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Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids – early experience
European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203 www.elsevier.com/locate/ejogrb
Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids – early experience Yutaka Morita a,*, Naoki Ito b, Hiromi Hikida a, Sawako Takeuchi a, Kouji Nakamura a, Hirofumi Ohashi a a
Department of Obstetrics & Gynecology, Itabashi Chuo Medical Center, 2-12-7 Azusawa, Itabashi-ku, Tokyo 174-0051, Japan b Department of Radiology, Itabashi Chuo Medical Center, Tokyo, Japan Received 8 May 2007; received in revised form 14 August 2007; accepted 25 October 2007
Abstract Objective: To describe early results regarding efficacy and safety of magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) for the treatment of uterine leiomyomas among a population of Japanese women. Study design: In this single site study, 48 Japanese women, over 18 years of age, who were candidates for surgical intervention due to symptomatic fibroids, were recruited. Fifty-five uterine fibroids were treated by MRgFUS and followed up for 12 months. Results: During the 12-month follow-up period, two patients (4%) required surgical interventions, and two patients required additional drug treatment for fibroids. The average reduction in fibroid volume determined by MR imaging at 6 months after treatment was 33%. This volume reduction is correlated with the fibroid’s treated volume. No serious complications were recorded during the treatments or follow-up period. Conclusion: MRgFUS can safely be used to non-invasively treat symptomatic uterine fibroids and avoid the need for surgical intervention in the short term. With large treatment volumes, MRgFUS also results in significant fibroid shrinkage in a relatively short time. Additional follow-up is needed to determine the long-term durability of this promising non-invasive approach. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Focused ultrasound; Leiomyoma; Magnetic resonance guided focused ultrasound; Uterine fibroids
1. Introduction Uterine leiomyomas are the most common benign tumor found in women of childbearing age [1,2] with symptoms appearing in 25% of women 30–50 years of age [1,3]. Symptoms include heavy and prolonged menstrual flow, pelvic pain and pressure, pain in the legs and back, pain during sexual intercourse, frequent urination, constipation, abnormally enlarged abdomen, and infertility [1,3–5]. In light of the morbidity posed by both uterine fibroids and by hysterectomy, which is the sole definitive treatment [6], and given the growing tendency of women to postpone pregnancy into the late thirties [7], less-invasive treatment alternatives with
* Corresponding author. Tel.: +81 3 3967 1181x555; fax: +81 3 3967 4941. E-mail address: [email protected] (Y. Morita).
shorter recovery times and the retention of childbearing potential have recently garnered much attention. Uterine-sparing treatments, such as myomectomy and uterine artery embolization (UAE), have recently become significant treatment options for uterine fibroids. The advantages of these treatment modalities are lower morbidity and shorter recovery times when compared with hysterectomy. However, these procedures remain associated with treatment-specific limitations on fibroid size and location (myomectomy), the probability of postoperative fever and pain (UAE), intraoperative blood loss, posttreatment hospital stay, lengthy time off work and suspension of normal activities during recovery [8]. Focused ultrasound (FUS) was originally proposed as a potential surgical tool in the early 1940s [9]. The ability to concentrate ultrasound energy at high power has given rise to surgical FUS—a powerful tissue-ablation technique that maintains precise, tightly focused temperatures required to
0301-2115/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2007.10.018
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Y. Morita et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203
produce protein denaturation, cell death and coagulative necrosis of pathological tissues while leaving tissues outside the target region preserved and unaffected [10,11]. Only recently has FUS been complemented with magnetic resonance (MR) real-time imaging, allowing physicians a high degree of accurate tumor localization, temperature monitoring, and tissue-destruction assessment [6,12–21]. The ExAblate1 2000 System (InSightec, Haifa, Israel) is FDA-approved for the ablation of uterine fibroid tissue in pre- or perimenopausal women who have completed their family [6,15–21]. Recent long-term (12-month) follow-up data from women treated with this system have shown significant long-term improvements in quality-of-life parameters (primary outcome) and an excellent safety profile [6,19]. At Itabashi Chuo Medical Center in Tokyo, MRgFUS has recently been added to the uterine-fibroid-treatment repertoire because it is non-invasive, and because it does not require anesthesia, and thus is suitable as an outpatient treatment. Women undergoing this treatment do not require a hospital stay, and can usually return to work and full resumption of normal activities within a day or two of the procedure. This paper describes the experience with the first 48 patients treated with MRgFUS at Itabashi Chuo Medical Center. The effects of MRgFUS are evaluated by measurements of uterine fibroid size reduction and non-perfused volume (NPV) ratio which is defined below.
