http://informahealthcare.com/hth ISSN: 0265-6736 (print), 1464-5157 (electronic) Int J Hyperthermia, Early Online: 1–8 ! 2015 Informa UK Ltd. DOI: 10.3109/02656736.2015.1010608
REVIEW ARTICLE
Thermal ablative treatment of uterine fibroids Stephen Derek Quinn1 & Wladyslaw M. Gedroyc2 Department of Obstetrics and Gynaecology, St Mary’s Hospital, Imperial College London and 2Department of Radiology, St Mary’s Hospital, Imperial College London, UK
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
1
Abstract
Keywords
In addition to surgical methods of treating uterine fibroids, numerous non-invasive treatments have been developed. Many of these involve the use of hyperthermia, the heating of tissue by a variety of methods. These include the use of lasers, radiofrequency, microwave energy and high intensity focused ultrasound, guided by both ultrasound and magnetic resonance imaging. In this review we examine the technology behind these treatment modalities and review the current evidence for their use.
HIFU, microwave ablation, MRgFUS, radiofrequency ablation, radiofrequency volumetric thermal ablation, ultrasound guided high intensity focused ultrasound (USgHIFU), uterine fibroids History Received 31 October 2014 Revised 17 January 2015 Accepted 18 January 2015 Published online 27 March 2015
Introduction Uterine fibroids (also known as leiomyomas or myomas) are the most common benign tumour found in women, with epidemiological studies indicating that up to 74% of premenopausal women will have evidence of uterine fibroids on histological examination [1]. The prevalence of fibroids increases with age up until the menopause [2]. Due in part to an increase in the average age of conception [3], fibroids are increasingly associated with fertility problems. A large study of randomly selected women between the ages of 35 and 49 found a prevalence of clinically significant fibroids in 10 to 15% of white women and 30 to 40% of black women [4]. Although these are benign tumours, uterine fibroids may have a significant impact on the quality of life of the individual [5]. Women with uterine fibroids may have a range of clinical manifestations related to their size and position. While many women with uterine fibroids will experience heavy menstrual bleeding, the mechanism for this is still not fully understood; though several mechanisms have been suggested [6,7]. One theory is that distortion of the uterine cavity and enlargement of the endometrial surface area leads to increased menstrual blood loss, with women with heavy menstrual bleeding having a higher prevalence of intramural and submucosal fibroids [8]. One study found that compared with asymptomatic women, premenopausal women with abnormal uterine bleeding had a higher prevalence of sub-mucous fibroids (21% vs. 1%), and intramural fibroids (58% vs. 13%) [8]. Correspondence: Stephen Quinn, Department of Obstetrics and Gynaecology, St Mary’s Hospital, Imperial College London, South Wharf Road, London, UK. Tel: 02033122325. E-mail: [email protected]
Larger fibroids, or uteri with multiple fibroids may cause pressure-related symptoms such as bladder frequency and nocturia, and urinary symptoms have been found to improve following reduction in fibroid volume [9,10]. At present fibroids may be treated surgically by hysteroscopic, laparoscopic, or open myomectomy, hysterectomy or by uterine artery embolisation (UAE). In addition to these well-established treatments for uterine fibroids, thermal ablative approaches have been developed. The destruction of tumour tissue by thermal injury can be achieved by using radiofrequency energy, focused ultrasound and microwave energy. Increasing the temperature of tissue to 50–52 C for 4–6 min is sufficient to produce irreversible cellular damage [11]. When temperatures reach 60–100 C rapid, irreversible damage caused by protein coagulation leads ultimately to coagulative necrosis [12,13]. When temperatures exceed 105 C, resultant tissue vaporisation and carbonisation can worsen further ablation within the tissue due to the reduction in energy transmission [11,13]. The aim of any thermal ablative treatment of uterine fibroids is to treat the maximum quantity of fibroid tissue safely, while preserving the surrounding uterine tissue.
Laser treatment of uterine fibroids The first use of high temperatures to ablate fibroid tissue was myoma coagulation or myolysis, which involved the use of a neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, either laparoscopically or hysteroscopically [14,15]. The infrared energy from the laser is converted into heat within the tissue, and at temperatures over 55 C the cells undergo irreversible damage, with protein denaturation and coagulative necrosis.
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
2
S. D. Quinn & W. M. Gedroyc
Usually women would be given 3 months of a gonadotropin releasing hormone analogue (GnRHa) prior to treatment and would require an average of 30–50 needle insertions per fibroid, over a period of 20 to 30 min [15]. Initial results were encouraging with a decrease in fibroid volume by around 50% [15,16]. This method of treating uterine fibroids was, however, associated with a high incidence of post-operative adhesion formation, presumed to be related to the multiple incisions through the serosa required to treat the uterine fibroids [17]. The risk of adhesion formation, in addition to the reported cases of uterine rupture in pregnancy following this treatment has limited the appeal of this modality [18,19]. Other concerns regarding this method of treatment include the inability to accurately predict the volume of ablated tissue or to visualise the effect of heating on tissues during the treatment process, leading to questions regarding the reproducibility of treatments and their safety. Percutaneous MRI-guided insertion of infra-red lasers was developed in order to better visualise the area under treatment, and perform a more controlled procedure [20]. These use light in the near infrared spectrum at a wavelength of 810 nm, and 18-gauge Turner needles introduced into the centre of the targeted fibroid under MRI guidance in a square configuration 1 cm apart. Mean treatment times are around 15 min per burn area, which are repeated in order to treat a larger volume. Initial results were very encouraging with a mean reduction of uterine fibroid volume of 31% [21]. By using magnetic resonance (MR) imaging to allow real-time thermal mapping of the uterus throughout the treatment, operators were able to achieve increased ablation volumes within the target tissue with minimal risk of damage to the serosa or any adjacent structures, which can be clearly visualised in relation to the area of treatment. The use of lasers to induce thermal injury to fibroid tissue has now though been superseded by other thermal ablation techniques.
Radiofrequency ablation of uterine fibroids The use of bipolar diathermy by the laparoscopic insertion of bipolar diathermy needles into the fibroid tissue produced results that were initially comparable to laser myolysis [21,22]. It was suggested that the risk of adhesions was reduced compared to that of laser myolysis; however, this was based on a small series [21]. Due to concerns regarding case reports of uterine rupture in pregnancies following bipolar myolysis this procedure was restricted to women in whom future fertility was no longer required [18,23]. Radiofrequency ablative techniques increase the temperature of tissue as a result of frictional heat produced by electrically resistive heating. The radiofrequency alternating current (typically 450–500 kHz) is applied to an electrode applicator producing a movement of ions and resultant frictional heating [24]. As with other thermal ablative therapies, once the temperature exceeds 50 C irreversible cell damage occurs with resultant coagulative necrosis. Radiofrequency electrode applicators have been used laparoscopically to create a large spherical area (up to a diameter of 5 cm) of tissue ablation within uterine fibroids [25]. This far exceeds the volumes achieved with laser myolysis, where multiple insertions of the needle were believed to contribute
Int J Hyperthermia, Early Online: 1–8
to post-treatment adhesion formation. The first report of radiofrequency ablation of fibroids at laparoscopy was in 2005 and the initial results have been encouraging, with reductions in fibroid size by 41.5 (77%) [25,26]. A study of 35 women undergoing image-guided radiofrequency ablation using 5-cm needle electrodes connected to a 460 kHz monopolar radiofrequency generator, following UAE, found a significant improvement in quantitative symptom severity scores and a 56.5% reduction in fibroid volume at 6 months [27]. This was achieved with no immediate percutaneous radiofrequency ablation-related complications. Another study reported results from a study of 25 women undergoing treatment with a laparoscopically inserted, ultrasound-guided radiofrequency needle with deployable tines that, when extended, have a Christmas tree-like arrangement [28]. In this study the mean volume of the dominant fibroid was 76.8 cm3 (range 14.8–332.8), and resultant volume reduction at one year was 77.9%. A recent randomised controlled trial compared radiofrequency volumetric thermal ablation at laparoscopy with laparoscopic myomectomy (with use of a morcellator) [29]. This study found significantly shorter hospital stays: (10.0 ± 5.5 h (median 7.8 (range 4.2–25.5)) for the radiofrequency ablation group and 29.9 ± 14.2 h (median 22.6 (range 16.1–68.1)) for the myomectomy group) and decreased intraoperative blood loss (16 ± 9 (median 20 mL (range 0–30)) for the radiofrequency ablation group and 51 ± 57 (median 35 mL (range 10–300)) for the myomectomy group) [29]. A prospective, multicentre study of 104 women undergoing volumetric radiofrequency ablation of their uterine fibroids found that at 3 years the surgical reintervention rate was 11%, and the improvement in symptom severity scores was 32.6% [30]. At 1 year the fibroids had decreased in volume by a mean of 45.1% and they reported one serious adverse event requiring readmission post-procedure [31]. A prospective study of 69 women following volumetric radiofrequency laparoscopic ablation of fibroids found a mean decrease in fibroid volume at 12 months of 28.7%, with one major adverse event – the development of a haematoma that resolved spontaneously post-operatively [32]. Overall, the rate of adverse events was 10%, including abdominal pain and urinary tract infections. Four pregnancies were reported in the first 12 months following ablation; these resulted in two caesarean sections at term, one vaginal delivery at term and one 10-week miscarriage [32]. There have been no reported cases of bladder or bowel perforation following laparoscopic radiofrequency ablation; however, there has been a case of recto-uterine fistula in a patient with co-existing endometriosis [33]. Given recent concerns regarding the safety of laparoscopic mechanical morcellation of uterine fibroids, radiofrequency ablation may be a promising alternative [34,35]. A transcervical radiofrequency ablation device has been developed, known as the VizAblateÔ System (Gynesonics, Redwood City, CA). This system uses an intra-uterine ultrasound probe and an intra-uterine radiofrequency generator, which allows real-time ultrasound imaging of the uterus and fibroid tissue while the VizAblate needle electrodes pass under ultrasound guidance into the target fibroids. When a safe position has been confirmed, the radiofrequency energy is delivered directly into the fibroid for a set period of time,
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
DOI: 10.3109/02656736.2015.1010608
Thermal ablative treatment of uterine fibroids
3
depending on the fibroid size [36]. This system produces ellipsoidal ablations of up to 5 4 cm in size and heats the tissue to a temperature of 105 C. The size of these ablations can be adjusted depending on the depth of the needle. This system calculates a thermal safety zone around the fibroid which prevents ablation of myometrium or uterine serosa and therefore minimises the risks of adhesion formation or uterine damage. Fibroids of up to 5 cm in size can be treated and the procedure takes around 30 min to complete [36]. A clinical trial of this device is currently on-going [37].
signal intensity when compared with skeletal muscle; these fibroids are referred to as hyperintense, isointense or hypointense respectively. Hypointense and isointense fibroids have a higher fibre content and lower cellular content, and a reduced blood supply compared with fibroids of hyperintense appearance [44]. A study of the thermal dose-related effectiveness of percutaneous microwave ablation found that the volumes of ablation achieved for a given microwave power were reduced in hyperintense fibroids compared with hypointense or isointense fibroids [43].
