Va s c u l a r a n d I n t e r ve n t i o n a l R a d i o l o g y • R ev i ew Kim et al. MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids
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Vascular and Interventional Radiology Review
Techniques to Expand Patient Selection for MRI-Guided HighIntensity Focused Ultrasound Ablation of Uterine Fibroids Young-sun Kim1 Duk-Soo Bae2 Min Jung Park1 Antti Viitala3 Bilgin Keserci 4 Hyunchul Rhim1 Hyo Keun Lim1 Kim YS, Bae DS, Park MJ, et al.
Keywords: high-intensity focused ultrasound, MRIguided intervention, patient exclusion, patient selection, uterine fibroid DOI:10.2214/AJR.13.10753 Received February 14, 2013; accepted after revision June 27, 2013. A. Viitala and B. Keserci are employees of Philips Healthcare. 1 Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2 Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 138-225, Korea. Address correspondence to D. S. Bae ([email protected]). 3
Philips Healthcare, Vantaa, Finland.
4
Philips Healthcare, Seoul, Korea.
This article is available for credit. AJR 2014; 202:443–451 0361–803X/14/2022–443 © American Roentgen Ray Society
OBJECTIVE. MRI-guided high-intensity focused ultrasound (HIFU) ablation is increasingly adopted for treating symptomatic uterine fibroids. As a noninvasive therapy performed on an outpatient basis, it has been viewed by patients to have distinct advantages over other treatment options. However, its breadth of clinical application is still limited. To address this issue, various techniques have been implemented. CONCLUSION. In this article, we discuss techniques that contribute to widening patient selection for MRI-guided HIFU therapy of uterine fibroids.
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terine fibroids are one of the most frequent benign tumors affecting women of child-bearing age [1– 3]. Symptoms include menorrhagia, dysmenorrhea, pelvic pain, and bulk-related symptoms, such as urinary frequency, which can significantly deteriorate the quality of life. Uterine fibroids can also interfere with fertility [4, 5]. As one of the nonsurgical therapeutic modalities for symptomatic uterine fibroids, MRI-guided high-intensity focused ultrasound (HIFU) ablation has been developed and increasingly adopted worldwide owing to its satisfactory therapeutic efficacy in controlling the symptoms, as well as a high level of safety [6–8]. In addition, MRI-guided HIFU ablation can be performed in a totally noninvasive manner; thus, the patients do not get a scar or experience bleeding from the procedure and may even avoid hospitalization. MRI-guided HIFU ablation therapy cannot be applied to all patients with symptomatic fibroids because of limiting factors. Two previous studies reported that only 16–25% of the referred patients were eligible for MRI-guided HIFU [9, 10]. Nontechnical limitations include the high cost of MRI-guided HIFU or the subject’s inability to withstand a stationary position for several hours as required for the treatment, which are issues that are challenging to overcome. However, there are also limiting factors that can be addressed by applying different patient preparation methods, as well as technologic development of the MRI-guid-
ed HIFU systems. Such limitations include the presence of scar tissue, bowel loops, or other obstacles in the sonication path; excessive thickness of subcutaneous layer of the anterior abdominal wall; fibroids that are too large or too deep; and excessive fibroid vascularity. It is known that the extent of ablation reached during MRI-guided HIFU therapy of uterine fibroid, as measured by nonperfused volume after the treatment, is a good predictor of the clinical outcome [11–13]. Anatomic factors can affect the available treatment window, which can limit the volume where thermal energy (sonications) can be delivered. If the treatment volume is severely reduced, sufficient nonperfused volume cannot be achieved and the patient is unlikely to benefit from the therapy. Therefore, all available methods should be used during patient preparation, positioning, and anatomic manipulation to gain maximal access to the fibroid. Alternatively, limitations related to fibroid properties, such as excessive size or vascularity, should be addressed through technologic development of the MRI-guided HIFU system or additional adoption of medication such as gonadotropin-releasing hormone (GnRH) agonist. Efforts in both areas not only would improve the therapeutic outcomes of the treated patients but also would expand the range of conditions that can be managed with this therapeutic modality. In this article, we comprehensively discuss techniques to expand patient selection and improve therapeutic outcomes, including manip-
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Manipulating Bowel Loops Bowel loops in the ultrasound beam path are generally considered to be a contraindication for MRI-guided HIFU treatment, because gas bubbles and hard particles contained in the bowel might reflect or absorb ultrasound en-
ergy in unpredictable ways, potentially leading to thermal damage and even bowel perforation [10, 14]. A search in the U.S. Food and Drug Administration (FDA) Manufacturers and User Facility Device Experience database produced reports of three adverse events in over 7000 cases that led to bowel perforation requiring surgical intervention [15]. Bowel loops may be in the near field of the ultrasound beam path and should be visualized with MRI techniques before therapy.
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ulating bowel loops, dealing with abdominal scars, alleviating fibroid size limitations, and overcoming excessive vascularity, on the basis of a literature review.
C Fig. 1—39-year-old woman with submucosal uterine fibroid who was treated with MRI-guided high-intensity focused ultrasound (HIFU) ablation. A, One small-bowel loop (arrow) was located anterior to uterus in screening MRI. Asterisk denotes submucosal uterine fibroid. B, Before initiation of MRI-guided HIFU therapy, urinary bladder was filled with saline, which resulted in displacing bowel; thus, acoustic window was satisfactorily established. Fibroid (asterisk) shrank after gonadotropin-releasing hormone analog pretreatment. C, MRI-guided HIFU therapy was performed successfully.
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Because it is not feasible to monitor accurately the whole near-field area on a real-time basis, it is very important to displace bowel loops in advance away from the sonication path to establish a safe acoustic window. Various methods have been reportedly used to gain a better acoustic window for uterine therapy with MRI-guided HIFU. Urinary Bladder Filling Bladder filling may be used to elevate the uterus in the superior, which can increase the acoustic window and avoid sonicating through a scar or can push bowel loops away from the area between the abdominal wall and the uterus (Fig. 1). This is easiest to do such that the flow of liquid from the Foley catheter is stopped using a clamp and a fluid (usually normal saline) is instilled. Natural bladder filling during the therapy creates slow and gradual anatomic changes caused by bladder distention. These changes should be closely monitored, and careful intermittent small-volume drainages should be performed, along with MRI-based reverification of the anatomy and intended sonication beam paths, to avoid misdirected sonications and to prevent undue patient discomfort. Care should be taken to avoid introducing air bubbles in the Foley balloon or the bladder, because the ultrasound does not propagate through air. Repeated filling and emptying of the Foley catheter balloon may help to reduce or remove possible air bubbles. Rectal Filling Filling the rectum with ultrasound coupling gel is often beneficial [16]. Rectal filling pushes the uterus anterior and restricts the free peritoneal space between the abdominal wall and the uterus where the bowel loops tend to move (Fig. 2). In addition, this technique increases the distance to sciatic nerves in the far field. An inflatable rectal balloon has also been used for manipulating the fibroid position with respect to the surrounding anatomy. This approach may be beneficial because it prevents the risk of material moving into the sigmoid colon, thus enabling greater spatial control of the mechanical force that pushes the uterus [17]. Miscellaneous Methods Successful use of a vaginal pessary for repositioning of the uterus has been reported [18]. This enabled a sufficient acoustic window to be obtained for therapy. Use of a convex gel pad to apply pressure to the central