2. Materials and methods Fifty-one pre-menopausal Japanese women with symptomatic uterine fibroids, diagnosed by clinical examination and ultrasound imaging, met the initial screening criteria for MRgFUS suitability, and were prepared to undergo
treatment at the Itabashi Chuo Medical Center in Tokyo between January 2005 and February 2006. The local institutional review board has approved MRgFUS for treating fibroids and all patients provided written, informed consent after the nature of the procedure was explained to them. The patients were screened for treatment eligibility as described according to the approved indication [16]. Before treatment, the bowels of two women were located between the fibroid and the abdominal wall, potentially compromising the beam path. A third woman was diagnosed as having adenomyosis. These three patients were not treated and therefore not further analyzed. The ExAblate 2000 is integrated with a 1.5-T MRI scanner (GE Medical Systems, Milwaukee, WI), and provides real-time thermal imaging during the treatment phase of the procedure. Prior to treatment, hair is shaved from the umbilicus to the pubis to ensure acoustic coupling. The patient lies prone on the treatment table, with her abdomen lying on a gel pad situated directly above the ultrasound transducer. The patient is pre-medicated with light conscious sedation (diazepam 5 mg PO, pentazocine 15 mg IV, and hydroxyzine hydrochloride 25 mg IV) to relieve anxiety, prevent movement, and to minimize discomfort. Light sedation allows patients to communicate with the medical staff throughout the procedure. In addition, patients are given a ‘‘stop button’’ so that they can immediately stop the energy pulse in the event of pain or discomfort. To identify and measure the target lesion(s) and to evaluate the surrounding pelvic anatomy during treatment, the patient goes through an initial MR scan using T2 weighted sequences (Fig. 1A) and a pre-treatment plan is initiated by a team including a gynecologist and a radiologist. Contours of the entire targeted fibroid(s) are drawn on the MR image by the treating physician using
Fig. 1. Intramural fibroid 7 cm in diameter with associated heavy bleeding in a 44-year-old patient. MRgFUS treatment comprised 60 sonications, resulting in a %NPV of almost 100%. Fibroid was reduced by 46.6% at month 6. A and B: MR image (T2W) before and at 6 months post-treatment.
Y. Morita et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203
ExAblate System software. Based on tumor volume and depth, the system computes the energy and the number of focal energy deliveries (‘‘sonications’’) required to completely treat the defined region. The treating physician manually optimizes the plan to cover as much fibroid volume as possible to achieve maximum tumor ablation. A low-energy test sonication is first delivered to ensure the accuracy of its location. Following confirmation of the test sonication and treatment plan, the treatment phase commences with multiple sonications of approximately 20 s each, followed by an approximately 90 s cool-down. After a sonication, the patient is asked to provide verbal feedback. When sufficient portion of the tumor has been treated, T1 weighted contrast enhanced (T1W CE) images are acquired to evaluate the ratio (%) of the treated areas of the fibroid to the untreated parts by measuring the nonenhanced regions. These non-enhanced regions represent non-perfusion, where the blood supply has been cut-off due to treatment, causing tissue ablation. These slice-by-slice measurements are then converted into volumetric results, and used later to assess treatment effectiveness [16,19]. The patients were asked about subjective relief of symptoms and whether they had sought additional treatments to deal with them at 1, 3, 6 and 12 months posttreatment. In addition, T2 and T1 (with and without contrast) weighted images were acquired at 6 months of follow-up and used to determine treatment outcome (fibroid size and NPV) (see Fig. 1B). Fibroid volume and NPV during treatment and at 6 months thereafter were calculated as the mean of all 8 mm fibroid slices in three axes with visible fibroid or NPV. NPV ratio was determined as the non-perfused volume divided by the fibroid volume. Fibroid shrinkage was calculated as volume change in a fibroid between the treatment day and at the 6-month follow-up, divided by the volume at treatment day. Student’s one-sample t-test was used for statistical comparisons of mean fibroid volume between baseline and that reported at 6 months. Correspondence between fibroid shrinkage and non-perfused volume was evaluated by linear regression. The stratification of the group of patients, for which shrinkage data is available, based on NPV ratio into two statistically significant sub-groups was performed using a two-sample t-test assuming equal variance. A p value below 0.05 was considered to indicate a significant difference.