Microwave ablation of uterine fibroids
High intensity focused ultrasound treatment of uterine fibroids
In 2005, Goldberg described fibroid degeneration following microwave ablation of the endometrium [38]. In addition, submucosal fibroids have been reported to become necrosed and reduced in volume following microwave endometrial ablation [39]. Based on these findings a system was developed to treat fibroids transcervically, using microwave ablation under ultrasound guidance [40]. Microwave ablation uses an antenna probe that emits microwaves (2.45 GHz) into the fibroid tissue. The microwaves excite polar molecules such as water, and as these molecules attempt to align with the electromagnetic field there is resultant friction and production of heat. Transcervical microwave ablation of fibroids has been described using a 14-gauge needle set in an adaptor attached to a transvaginal ultrasound probe, which is inserted into the endometrial cavity following endometrial ablation [40]. Under transvaginal ultrasound guidance the guiding needle is inserted into the fibroid, then the inner part this is replaced by a needle applicator emitting microwaves at 2.45 GHz. A continuous infusion of saline through the space between the guiding needle and microwave applicator allows the heat generation rate to be maintained while preventing the tissue from drying, while a separate saline pump cools the transcervical probe, reducing thermal injury to the cervix. A study of nine women undergoing transcervical microwave ablation of their fibroids found a decrease in volume of between 37–69% at 6 months with no significant complications [40]. Percutaneous microwave ablation of fibroids involves the insertion of a microwave antenna and thermocouple needle into the fibroid tissue under conscious sedation [41]. The thermocouple needle allows real-time thermal feedback during the treatment. A 15-gauge diameter microwave needle antenna is used (20 mm in length), capable of both continuous and pulsed microwave modes [41]. A single microwave antenna is used for fibroids of less than 5 cm diameter; for fibroids of greater than 5 cm, double antennas (spaced 1 cm apart) are used. Fibroids of greater than 7 cm in diameter have an initial ablation with the two antennas of 50 W for 300 s, followed by a second ablation after withdrawing the antennas by 1 cm [41]. The mean fibroid volume reduction following this treatment is between 90 and 94%, and there have been no major adverse events described [41,42]. The effectiveness of microwave ablation of uterine fibroids in terms of the thermal dose effect is related to the appearance of fibroids on T2-weighted MRI [43]. When viewing uterine fibroids on T2-weighted MRI, these tumours can be described as being higher in signal intensity, equal to, or less high in
High intensity ultrasound can be focused into a small volume to produce a rise in tissue temperature sufficient to cause irreparable cell damage in the target at depth within the body [45]. Therapeutic focused ultrasound can be guided by both MRI and diagnostic ultrasound to direct the energy to the targeted tissue. Ultrasound guidance is relatively less expensive and more portable; however, MRI has the advantage of accurate real-time thermal mapping [46], which is limited when diagnostic ultrasound is utilised for targeting. The first report of the use of MR imaging to direct focused ultrasound in the treatment of tumours was published in 1992 [47]. High intensity focused ultrasound (HIFU) uses ultrasonic waves as a source of thermal injury within tissues. Ultrasound waves are generated by a transducer, a device that converts electrical pulses into pressure pulses. The transducer most commonly uses a piezoelectric plate that generates the ultrasound pulse. Piezoelectric materials expand or contract when a positive or negative charge is applied [48]. It is this expansion and contraction that results in the production of ultrasound waves. Ultrasound is a longitudinal pressure wave. When an ultrasound wave passes through a medium, the molecules of that medium oscillate back and forth along the direction of propagation of the wave. The resulting friction transforms acoustic energy into heat and contributes to the attenuation of the ultrasonic beam. Diagnostic medical ultrasound commonly uses frequencies in the range 2–15 MHz. In HIFU, frequencies of between 0.9 and 12 MHz have been used [49]. The intensity of the ultrasound beam is a measure of energy flowing through an area of the beam, which is quoted in Wcm2. The intensities of typical diagnostic ultrasound scanning (B-mode, pulsed or continuous Doppler) can be up to 720 mWcm2. In contrast, the intensity of focused ultrasound in the focal region is about 100–10 000 Wcm2 [50]. Ultrasound waves can be focused into a small volume either by a lens, a curved transducer, or a phased array into a small focal zone, in a similar way to light being focused through a magnifying glass to a single point. The phased array transducer is constructed using multiple parallel transducer units [48]. The signal from each transducer is emitted at a different phase from that preceding it. Appropriate timing of these signals allows the ultrasound beam to be focused. By using ultrasound with energies of up to 7000 J focused into a cigar-shaped focal spot of between 2 2 4 mm3 and 10 10 70 mm3, the tissues within the focal point are heated to greater than 56 C for a period of 1 s. Each focal
4
S. D. Quinn & W. M. Gedroyc
Int J Hyperthermia, Early Online: 1–8
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
Figure 1. Visualising the ultrasound beam path under MRI guidance.
exposure is commonly referred to as a sonication. The thermal threshold of 56 C has been established as the minimum temperature at the edges of a sonication [51]. Temperatures at the centre of the sonication may be greater than 90 C [52]. This results in coagulative necrosis and apoptotic cell death of the targeted tissue. Sonications within tissue can vary in size from 1–7 cm in length. The absorption coefficients of tissues vary significantly: bone absorbs most ultrasound energy, fluids such as blood absorb very little ultrasound energy, and soft tissue such as myometrium falls someway in between [48]. When ultrasound is applied in the linear pressure regime (for biological tissues typically below 5 MPa), the energy is absorbed at a rate that is directly proportional to the local intensity, meaning that the highest rise in temperature will be at the focus of the beam. The temperature continues to rise as more energy is absorbed; although some heat is lost by the process of conduction to surrounding cooler areas. HIFU has been used to treat uterine fibroids under the guidance of both ultrasound and MRI. Sonographically guided focused ultrasound uses changes in either greyscale or echogenicity to determine the area of fibroid ablation [53]. The HIFUNIT 9000 tumour therapy system (Shanghai Aishen Technology, Shanghai, China) comprises six self-focusing acoustic therapeutic transducers which focus the ultrasound beam, and a diagnostic transducer located in the centre of the therapeutic transducers [54]. This allows tissues in the path of therapeutic ultrasound waves to be viewed in diagnostic ultrasound images. Initial results with this system were encouraging, with 85.5% of patients undergoing this treatment experiencing an improvement in their symptoms at 1 year, 59.3% having total relief from their symptoms at 1 year, and a 9.7% reintervention rate at 1 year (n ¼ 145) [55]. An alternative system has been used with a similar arrangement of a central 3.5–5.0-MHz convex diagnostic ultrasound probe and a 20-cm diameter therapeutic transducer with a focal length of 150 mm operating at a frequency of 0.9 MHz (Model JC; Chongqing Haifu Technology, Chongqing, China) [56]. This system has been used to treat submucosal uterine fibroids achieving a mean non-perfused volume of 80%, a mean reduction in fibroid volume of 90.1% at 24 months and vaginal expulsion of necrosed fibroid material in 58% [56]. The reduction in fibroid volumes following sonographically guided focused ultrasound has been impressive, with reductions of between 50.3% and 78.9% at 12 months [55,56].
These studies, however, are small, and compared with magnetic resonance-guided focused ultrasound (MRgFUS), long-term data is limited. Sonographically guided focused ultrasound may have advantages over MRgFUS, including the cost of treatment and potentially shorter treatment times. A recent study used a modified treatment protocol consisting of repeated and shortened (less than 25 min) treatment sessions of high intensity (1000–1500 W/cm2), and repeated sonication pulses (1500–2000) at each spot [59]. This modified protocol was associated with a third degree skin burn in one of the 20 subjects, two cases of skin blisters, and eight patients experiencing pain after the treatment. MRI enables assessment of the pelvic anatomy in three dimensions, allowing accurate targeting of the uterine fibroids. By using MRI the ultrasound beam path can be visualised, therefore avoiding damage to structures such as the bowel (Figure 1) by possible reflection at gas–soft tissue interfaces. Prior to treatments patients are catheterised, ensuring a static bladder volume during the treatment. Initial detailed MR imaging of the pelvis allows treatments to be carefully planned prior to the first sonication, and the position of surrounding bowel and far-field bone are noted. MRI allows near real-time thermometry of the tissue to achieve the planned outcome (Figure 2). MR thermometry is based on the temperature dependence of the proton-resonance phase shift of water molecules [58,59]. This effect results in a phase shift of the gradient recalled MR-images: an effect which is both linear with the observed temperature change, and independent of the type of tissue. MRI also enables the post-treatment assessment of the volume of fibroid ablated. Following the completed sonications, an intravascular contrast agent is given and T1-fat saturated images of the pelvis are obtained. From these the degree of non-perfused volume of the fibroid can be assessed (Figure 3). Since its introduction, increasing experience of this treatment has led to a refinement of patient selection, with a tendency toward treating women with fewer fibroids and smaller uteri [60]. In addition to patient selection, several clinical tactics have been used to treat fibroids, where treatments would be otherwise limited. The passage of the focused ultrasound beam through bowel in the treatment of uterine fibroids is contraindicated due to concerns regarding this organ’s absorption of energy. Various methods have been used to move loops of bowel from the beam path including
DOI: 10.3109/02656736.2015.1010608
Thermal ablative treatment of uterine fibroids
5
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
Figure 2. Real-time thermometry employed during MRgFUS.
Figure 3. Post-treatment non-perfused volume of the uterine fibroid on T1-weighted MRI.
filling the bladder with normal saline, or by rectal filling using either a rectal balloon filled with normal saline or inserting rectal ultrasound gel [61]. One group has described applying pressure to the central abdominal wall in order to displace bowel via the use of a convex gel pad [62]. It is known that the signal intensity of fibroids can correspond to their cellular density, fibre content and vascularity [44,63], and the signal intensity of uterine fibroids is a known predictor of the success of HIFU [64]. A study of 91 women undergoing MRgFUS in Japan found a 2-year reintervention rate of 14% in women with hypointense or iso-intense fibroids [65]. These women had a mean non-perfused volume (NPV) of 54.7% and a mean tumour volume of 129.0 mL (SD 145.2 mL) [65]. A recent systematic review of the literature regarding HIFU found 38 prospective and retrospective studies, no randomised control trials, and studies of limited quality [87]. A summary of the studies identified is given in Table 1. The available data on long-term outcomes is currently very limited. Funaki et al. found a 2-year reintervention rate of 21.6% for hyperintense uterine fibroids (with a mean NPV of 36.2%) and 14.0% at 2 years for normo-intense fibroids (with a mean NPV of 54.35%) [65]. This was the first study to examine how the overall percentage of fibroid tissue treated successfully (as defined by the post-contrast NPV appearance of the MR image) related to subsequent symptomatic
response over a longer follow-up period. A more recent prospective study found a 2-year reintervention rate of 24%, with an overall NPV of 40.9% [79]. This study also stratified outcome by signal intensity and NPV and found that women with hyperintense fibroids had a higher risk of requiring further treatment at 2 years compared with women with hypointense fibroids, although on multivariate analysis this failed to reach significance (odds ratio (OR) 2.87 (0.64– 14.4)). Treatment resulting in greater than 45% NPV had a 15% risk of reintervention by 2 years, whereas treatments resulting in a 10–20% NPV had a 40% risk of reintervention at 2 years (OR 5.22 (1.1–26.0) [79]. A recent retrospective study of women undergoing UAE and MRgFUS found a 5-year reintervention rate of 66.7% at 5 years following a mean NPV of 36.4% [85]. In this study, however, the less accurate ellipsoid formula method was used to calculate the NPV, no mention of fibroid signal intensity was made and 37% of their patients were lost to follow-up. A cohort study of 280 women undergoing MRgFUS found that the overall reintervention rate at 5 years was 58.64%, but in those treatments with greater than 50% NPV the reintervention rate was 50% [88]. Further improvement of the 5-year reintervention rate was also found when 3 months pre-treatment of gonadotropin releasing hormone agonist (GnRHa) had been used. In addition to the long-term outcomes, specific data regarding the safety of MRgFUS is encouraging. The initial multicentre prospective study by Stewart et al. (n ¼ 155) found no deaths, life-threatening events or hysterectomies following MRgFUS [32]. There have been no recorded deaths, or hysterectomies following MRgFUS in any of the current literature. The most serious complication reported by that study was a sciatic nerve palsy in one woman, which resolved by 1 year post-treatment. This was believed to be a result of indirect injury of the nerve, caused by heating of the nearby bone following absorption of ultrasound energy in the far field of the treatment sonication. A cohort study of 280 women undergoing MRgFUS found a 1.4% risk of urinary tract infection (patients undergoing MRgFUS have a urinary catheter during the procedure), a 1.1% risk of minor skin burns requiring no repair and a 0.4% risk of major skin burn requiring secondary repair [31]. In this cohort there was, again, one woman who experienced persistent neuropathy following absorption of energy in the far-field bone. As a result of these cases, changes to the system and to treatment planning have been developed to reduce far-field bone absorption by directing the beam with greater accuracy.
