with an average of 73.2 ± 23.6% (range 21–100%) of NPV ratio. The average treatment time was 93.3 ± 55.4 min (range 15–240 min) for patients with adenomyosis, and the sonication time was 1169.7 ± 707.7 s (range 185–3600 s) for adenomyosis (Table 2).

Cervicitis and vulvar disease

Focused ultrasound is used not only to treat solid tumours, but also to treat cervicitis and vulvar disease. A Model CZF-focused ultrasound therapeutic device developed by Chongqing Haifu Medical Technology, Chonqing, was used to perform focused ultrasound treatment for those diseases. The patients were requested to come 3–7 days after menstruation. The treatment procedure was performed after local infiltration anaesthesia with 0.5% lidocaine. The treatment parameters used were as follows: a power of 3.5–4.0 W, a frequency of 9.4 MHz, and a pulse of 1000 Hz. The probe was in close contact with the skin above the lesion via the ultrasound couplant to scan at a speed of 3–5 mm/s. A linear scan was applied for vulvar disease, while a circular scan was for cervicitis. If the treated area showed signs of mild congestion, swelling and hyperthermia, the treatment was terminated. An ice pack was then intermittently applied on the affected skin of the patient for 24 h after the treatment.

Cervicitis is a common condition in women. The treatment of choice for cervicitis is local treatment. As a non-invasive local treatment, focused ultrasound therapy showed a similar symptomatic cure rate to laser therapy. However, the frequency of adverse effects was significantly lower in the group treated with focused ultrasound therapy than in the group treated with laser therapy [29]. In another study, Li et al. performed focused ultrasound therapy for recurrent cervicitis with high risk HPV infection of the cervix in 20 patients. Their follow-up results showed that the negative rate of high risk HPV at 6 months after focused ultrasound therapy was 75% (15/20). Their results suggested that focused ultrasound therapy may help to clear high risk HPV infection by removing all or most of the HPV-infected cervical cells [30].

Focused ultrasound therapy is also effective in treating vulvar disease. From 1999 to 2002, a randomised study was conducted by Li et al. [31]. They treated 76 patients with vulvar dystrophies and their results showed that focused ultrasound therapy is feasible and effective in treating patients with vulvar dystrophy. Later, in another study, Sun et al. [32] demonstrated that focused ultrasound is safe and effective in the treatment of the non-neoplastic epithelial disorders of the vulva (NNEDV). NNEDV has been regarded as a ‘refractory disease’ featuring prolonged course, severe symptoms, refractoriness to treatments and high recurrence rates. However, their results showed that the total effective rate was 99.74% [32]. Today, this technique is regularly used for treating this condition in many centres in China.

Other applications in gynaecological practice

Over the last few years, USgHIFU has also been used to treat abdominal wall endometriosis [33]. As a non-invasive technique, HIFU has also been used to treat caesarean scar pregnancies. Xiao et al. [34] reported their results from 16 cases and found that USgHIFU was feasible and effective in treating caesarean scar pregnancies. In another study, Huang et al. [35] first used USgHIFU to heat the tissue at a focal point to stop embryonic cardiac activity and subsequently performed dilatation and curettage under hysteroscopic guidance to remove the products of conception. Another group from China has treated more than 60 cases of caesarean scar pregnancies by using USgHIFU combined with dilatation and curettage under hysteroscopic guidance this year (this data will be published soon). Their results showed that HIFU can significantly reduce the volume of bleeding during dilatation and curettage.

Safety evaluation of HIFU treatment for uterine benign diseases

Many studies have demonstrated that HIFU is safe in treating uterine benign diseases (uterine fibroids and adenomyosis). However, at the early stage of HIFU treatment for uterine benign diseases, the rate of adverse effects was relatively high. Skin burn and nerve injury have often been reported [8,18]. With the improvement of this technique and increase of physicians’ treatment experience, the rate of adverse effects has decreased dramatically.

A retrospective review of the adverse effects of 10,018 patients who were treated with USgHIFU in 10 centres in China between 2006 and 2013 was made. Among these patients, 7439 had uterine fibroids, 2549 patients had adenomyosis, 25 patients had placenta implantation, 60 had abdominal wall endometriosis, and 5 patients had caesarean scar pregnancy. After HIFU treatment, a total of 1062 of patients (10.6%) presented with 1338 adverse events. According to the Society of Interventional Radiology classification system, 1281 (95.7%) of these events were classified as class A; 45 (3.4%) as class B; 6 (0.45%) as Class C and 6 (0.45%) as Class D. Among the adverse effects of class A and B, the most frequent adverse event was a small volume of vaginal discharge (874 cases). However, this adverse effect subsided in most of the patients in 1 week without any further treatment. Another adverse effect often seen was lower abdominal pain. During HIFU treatment most patients experienced lower abdominal pain and 225 (2.23%) complained of pain 24 h after HIFU. Most of these adverse effects subsided in 7 days, but 19 patients had to take non-steroid anti-inflammatory drugs. Among the adverse effects of class C and D, four patients had burns to their abdominal skin and required surgical removal of the necrotic tissue, but all of them recovered within 2 weeks. Two other patients experienced leg pain for over two months, which occurred because of thermal injury to the sciatic nerve. Acute renal failure was seen in three patients; the renal function fully recovered after renal dialysis. Since such cases were not reported when not using SonoVue to evaluate HIFU treatment efficacy over the last ten years, this complication is potentially related to SonoVue. Among these 10,018 patients, two (0.02%) patients with adenomyosis suffered intestinal perforation for 10 days and 20 days respectively after HIFU treatment, which were confirmed and repaired by surgery. These two patients did not follow the protocol to have careful bowel preparation and the lesions were over treated. One patient (0.01%) who felt hypogastralgia when coughing 1.5 years after HIFU treatment was found to have lateral ventral syndrome, but we could not explain this adverse effect because this patient did not complain of any discomfort within 1.5 years after HIFU treatment.

In summary, as a non-surgical treatment, HIFU has received increasing interest for the treatment of uterine benign diseases. Based on evidence from the literature, USgHIFU can be used to treat patients with gynaecological diseases safely and effectively. Our results show that the rate of severe adverse effects has been lowered with the development of this non-invasive technique. Therefore, we conclude that HIFU is a promising technique for treating gynaecological diseases.

Declaration of interest

Lian Zhang and Wenzhi Zhang are senior consultants for Chongqing Haifu. Zhibiao Wang is a shareholder of Chongqing Haifu. The authors alone are responsible for the content and writing of the paper.