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids part of the abdominal wall and displace the bowel loops peripherally was also reported to be helpful [16]. In the same context, when the fibroid is large, a bowel loop on the edge between the tumor and the abdominal wall may spontaneously move out of the beam path, as a result of gravity-induced compression. Dealing With Abdominal Scars Abdominal scars pose a challenge in MRIguided HIFU therapy. The presence of abdominal scars may affect patient selection, limit access to the treatment target area, and increase the risk of skin burn during therapy. A search in the FDA’s Manufacturers and User Facility Device Experience database revealed one report of full-thickness skin burns at the location of the previous laparoscopic scar area due to sonications through scar area. The patient was referred to a plastic surgeon for treatment [19]. This clinical limitation stems from differences in the acoustic properties of scar tissue from those of the surrounding tissue. Scar tissue may be denser, with higher ultrasound absorption than the surrounding normal tissue, which may lead to increased heating and thermal damage [20]. Scar tissues may also have a reduced blood supply compared with surrounding tissue, leading to reduced cooling, thereby potentially increasing the accumulated heating over the course of the treatment. There may be less sensation in scars than in surrounding tissue, making the patient less likely to perceive pain or heating during treatment through a scar. Moreover, one should be also aware that once a second- or third-degree skin burn is formed, the sense of heating is degraded because of the injury of nerve endings; therefore, patients may not be able to feel heating on the involved skin. In these cases, MR thermometric monitoring of the skin would be the only sign of overheating. To effectively monitor scar tissue heating, one must be able to visualize the scar on MRI. Older well-healed scars may be easy to see with visual inspection of the skin, but still difficult or impossible to identify on MRI. Typically, scars are easier to identify on the epidermis, dermis, and subcutaneous fat layer, but more difficult to identify in abdominal muscle and myometrium. Scars are usually identifiable on coronal or sagittal scans of T2-weighted images. To visualize scars better, dedicated MRI sequences or MRI-visible paint can help. One example of images produced by a dedicated MRI sequence for scar visualization is seen in Figure 3 (3D fast-field echo; TR/TE, 21/6.0; flip angle, 15°; slice thickness, 2 mm;
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Fig. 2—34-year-old woman with intramural uterine fibroid. A, Survey MRI on treatment day shows interposition of small-bowel loop (arrow) between uterus and abdominal wall. Asterisk denotes fibroid. B, To move bowel loop away, urinary bladder was filled with about 400 mL of saline, and small-bowel loop was displaced sufficiently. However, fibroid (asterisk) was elevated too high, which was not desirable because of possible stimulations of bony structures. C, Half of saline in urinary bladder was drained, but small-bowel loop (arrow) again moved close to planned sonication path (orange triangles). Asterisk denotes fibroid. D, Urinary bladder was further drained, and, simultaneously, rectum was filled with ultrasound gel, which resulted in displacement of fibroid (asterisk) closer to abdominal wall and descent of fibroid with no motion of bowel loop (arrow). Orange triangles denote planned sonication path.
FOV, 20 cm). MRI-visible paint, a mixture of nail varnish and MRI contrast agent containing paramagnetic iron oxide particles (Endorem, Guerbet), reportedly provides an alternative solution to highlight the scar location [14, 21]. Importantly, care should be taken when choosing MRI-visible paint, because some materials may cause image distortions or local heating due to radiofrequency absorption. Basic Methods to Avoid Scar Because of the risks described in the previous section, many clinicians have used patient positioning and manipulation techniques
to completely remove the scar from the beam path [10, 14, 22]. Basic approaches to deal with abdominal scars include tilting the transducer, filling the bladder as when displacing bowel loops, and stretching the skin to move the scar out of the beam path. However, they are effective only to a certain degree and depend on locations of the scar and target area. Usually, a combination of those approaches is necessary (Fig. 4). Through-the-Scar Sonication Although abdominal scarring is widely acknowledged as a challenge for MRI-guided
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Kim et al.
Fig. 3—43-year-old woman with history of cesarean section. Location of transverse scar (arrows) was clearly seen in scar scan image.
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Fig. 4—50-year-old woman with subserosal uterine fibroid who was treated with MRI-guided high-intensity focused ultrasound (HIFU) therapy. A, On screening MRI, scar (arrow) was located at level of center of fibroid (asterisk). B, Fibroid (asterisk) was pushed upward by saline-distended urinary bladder to avoid scar (arrow). Lowest part of tumor was able to be treated without traversing scar by tilting sonication path (orange triangles) downward.
HIFU uterine fibroid therapy, in a survey of clinicians treating patients with MRI-guided HIFU [23], it was rated as 4.75 ± 2.17 on a scale where 1 indicates “No impediment to therapy” and 10 indicates “Absolute contraindication to therapy,” implying that treating through or around the scar is acceptable in some instances. A small number of “through-the-scar” sonications may not be problematic; instead, accumulated heat over the course of multiple sonications appears to be the root cause for a skin burn. The outcomes of through-the-scar sonication seem to depend greatly on the histologic characteristics of the scar tissue, the age and size of the scar, the distance between the skin
and the HIFU target, and the fibroid vascularity and type. Older well-healed thin scars are safer to sonicate through than are scars that are new and composed of thick, pronounced, or raised tissue. Sonications involving a deeper HIFU target region are safer than are sonications applied in a more shallow location, because increasing sonication depth decreases the ultrasound intensity on the skin surface. When treating highly vascular or cellular fibroids that are usually more resistant to heating, higher acoustic power must be delivered, which increases the risk of skin surface heating. In the cases where the ultrasound beam passes through a scar, temperature changes
must be monitored carefully to detect unwanted heating in the region by MR thermometry (Fig. 5). Sufficient cooling intervals between sonications are necessary to reduce the possibility of damage due to accumulated heating [24]. Continuous and clear communication with the patient is critical to obtain immediate information of any abnormal sensations in the scar region. Safety of the sonication is further compromised if the patient has reduced sensitivity in the scar region.
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Use of Acoustic Patches Reports describing the use of acoustic patches to reflect the ultrasound energy indi-
Fig. 5—29-year-old woman with multiple uterine fibroids who was treated with MRI-guided high-intensity focused ultrasound (HIFU) therapy. A, Multiple fibroids (asterisks) retained intermediate-to-high signal intensity on T2-weighted screening MRI. B and C, MR thermometric images, including sagittal scan centered at HIFU target (B) and coronal scan on skin (C) during sonication of lower anterior fibroid using high acoustic power (200 W) show that 240 equivalent minutes (i.e., lethal thermal dose) contours (white outlines) were formed not only at HIFU target (arrow, B) but also on skin (arrowheads, B and C) at right inguinal area where depilation was not perfect. This sonication induced second-degree skin burn as complication.
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids
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Fig. 6—Scar patch experiment. A, Scar patch made of polyethylene foam was applied to 36-year-old woman with scar. B, Test performed in phantom sonication indicated that patch functions mainly as reflecting object, because no ultrasound absorption-induced local heating was detected. Distortions in focal shape and location were not seen either (sagittal MR thermometric image centered at high-intensity focused ultrasound target). Marker #1 is center point of horizontally applied scar patch.
cate that these could be a viable solution for patients with scars in the planned beam path. Such acoustic patches should be made of material that is water resistant, visible on MRI, easily attachable to the skin, and suitable to be applied to scars of different shapes [25, 26] (Fig. 6). A recent clinical study [26] assessed the effectiveness of acoustic patches in 20 patients with uterine leiomyoma where scars were blocking the beam path. The scar patch described in that study was made of an isolation polyethylene foam (1.5-mmthick Cell-Aire, Sealed Air), attached with
double-coated medical tape (9889, 3M). Potential risks in the use of an acoustic patch include skin burns due to locally absorbed ultrasound energy, a reduction in the quality of the focus due to blocked ultrasound energy, and damage to the transducer surface due to heating from reflected ultrasound energy. Although two patients had a few red spots on the skin surface after the treatment and three other patients had slight hyperemic changes in the abdominal muscle, as observed on fat-suppressed T2-weighted MRI, no serious adverse events were reported. The authors
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concluded that this approach was an effective option for patients with scars in the ultrasound beam path [26]. Beam Shaping Beam shaping can be used to selectively disable part of the ultrasound cone passing through the scar area while still delivering ultrasound through the surrounding tissue [27]. Beam shaping can also be used to avoid ultrasound delivery through the umbilicus, skin folds, air bubbles on the skin, or risky internal organs, such as bowel loops. This feature
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Fig. 7—Treatment planning of beam shaping feature in 42-year-old woman with uterine fibroid and transverse scar. A, Scar was manually localized by drawing free region of interest (gray outline) on scar scan. Planned sonication path was also illustrated (white circle). B, Sagittal image shows automatically computed available treatment area (blue shaded area). Planned treatment cell (green line), sonication path (yellow triangles), and safety margin (yellow rectangle) were also illustrated.