6
S. D. Quinn & W. M. Gedroyc
Int J Hyperthermia, Early Online: 1–8
Table 1. Collated data from previous MRgFUS Studies Mean Volume of Fibroids treated (mL)
45.4 44.8 41 45.9 45 42.6 44 45.4 40.4
155 109 52 64 102 48 32 66 91
61.7 61.7 –– 62.1 61.5 –– –– 61.5 ––
353 284.7 191.1 –– –– –– 306 255.5 101.5
42.5 39.4 46 37.2 41.1 45.6 45.6 44.8 39 42 44.5 42 36.2 42.2
279 21 80 51 20 130 81 33 9 100 27 115 36 163
–– –– –– –– 43.3 –– 48.82 –– 30 59 64.8 –– 60.7 62.4
326 97 175 268 –– 350.3 213 –– 197.8 185.0 502.5 89 53.2 396.3
38 25 69.63 25.79 –– 60 –– 16.3 54.35 NI 36.2 HI 46.6 75 55 40 53.5 45.4 40.9 21.7 66.9 67.00 64.2 88 36.4 44.2
42.7
Total n= 1864
56.5
241.4
48.6
Mean Age
Stewart et al., 2006 [66] Stewart et al., 2007 [67] Funaki et al., 2007 [68] Fennessy et al., 2007 [69] Harding et al., 2008 [70] Morita et al., 2008 [71] Mikami et al., 2008 [72] Le´na´rd et al., 2008 [64] Funaki et al 2009 [65]
Meta-analysis Pros Pros Pros Pros Pros Pros Retro Pros
Okada et al., 2009 [73] Zhang et al., 2010 [74] LeBlang et al., 2010 [75] Rabinovici et al., 2010 [76] Yoon et al, 2011 [77] Gorny et al., 2011 [78] Machtinger et al., 2012 [79] Voogt et al., 2012 [80] Park et al., 2012 [81] Dobrotwir and Pun, 2012 [82] Kim et al., 2012 [83] Trumm et al, 2013 [84] Froeling et al., 2013 [85] Quinn et al, 2014 [86]
Pros Pros Pros Pros Pros Retro Pros Pros Retro Pros Pros Retro Retro Retro
Authors, years
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
N
SSS at baseline
Study Design
Mean
NPV ratio (%)
Re-intervention 21.9% at 1yr –– 11.8% at 1yr –– –– 8.3% at 6 months –– –– 14.0% at 2yrs NI 21.6% at 2yrs HI 8% at 1yr –– –– –– –– 7.4% at 1yr 24% at 2yrs –– –– 13.7% at 1yr –– –– 66.7% at 5yrs 58.64% at 5yrs 52.3% at 5yrs (NI) 79.5% at 5yrs (HI)
HI = Hyperintense fibroid, NI = Normointense fibroid, NPV = Non-perfused volume, N = Numbers, SSS = Symptom severity score SSS = Symptom severity score
Skin burns have greatly reduced due to the experience and reporting of adverse events. All reported cases of major skin burns have been reported in women with significant abdominal scarring, and avoidance of treating fibroids through significant abdominal scars, or the use of an energydisplacing abdominal scar patch have reduced the incidents of further skin burns in recent years [77]. Recent developments in MRgFUS have been aimed at improving the ablation volumes achieved, including the use of an automatic three-dimensional treatment planner that automatically arranges sonication spots to cover a maximum targeted fibroid volume. By closing elements in the transducer the HIFU beam may be shaped in such a way as to produce a greater treatment volume. The transducer is able to get much closer to patients’ skin resulting in a reduced energy density in the beam path. The beam path will be wider at the skin and at the posterior bony structures leading to reduced energy absorption. This also allows an increased energy density to be produced safely without producing an increased energy absorption in the skin and spine. Early results utilising this newer system suggest that it can produce a consistently larger area of fibroid destruction in most patients, with NPVs of 88% (range 38–100%) reported [84].
alternative to laparoscopic myomectomy. While the noninvasive nature of HIFU is appealing, the long-term outcomes in terms of fibroid volume reduction and reintervention rates are disappointing. It is to be hoped that developments in the technology, as well as improved patient selection will further improve outcomes. Further evidence for the use of this technology should be obtained from randomised trials; however, in the meantime evidence from cohort studies continues to accumulate.
Conclusions
References
Treatment modalities using hyperthermic principles offer attractive alternatives to traditional surgical approaches. Initial results using volumetric radiofrequency ablation have been encouraging, and this may provide an effective
Acknowledgments The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Declaration of interest Stephen Quinn previously worked as a clinical research fellow at Imperial College London, and the funding for this post was provided by Insightec. The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the UK Department of Health. The authors alone are responsible for the content and writing of the paper.
1. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94:435–8. 2. Lurie S, Piper I, Woliovitch I, Glezerman M. Age-related prevalence of sonographically confirmed uterine myomas. J Obstet Gynaecol 2005;25:42–4.
Thermal ablative treatment of uterine fibroids
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
DOI: 10.3109/02656736.2015.1010608
3. McDonald JW, Rosina A, Rizzi E, Colombo B. Age and fertility: Can women wait until their early thirties to try for a first birth? J Biosoc Sci 2011;43:685–700. 4. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. Am J Obstet Gynecol 2003;188: 100–7. 5. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007;87:725–36. 6. Stovall DW. Clinical symptomatology of uterine leiomyomas. Clin Obstet Gynecol 2001;44:364–71. 7. Lockwood CJ. Mechanisms of normal and abnormal endometrial bleeding. Menopause 2011;18:408–11. 8. Murase E, Siegelman ES, Outwater EK, Perez-Jaffe LA, Tureck RW. Uterine leiomyomas: Histopathologic features, MR imaging findings, differential diagnosis, and treatment. Radiographics 1999;19:1179–97. 9. Langer R, Golan A, Neuman M, Schneider D, Bukovsky I, Caspi E. The effect of large uterine fibroids on urinary bladder function and symptoms. Am J Obstet Gynecol 1990;163:1139–41. 10. Pron G, Bennett J, Common A, Wall J, Asch M, Sniderman K, et al. The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertil Steril 2003;79:120–7. 11. Goldberg SN, Gazelle GS, Halpern EF, Rittman WJ, Mueller PR, Rosenthal DI. Radiofrequency tissue ablation: Importance of local temperature along the electrode tip exposure in determining lesion shape and size. Acad Radiol 1996;3:212–18. 12. Solbiati L, Ierace T, Goldberg SN, Sironi S, Livraghi T, Fiocca R, et al. Percutaneous US-guided radio-frequency tissue ablation of liver metastases: treatment and follow-up in 16 patients. Radiology 1997;202:195–203. 13. Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: A unified approach to underlying principles, techniques, and diagnostic imaging guidance. Am J Roentgenol 2000;174:323–31. 14. Donnez J, Gillerot S, Bourgonjon D, Clerckx F, Nisolle M. Neodymium: YAG laser hysteroscopy in large submucous fibroids. Fertil Steril 1990;54:999–1003. 15. Goldfarb HA. Laparoscopic coagulation of myoma (myolysis). Obstet Gynecol Clin North Am 1995;22:807–19. 16. Phillips DR, Milim SJ, Nathanson HG, Haselkorn JS. Experience with laparoscopic leiomyoma coagulation and concomitant operative hysteroscopy. J Am Assoc Gynecol Laparosc 1997;4:425–33. 17. Nisolle M, Smets M, Malvaux V, Anaf V, Donnez J. Laparoscopic myolysis with the Nd:YAG laser. J Gynecol Surg 1993;9:95–9. 18. Arcangeli S, Pasquarette MM. Gravid uterine rupture after myolysis. Obstet Gynecol 1997;89:857. 19. Law P, Gedroyc WM, Regan L. Magnetic-resonance-guided percutaneous laser ablation of uterine fibroids. Lancet 1999; 354(9195):2049–50. 20. Hindley JT, Law PA, Hickey M, Smith SC, Lamping DL, Gedroyc WM, et al. Clinical outcomes following percutaneous magnetic resonance image guided laser ablation of symptomatic uterine fibroids. Hum Reprod 2002;17:2737–41. 21. Goldfarb HA. Bipolar laparoscopic needles for myoma coagulation. J Am Assoc Gynecol Laparosc 1995;2:175–9. 22. Goldfarb HA. Comparison of bipolar electrocoagulation and Nd:YAG laser coagulation for symptomatic reduction of uterine myomas. J Am Assoc Gynecol Laparosc 1994;1:S13. 23. Vilos GA, Daly LJ, Tse BM. Pregnancy outcome after laparoscopic electromyolysis. J Am Assoc Gynecol Laparosc 1998;5:289–92. 24. Haemmerich D, Laeseke PF. Thermal tumour ablation: Devices, clinical applications and future directions. Int J Hyperthermia 2005; 21:755–60. 25. Bergamini V, Ghezzi F, Cromi A, Bellini G, Zanconato G, Scarperi S, et al. Laparoscopic radiofrequency thermal ablation: A new approach to symptomatic uterine myomas. Am J Obstet Gynecol 2005;192:768–73. 26. Milic A, Asch MR, Hawrylyshyn PA, Allen LM, Colgan TJ, Kachura JR, et al. Laparoscopic ultrasound-guided radiofrequency ablation of uterine fibroids. Cardiovasc Intervent Radiol 2006;29: 694–8. 27. Kim HS, Tsai J, Jacobs MA, Kamel IR. Percutaneous image-guided radiofrequency thermal ablation for large symptomatic uterine
28. 29.
30.
31.
32. 33. 34. 35. 36.
37.
38. 39. 40.
41.
42.
43.
44.
45. 46. 47.