3. Results Forty-eight Japanese women aged 42.6 5.8 years (mean S.D.; range, 24–51) (Table 1) were treated using MRgFUS. Symptomology demonstrated by this patient population included heavy menstrual bleeding (30 patients, 63%), abdominal discomfort (21 patients, 44%), anemia (determined from laboratory testing: 9 patients, 19%), frequent urination (16 patients, 33%), and menstrual pain (5
201
Table 1 Baseline characteristics of treatment group Baseline demographics
All patients (n = 48)
Age (years); mean S.D. (minimum, maximum) Body mass index (kg/m2); mean S.D. (minimum, maximum) Nationality
42.6 5.8 (24, 51) 21.6 3.0 (n = 41) (17, 35)
Japanese
patients, 10%). We treated 55 fibroids with a mean (S.D.) diameter of 80.4 19.1 mm (range: 35–115 mm). In an attempt to treat the complete volume of each fibroid, five patients with large fibroids (mean S.D., 94 8 mm) required a second procedure. No serious or unexpected adverse events arose during the study. Four patients (8.3%) developed skin redness, which was considered to be related to the MRgFUS procedure. Dimethyl isopropyl azulene ointment (10 g) resolved this symptom in three of the patients within 3 days, and in the other within 1 week. One patient developed transitory sciatic neuralgia because of disc herniation at L4-L5 and L5-S1, which was confirmed by anteroposterior radiography and MRI. This was caused by an underlying disease and was not a complication of MRgFUS. It took about a month for the symptoms related to that disease to cease. Three patients (6%) had occasional severe pain during the procedure, which was managed by changing treatment parameters and an additional dose of sedation (pentazocine 15 mg IV, and hydroxyzine hydrochloride 25 mg IV) so that none of the patients aborted the treatment due to pain. All patients were followed up for the duration of 12 months, and throughout this period no additional procedure-related complications were recorded. The mean (S.D.) non-perfused volume ratio (NPV%) was 60 18% (n = 48, range, 22–100%) immediately upon completion of MRgFUS treatment. Thirty-nine patients underwent MR imaging at the 6-month follow-up visit. For these patients, the mean (S.D.) fibroid size had been reduced from baseline by 33% 19% (n = 39). This decrease was statistically significant ( p < 0.0001). The population of patients, for which shrinkage data was available at the 6-month follow-up visit, was further stratified into similar size groups, based on NPV ratio values. This additional stratification of the shrinkage data at 6 months revealed that when the NPV ratio at the end of the treatment was above 60%, the mean (S.D.) shrinkage value was 39 16% (n = 18), while that of the lower NPV group was only 27 20% (n = 21). This difference was statistically significant ( p = 0.05). Linear regression of the data regarding fibroid shrinkage at 6 months of follow-up showed that a larger treatment NPV ratio resulted in more fibroid shrinkage by 6 months ( p = 0.037; Fig. 2). The treating physician used a subjective questionnaire for patients returning for follow-up appointments. Patients were asked whether their symptoms had improved or not in the period following treatment. Seven patients (14.6%) were not
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Fig. 2. Relationship between 6 months fibroid shrinkage and treatment nonperfused volume ratio (n = 39). The points describe the patients data and the line is the linear regression ( p = 0.037).
satisfied with the outcome of the MRgFUS procedure. Three of these patients have decided not to pursue alternative forms of treatments; one resumed usage of painkillers, another continued her treatment for anemia, while the third patient was not prescribed with therapy. Regarding the other four, patients were followed up for having alternative treatments for their fibroids; two were referred to alternative forms of surgical treatments: one patient was treated with UAE, and another one with myomectomy. Two additional patients were prescribed GnRH until the onset of natural menopause. Although women seeking future pregnancies were excluded, one patient became pregnant after treatment. A 29-year-old with no previous pregnancies was treated for one intramural fibroid with a total volume of 215 cc. The estimated conception date was 4 months after the ExAblate treatment. Her pregnancy course was uneventful and on the 39th week, she vaginally delivered a normal boy weighing 3212 g with Apgar scores of 8/9. The postpartum course was uneventful [22].