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Kim et al. (available in ExAblate O.R./ExAblate One, InSightec; and Sonalleve R3.2 software, Philips Healthcare) can be activated by drawing the areas to be avoided. The avoidance area indicates the location where reduced ultrasound intensity is desired, and subsequent sonications are then performed with a number of transducer elements that contribute to the intensity traversing through the area switched off. The reduction in ultrasound intensity at the focus due to the switched-off elements is compensated for by increasing the power delivered by the remaining active elements (Fig. 7). Alleviating Fibroid Size Limitations Considering the patients’ tolerability and the risk of deep venous thrombosis, 3–4 hours seems to be the limit of treatment time for MRI-guided HIFU therapy [8]. Because the ablation speed is limited by physical constraints, such as diffusion of the heat energy away from the focus and near-field heating, and because time is needed between sonications to allow near-field cooling, the size limit of uterine fibroids at most institutions using the MRI-guided HIFU system adopting a conventional “point-by-point” sonication method has been reported to be 10 cm in diameter [28, 29]. However, several new techniques have been developed to address the ablation of large fibroid volumes, which, in turn, expands the size range of uterine fibroids that are treatable by MRI-guided HIFU. Hormonal Therapy Pretreatment Since the 1980s, GnRH agonists have been used for medical therapy of uterine fibroids via a state of hypoestrogenism [30]. However, the reduced volume persists only while the patient is actively treated, and GnRH agonists unfortunately cannot be used long term because of substantial menopause-like adverse effects. Therefore, treatment should be restricted to less than 6 months [31]. The use of GnRH agonists before MRIguided HIFU has been reported elsewhere. Smart et al. [32] published the results of a clinical study of 50 patients treated with MRIguided HIFU, where 27 patients underwent pretreatment with GnRH agonists and the remaining patients did not. Criteria for receiving the 3-month course of GnRH agonists was a uterine diameter of 10 cm or greater. The authors reported a mean reduction in the size of the target fibroid of 36%, concluding that this approach enabled successful therapy in patients who otherwise would have been ex-
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cluded on the basis of uterine size alone [32]. Zaher et al. [14] addressed patient suitability and potential mitigation strategies in 144 patients, 100 of whom were viable candidates for MRI-guided HIFU. In that study, all patients with a total fibroid volume of more than 500 cm3 or whose fibroid was hyperintense on T2weighted imaging were treated with a 3-month course of GnRH agonists before MRI-guided HIFU therapy. Of the patients treated with MRI-guided HIFU, 88% underwent GnRH agonist therapy pretreatment. The authors stated that this approach helped to reduce fibroid volume and increase the fibroid tissue’s susceptibility to the treatment [14] (Fig. 1). GnRH agonist pretreatment could be used to modulate the vascularity of uterine fibroids, which is another limiting factor of this modality when it is excessive (as discussed later in this article), in addition to its effect on the fibroid size. Although its effects on the outcome of MRI-guided HIFU therapy through devascularization have not been methodically evaluated, GnRH agonist therapy is known to decrease the vascularity of fibroids, as evidenced by a decrease in a microvascular density marker, CD34, in surgical specimens [33].
Volumetric Ablation Technique To improve the treatment speed of MRIguided HIFU therapy, a new volumetric ablation technique has recently been introduced. The conventional point-by-point sonication method is only able to create a relatively small ablation zone of approximately 5 mm in axial diameter. With a volumetric ablation method (available with the Sonalleve MRI-guided HIFU system, Philips Healthcare), the focus of the HIFU beam is electronically steered along a trajectory composed of multiple outward-moving concentric circles with automated temperature feedback and is, therefore, able to induce relatively larger and homogeneous ablation zones with an axial diameter of 4–16 mm. This volumetric ablation method is expected to be more energy efficient and, therefore, has improved treatment speed compared to the conventional method, because it uses the heat already deposited during sonication of the inner part of the trajectory to preheat the outer parts, instead of allowing the heat to dissipate out of the target area [34]. On the basis of a clinical study of uterine fibroid treatment using volumetric MRI-guided HIFU [35], the energy efficiency improved with in-
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Fig. 8—34-year-old woman with 11.8-cm uterine fibroid treated with volumetric MRI-guided high-intensity focused ultrasound (HIFU) ablation with one-layer strategy. A, Treatment cells of 16 mm in axial diameter (orange bullets) were placed at middle of fibroid depth as single layer. B, MRI-guided HIFU ablation was successfully performed, and immediate contrast-enhanced scan showed excellent nonperfused volume ratio measuring 90.5%.
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids
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Fig. 9—41-year-old woman with 18-cm uterine fibroid treated with MRI-guided high-intensity focused ultrasound (HIFU) ablation with vessel targeting strategy. A, Screening MRI shows 18-cm uterine fibroid. Patient refused surgery, and MRI-guided HIFU therapy was performed for palliative purpose. B, Unenhanced MR angiography using B-TRANCE (balanced turbo field echo triggered angiography noncontrast-enhanced) technique performed immediately before MRI-guided HIFU ablation shows one supplying vessel (arrows) running into tumor. C, Unenhanced MR angiography after treatment shows disappearance of supplying vessel (arrows). D, Immediate posttreatment contrast-enhanced T1-weighted image shows nonperfused volume was extended superiorly (dotted outline) beyond area of treatment cell (orange triangles) placements, which was presumably formed by occlusion of supplying vessel.
creased treatment cell size, where energy efficiency was defined as the tissue volume of a lethal thermal dose (i.e., 240 equivalent minutes) achieved per unit of acoustic energy applied. In this study, the energy efficiency of a 16-mm treatment cell was about 15 times of that of a 4-mm cell. One-Layer Strategy in Volumetric Ablation Despite the improved energy efficiency of the volumetric ablation technique, quite a large amount of acoustic energy is still wasted in the form of near-field heat accumulation. This heat needs to dissipate to prevent thermal injury to intervening tissues and thus requires cooling intervals. In the “one-layer strategy,” the heat accumulation in the immediate nearfield of the focal plane was exploited by placing all treatment cells at one single coronal plane located at a depth from half to the anterior two thirds of the fibroid, thereby accu-
mulating heat in the anterior of the fibroid and enhancing the treatment speed. In the study where this was applied [8], large uterine fibroids of more than 10 cm in diameter were effectively treated with a mean nonperfused volume ratio of 64.2% and within an acceptable treatment time (mean, 2.8 hours) (Fig. 8). This strategy was more effective in cases of fibroids with lower vascularity, as assessed by dynamic contrast-enhanced MRI [35]. Variable Length Sonication Technique Other volumetric techniques without automated temperature feedback, including a variable-length sonication technique (available in ExAblate O.R./ExAblate One, InSightec), are being explored clinically [36]. In this strategy, HIFU focus is mechanically shifted forward during a single burst of ultrasound energy, which forms variable lengths of elongated ablation zone ranging from 10 to 70 mm. As
D a result, treatment cells are able to be tailored to conform to a large fibroid contour without a need for multiple layers. However, the improvements in energy efficiency, treatment speed, or safety data in clinical fibroid therapy have not been reported yet.