7
leiomyomata after uterine artery embolization: A feasibility and safety study. J Vasc Interv Radiol 2007;18:41–8. Ghezzi F, Cromi A, Bergamini V, Scarperi S, Bolis P, Franchi M. Midterm outcome of radiofrequency thermal ablation for symptomatic uterine myomas. Surg Endosc 2007;21:2081–5. Brucker SY, Hahn M, Kraemer D, Taran FA, Isaacson KB, Kra¨mer B. Laparoscopic radiofrequency volumetric thermal ablation of fibroids versus laparoscopic myomectomy. Int J Gynaecol Obstet 2014;125:261–5. Berman JM, Guido RS, Garza Leal JG, Pemueller RR, Whaley FS, Chudnoff SG, et al. Three-year outcome of the Halt trial: A prospective analysis of radiofrequency volumetric thermal ablation of myomas. J Minim Invasive Gynecol 2014; 21:767–74. Chudnoff SG, Berman JM, Levine DJ, Harris M, Guido RS, Banks E. Outpatient procedure for the treatment and relief of symptomatic uterine myomas. Obstet Gynecol 2013;121: 1075–82. Galen DI, Pemueller RR, Leal JG, Abbott KR, Falls JL, Macer J. Laparoscopic radiofrequency fibroid ablation: phase II and phase III results. J Soc Laparoscopic Surg 2014;18:182–90. Jeong HJ, Kwon BS, Choi YJ, Huh CY. Rectouterine fistula after laparoscopic ultrasound-guided radiofrequency ablation of a uterine fibroid. Obstet Gynecol Sci 2014;57:553–6. Brower V. FDA considers restricting or banning laparoscopic morcellation. J Natl Cancer Inst 2014;106:dju339. Senapati S, Tu FF, Magrina JF. Power morcellators: aA review of current practice and assessment of risk. Am J Obstet Gynecol 2015; 212:18–23. Garza-Leal JG. Transcervical, intrauterine ultrasound-guided radiofrequency ablation of uterine fibroids with the VizAblate System: Safety, tolerability, and ablation results in a closed abdomen setting. In: Toub D, Herna´ndez Leo´n I, Castillo Saenz L, Uecker D, Munrow M, King D, et al., editors. Gynecological Surgery. New York: Springer, 2011, pp. 327–34. Gynesonics. Symptom effectiveness study of VizAblateÔ intrauterine ultrasound-guided RF ablation (IUUSgRFA) in the ablation of uterine fibroids. U.S. National Institutes of Health clinical trial, 2013. Available from https://clinicaltrials.gov/ct2/show/ NCT01226290. Goldberg J, McCrosson S, Kaulback KR. Delayed leiomyoma degeneration after microwave endometrial ablation. Obstet Gynecol 2005;106:1176–8. Kanaoka Y, Hirai K, Ishiko O. Microwave endometrial ablation for menorrhagia caused by large submucous myomas. J Obstet Gynaecol Res 2005;31:565–70. Kanaoka Y, Yoshida C, Fukuda T, Kajitani K, Ishiko O. Transcervical microwave myolysis for uterine myomas assisted by transvaginal ultrasonic guidance. J Obstet Gynaecol Res 2009;35: 145–51. Zhang J, Feng L, Zhang B, Ren J, Li Z, Hu D, et al. Ultrasoundguided percutaneous microwave ablation for symptomatic uterine fibroid treatment – A clinical study. Int J Hyperthermia 2011;27: 510–16. Yang Y, Zhang J, Han ZY, Yu MA, Ma X, Zhou HY, et al. Ultrasound-guided percutaneous microwave ablation for submucosal uterine fibroids. J Minim Invasive Gynecol 2014;21: 436–41. Xia M, Jing Z, Han ZY, Yu Y, Hao YL, Xu CT, et al. Research of dose–effect relationship parameters of percutaneous microwave ablation for uterine leiomyomas – A quantitative study. Sci Rep 2014;4:6469. Swe TT, Onitsuka H, Kawamoto K, Ueyama T, Tsuruchi N, Masuda K. Uterine leiomyoma: Correlation between signal intensity on magnetic resonance imaging and pathologic characteristics. Radiat Med 1992;10:235–42. Lynn JG, Zwemer RL, Chick AJ, Miller AE. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol 1942;26:179–93. Rivens I, Shaw A, Civale J, Morris H. Treatment monitoring and thermometry for therapeutic focused ultrasound. Int J Hyperthermia 2007;23:121–39. Cline HE, Schenck JF, Hynynen K, Watkins RD, Souza SP, Jolesz FA. MR-guided focused ultrasound surgery. J Comput Assist Tomogr 1992;16:956–65.
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
8
S. D. Quinn & W. M. Gedroyc
48. Hoskins PR, Martin K, Thrush A. Diagnostic Ultrasound: Physics and Equipment. 2nd ed. Cambridge: Cambridge University Press, 2010. 49. Schlesinger D, Benedict S, Diederich C, Gedroyc W, Klibanov A, Larner J. MR-guided focused ultrasound surgery, present and future. Med Phys 2013;40:080901. 50. Zhou YF. High intensity focused ultrasound in clinical tumor ablation. World J Clin Oncol 2011;2:8–27. 51. Hill CR, Rivens I, Vaughan MG, ter Haar GR. Lesion development in focused ultrasound surgery: A general model. Ultrasound Med Biol 1994;20:259–69. 52. ter Haar G. Ultrasound focal beam surgery. Ultrasound Med Biol 1995;21:1089–100. 53. Cheung VY. Sonographically guided high-intensity focused ultrasound for the management of uterine fibroids. J Ultrasound Med 2013;32:1353–8. 54. Ren XL, Zhou XD, Zhang J, He GB, Han ZH, Zheng MJ, et al. Extracorporeal ablation of uterine fibroids with high-intensity focused ultrasound: Imaging and histopathologic evaluation. J Ultrasound Med 2007;26:201–12. 55. Ren XL, Zhou XD, Yan RL, Liu D, Zhang J, He GB, et al. Sonographically guided extracorporeal ablation of uterine fibroids with high-intensity focused ultrasound: midterm results. J Ultrasound Med 2009;28:100–3. 56. Wang W, Wang Y, Wang T, Wang J, Wang L, Tang J. Safety and efficacy of US-guided high-intensity focused ultrasound for treatment of submucosal fibroids. Eur Radiol 2012;22:2553–8. 57. Leung JH, Yu SC, Cheung EC, Wong AS, Tong MM, Ho SS, et al. Safety and efficacy of sonographically guided high-intensity focused ultrasound for symptomatic uterine fibroids: Preliminary study of a modified protocol. J Ultrasound Med 2014;33:1811–18. 58. McDannold N. Quantitative MRI-based temperature mapping based on the proton resonant frequency shift: Review of validation studies. Int J Hyperthermia 2005;21:533–46. 59. Ishihara Y, Calderon A, Watanabe H, Okamoto K, Suzuki Y, Kuroda K. A precise and fast temperature mapping using water proton chemical shift. Magn Reson Med 1995;34:814–23. 60. Zaher S, Gedroyc WM, Regan L. Patient suitability for magnetic resonance guided focused ultrasound surgery of uterine fibroids. Eur J Obstet Gynecol Reprod Biol 2009;143:98–102. 61. Kim YS, Bae DS, Park MJ, Viitala A, Keserci B, Rhim H, et al. Techniques to expand patient selection for MRI-guided highintensity focused ultrasound ablation of uterine fibroids. Am J Roentgenol 2014;202:443–51. 62. Hesley GK, Felmlee JP, Gebhart JB, Dunagan KT, Gorny KR, Kesler JB, et al. Noninvasive treatment of uterine fibroids: Early Mayo Clinic experience with magnetic resonance imaging-guided focused ultrasound. Mayo Clin Proc 2006;81:936–42. 63. Yamashita Y, Torashima M, Takahashi M, Tanaka N, Katabuchi H, Miyazaki K, et al. Hyperintense uterine leiomyoma at T2-weighted MR imaging: differentiation with dynamic enhanced MR imaging and clinical implications. Radiology 1993;189:721–5. 64. Le´na´rd ZM, McDannold NJ, Fennessy FM, Stewart EA, Jolesz FA, Hynynen K, et al. Uterine leiomyomas: MR imaging-guided focused ultrasound surgery–imaging predictors of success. Radiology 2008;249:187–94. 65. Funaki K, Fukunishi H, Sawada K. Clinical outcomes of magnetic resonance-guided focused ultrasound surgery for uterine myomas: 24-month follow-up. Ultrasound Obstet Gynecol 2009;34:584–9. 66. Stewart EA, Rabinovici J, Tempany CM, Inbar Y, Regan L, Gostout B, et al. Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids. Fertil Steril 2006;85:22–9. 67. Stewart EA, Gostout B, Rabinovici J, Kim HS, Regan L, Tempany CM. Sustained relief of leiomyoma symptoms by using focused ultrasound surgery. Obstet Gynecol 2007;110:279–87. 68. Funaki K, Fukunishi H, Funaki T, Sawada K, Kaji Y, Maruo T. Magnetic resonance-guided focused ultrasound surgery for uterine fibroids: Relationship between the therapeutic effects and signal intensity of preexisting T2-weighted magnetic resonance images. Am J Obstet Gynecol 2007;196:184.e1–6. 69. Fennessy FM, Tempany CM, McDannold NJ, So MJ, Hesley G, Gostout B, et al. Uterine leiomyomas: MR imaging-guided focused ultrasound surgery–results of different treatment protocols. Radiology 2007;243:885–93.
Int J Hyperthermia, Early Online: 1–8
70. Harding G, Coyne KS, Thompson CL, Spies JB. The responsiveness of the uterine fibroid symptom and health-related quality of life questionnaire (UFS-QOL). Health Qual Life Outcomes 2008;6:99. 71. Morita Y, Ito N, Hikida H, Takeuchi S, Nakamura K, Ohashi H. Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids - early experience. Eur J Obstet Gynecol Reprod Biol 2008;139:199–203. 72. Mikami K, Murakami T, Okada A, Osuga K, Tomoda K, Nakamura H. Magnetic resonance imaging-guided focused ultrasound ablation of uterine fibroids: Early clinical experience. Radiat Med 2008;26:198–205. 73. Okada A, Morita Y, Fukunishi H, Takeichi K, Murakami T. Noninvasive magnetic resonance-guided focused ultrasound treatment of uterine fibroids in a large Japanese population: Impact of the learning curve on patient outcome. Ultrasound Obstet Gynecol 2009;34:579–83. 74. Zhang L, Wang ZB. High-intensity focused ultrasound tumor ablation: Review of ten years of clinical experience. Front Med China 2010;4:294–302. 75. LeBlang SD, Hoctor K, Steinberg FL. Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: Report of 80 patients. AJR Am J Roentgenol 2010;194:274–80. 76. Rabinovici J, David M, Fukunishi H, Morita Y, Gostout BS, Stewart EA. Pregnancy outcome after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids. Fertil Steril 2010;93:199–209. 77. Yoon SW, Seong SJ, Jung SG, Lee SY, Jun HS, Lee JT. Mitigation of abdominal scars during MR-guided focused ultrasound treatment of uterine leiomyomas with the use of an energy-blocking scar patch. J Vasc Interv Radiol 2011;22:1747–50. 78. Gorny KR, Woodrum DA, Brown DL, Henrichsen TL, Weaver AL, Amrami KK, et al. Magnetic resonance-guided focused ultrasound of uterine leiomyomas: Review of a 12-month outcome of 130 clinical patients. J Vasc Interv Radiol 2011;22:857–64. 79. Machtinger R, Inbar Y, Cohen-Eylon S, Admon D, AlagemMizrachi A, Rabinovici J. MR-guided focus ultrasound (MRgFUS) for symptomatic uterine fibroids: Predictors of treatment success. Hum Reprod 2012;27:3425–31. 80. Voogt MJ, Trillaud H, Kim YS, Mali WP, Barkhausen J, Bartels LW, et al. Volumetric feedback ablation of uterine fibroids using magnetic resonance-guided high intensity focused ultrasound therapy. Eur Radiol 2012;22:411–17. 81. Park H, Yoon SW, Kim KA, Jung Kim D, Jung SG. Magnetic resonance imaging-guided focused ultrasound treatment of pedunculated subserosal uterine fibroids: A preliminary report. J Vasc Interv Radiol 2012;23:1589–93. 82. Dobrotwir A, Pun E. Clinical 24 month experience of the first MRgFUS unit for treatment of uterine fibroids in Australia. J Med Imaging Radiat Oncol 2012;56:409–16. 83. Kim YS, Trillaud H, Rhim H, Lim HK, Mali W, Voogt M, et al. MR thermometry analysis of sonication accuracy and safety margin of volumetric MR imaging-guided high-intensity focused ultrasound ablation of symptomatic uterine fibroids. Radiology 2012;265:627–37. 84. Trumm CG, Stahl R, Clevert DA, Herzog P, Mindjuk I, Kornprobst S, et al. Magnetic resonance imaging-guided focused ultrasound treatment of symptomatic uterine fibroids: Impact of technology advancement on ablation volumes in 115 patients. Invest Radiol 2013;48:359–65. 85. Froeling V, Meckelburg K, Schreiter NF, Scheurig-Muenkler C, Kamp J, Maurer MH, et al. Outcome of uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for uterine fibroids: Long-term results. Eur J Radiol 2013. 86. Quinn SD, Vedelago J, Regan L, Gedroyc W. Five-year reintervention and safety following MRgFUS for uterine fibroids. Eur J Obstetr Gynecol Reprod Biol 2014;182:247–51. 87. Gizzo S, Saccardi C, Patrelli TS, Ancona E, Noventa M, Fagherazzi S, et al. Magnetic Resonance-Guided Focused Ultrasound Myomectomy: Safety, Efficacy, Subsequent Fertility and Qualityof-Life Improvements, A Systematic Review. Reprod Sci 2013;21:465–76. 88. Quinn SD, Vedelago J, Gedroyc W, Regan L. Safety and five-year re-intervention following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids. Eur J Obstet Gynecol Reprod Biol 2014;182:247–51.
REVIEW ARTICLE
Thermal ablative treatment of uterine fibroids Stephen Derek Quinn1 & Wladyslaw M. Gedroyc2 Department of Obstetrics and Gynaecology, St Mary’s Hospital, Imperial College London and 2Department of Radiology, St Mary’s Hospital, Imperial College London, UK
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
1
Abstract
Keywords
In addition to surgical methods of treating uterine fibroids, numerous non-invasive treatments have been developed. Many of these involve the use of hyperthermia, the heating of tissue by a variety of methods. These include the use of lasers, radiofrequency, microwave energy and high intensity focused ultrasound, guided by both ultrasound and magnetic resonance imaging. In this review we examine the technology behind these treatment modalities and review the current evidence for their use.
HIFU, microwave ablation, MRgFUS, radiofrequency ablation, radiofrequency volumetric thermal ablation, ultrasound guided high intensity focused ultrasound (USgHIFU), uterine fibroids History Received 31 October 2014 Revised 17 January 2015 Accepted 18 January 2015 Published online 27 March 2015
Introduction Uterine fibroids (also known as leiomyomas or myomas) are the most common benign tumour found in women, with epidemiological studies indicating that up to 74% of premenopausal women will have evidence of uterine fibroids on histological examination [1]. The prevalence of fibroids increases with age up until the menopause [2]. Due in part to an increase in the average age of conception [3], fibroids are increasingly associated with fertility problems. A large study of randomly selected women between the ages of 35 and 49 found a prevalence of clinically significant fibroids in 10 to 15% of white women and 30 to 40% of black women [4]. Although these are benign tumours, uterine fibroids may have a significant impact on the quality of life of the individual [5]. Women with uterine fibroids may have a range of clinical manifestations related to their size and position. While many women with uterine fibroids will experience heavy menstrual bleeding, the mechanism for this is still not fully understood; though several mechanisms have been suggested [6,7]. One theory is that distortion of the uterine cavity and enlargement of the endometrial surface area leads to increased menstrual blood loss, with women with heavy menstrual bleeding having a higher prevalence of intramural and submucosal fibroids [8]. One study found that compared with asymptomatic women, premenopausal women with abnormal uterine bleeding had a higher prevalence of sub-mucous fibroids (21% vs. 1%), and intramural fibroids (58% vs. 13%) [8]. Correspondence: Stephen Quinn, Department of Obstetrics and Gynaecology, St Mary’s Hospital, Imperial College London, South Wharf Road, London, UK. Tel: 02033122325. E-mail: [email protected]
Larger fibroids, or uteri with multiple fibroids may cause pressure-related symptoms such as bladder frequency and nocturia, and urinary symptoms have been found to improve following reduction in fibroid volume [9,10]. At present fibroids may be treated surgically by hysteroscopic, laparoscopic, or open myomectomy, hysterectomy or by uterine artery embolisation (UAE). In addition to these well-established treatments for uterine fibroids, thermal ablative approaches have been developed. The destruction of tumour tissue by thermal injury can be achieved by using radiofrequency energy, focused ultrasound and microwave energy. Increasing the temperature of tissue to 50–52 C for 4–6 min is sufficient to produce irreversible cellular damage [11]. When temperatures reach 60–100 C rapid, irreversible damage caused by protein coagulation leads ultimately to coagulative necrosis [12,13]. When temperatures exceed 105 C, resultant tissue vaporisation and carbonisation can worsen further ablation within the tissue due to the reduction in energy transmission [11,13]. The aim of any thermal ablative treatment of uterine fibroids is to treat the maximum quantity of fibroid tissue safely, while preserving the surrounding uterine tissue.
Laser treatment of uterine fibroids The first use of high temperatures to ablate fibroid tissue was myoma coagulation or myolysis, which involved the use of a neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, either laparoscopically or hysteroscopically [14,15]. The infrared energy from the laser is converted into heat within the tissue, and at temperatures over 55 C the cells undergo irreversible damage, with protein denaturation and coagulative necrosis.
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
2
S. D. Quinn & W. M. Gedroyc
Usually women would be given 3 months of a gonadotropin releasing hormone analogue (GnRHa) prior to treatment and would require an average of 30–50 needle insertions per fibroid, over a period of 20 to 30 min [15]. Initial results were encouraging with a decrease in fibroid volume by around 50% [15,16]. This method of treating uterine fibroids was, however, associated with a high incidence of post-operative adhesion formation, presumed to be related to the multiple incisions through the serosa required to treat the uterine fibroids [17]. The risk of adhesion formation, in addition to the reported cases of uterine rupture in pregnancy following this treatment has limited the appeal of this modality [18,19]. Other concerns regarding this method of treatment include the inability to accurately predict the volume of ablated tissue or to visualise the effect of heating on tissues during the treatment process, leading to questions regarding the reproducibility of treatments and their safety. Percutaneous MRI-guided insertion of infra-red lasers was developed in order to better visualise the area under treatment, and perform a more controlled procedure [20]. These use light in the near infrared spectrum at a wavelength of 810 nm, and 18-gauge Turner needles introduced into the centre of the targeted fibroid under MRI guidance in a square configuration 1 cm apart. Mean treatment times are around 15 min per burn area, which are repeated in order to treat a larger volume. Initial results were very encouraging with a mean reduction of uterine fibroid volume of 31% [21]. By using magnetic resonance (MR) imaging to allow real-time thermal mapping of the uterus throughout the treatment, operators were able to achieve increased ablation volumes within the target tissue with minimal risk of damage to the serosa or any adjacent structures, which can be clearly visualised in relation to the area of treatment. The use of lasers to induce thermal injury to fibroid tissue has now though been superseded by other thermal ablation techniques.
Radiofrequency ablation of uterine fibroids The use of bipolar diathermy by the laparoscopic insertion of bipolar diathermy needles into the fibroid tissue produced results that were initially comparable to laser myolysis [21,22]. It was suggested that the risk of adhesions was reduced compared to that of laser myolysis; however, this was based on a small series [21]. Due to concerns regarding case reports of uterine rupture in pregnancies following bipolar myolysis this procedure was restricted to women in whom future fertility was no longer required [18,23]. Radiofrequency ablative techniques increase the temperature of tissue as a result of frictional heat produced by electrically resistive heating. The radiofrequency alternating current (typically 450–500 kHz) is applied to an electrode applicator producing a movement of ions and resultant frictional heating [24]. As with other thermal ablative therapies, once the temperature exceeds 50 C irreversible cell damage occurs with resultant coagulative necrosis. Radiofrequency electrode applicators have been used laparoscopically to create a large spherical area (up to a diameter of 5 cm) of tissue ablation within uterine fibroids [25]. This far exceeds the volumes achieved with laser myolysis, where multiple insertions of the needle were believed to contribute
Int J Hyperthermia, Early Online: 1–8
to post-treatment adhesion formation. The first report of radiofrequency ablation of fibroids at laparoscopy was in 2005 and the initial results have been encouraging, with reductions in fibroid size by 41.5 (77%) [25,26]. A study of 35 women undergoing image-guided radiofrequency ablation using 5-cm needle electrodes connected to a 460 kHz monopolar radiofrequency generator, following UAE, found a significant improvement in quantitative symptom severity scores and a 56.5% reduction in fibroid volume at 6 months [27]. This was achieved with no immediate percutaneous radiofrequency ablation-related complications. Another study reported results from a study of 25 women undergoing treatment with a laparoscopically inserted, ultrasound-guided radiofrequency needle with deployable tines that, when extended, have a Christmas tree-like arrangement [28]. In this study the mean volume of the dominant fibroid was 76.8 cm3 (range 14.8–332.8), and resultant volume reduction at one year was 77.9%. A recent randomised controlled trial compared radiofrequency volumetric thermal ablation at laparoscopy with laparoscopic myomectomy (with use of a morcellator) [29]. This study found significantly shorter hospital stays: (10.0 ± 5.5 h (median 7.8 (range 4.2–25.5)) for the radiofrequency ablation group and 29.9 ± 14.2 h (median 22.6 (range 16.1–68.1)) for the myomectomy group) and decreased intraoperative blood loss (16 ± 9 (median 20 mL (range 0–30)) for the radiofrequency ablation group and 51 ± 57 (median 35 mL (range 10–300)) for the myomectomy group) [29]. A prospective, multicentre study of 104 women undergoing volumetric radiofrequency ablation of their uterine fibroids found that at 3 years the surgical reintervention rate was 11%, and the improvement in symptom severity scores was 32.6% [30]. At 1 year the fibroids had decreased in volume by a mean of 45.1% and they reported one serious adverse event requiring readmission post-procedure [31]. A prospective study of 69 women following volumetric radiofrequency laparoscopic ablation of fibroids found a mean decrease in fibroid volume at 12 months of 28.7%, with one major adverse event – the development of a haematoma that resolved spontaneously post-operatively [32]. Overall, the rate of adverse events was 10%, including abdominal pain and urinary tract infections. Four pregnancies were reported in the first 12 months following ablation; these resulted in two caesarean sections at term, one vaginal delivery at term and one 10-week miscarriage [32]. There have been no reported cases of bladder or bowel perforation following laparoscopic radiofrequency ablation; however, there has been a case of recto-uterine fistula in a patient with co-existing endometriosis [33]. Given recent concerns regarding the safety of laparoscopic mechanical morcellation of uterine fibroids, radiofrequency ablation may be a promising alternative [34,35]. A transcervical radiofrequency ablation device has been developed, known as the VizAblateÔ System (Gynesonics, Redwood City, CA). This system uses an intra-uterine ultrasound probe and an intra-uterine radiofrequency generator, which allows real-time ultrasound imaging of the uterus and fibroid tissue while the VizAblate needle electrodes pass under ultrasound guidance into the target fibroids. When a safe position has been confirmed, the radiofrequency energy is delivered directly into the fibroid for a set period of time,
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
DOI: 10.3109/02656736.2015.1010608
Thermal ablative treatment of uterine fibroids
3
depending on the fibroid size [36]. This system produces ellipsoidal ablations of up to 5 4 cm in size and heats the tissue to a temperature of 105 C. The size of these ablations can be adjusted depending on the depth of the needle. This system calculates a thermal safety zone around the fibroid which prevents ablation of myometrium or uterine serosa and therefore minimises the risks of adhesion formation or uterine damage. Fibroids of up to 5 cm in size can be treated and the procedure takes around 30 min to complete [36]. A clinical trial of this device is currently on-going [37].
signal intensity when compared with skeletal muscle; these fibroids are referred to as hyperintense, isointense or hypointense respectively. Hypointense and isointense fibroids have a higher fibre content and lower cellular content, and a reduced blood supply compared with fibroids of hyperintense appearance [44]. A study of the thermal dose-related effectiveness of percutaneous microwave ablation found that the volumes of ablation achieved for a given microwave power were reduced in hyperintense fibroids compared with hypointense or isointense fibroids [43].