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Kim et al. Overcoming Excessive Vascularity On the basis of Pennes’s [37] bio-heat equation, tissue perfusion, which dissipates heat, is the most important tissue property in the determination of ablation results. This consensus is currently accepted for any kind of hyperthermic ablation therapy, and MRI-guided HIFU therapy cannot be an exception. A recent study proved this concept in MRI-guided HIFU therapy with the use of dynamic contrast-enhanced MRI [38] showing that hypervascularity manifested by high Ktrans (volume transfer constant) values was associated with poor ablation efficacy. There have been efforts to overcome high vascularity of uterine fibroids, including vessel targeting and various medical pretreatment therapies. Vessel Targeting A recent publication reported success in selective targeting of the feeding vessels of the fibroid based on contrast-enhanced MR angiography registered to the treatment planning images [39]. Sonications were performed focusing primarily on the area where the vessels entered the fibroid, and ablation of the fibroid tissue was also performed. In two tumors, the resulting nonperfused volumes were reported as nearly complete ablation, although the peripheral parts of the fibroid were not ablated for safety reasons. In that study, the authors used data from contrast-enhanced MR angiography performed before the day of therapy, because there were concerns that the use of gadolinium-based MRI contrast agent just before MRI-guided HIFU therapy may have been harmful because of the effect of heat on contrast agent stability. Furthermore, if MRIguided HIFU is performed on a different day from MR angiography, it would require image registration, which may be difficult because of possible motion of the internal organs. Considering these items, unenhanced MR angiography performed immediately before MRIguided HIFU therapy might be desirable for vessel targeting, as shown in Figure 9. Repeated high-powered sonications seem to induce delayed thrombotic occlusion of the supplying vessel via endothelial injuries [40]. Oxytocin Pretreatment Oxytocin is a hormone known to cause uterine contraction. Therefore, oxytocin is commonly used for facilitating labor or suppressing postpartum bleeding. Oxytocin-induced uterine contraction may contribute to decreasing blood flow of the uterus as well as the fibroids. One recent study described the useful-
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ness of oxytocin in MRI-guided HIFU therapy of uterine fibroids in 26 patients [41]. In that study, the energy required to reach 60°C decreased from 5320 to 2890 J, on average, and the time taken to achieve 60°C also decreased from 21 to 12 seconds, on average, after IV infusion of oxytocin. Miscellaneous Methods The use of higher acoustic energy by increasing either the acoustic power or the sonication time beyond the currently available level may also be helpful. However, in this case, attention should be paid to the temperature changes of the intervening structures, including the skin, to prevent complications. In a similar context, the concurrent use of an IV microbubble agent has been shown to enhance the ablation efficiency of HIFU, as published in a recent study performed with a sonography-guided HIFU system [42]. However, one should note that the application of concurrent use of microbubble agents and HIFU ablation has not been proved safe and, thus, cannot be currently advocated. Similarly, nonlinear or cavitation-enhanced HIFU can also potentially be used to improve the acoustic energy absorption at the focus by using a lower duty cycle but higher acoustic power to maintain the total amount of energy used unchanged [43–45]. Conclusion Since the first feasibility study in 2003 [46] and approval by the FDA in 2004, thousands of MRI-guided HIFU ablation procedures and significant research works have been performed worldwide. From these experiences, a variety of techniques have been accumulated from the perspectives of clinical practice or engineering, as discussed in this article. These techniques have been expanding the range of patients for whom this therapeutic modality could be effectively applied. In spite of such efforts, the aforementioned issues are not completely resolved as yet, and there is still more work to be done, including addressing fibroid accessibility for locations beyond the reachable depth of the system and excessively thick subcutaneous fat of the abdominal wall, which attenuates acoustic energy and has a negative effect on the quality of the focus. As a consequence, some patients continue to not be candidates for MRI-guided HIFU therapy. Even now, there is room for further advances in MRIguided HIFU technology as well as improvement in its clinical application, which will benefit more patients in the future.
Acknowledgments We thank Pirjo Wirtanen, Paula Syrenius, Joy Polefrone, Max O. Köhler, and Shunmugavelu Sokka (Philips Healthcare, Vantaa, Finland) for their assistance with this work. References 1. Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94:435–438 2. Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science 2005; 308:1589–1592 3. Parker WH. Uterine myomas: management. Fertil Steril 2007; 88:255–271 4. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007; 87:725–736 5. Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosignani PG. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update 2007; 13:465–476 6. Al Hilli MM, Stewart EA. Magnetic resonanceguided focused ultrasound surgery. Semin Reprod Med 2010; 28:242–249 7. Funaki K, Fukunishi H, Funaki T, Kawakami C. Mid-term outcome of magnetic resonance-guided focused ultrasound surgery for uterine myomas: from six to twelve months after volume reduction. J Minim Invasive Gynecol 2007; 14:616–621 8. Kim YS, Kim JH, Rhim H, et al. Volumetric MRguided high-intensity focused ultrasound ablation with a one-layer strategy to treat large uterine fibroids: initial clinical outcomes. Radiology 2012; 263:600–609 9. Behera MA, Leong M, Johnson L, Brown H. Eligibility and accessibility of magnetic resonanceguided focused ultrasound (MRgFUS) for the treatment of uterine leiomyomas. Fertil Steril 2010; 94:1864–1868 10. Arleo EK, Khilnani NM, Ng A, Min RJ. Features influencing patient selection for fibroid treatment with magnetic resonance-guided focused ultrasound. J Vasc Interv Radiol 2007; 18:681–685 11. Lénárd ZM, McDannold NJ, Fennessy FM, et al. Uterine leiomyomas: MR imaging-guided focused ultrasound surgery—imaging predictors of success. Radiology 2008; 249:187–194 12. 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; 110:279–287 13. LeBlang SD, Hoctor K, Steinberg FL. Leiomyoma shrinkage after MRI-guided focused ultrasound treatment: report of 80 patients. AJR 2010; 194:274–280 14. 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
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids 15. U.S. Food and Drug Administration. MAUDE: Manufacturer and User Facility Device Experience. MAUDE Adverse Event Report: INSIGHTEC, LTD. EXABLATE 2000MRGFUS. FDA website. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm. Published 2012. Updated July 1, 2012. Accessed October 16, 2013 16. Hesley GK, Felmlee JP, Gebhart JB, et al. Noninvasive treatment of uterine fibroids: early Mayo Clinic experience with magnetic resonance imaging-guided focused ultrasound. Mayo Clin Proc 2006; 81:936–942 17. Nyapathy V, Polina L. MRgFUS treatment of uterine fibroid in a nulliparous woman with acute retention of urine. J Radiol Case Rep 2012; 6:1–8 18. Pulanic TK, Venkatesan A, Segars J, et al. Novel use of vaginal pessary to optimize the position the uterus for magnetic resonance imaging-guided high intensity focused ultrasound ablation of uterine fibroids. (abstract) Reprod Sci 2010; 17:271A 19. U.S. Food and Drug Administration. MAUDE: Manufacturer and User Facility Device Experience. MAUDE Adverse Event Report: INSIGHTEC LTDMRGFUS EXBLATE ULTRASOUND. FDA website. www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm. Published 1996. Updated July 1, 2012. Accessed October 16, 2013 20. Hindley J, Gedroyc WM, Regan L, et al. MRI guidance of focused ultrasound therapy of uterine fibroids: early results. AJR 2004; 183:1713–1719 21. Zaher S, Gedroyc W, Lyons D, Regan L. A novel method to aid in the visualisation and treatment of uterine fibroids with MRgFUS in patients with abdominal scars. Eur J Radiol 2010; 76:269–273 22. Huang J, Holt RG, Cleveland RO, Roy RA. Experimental validation of a tractable numerical model for focused ultrasound heating in flow-through tissue phantoms. J Acoust Soc Am 2004; 116:2451–2458 23. Taran FA, Hesley GK, Gorny KR, Stewart EA. What factors currently limit magnetic resonanceguided focused ultrasound of leiomyomas? A survey conducted at the first international symposium devoted to clinical magnetic resonance-guided focused ultrasound. Fertil Steril 2010; 94:331–334 24. Mougenot C, Köhler MO, Enholm J, Quesson B, Moonen C. Quantification of near-field heating during volumetric MR-HIFU ablation. Med Phys 2011; 38:272–282 25. Gorny KR, Chen S, Hangiandreou NJ, et al. Ini-
tial evaluation of acoustic reflectors for the preservation of sensitive abdominal skin areas during MRgFUS treatment. Phys Med Biol 2009; 54:N125–N133 26. 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; 22:1747–1750 27. Quesson B, Merle M, Köhler MO, et al. A method for MRI guidance of intercostal high intensity focused ultrasound ablation in the liver. Med Phys 2010; 37:2533–2540 28. Yoon SW, Lee C, Cha SH, et al. Patient selection guidelines in MR-guided focused ultrasound surgery of uterine fibroids: a pictorial guide to relevant findings in screening pelvic MRI. Eur Radiol 2008; 18:2997–3006 29. Hesley GK, Gorny KR, Woodrum DA. MR-guided focused ultrasound for the treatment of uterine fibroids. Cardiovasc Intervent Radiol 2012; 36:5–13 30. Golan A, Bukovsky I, Schneider D, Ron-el R, Herman A, Caspi E. D-Trp-6-luteinizing hormone-releasing hormone microcapsules in the treatment of uterine leiomyomas. Fertil Steril 1989; 52:406–411 31. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001; CD000547 32. Smart OC, Hindley JT, Regan L, Gedroyc WM. Magnetic resonance guided focused ultrasound surgery of uterine fibroids: the tissue effects of GnRH agonist pre-treatment. Eur J Radiol 2006; 59:163–167 33. Di Lieto A, De Falco M, Staibano S, et al. Effects of gonadotropin-releasing hormone agonists on uterine volume and vasculature and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) in uterine leiomyomas. Int J Gynecol Pathol 2003; 22:353–358 34. Köhler MO, Mougenot C, Quesson B, et al. Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry. Med Phys 2009; 36:3521– 3535 35. Kim YS, Keserci B, Partanen A, et al. Volumetric MR-HIFU ablation of uterine fibroids: role of treatment cell size in the improvement of energy efficiency. Eur J Radiol 2012; 81:3652–3659
36. InSightec. ExAblate O.R.: the operation room of the future. InSightec website. www.insightec. com/ExAblate-Operation-Room-Future.html. Published September 1, 2012. Accessed September 22, 2012 37. Pennes HH. Analysis of tissue and arterial blood temperatures in the resting human forearm. J Appl Physiol 1948; 1:93–122 38. Kim YS, Lim HK, Kim JH, et al. Dynamic contrast-enhanced magnetic resonance imaging predicts immediate therapeutic response of magnetic resonance-guided high-intensity focused ultrasound ablation of symptomatic uterine fibroids. Invest Radiol 2011; 46:639–647 39. Voogt MJ, van Stralen M, Ikink ME, et al. Targeted vessel ablation for more efficient magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroids. Cardiovasc Intervent Radiol 2012; 35:1205–1210 40. Hwang JH, Zhou Y, Warren C, Brayman AA, Crum LA. Targeted venous occlusion using pulsed high-intensity focused ultrasound. IEEE Trans Biomed Eng 2010; 57:37–40 41. Huang X, He M, Liu YJ, Zhang L, Wang ZB. Effect of oxytocin on uterine fibroids treated by ultrasound ablation (in Chinese). Zhonghua Fu Chan Ke Za Zhi 2011; 46:412–415 42. Peng S, Xiong Y, Li K, et al. Clinical utility of a microbubble-enhancing contrast (“SonoVue”) in treatment of uterine fibroids with high intensity focused ultrasound: a retrospective study. Eur J Radiol 2012; 81:3832–3838 43. Sokka SD, King R, Hynynen K. MRI-guided gas bubble enhanced ultrasound heating in in vivo rabbit thigh. Phys Med Biol 2003; 48:223–241 44. Kopelman D, Inbar Y, Hanannel A, et al. Magnetic resonance-guided focused ultrasound surgery using an enhanced sonication technique in a pig muscle model. Eur J Radiol 2006; 59:190–197 45. Tillander M, Köhler MO, Ylihautala M. Nonlinear heating enhancement of high-intensity pulsed volumetric sonications. In: Meairs S, ed. 12th International Symposium on Therapeutic Ultrasound. Laurel, MD: International Society for Therapeutic Ultrasound, 2012:55–56 46. Tempany CM, Stewart EA, McDannold N, Quade BJ, Jolesz FA, Hynynen K. MR imaging-guided focused ultrasound surgery of uterine leiomyomas: a feasibility study. Radiology 2003; 226:897–905
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Vascular and Interventional Radiology Review
Techniques to Expand Patient Selection for MRI-Guided HighIntensity Focused Ultrasound Ablation of Uterine Fibroids Young-sun Kim1 Duk-Soo Bae2 Min Jung Park1 Antti Viitala3 Bilgin Keserci 4 Hyunchul Rhim1 Hyo Keun Lim1 Kim YS, Bae DS, Park MJ, et al.
Keywords: high-intensity focused ultrasound, MRIguided intervention, patient exclusion, patient selection, uterine fibroid DOI:10.2214/AJR.13.10753 Received February 14, 2013; accepted after revision June 27, 2013. A. Viitala and B. Keserci are employees of Philips Healthcare. 1 Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2 Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 138-225, Korea. Address correspondence to D. S. Bae ([email protected]). 3
Philips Healthcare, Vantaa, Finland.
4
Philips Healthcare, Seoul, Korea.
This article is available for credit. AJR 2014; 202:443–451 0361–803X/14/2022–443 © American Roentgen Ray Society
OBJECTIVE. MRI-guided high-intensity focused ultrasound (HIFU) ablation is increasingly adopted for treating symptomatic uterine fibroids. As a noninvasive therapy performed on an outpatient basis, it has been viewed by patients to have distinct advantages over other treatment options. However, its breadth of clinical application is still limited. To address this issue, various techniques have been implemented. CONCLUSION. In this article, we discuss techniques that contribute to widening patient selection for MRI-guided HIFU therapy of uterine fibroids.
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terine fibroids are one of the most frequent benign tumors affecting women of child-bearing age [1– 3]. Symptoms include menorrhagia, dysmenorrhea, pelvic pain, and bulk-related symptoms, such as urinary frequency, which can significantly deteriorate the quality of life. Uterine fibroids can also interfere with fertility [4, 5]. As one of the nonsurgical therapeutic modalities for symptomatic uterine fibroids, MRI-guided high-intensity focused ultrasound (HIFU) ablation has been developed and increasingly adopted worldwide owing to its satisfactory therapeutic efficacy in controlling the symptoms, as well as a high level of safety [6–8]. In addition, MRI-guided HIFU ablation can be performed in a totally noninvasive manner; thus, the patients do not get a scar or experience bleeding from the procedure and may even avoid hospitalization. MRI-guided HIFU ablation therapy cannot be applied to all patients with symptomatic fibroids because of limiting factors. Two previous studies reported that only 16–25% of the referred patients were eligible for MRI-guided HIFU [9, 10]. Nontechnical limitations include the high cost of MRI-guided HIFU or the subject’s inability to withstand a stationary position for several hours as required for the treatment, which are issues that are challenging to overcome. However, there are also limiting factors that can be addressed by applying different patient preparation methods, as well as technologic development of the MRI-guid-
ed HIFU systems. Such limitations include the presence of scar tissue, bowel loops, or other obstacles in the sonication path; excessive thickness of subcutaneous layer of the anterior abdominal wall; fibroids that are too large or too deep; and excessive fibroid vascularity. It is known that the extent of ablation reached during MRI-guided HIFU therapy of uterine fibroid, as measured by nonperfused volume after the treatment, is a good predictor of the clinical outcome [11–13]. Anatomic factors can affect the available treatment window, which can limit the volume where thermal energy (sonications) can be delivered. If the treatment volume is severely reduced, sufficient nonperfused volume cannot be achieved and the patient is unlikely to benefit from the therapy. Therefore, all available methods should be used during patient preparation, positioning, and anatomic manipulation to gain maximal access to the fibroid. Alternatively, limitations related to fibroid properties, such as excessive size or vascularity, should be addressed through technologic development of the MRI-guided HIFU system or additional adoption of medication such as gonadotropin-releasing hormone (GnRH) agonist. Efforts in both areas not only would improve the therapeutic outcomes of the treated patients but also would expand the range of conditions that can be managed with this therapeutic modality. In this article, we comprehensively discuss techniques to expand patient selection and improve therapeutic outcomes, including manip-
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Manipulating Bowel Loops Bowel loops in the ultrasound beam path are generally considered to be a contraindication for MRI-guided HIFU treatment, because gas bubbles and hard particles contained in the bowel might reflect or absorb ultrasound en-
ergy in unpredictable ways, potentially leading to thermal damage and even bowel perforation [10, 14]. A search in the U.S. Food and Drug Administration (FDA) Manufacturers and User Facility Device Experience database produced reports of three adverse events in over 7000 cases that led to bowel perforation requiring surgical intervention [15]. Bowel loops may be in the near field of the ultrasound beam path and should be visualized with MRI techniques before therapy.