Microwave ablation of uterine fibroids
High intensity focused ultrasound treatment of uterine fibroids
In 2005, Goldberg described fibroid degeneration following microwave ablation of the endometrium [38]. In addition, submucosal fibroids have been reported to become necrosed and reduced in volume following microwave endometrial ablation [39]. Based on these findings a system was developed to treat fibroids transcervically, using microwave ablation under ultrasound guidance [40]. Microwave ablation uses an antenna probe that emits microwaves (2.45 GHz) into the fibroid tissue. The microwaves excite polar molecules such as water, and as these molecules attempt to align with the electromagnetic field there is resultant friction and production of heat. Transcervical microwave ablation of fibroids has been described using a 14-gauge needle set in an adaptor attached to a transvaginal ultrasound probe, which is inserted into the endometrial cavity following endometrial ablation [40]. Under transvaginal ultrasound guidance the guiding needle is inserted into the fibroid, then the inner part this is replaced by a needle applicator emitting microwaves at 2.45 GHz. A continuous infusion of saline through the space between the guiding needle and microwave applicator allows the heat generation rate to be maintained while preventing the tissue from drying, while a separate saline pump cools the transcervical probe, reducing thermal injury to the cervix. A study of nine women undergoing transcervical microwave ablation of their fibroids found a decrease in volume of between 37–69% at 6 months with no significant complications [40]. Percutaneous microwave ablation of fibroids involves the insertion of a microwave antenna and thermocouple needle into the fibroid tissue under conscious sedation [41]. The thermocouple needle allows real-time thermal feedback during the treatment. A 15-gauge diameter microwave needle antenna is used (20 mm in length), capable of both continuous and pulsed microwave modes [41]. A single microwave antenna is used for fibroids of less than 5 cm diameter; for fibroids of greater than 5 cm, double antennas (spaced 1 cm apart) are used. Fibroids of greater than 7 cm in diameter have an initial ablation with the two antennas of 50 W for 300 s, followed by a second ablation after withdrawing the antennas by 1 cm [41]. The mean fibroid volume reduction following this treatment is between 90 and 94%, and there have been no major adverse events described [41,42]. The effectiveness of microwave ablation of uterine fibroids in terms of the thermal dose effect is related to the appearance of fibroids on T2-weighted MRI [43]. When viewing uterine fibroids on T2-weighted MRI, these tumours can be described as being higher in signal intensity, equal to, or less high in
High intensity ultrasound can be focused into a small volume to produce a rise in tissue temperature sufficient to cause irreparable cell damage in the target at depth within the body [45]. Therapeutic focused ultrasound can be guided by both MRI and diagnostic ultrasound to direct the energy to the targeted tissue. Ultrasound guidance is relatively less expensive and more portable; however, MRI has the advantage of accurate real-time thermal mapping [46], which is limited when diagnostic ultrasound is utilised for targeting. The first report of the use of MR imaging to direct focused ultrasound in the treatment of tumours was published in 1992 [47]. High intensity focused ultrasound (HIFU) uses ultrasonic waves as a source of thermal injury within tissues. Ultrasound waves are generated by a transducer, a device that converts electrical pulses into pressure pulses. The transducer most commonly uses a piezoelectric plate that generates the ultrasound pulse. Piezoelectric materials expand or contract when a positive or negative charge is applied [48]. It is this expansion and contraction that results in the production of ultrasound waves. Ultrasound is a longitudinal pressure wave. When an ultrasound wave passes through a medium, the molecules of that medium oscillate back and forth along the direction of propagation of the wave. The resulting friction transforms acoustic energy into heat and contributes to the attenuation of the ultrasonic beam. Diagnostic medical ultrasound commonly uses frequencies in the range 2–15 MHz. In HIFU, frequencies of between 0.9 and 12 MHz have been used [49]. The intensity of the ultrasound beam is a measure of energy flowing through an area of the beam, which is quoted in Wcm2. The intensities of typical diagnostic ultrasound scanning (B-mode, pulsed or continuous Doppler) can be up to 720 mWcm2. In contrast, the intensity of focused ultrasound in the focal region is about 100–10 000 Wcm2 [50]. Ultrasound waves can be focused into a small volume either by a lens, a curved transducer, or a phased array into a small focal zone, in a similar way to light being focused through a magnifying glass to a single point. The phased array transducer is constructed using multiple parallel transducer units [48]. The signal from each transducer is emitted at a different phase from that preceding it. Appropriate timing of these signals allows the ultrasound beam to be focused. By using ultrasound with energies of up to 7000 J focused into a cigar-shaped focal spot of between 2 2 4 mm3 and 10 10 70 mm3, the tissues within the focal point are heated to greater than 56 C for a period of 1 s. Each focal
4
S. D. Quinn & W. M. Gedroyc
Int J Hyperthermia, Early Online: 1–8
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
Figure 1. Visualising the ultrasound beam path under MRI guidance.
exposure is commonly referred to as a sonication. The thermal threshold of 56 C has been established as the minimum temperature at the edges of a sonication [51]. Temperatures at the centre of the sonication may be greater than 90 C [52]. This results in coagulative necrosis and apoptotic cell death of the targeted tissue. Sonications within tissue can vary in size from 1–7 cm in length. The absorption coefficients of tissues vary significantly: bone absorbs most ultrasound energy, fluids such as blood absorb very little ultrasound energy, and soft tissue such as myometrium falls someway in between [48]. When ultrasound is applied in the linear pressure regime (for biological tissues typically below 5 MPa), the energy is absorbed at a rate that is directly proportional to the local intensity, meaning that the highest rise in temperature will be at the focus of the beam. The temperature continues to rise as more energy is absorbed; although some heat is lost by the process of conduction to surrounding cooler areas. HIFU has been used to treat uterine fibroids under the guidance of both ultrasound and MRI. Sonographically guided focused ultrasound uses changes in either greyscale or echogenicity to determine the area of fibroid ablation [53]. The HIFUNIT 9000 tumour therapy system (Shanghai Aishen Technology, Shanghai, China) comprises six self-focusing acoustic therapeutic transducers which focus the ultrasound beam, and a diagnostic transducer located in the centre of the therapeutic transducers [54]. This allows tissues in the path of therapeutic ultrasound waves to be viewed in diagnostic ultrasound images. Initial results with this system were encouraging, with 85.5% of patients undergoing this treatment experiencing an improvement in their symptoms at 1 year, 59.3% having total relief from their symptoms at 1 year, and a 9.7% reintervention rate at 1 year (n ¼ 145) [55]. An alternative system has been used with a similar arrangement of a central 3.5–5.0-MHz convex diagnostic ultrasound probe and a 20-cm diameter therapeutic transducer with a focal length of 150 mm operating at a frequency of 0.9 MHz (Model JC; Chongqing Haifu Technology, Chongqing, China) [56]. This system has been used to treat submucosal uterine fibroids achieving a mean non-perfused volume of 80%, a mean reduction in fibroid volume of 90.1% at 24 months and vaginal expulsion of necrosed fibroid material in 58% [56]. The reduction in fibroid volumes following sonographically guided focused ultrasound has been impressive, with reductions of between 50.3% and 78.9% at 12 months [55,56].
These studies, however, are small, and compared with magnetic resonance-guided focused ultrasound (MRgFUS), long-term data is limited. Sonographically guided focused ultrasound may have advantages over MRgFUS, including the cost of treatment and potentially shorter treatment times. A recent study used a modified treatment protocol consisting of repeated and shortened (less than 25 min) treatment sessions of high intensity (1000–1500 W/cm2), and repeated sonication pulses (1500–2000) at each spot [59]. This modified protocol was associated with a third degree skin burn in one of the 20 subjects, two cases of skin blisters, and eight patients experiencing pain after the treatment. MRI enables assessment of the pelvic anatomy in three dimensions, allowing accurate targeting of the uterine fibroids. By using MRI the ultrasound beam path can be visualised, therefore avoiding damage to structures such as the bowel (Figure 1) by possible reflection at gas–soft tissue interfaces. Prior to treatments patients are catheterised, ensuring a static bladder volume during the treatment. Initial detailed MR imaging of the pelvis allows treatments to be carefully planned prior to the first sonication, and the position of surrounding bowel and far-field bone are noted. MRI allows near real-time thermometry of the tissue to achieve the planned outcome (Figure 2). MR thermometry is based on the temperature dependence of the proton-resonance phase shift of water molecules [58,59]. This effect results in a phase shift of the gradient recalled MR-images: an effect which is both linear with the observed temperature change, and independent of the type of tissue. MRI also enables the post-treatment assessment of the volume of fibroid ablated. Following the completed sonications, an intravascular contrast agent is given and T1-fat saturated images of the pelvis are obtained. From these the degree of non-perfused volume of the fibroid can be assessed (Figure 3). Since its introduction, increasing experience of this treatment has led to a refinement of patient selection, with a tendency toward treating women with fewer fibroids and smaller uteri [60]. In addition to patient selection, several clinical tactics have been used to treat fibroids, where treatments would be otherwise limited. The passage of the focused ultrasound beam through bowel in the treatment of uterine fibroids is contraindicated due to concerns regarding this organ’s absorption of energy. Various methods have been used to move loops of bowel from the beam path including
DOI: 10.3109/02656736.2015.1010608
Thermal ablative treatment of uterine fibroids
5
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
Figure 2. Real-time thermometry employed during MRgFUS.
Figure 3. Post-treatment non-perfused volume of the uterine fibroid on T1-weighted MRI.
filling the bladder with normal saline, or by rectal filling using either a rectal balloon filled with normal saline or inserting rectal ultrasound gel [61]. One group has described applying pressure to the central abdominal wall in order to displace bowel via the use of a convex gel pad [62]. It is known that the signal intensity of fibroids can correspond to their cellular density, fibre content and vascularity [44,63], and the signal intensity of uterine fibroids is a known predictor of the success of HIFU [64]. A study of 91 women undergoing MRgFUS in Japan found a 2-year reintervention rate of 14% in women with hypointense or iso-intense fibroids [65]. These women had a mean non-perfused volume (NPV) of 54.7% and a mean tumour volume of 129.0 mL (SD 145.2 mL) [65]. A recent systematic review of the literature regarding HIFU found 38 prospective and retrospective studies, no randomised control trials, and studies of limited quality [87]. A summary of the studies identified is given in Table 1. The available data on long-term outcomes is currently very limited. Funaki et al. found a 2-year reintervention rate of 21.6% for hyperintense uterine fibroids (with a mean NPV of 36.2%) and 14.0% at 2 years for normo-intense fibroids (with a mean NPV of 54.35%) [65]. This was the first study to examine how the overall percentage of fibroid tissue treated successfully (as defined by the post-contrast NPV appearance of the MR image) related to subsequent symptomatic
response over a longer follow-up period. A more recent prospective study found a 2-year reintervention rate of 24%, with an overall NPV of 40.9% [79]. This study also stratified outcome by signal intensity and NPV and found that women with hyperintense fibroids had a higher risk of requiring further treatment at 2 years compared with women with hypointense fibroids, although on multivariate analysis this failed to reach significance (odds ratio (OR) 2.87 (0.64– 14.4)). Treatment resulting in greater than 45% NPV had a 15% risk of reintervention by 2 years, whereas treatments resulting in a 10–20% NPV had a 40% risk of reintervention at 2 years (OR 5.22 (1.1–26.0) [79]. A recent retrospective study of women undergoing UAE and MRgFUS found a 5-year reintervention rate of 66.7% at 5 years following a mean NPV of 36.4% [85]. In this study, however, the less accurate ellipsoid formula method was used to calculate the NPV, no mention of fibroid signal intensity was made and 37% of their patients were lost to follow-up. A cohort study of 280 women undergoing MRgFUS found that the overall reintervention rate at 5 years was 58.64%, but in those treatments with greater than 50% NPV the reintervention rate was 50% [88]. Further improvement of the 5-year reintervention rate was also found when 3 months pre-treatment of gonadotropin releasing hormone agonist (GnRHa) had been used. In addition to the long-term outcomes, specific data regarding the safety of MRgFUS is encouraging. The initial multicentre prospective study by Stewart et al. (n ¼ 155) found no deaths, life-threatening events or hysterectomies following MRgFUS [32]. There have been no recorded deaths, or hysterectomies following MRgFUS in any of the current literature. The most serious complication reported by that study was a sciatic nerve palsy in one woman, which resolved by 1 year post-treatment. This was believed to be a result of indirect injury of the nerve, caused by heating of the nearby bone following absorption of ultrasound energy in the far field of the treatment sonication. A cohort study of 280 women undergoing MRgFUS found a 1.4% risk of urinary tract infection (patients undergoing MRgFUS have a urinary catheter during the procedure), a 1.1% risk of minor skin burns requiring no repair and a 0.4% risk of major skin burn requiring secondary repair [31]. In this cohort there was, again, one woman who experienced persistent neuropathy following absorption of energy in the far-field bone. As a result of these cases, changes to the system and to treatment planning have been developed to reduce far-field bone absorption by directing the beam with greater accuracy.