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ulating bowel loops, dealing with abdominal scars, alleviating fibroid size limitations, and overcoming excessive vascularity, on the basis of a literature review.
C Fig. 1—39-year-old woman with submucosal uterine fibroid who was treated with MRI-guided high-intensity focused ultrasound (HIFU) ablation. A, One small-bowel loop (arrow) was located anterior to uterus in screening MRI. Asterisk denotes submucosal uterine fibroid. B, Before initiation of MRI-guided HIFU therapy, urinary bladder was filled with saline, which resulted in displacing bowel; thus, acoustic window was satisfactorily established. Fibroid (asterisk) shrank after gonadotropin-releasing hormone analog pretreatment. C, MRI-guided HIFU therapy was performed successfully.
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Because it is not feasible to monitor accurately the whole near-field area on a real-time basis, it is very important to displace bowel loops in advance away from the sonication path to establish a safe acoustic window. Various methods have been reportedly used to gain a better acoustic window for uterine therapy with MRI-guided HIFU. Urinary Bladder Filling Bladder filling may be used to elevate the uterus in the superior, which can increase the acoustic window and avoid sonicating through a scar or can push bowel loops away from the area between the abdominal wall and the uterus (Fig. 1). This is easiest to do such that the flow of liquid from the Foley catheter is stopped using a clamp and a fluid (usually normal saline) is instilled. Natural bladder filling during the therapy creates slow and gradual anatomic changes caused by bladder distention. These changes should be closely monitored, and careful intermittent small-volume drainages should be performed, along with MRI-based reverification of the anatomy and intended sonication beam paths, to avoid misdirected sonications and to prevent undue patient discomfort. Care should be taken to avoid introducing air bubbles in the Foley balloon or the bladder, because the ultrasound does not propagate through air. Repeated filling and emptying of the Foley catheter balloon may help to reduce or remove possible air bubbles. Rectal Filling Filling the rectum with ultrasound coupling gel is often beneficial [16]. Rectal filling pushes the uterus anterior and restricts the free peritoneal space between the abdominal wall and the uterus where the bowel loops tend to move (Fig. 2). In addition, this technique increases the distance to sciatic nerves in the far field. An inflatable rectal balloon has also been used for manipulating the fibroid position with respect to the surrounding anatomy. This approach may be beneficial because it prevents the risk of material moving into the sigmoid colon, thus enabling greater spatial control of the mechanical force that pushes the uterus [17]. Miscellaneous Methods Successful use of a vaginal pessary for repositioning of the uterus has been reported [18]. This enabled a sufficient acoustic window to be obtained for therapy. Use of a convex gel pad to apply pressure to the central
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids part of the abdominal wall and displace the bowel loops peripherally was also reported to be helpful [16]. In the same context, when the fibroid is large, a bowel loop on the edge between the tumor and the abdominal wall may spontaneously move out of the beam path, as a result of gravity-induced compression. Dealing With Abdominal Scars Abdominal scars pose a challenge in MRIguided HIFU therapy. The presence of abdominal scars may affect patient selection, limit access to the treatment target area, and increase the risk of skin burn during therapy. A search in the FDA’s Manufacturers and User Facility Device Experience database revealed one report of full-thickness skin burns at the location of the previous laparoscopic scar area due to sonications through scar area. The patient was referred to a plastic surgeon for treatment [19]. This clinical limitation stems from differences in the acoustic properties of scar tissue from those of the surrounding tissue. Scar tissue may be denser, with higher ultrasound absorption than the surrounding normal tissue, which may lead to increased heating and thermal damage [20]. Scar tissues may also have a reduced blood supply compared with surrounding tissue, leading to reduced cooling, thereby potentially increasing the accumulated heating over the course of the treatment. There may be less sensation in scars than in surrounding tissue, making the patient less likely to perceive pain or heating during treatment through a scar. Moreover, one should be also aware that once a second- or third-degree skin burn is formed, the sense of heating is degraded because of the injury of nerve endings; therefore, patients may not be able to feel heating on the involved skin. In these cases, MR thermometric monitoring of the skin would be the only sign of overheating. To effectively monitor scar tissue heating, one must be able to visualize the scar on MRI. Older well-healed scars may be easy to see with visual inspection of the skin, but still difficult or impossible to identify on MRI. Typically, scars are easier to identify on the epidermis, dermis, and subcutaneous fat layer, but more difficult to identify in abdominal muscle and myometrium. Scars are usually identifiable on coronal or sagittal scans of T2-weighted images. To visualize scars better, dedicated MRI sequences or MRI-visible paint can help. One example of images produced by a dedicated MRI sequence for scar visualization is seen in Figure 3 (3D fast-field echo; TR/TE, 21/6.0; flip angle, 15°; slice thickness, 2 mm;
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Fig. 2—34-year-old woman with intramural uterine fibroid. A, Survey MRI on treatment day shows interposition of small-bowel loop (arrow) between uterus and abdominal wall. Asterisk denotes fibroid. B, To move bowel loop away, urinary bladder was filled with about 400 mL of saline, and small-bowel loop was displaced sufficiently. However, fibroid (asterisk) was elevated too high, which was not desirable because of possible stimulations of bony structures. C, Half of saline in urinary bladder was drained, but small-bowel loop (arrow) again moved close to planned sonication path (orange triangles). Asterisk denotes fibroid. D, Urinary bladder was further drained, and, simultaneously, rectum was filled with ultrasound gel, which resulted in displacement of fibroid (asterisk) closer to abdominal wall and descent of fibroid with no motion of bowel loop (arrow). Orange triangles denote planned sonication path.
FOV, 20 cm). MRI-visible paint, a mixture of nail varnish and MRI contrast agent containing paramagnetic iron oxide particles (Endorem, Guerbet), reportedly provides an alternative solution to highlight the scar location [14, 21]. Importantly, care should be taken when choosing MRI-visible paint, because some materials may cause image distortions or local heating due to radiofrequency absorption. Basic Methods to Avoid Scar Because of the risks described in the previous section, many clinicians have used patient positioning and manipulation techniques
to completely remove the scar from the beam path [10, 14, 22]. Basic approaches to deal with abdominal scars include tilting the transducer, filling the bladder as when displacing bowel loops, and stretching the skin to move the scar out of the beam path. However, they are effective only to a certain degree and depend on locations of the scar and target area. Usually, a combination of those approaches is necessary (Fig. 4). Through-the-Scar Sonication Although abdominal scarring is widely acknowledged as a challenge for MRI-guided
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Kim et al.
Fig. 3—43-year-old woman with history of cesarean section. Location of transverse scar (arrows) was clearly seen in scar scan image.
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Fig. 4—50-year-old woman with subserosal uterine fibroid who was treated with MRI-guided high-intensity focused ultrasound (HIFU) therapy. A, On screening MRI, scar (arrow) was located at level of center of fibroid (asterisk). B, Fibroid (asterisk) was pushed upward by saline-distended urinary bladder to avoid scar (arrow). Lowest part of tumor was able to be treated without traversing scar by tilting sonication path (orange triangles) downward.
HIFU uterine fibroid therapy, in a survey of clinicians treating patients with MRI-guided HIFU [23], it was rated as 4.75 ± 2.17 on a scale where 1 indicates “No impediment to therapy” and 10 indicates “Absolute contraindication to therapy,” implying that treating through or around the scar is acceptable in some instances. A small number of “through-the-scar” sonications may not be problematic; instead, accumulated heat over the course of multiple sonications appears to be the root cause for a skin burn. The outcomes of through-the-scar sonication seem to depend greatly on the histologic characteristics of the scar tissue, the age and size of the scar, the distance between the skin
and the HIFU target, and the fibroid vascularity and type. Older well-healed thin scars are safer to sonicate through than are scars that are new and composed of thick, pronounced, or raised tissue. Sonications involving a deeper HIFU target region are safer than are sonications applied in a more shallow location, because increasing sonication depth decreases the ultrasound intensity on the skin surface. When treating highly vascular or cellular fibroids that are usually more resistant to heating, higher acoustic power must be delivered, which increases the risk of skin surface heating. In the cases where the ultrasound beam passes through a scar, temperature changes
must be monitored carefully to detect unwanted heating in the region by MR thermometry (Fig. 5). Sufficient cooling intervals between sonications are necessary to reduce the possibility of damage due to accumulated heating [24]. Continuous and clear communication with the patient is critical to obtain immediate information of any abnormal sensations in the scar region. Safety of the sonication is further compromised if the patient has reduced sensitivity in the scar region.
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Use of Acoustic Patches Reports describing the use of acoustic patches to reflect the ultrasound energy indi-
Fig. 5—29-year-old woman with multiple uterine fibroids who was treated with MRI-guided high-intensity focused ultrasound (HIFU) therapy. A, Multiple fibroids (asterisks) retained intermediate-to-high signal intensity on T2-weighted screening MRI. B and C, MR thermometric images, including sagittal scan centered at HIFU target (B) and coronal scan on skin (C) during sonication of lower anterior fibroid using high acoustic power (200 W) show that 240 equivalent minutes (i.e., lethal thermal dose) contours (white outlines) were formed not only at HIFU target (arrow, B) but also on skin (arrowheads, B and C) at right inguinal area where depilation was not perfect. This sonication induced second-degree skin burn as complication.
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids
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Fig. 6—Scar patch experiment. A, Scar patch made of polyethylene foam was applied to 36-year-old woman with scar. B, Test performed in phantom sonication indicated that patch functions mainly as reflecting object, because no ultrasound absorption-induced local heating was detected. Distortions in focal shape and location were not seen either (sagittal MR thermometric image centered at high-intensity focused ultrasound target). Marker #1 is center point of horizontally applied scar patch.
cate that these could be a viable solution for patients with scars in the planned beam path. Such acoustic patches should be made of material that is water resistant, visible on MRI, easily attachable to the skin, and suitable to be applied to scars of different shapes [25, 26] (Fig. 6). A recent clinical study [26] assessed the effectiveness of acoustic patches in 20 patients with uterine leiomyoma where scars were blocking the beam path. The scar patch described in that study was made of an isolation polyethylene foam (1.5-mmthick Cell-Aire, Sealed Air), attached with
double-coated medical tape (9889, 3M). Potential risks in the use of an acoustic patch include skin burns due to locally absorbed ultrasound energy, a reduction in the quality of the focus due to blocked ultrasound energy, and damage to the transducer surface due to heating from reflected ultrasound energy. Although two patients had a few red spots on the skin surface after the treatment and three other patients had slight hyperemic changes in the abdominal muscle, as observed on fat-suppressed T2-weighted MRI, no serious adverse events were reported. The authors
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concluded that this approach was an effective option for patients with scars in the ultrasound beam path [26]. Beam Shaping Beam shaping can be used to selectively disable part of the ultrasound cone passing through the scar area while still delivering ultrasound through the surrounding tissue [27]. Beam shaping can also be used to avoid ultrasound delivery through the umbilicus, skin folds, air bubbles on the skin, or risky internal organs, such as bowel loops. This feature
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Fig. 7—Treatment planning of beam shaping feature in 42-year-old woman with uterine fibroid and transverse scar. A, Scar was manually localized by drawing free region of interest (gray outline) on scar scan. Planned sonication path was also illustrated (white circle). B, Sagittal image shows automatically computed available treatment area (blue shaded area). Planned treatment cell (green line), sonication path (yellow triangles), and safety margin (yellow rectangle) were also illustrated.
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Kim et al. (available in ExAblate O.R./ExAblate One, InSightec; and Sonalleve R3.2 software, Philips Healthcare) can be activated by drawing the areas to be avoided. The avoidance area indicates the location where reduced ultrasound intensity is desired, and subsequent sonications are then performed with a number of transducer elements that contribute to the intensity traversing through the area switched off. The reduction in ultrasound intensity at the focus due to the switched-off elements is compensated for by increasing the power delivered by the remaining active elements (Fig. 7). Alleviating Fibroid Size Limitations Considering the patients’ tolerability and the risk of deep venous thrombosis, 3–4 hours seems to be the limit of treatment time for MRI-guided HIFU therapy [8]. Because the ablation speed is limited by physical constraints, such as diffusion of the heat energy away from the focus and near-field heating, and because time is needed between sonications to allow near-field cooling, the size limit of uterine fibroids at most institutions using the MRI-guided HIFU system adopting a conventional “point-by-point” sonication method has been reported to be 10 cm in diameter [28, 29]. However, several new techniques have been developed to address the ablation of large fibroid volumes, which, in turn, expands the size range of uterine fibroids that are treatable by MRI-guided HIFU. Hormonal Therapy Pretreatment Since the 1980s, GnRH agonists have been used for medical therapy of uterine fibroids via a state of hypoestrogenism [30]. However, the reduced volume persists only while the patient is actively treated, and GnRH agonists unfortunately cannot be used long term because of substantial menopause-like adverse effects. Therefore, treatment should be restricted to less than 6 months [31]. The use of GnRH agonists before MRIguided HIFU has been reported elsewhere. Smart et al. [32] published the results of a clinical study of 50 patients treated with MRIguided HIFU, where 27 patients underwent pretreatment with GnRH agonists and the remaining patients did not. Criteria for receiving the 3-month course of GnRH agonists was a uterine diameter of 10 cm or greater. The authors reported a mean reduction in the size of the target fibroid of 36%, concluding that this approach enabled successful therapy in patients who otherwise would have been ex-
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cluded on the basis of uterine size alone [32]. Zaher et al. [14] addressed patient suitability and potential mitigation strategies in 144 patients, 100 of whom were viable candidates for MRI-guided HIFU. In that study, all patients with a total fibroid volume of more than 500 cm3 or whose fibroid was hyperintense on T2weighted imaging were treated with a 3-month course of GnRH agonists before MRI-guided HIFU therapy. Of the patients treated with MRI-guided HIFU, 88% underwent GnRH agonist therapy pretreatment. The authors stated that this approach helped to reduce fibroid volume and increase the fibroid tissue’s susceptibility to the treatment [14] (Fig. 1). GnRH agonist pretreatment could be used to modulate the vascularity of uterine fibroids, which is another limiting factor of this modality when it is excessive (as discussed later in this article), in addition to its effect on the fibroid size. Although its effects on the outcome of MRI-guided HIFU therapy through devascularization have not been methodically evaluated, GnRH agonist therapy is known to decrease the vascularity of fibroids, as evidenced by a decrease in a microvascular density marker, CD34, in surgical specimens [33].