6
S. D. Quinn & W. M. Gedroyc
Int J Hyperthermia, Early Online: 1–8
Table 1. Collated data from previous MRgFUS Studies Mean Volume of Fibroids treated (mL)
45.4 44.8 41 45.9 45 42.6 44 45.4 40.4
155 109 52 64 102 48 32 66 91
61.7 61.7 –– 62.1 61.5 –– –– 61.5 ––
353 284.7 191.1 –– –– –– 306 255.5 101.5
42.5 39.4 46 37.2 41.1 45.6 45.6 44.8 39 42 44.5 42 36.2 42.2
279 21 80 51 20 130 81 33 9 100 27 115 36 163
–– –– –– –– 43.3 –– 48.82 –– 30 59 64.8 –– 60.7 62.4
326 97 175 268 –– 350.3 213 –– 197.8 185.0 502.5 89 53.2 396.3
38 25 69.63 25.79 –– 60 –– 16.3 54.35 NI 36.2 HI 46.6 75 55 40 53.5 45.4 40.9 21.7 66.9 67.00 64.2 88 36.4 44.2
42.7
Total n= 1864
56.5
241.4
48.6
Mean Age
Stewart et al., 2006 [66] Stewart et al., 2007 [67] Funaki et al., 2007 [68] Fennessy et al., 2007 [69] Harding et al., 2008 [70] Morita et al., 2008 [71] Mikami et al., 2008 [72] Le´na´rd et al., 2008 [64] Funaki et al 2009 [65]
Meta-analysis Pros Pros Pros Pros Pros Pros Retro Pros
Okada et al., 2009 [73] Zhang et al., 2010 [74] LeBlang et al., 2010 [75] Rabinovici et al., 2010 [76] Yoon et al, 2011 [77] Gorny et al., 2011 [78] Machtinger et al., 2012 [79] Voogt et al., 2012 [80] Park et al., 2012 [81] Dobrotwir and Pun, 2012 [82] Kim et al., 2012 [83] Trumm et al, 2013 [84] Froeling et al., 2013 [85] Quinn et al, 2014 [86]
Pros Pros Pros Pros Pros Retro Pros Pros Retro Pros Pros Retro Retro Retro
Authors, years
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
N
SSS at baseline
Study Design
Mean
NPV ratio (%)
Re-intervention 21.9% at 1yr –– 11.8% at 1yr –– –– 8.3% at 6 months –– –– 14.0% at 2yrs NI 21.6% at 2yrs HI 8% at 1yr –– –– –– –– 7.4% at 1yr 24% at 2yrs –– –– 13.7% at 1yr –– –– 66.7% at 5yrs 58.64% at 5yrs 52.3% at 5yrs (NI) 79.5% at 5yrs (HI)
HI = Hyperintense fibroid, NI = Normointense fibroid, NPV = Non-perfused volume, N = Numbers, SSS = Symptom severity score SSS = Symptom severity score
Skin burns have greatly reduced due to the experience and reporting of adverse events. All reported cases of major skin burns have been reported in women with significant abdominal scarring, and avoidance of treating fibroids through significant abdominal scars, or the use of an energydisplacing abdominal scar patch have reduced the incidents of further skin burns in recent years [77]. Recent developments in MRgFUS have been aimed at improving the ablation volumes achieved, including the use of an automatic three-dimensional treatment planner that automatically arranges sonication spots to cover a maximum targeted fibroid volume. By closing elements in the transducer the HIFU beam may be shaped in such a way as to produce a greater treatment volume. The transducer is able to get much closer to patients’ skin resulting in a reduced energy density in the beam path. The beam path will be wider at the skin and at the posterior bony structures leading to reduced energy absorption. This also allows an increased energy density to be produced safely without producing an increased energy absorption in the skin and spine. Early results utilising this newer system suggest that it can produce a consistently larger area of fibroid destruction in most patients, with NPVs of 88% (range 38–100%) reported [84].
alternative to laparoscopic myomectomy. While the noninvasive nature of HIFU is appealing, the long-term outcomes in terms of fibroid volume reduction and reintervention rates are disappointing. It is to be hoped that developments in the technology, as well as improved patient selection will further improve outcomes. Further evidence for the use of this technology should be obtained from randomised trials; however, in the meantime evidence from cohort studies continues to accumulate.
Conclusions
References
Treatment modalities using hyperthermic principles offer attractive alternatives to traditional surgical approaches. Initial results using volumetric radiofrequency ablation have been encouraging, and this may provide an effective
Acknowledgments The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Declaration of interest Stephen Quinn previously worked as a clinical research fellow at Imperial College London, and the funding for this post was provided by Insightec. The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the UK Department of Health. The authors alone are responsible for the content and writing of the paper.
1. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94:435–8. 2. Lurie S, Piper I, Woliovitch I, Glezerman M. Age-related prevalence of sonographically confirmed uterine myomas. J Obstet Gynaecol 2005;25:42–4.
Thermal ablative treatment of uterine fibroids
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
DOI: 10.3109/02656736.2015.1010608
3. McDonald JW, Rosina A, Rizzi E, Colombo B. Age and fertility: Can women wait until their early thirties to try for a first birth? J Biosoc Sci 2011;43:685–700. 4. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. Am J Obstet Gynecol 2003;188: 100–7. 5. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007;87:725–36. 6. Stovall DW. Clinical symptomatology of uterine leiomyomas. Clin Obstet Gynecol 2001;44:364–71. 7. Lockwood CJ. Mechanisms of normal and abnormal endometrial bleeding. Menopause 2011;18:408–11. 8. Murase E, Siegelman ES, Outwater EK, Perez-Jaffe LA, Tureck RW. Uterine leiomyomas: Histopathologic features, MR imaging findings, differential diagnosis, and treatment. Radiographics 1999;19:1179–97. 9. Langer R, Golan A, Neuman M, Schneider D, Bukovsky I, Caspi E. The effect of large uterine fibroids on urinary bladder function and symptoms. Am J Obstet Gynecol 1990;163:1139–41. 10. Pron G, Bennett J, Common A, Wall J, Asch M, Sniderman K, et al. The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertil Steril 2003;79:120–7. 11. Goldberg SN, Gazelle GS, Halpern EF, Rittman WJ, Mueller PR, Rosenthal DI. Radiofrequency tissue ablation: Importance of local temperature along the electrode tip exposure in determining lesion shape and size. Acad Radiol 1996;3:212–18. 12. Solbiati L, Ierace T, Goldberg SN, Sironi S, Livraghi T, Fiocca R, et al. Percutaneous US-guided radio-frequency tissue ablation of liver metastases: treatment and follow-up in 16 patients. Radiology 1997;202:195–203. 13. Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: A unified approach to underlying principles, techniques, and diagnostic imaging guidance. Am J Roentgenol 2000;174:323–31. 14. Donnez J, Gillerot S, Bourgonjon D, Clerckx F, Nisolle M. Neodymium: YAG laser hysteroscopy in large submucous fibroids. Fertil Steril 1990;54:999–1003. 15. Goldfarb HA. Laparoscopic coagulation of myoma (myolysis). Obstet Gynecol Clin North Am 1995;22:807–19. 16. Phillips DR, Milim SJ, Nathanson HG, Haselkorn JS. Experience with laparoscopic leiomyoma coagulation and concomitant operative hysteroscopy. J Am Assoc Gynecol Laparosc 1997;4:425–33. 17. Nisolle M, Smets M, Malvaux V, Anaf V, Donnez J. Laparoscopic myolysis with the Nd:YAG laser. J Gynecol Surg 1993;9:95–9. 18. Arcangeli S, Pasquarette MM. Gravid uterine rupture after myolysis. Obstet Gynecol 1997;89:857. 19. Law P, Gedroyc WM, Regan L. Magnetic-resonance-guided percutaneous laser ablation of uterine fibroids. Lancet 1999; 354(9195):2049–50. 20. Hindley JT, Law PA, Hickey M, Smith SC, Lamping DL, Gedroyc WM, et al. Clinical outcomes following percutaneous magnetic resonance image guided laser ablation of symptomatic uterine fibroids. Hum Reprod 2002;17:2737–41. 21. Goldfarb HA. Bipolar laparoscopic needles for myoma coagulation. J Am Assoc Gynecol Laparosc 1995;2:175–9. 22. Goldfarb HA. Comparison of bipolar electrocoagulation and Nd:YAG laser coagulation for symptomatic reduction of uterine myomas. J Am Assoc Gynecol Laparosc 1994;1:S13. 23. Vilos GA, Daly LJ, Tse BM. Pregnancy outcome after laparoscopic electromyolysis. J Am Assoc Gynecol Laparosc 1998;5:289–92. 24. Haemmerich D, Laeseke PF. Thermal tumour ablation: Devices, clinical applications and future directions. Int J Hyperthermia 2005; 21:755–60. 25. Bergamini V, Ghezzi F, Cromi A, Bellini G, Zanconato G, Scarperi S, et al. Laparoscopic radiofrequency thermal ablation: A new approach to symptomatic uterine myomas. Am J Obstet Gynecol 2005;192:768–73. 26. Milic A, Asch MR, Hawrylyshyn PA, Allen LM, Colgan TJ, Kachura JR, et al. Laparoscopic ultrasound-guided radiofrequency ablation of uterine fibroids. Cardiovasc Intervent Radiol 2006;29: 694–8. 27. Kim HS, Tsai J, Jacobs MA, Kamel IR. Percutaneous image-guided radiofrequency thermal ablation for large symptomatic uterine
28. 29.
30.
31.
32. 33. 34. 35. 36.
37.
38. 39. 40.
41.
42.
43.
44.
45. 46. 47.
7
leiomyomata after uterine artery embolization: A feasibility and safety study. J Vasc Interv Radiol 2007;18:41–8. Ghezzi F, Cromi A, Bergamini V, Scarperi S, Bolis P, Franchi M. Midterm outcome of radiofrequency thermal ablation for symptomatic uterine myomas. Surg Endosc 2007;21:2081–5. Brucker SY, Hahn M, Kraemer D, Taran FA, Isaacson KB, Kra¨mer B. Laparoscopic radiofrequency volumetric thermal ablation of fibroids versus laparoscopic myomectomy. Int J Gynaecol Obstet 2014;125:261–5. Berman JM, Guido RS, Garza Leal JG, Pemueller RR, Whaley FS, Chudnoff SG, et al. Three-year outcome of the Halt trial: A prospective analysis of radiofrequency volumetric thermal ablation of myomas. J Minim Invasive Gynecol 2014; 21:767–74. Chudnoff SG, Berman JM, Levine DJ, Harris M, Guido RS, Banks E. Outpatient procedure for the treatment and relief of symptomatic uterine myomas. Obstet Gynecol 2013;121: 1075–82. Galen DI, Pemueller RR, Leal JG, Abbott KR, Falls JL, Macer J. Laparoscopic radiofrequency fibroid ablation: phase II and phase III results. J Soc Laparoscopic Surg 2014;18:182–90. Jeong HJ, Kwon BS, Choi YJ, Huh CY. Rectouterine fistula after laparoscopic ultrasound-guided radiofrequency ablation of a uterine fibroid. Obstet Gynecol Sci 2014;57:553–6. Brower V. FDA considers restricting or banning laparoscopic morcellation. J Natl Cancer Inst 2014;106:dju339. Senapati S, Tu FF, Magrina JF. Power morcellators: aA review of current practice and assessment of risk. Am J Obstet Gynecol 2015; 212:18–23. Garza-Leal JG. Transcervical, intrauterine ultrasound-guided radiofrequency ablation of uterine fibroids with the VizAblate System: Safety, tolerability, and ablation results in a closed abdomen setting. In: Toub D, Herna´ndez Leo´n I, Castillo Saenz L, Uecker D, Munrow M, King D, et al., editors. Gynecological Surgery. New York: Springer, 2011, pp. 327–34. Gynesonics. Symptom effectiveness study of VizAblateÔ intrauterine ultrasound-guided RF ablation (IUUSgRFA) in the ablation of uterine fibroids. U.S. National Institutes of Health clinical trial, 2013. Available from https://clinicaltrials.gov/ct2/show/ NCT01226290. Goldberg J, McCrosson S, Kaulback KR. Delayed leiomyoma degeneration after microwave endometrial ablation. Obstet Gynecol 2005;106:1176–8. Kanaoka Y, Hirai K, Ishiko O. Microwave endometrial ablation for menorrhagia caused by large submucous myomas. J Obstet Gynaecol Res 2005;31:565–70. Kanaoka Y, Yoshida C, Fukuda T, Kajitani K, Ishiko O. Transcervical microwave myolysis for uterine myomas assisted by transvaginal ultrasonic guidance. J Obstet Gynaecol Res 2009;35: 145–51. Zhang J, Feng L, Zhang B, Ren J, Li Z, Hu D, et al. Ultrasoundguided percutaneous microwave ablation for symptomatic uterine fibroid treatment – A clinical study. Int J Hyperthermia 2011;27: 510–16. Yang Y, Zhang J, Han ZY, Yu MA, Ma X, Zhou HY, et al. Ultrasound-guided percutaneous microwave ablation for submucosal uterine fibroids. J Minim Invasive Gynecol 2014;21: 436–41. Xia M, Jing Z, Han ZY, Yu Y, Hao YL, Xu CT, et al. Research of dose–effect relationship parameters of percutaneous microwave ablation for uterine leiomyomas – A quantitative study. Sci Rep 2014;4:6469. Swe TT, Onitsuka H, Kawamoto K, Ueyama T, Tsuruchi N, Masuda K. Uterine leiomyoma: Correlation between signal intensity on magnetic resonance imaging and pathologic characteristics. Radiat Med 1992;10:235–42. Lynn JG, Zwemer RL, Chick AJ, Miller AE. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol 1942;26:179–93. Rivens I, Shaw A, Civale J, Morris H. Treatment monitoring and thermometry for therapeutic focused ultrasound. Int J Hyperthermia 2007;23:121–39. Cline HE, Schenck JF, Hynynen K, Watkins RD, Souza SP, Jolesz FA. MR-guided focused ultrasound surgery. J Comput Assist Tomogr 1992;16:956–65.