Volumetric Ablation Technique To improve the treatment speed of MRIguided HIFU therapy, a new volumetric ablation technique has recently been introduced. The conventional point-by-point sonication method is only able to create a relatively small ablation zone of approximately 5 mm in axial diameter. With a volumetric ablation method (available with the Sonalleve MRI-guided HIFU system, Philips Healthcare), the focus of the HIFU beam is electronically steered along a trajectory composed of multiple outward-moving concentric circles with automated temperature feedback and is, therefore, able to induce relatively larger and homogeneous ablation zones with an axial diameter of 4–16 mm. This volumetric ablation method is expected to be more energy efficient and, therefore, has improved treatment speed compared to the conventional method, because it uses the heat already deposited during sonication of the inner part of the trajectory to preheat the outer parts, instead of allowing the heat to dissipate out of the target area [34]. On the basis of a clinical study of uterine fibroid treatment using volumetric MRI-guided HIFU [35], the energy efficiency improved with in-
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Fig. 8—34-year-old woman with 11.8-cm uterine fibroid treated with volumetric MRI-guided high-intensity focused ultrasound (HIFU) ablation with one-layer strategy. A, Treatment cells of 16 mm in axial diameter (orange bullets) were placed at middle of fibroid depth as single layer. B, MRI-guided HIFU ablation was successfully performed, and immediate contrast-enhanced scan showed excellent nonperfused volume ratio measuring 90.5%.
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MRI-Guided High-Intensity Focused Ultrasound Ablation of Uterine Fibroids
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Fig. 9—41-year-old woman with 18-cm uterine fibroid treated with MRI-guided high-intensity focused ultrasound (HIFU) ablation with vessel targeting strategy. A, Screening MRI shows 18-cm uterine fibroid. Patient refused surgery, and MRI-guided HIFU therapy was performed for palliative purpose. B, Unenhanced MR angiography using B-TRANCE (balanced turbo field echo triggered angiography noncontrast-enhanced) technique performed immediately before MRI-guided HIFU ablation shows one supplying vessel (arrows) running into tumor. C, Unenhanced MR angiography after treatment shows disappearance of supplying vessel (arrows). D, Immediate posttreatment contrast-enhanced T1-weighted image shows nonperfused volume was extended superiorly (dotted outline) beyond area of treatment cell (orange triangles) placements, which was presumably formed by occlusion of supplying vessel.
creased treatment cell size, where energy efficiency was defined as the tissue volume of a lethal thermal dose (i.e., 240 equivalent minutes) achieved per unit of acoustic energy applied. In this study, the energy efficiency of a 16-mm treatment cell was about 15 times of that of a 4-mm cell. One-Layer Strategy in Volumetric Ablation Despite the improved energy efficiency of the volumetric ablation technique, quite a large amount of acoustic energy is still wasted in the form of near-field heat accumulation. This heat needs to dissipate to prevent thermal injury to intervening tissues and thus requires cooling intervals. In the “one-layer strategy,” the heat accumulation in the immediate nearfield of the focal plane was exploited by placing all treatment cells at one single coronal plane located at a depth from half to the anterior two thirds of the fibroid, thereby accu-
mulating heat in the anterior of the fibroid and enhancing the treatment speed. In the study where this was applied [8], large uterine fibroids of more than 10 cm in diameter were effectively treated with a mean nonperfused volume ratio of 64.2% and within an acceptable treatment time (mean, 2.8 hours) (Fig. 8). This strategy was more effective in cases of fibroids with lower vascularity, as assessed by dynamic contrast-enhanced MRI [35]. Variable Length Sonication Technique Other volumetric techniques without automated temperature feedback, including a variable-length sonication technique (available in ExAblate O.R./ExAblate One, InSightec), are being explored clinically [36]. In this strategy, HIFU focus is mechanically shifted forward during a single burst of ultrasound energy, which forms variable lengths of elongated ablation zone ranging from 10 to 70 mm. As
D a result, treatment cells are able to be tailored to conform to a large fibroid contour without a need for multiple layers. However, the improvements in energy efficiency, treatment speed, or safety data in clinical fibroid therapy have not been reported yet.
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Kim et al. Overcoming Excessive Vascularity On the basis of Pennes’s [37] bio-heat equation, tissue perfusion, which dissipates heat, is the most important tissue property in the determination of ablation results. This consensus is currently accepted for any kind of hyperthermic ablation therapy, and MRI-guided HIFU therapy cannot be an exception. A recent study proved this concept in MRI-guided HIFU therapy with the use of dynamic contrast-enhanced MRI [38] showing that hypervascularity manifested by high Ktrans (volume transfer constant) values was associated with poor ablation efficacy. There have been efforts to overcome high vascularity of uterine fibroids, including vessel targeting and various medical pretreatment therapies. Vessel Targeting A recent publication reported success in selective targeting of the feeding vessels of the fibroid based on contrast-enhanced MR angiography registered to the treatment planning images [39]. Sonications were performed focusing primarily on the area where the vessels entered the fibroid, and ablation of the fibroid tissue was also performed. In two tumors, the resulting nonperfused volumes were reported as nearly complete ablation, although the peripheral parts of the fibroid were not ablated for safety reasons. In that study, the authors used data from contrast-enhanced MR angiography performed before the day of therapy, because there were concerns that the use of gadolinium-based MRI contrast agent just before MRI-guided HIFU therapy may have been harmful because of the effect of heat on contrast agent stability. Furthermore, if MRIguided HIFU is performed on a different day from MR angiography, it would require image registration, which may be difficult because of possible motion of the internal organs. Considering these items, unenhanced MR angiography performed immediately before MRIguided HIFU therapy might be desirable for vessel targeting, as shown in Figure 9. Repeated high-powered sonications seem to induce delayed thrombotic occlusion of the supplying vessel via endothelial injuries [40]. Oxytocin Pretreatment Oxytocin is a hormone known to cause uterine contraction. Therefore, oxytocin is commonly used for facilitating labor or suppressing postpartum bleeding. Oxytocin-induced uterine contraction may contribute to decreasing blood flow of the uterus as well as the fibroids. One recent study described the useful-
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ness of oxytocin in MRI-guided HIFU therapy of uterine fibroids in 26 patients [41]. In that study, the energy required to reach 60°C decreased from 5320 to 2890 J, on average, and the time taken to achieve 60°C also decreased from 21 to 12 seconds, on average, after IV infusion of oxytocin. Miscellaneous Methods The use of higher acoustic energy by increasing either the acoustic power or the sonication time beyond the currently available level may also be helpful. However, in this case, attention should be paid to the temperature changes of the intervening structures, including the skin, to prevent complications. In a similar context, the concurrent use of an IV microbubble agent has been shown to enhance the ablation efficiency of HIFU, as published in a recent study performed with a sonography-guided HIFU system [42]. However, one should note that the application of concurrent use of microbubble agents and HIFU ablation has not been proved safe and, thus, cannot be currently advocated. Similarly, nonlinear or cavitation-enhanced HIFU can also potentially be used to improve the acoustic energy absorption at the focus by using a lower duty cycle but higher acoustic power to maintain the total amount of energy used unchanged [43–45]. Conclusion Since the first feasibility study in 2003 [46] and approval by the FDA in 2004, thousands of MRI-guided HIFU ablation procedures and significant research works have been performed worldwide. From these experiences, a variety of techniques have been accumulated from the perspectives of clinical practice or engineering, as discussed in this article. These techniques have been expanding the range of patients for whom this therapeutic modality could be effectively applied. In spite of such efforts, the aforementioned issues are not completely resolved as yet, and there is still more work to be done, including addressing fibroid accessibility for locations beyond the reachable depth of the system and excessively thick subcutaneous fat of the abdominal wall, which attenuates acoustic energy and has a negative effect on the quality of the focus. As a consequence, some patients continue to not be candidates for MRI-guided HIFU therapy. Even now, there is room for further advances in MRIguided HIFU technology as well as improvement in its clinical application, which will benefit more patients in the future.
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