Int J Hyperthermia Downloaded from informahealthcare.com by McMaster University on 04/06/15 For personal use only.
8
S. D. Quinn & W. M. Gedroyc
48. Hoskins PR, Martin K, Thrush A. Diagnostic Ultrasound: Physics and Equipment. 2nd ed. Cambridge: Cambridge University Press, 2010. 49. Schlesinger D, Benedict S, Diederich C, Gedroyc W, Klibanov A, Larner J. MR-guided focused ultrasound surgery, present and future. Med Phys 2013;40:080901. 50. Zhou YF. High intensity focused ultrasound in clinical tumor ablation. World J Clin Oncol 2011;2:8–27. 51. Hill CR, Rivens I, Vaughan MG, ter Haar GR. Lesion development in focused ultrasound surgery: A general model. Ultrasound Med Biol 1994;20:259–69. 52. ter Haar G. Ultrasound focal beam surgery. Ultrasound Med Biol 1995;21:1089–100. 53. Cheung VY. Sonographically guided high-intensity focused ultrasound for the management of uterine fibroids. J Ultrasound Med 2013;32:1353–8. 54. Ren XL, Zhou XD, Zhang J, He GB, Han ZH, Zheng MJ, et al. Extracorporeal ablation of uterine fibroids with high-intensity focused ultrasound: Imaging and histopathologic evaluation. J Ultrasound Med 2007;26:201–12. 55. Ren XL, Zhou XD, Yan RL, Liu D, Zhang J, He GB, et al. Sonographically guided extracorporeal ablation of uterine fibroids with high-intensity focused ultrasound: midterm results. J Ultrasound Med 2009;28:100–3. 56. Wang W, Wang Y, Wang T, Wang J, Wang L, Tang J. Safety and efficacy of US-guided high-intensity focused ultrasound for treatment of submucosal fibroids. Eur Radiol 2012;22:2553–8. 57. Leung JH, Yu SC, Cheung EC, Wong AS, Tong MM, Ho SS, et al. Safety and efficacy of sonographically guided high-intensity focused ultrasound for symptomatic uterine fibroids: Preliminary study of a modified protocol. J Ultrasound Med 2014;33:1811–18. 58. McDannold N. Quantitative MRI-based temperature mapping based on the proton resonant frequency shift: Review of validation studies. Int J Hyperthermia 2005;21:533–46. 59. Ishihara Y, Calderon A, Watanabe H, Okamoto K, Suzuki Y, Kuroda K. A precise and fast temperature mapping using water proton chemical shift. Magn Reson Med 1995;34:814–23. 60. Zaher S, Gedroyc WM, Regan L. Patient suitability for magnetic resonance guided focused ultrasound surgery of uterine fibroids. Eur J Obstet Gynecol Reprod Biol 2009;143:98–102. 61. Kim YS, Bae DS, Park MJ, Viitala A, Keserci B, Rhim H, et al. Techniques to expand patient selection for MRI-guided highintensity focused ultrasound ablation of uterine fibroids. Am J Roentgenol 2014;202:443–51. 62. Hesley GK, Felmlee JP, Gebhart JB, Dunagan KT, Gorny KR, Kesler JB, et al. Noninvasive treatment of uterine fibroids: Early Mayo Clinic experience with magnetic resonance imaging-guided focused ultrasound. Mayo Clin Proc 2006;81:936–42. 63. Yamashita Y, Torashima M, Takahashi M, Tanaka N, Katabuchi H, Miyazaki K, et al. Hyperintense uterine leiomyoma at T2-weighted MR imaging: differentiation with dynamic enhanced MR imaging and clinical implications. Radiology 1993;189:721–5. 64. Le´na´rd ZM, McDannold NJ, Fennessy FM, Stewart EA, Jolesz FA, Hynynen K, et al. Uterine leiomyomas: MR imaging-guided focused ultrasound surgery–imaging predictors of success. Radiology 2008;249:187–94. 65. Funaki K, Fukunishi H, Sawada K. Clinical outcomes of magnetic resonance-guided focused ultrasound surgery for uterine myomas: 24-month follow-up. Ultrasound Obstet Gynecol 2009;34:584–9. 66. Stewart EA, Rabinovici J, Tempany CM, Inbar Y, Regan L, Gostout B, et al. Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids. Fertil Steril 2006;85:22–9. 67. Stewart EA, Gostout B, Rabinovici J, Kim HS, Regan L, Tempany CM. Sustained relief of leiomyoma symptoms by using focused ultrasound surgery. Obstet Gynecol 2007;110:279–87. 68. Funaki K, Fukunishi H, Funaki T, Sawada K, Kaji Y, Maruo T. Magnetic resonance-guided focused ultrasound surgery for uterine fibroids: Relationship between the therapeutic effects and signal intensity of preexisting T2-weighted magnetic resonance images. Am J Obstet Gynecol 2007;196:184.e1–6. 69. Fennessy FM, Tempany CM, McDannold NJ, So MJ, Hesley G, Gostout B, et al. Uterine leiomyomas: MR imaging-guided focused ultrasound surgery–results of different treatment protocols. Radiology 2007;243:885–93.
Int J Hyperthermia, Early Online: 1–8
70. Harding G, Coyne KS, Thompson CL, Spies JB. The responsiveness of the uterine fibroid symptom and health-related quality of life questionnaire (UFS-QOL). Health Qual Life Outcomes 2008;6:99. 71. Morita Y, Ito N, Hikida H, Takeuchi S, Nakamura K, Ohashi H. Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids - early experience. Eur J Obstet Gynecol Reprod Biol 2008;139:199–203. 72. Mikami K, Murakami T, Okada A, Osuga K, Tomoda K, Nakamura H. Magnetic resonance imaging-guided focused ultrasound ablation of uterine fibroids: Early clinical experience. Radiat Med 2008;26:198–205. 73. Okada A, Morita Y, Fukunishi H, Takeichi K, Murakami T. Noninvasive magnetic resonance-guided focused ultrasound treatment of uterine fibroids in a large Japanese population: Impact of the learning curve on patient outcome. Ultrasound Obstet Gynecol 2009;34:579–83. 74. Zhang L, Wang ZB. High-intensity focused ultrasound tumor ablation: Review of ten years of clinical experience. Front Med China 2010;4:294–302. 75. LeBlang SD, Hoctor K, Steinberg FL. Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: Report of 80 patients. AJR Am J Roentgenol 2010;194:274–80. 76. Rabinovici J, David M, Fukunishi H, Morita Y, Gostout BS, Stewart EA. Pregnancy outcome after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids. Fertil Steril 2010;93:199–209. 77. Yoon SW, Seong SJ, Jung SG, Lee SY, Jun HS, Lee JT. Mitigation of abdominal scars during MR-guided focused ultrasound treatment of uterine leiomyomas with the use of an energy-blocking scar patch. J Vasc Interv Radiol 2011;22:1747–50. 78. Gorny KR, Woodrum DA, Brown DL, Henrichsen TL, Weaver AL, Amrami KK, et al. Magnetic resonance-guided focused ultrasound of uterine leiomyomas: Review of a 12-month outcome of 130 clinical patients. J Vasc Interv Radiol 2011;22:857–64. 79. Machtinger R, Inbar Y, Cohen-Eylon S, Admon D, AlagemMizrachi A, Rabinovici J. MR-guided focus ultrasound (MRgFUS) for symptomatic uterine fibroids: Predictors of treatment success. Hum Reprod 2012;27:3425–31. 80. Voogt MJ, Trillaud H, Kim YS, Mali WP, Barkhausen J, Bartels LW, et al. Volumetric feedback ablation of uterine fibroids using magnetic resonance-guided high intensity focused ultrasound therapy. Eur Radiol 2012;22:411–17. 81. Park H, Yoon SW, Kim KA, Jung Kim D, Jung SG. Magnetic resonance imaging-guided focused ultrasound treatment of pedunculated subserosal uterine fibroids: A preliminary report. J Vasc Interv Radiol 2012;23:1589–93. 82. Dobrotwir A, Pun E. Clinical 24 month experience of the first MRgFUS unit for treatment of uterine fibroids in Australia. J Med Imaging Radiat Oncol 2012;56:409–16. 83. Kim YS, Trillaud H, Rhim H, Lim HK, Mali W, Voogt M, et al. MR thermometry analysis of sonication accuracy and safety margin of volumetric MR imaging-guided high-intensity focused ultrasound ablation of symptomatic uterine fibroids. Radiology 2012;265:627–37. 84. Trumm CG, Stahl R, Clevert DA, Herzog P, Mindjuk I, Kornprobst S, et al. Magnetic resonance imaging-guided focused ultrasound treatment of symptomatic uterine fibroids: Impact of technology advancement on ablation volumes in 115 patients. Invest Radiol 2013;48:359–65. 85. Froeling V, Meckelburg K, Schreiter NF, Scheurig-Muenkler C, Kamp J, Maurer MH, et al. Outcome of uterine artery embolization versus MR-guided high-intensity focused ultrasound treatment for uterine fibroids: Long-term results. Eur J Radiol 2013. 86. Quinn SD, Vedelago J, Regan L, Gedroyc W. Five-year reintervention and safety following MRgFUS for uterine fibroids. Eur J Obstetr Gynecol Reprod Biol 2014;182:247–51. 87. Gizzo S, Saccardi C, Patrelli TS, Ancona E, Noventa M, Fagherazzi S, et al. Magnetic Resonance-Guided Focused Ultrasound Myomectomy: Safety, Efficacy, Subsequent Fertility and Qualityof-Life Improvements, A Systematic Review. Reprod Sci 2013;21:465–76. 88. Quinn SD, Vedelago J, Gedroyc W, Regan L. Safety and five-year re-intervention following magnetic resonance-guided focused ultrasound (MRgFUS) for uterine fibroids. Eur J Obstet Gynecol Reprod Biol 2014;182:247–51.