4. Comments Hysterectomy has been the definitive curative option available to women with uterine fibroids for many years. This procedure is widely effective, but not without limitations. Hysterectomy is an irreversible open surgical technique with an established history of effectiveness that is tarnished predominantly by its associated morbidity. Cost, blood loss, pain, lengthy hospitalization and recovery time, and the psychological distress caused to some women due to the loss of the uterus, are some of the negative features of this procedure. Patients were followed up at 6 months for MR imaging to visualize fibroid changes. Persistent fibroid shrinkage was evident at 6 months and the amount of shrinkage closely correlated with the NPV ratio achieved during treatment. This indicates that the ablated fibroid tissue is absorbed by
the body over time, and thus translates into fibroid shrinkage. In other words, more fibroid ablation during treatment generates better outcomes. If a benchmark NPV ratio of 60% at treatment is presumed, fibroids with values higher than this will shrink by about 39% at 6 months. If an NPV ratio of 60% is not achieved during treatment (e.g. due to technical limitations), then the linear regression results imply that a larger NPV at the end of treatment will also indicate more fibroid shrinkage. At the 12-month follow-up, seven women (15%) were not satisfied with the treatment. The satisfaction feedback form used is not of a quantitative nature. However, all patients were followed up for having any additional fibroid treatment. Since all patients were seeking a treatment for their symptomatic uterine fibroids, recording their decision to get another intervention serves as a quantitative measure of efficacy, as often used to describe outcomes of minimally invasive treatment techniques [23,24]. Two patients (4%) underwent an alternative form of surgical intervention, and two more required additional non-invasive drug therapy. Albeit reporting on a small sample in this study, these results seem to be comparable to the outcome of uterine artery embolization treatments, whose interim value of 7% treatment failures is reported 1 year post-treatment [25]. Patients will be followed up for a longer term to examine the option of symptom recurrence, but these are promising results. Four cases of adverse events were reported following the treatment and all were resolved within 1 week. Three patients developed mild skin redness, which might be caused by a reaction to the gel pad interface or imperfect acoustic coupling at the skin (e.g., presence of air or hair). One patient had neuralgia that was part of an underlying condition, which was possibly exacerbated due to remaining prone for a prolonged period during the procedure. These are known adverse events that can occur after MRgFUS, and are similar to those observed in previous studies [6,19]. In conclusion, MRgFUS is an effective and safe treatment for Japanese women with uterine fibroids. The procedure has an excellent safety record and patient satisfaction is high. Fibroids significantly shrink by 6 months after treatment, and the amount of shrinkage depends on the fibroid volume treated.
References [1] Akinyemi BO, Adewoye BR, Fakoya TA. Uterine fibroid: a review. Niger J Med 2004;13(4):318–29. [2] Haney AF. Clinical decision making regarding leiomyomata: what we need in the next millennium. Environ Health Perspect 2000;108(Suppl. 5):835–9. [3] Vollenhoven BJ, Lawrence AS, Healy DL. Uterine fibroids: a clinical review. Br J Obstet Gynaecol 1990;97(4):285–98. [4] Falcone T, Bedaiwy MA. Minimally invasive management of uterine fibroids. Curr Opin Obstet Gynecol 2002;14(4):401–7. [5] Middendorf K, Burges A, Strauss A, Hepp H. Uterine fibroids— therapy from the point of view of the gynaecologist. Radiologe 2003;43(8):615–23.
Y. Morita et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203 [6] Stewart EA, Rabinovici J, Tempany CM, et al. Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids. Fertil Steril 2006;85(1):22–9. [7] Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2004. National vital statistics reports. vol. 55, no. 1. Hyattsville, MD: National Center for Health Statistics; 2006. [8] Pron G, Mocarski E, Bennett J, et al. Tolerance, hospital stay, and recovery after uterine artery embolization for fibroids: the ontario uterine fibroid embolization trial. J Vasc Interv Radiol 2003;14: 1243–50. [9] 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. [10] Fry WJ. Intense ultrasound; a new tool for neurological research. J Ment Sci 1954;100(418):85–96. [11] Lele PP. Ultrasound in surgery. Fundamental and applied aspects of nonionizing radiation. New York: Plenum Press; 1975. p. 325–40. [12] Jolesz FA, Hynynen K, McDannold N, Tempany C. MR imagingcontrolled focused ultrasound ablation: a noninvasive image-guided surgery. Magn Reson Imaging Clin N Am 2005;13(3):545–60. [13] Jolesz FA, Hynynen K. Magnetic resonance image-guided focused ultrasound surgery. Cancer J 2002;8(Suppl. 1):S100–12. [14] Moonen CT, Quesson B, Salomir R, et al. Thermal therapies in interventional MR imaging. Focused ultrasound. Neuroimaging Clin N Am 2001;11(4):737–47. xi. [15] Fennessy FM, Tempany CM. MRI-guided focused ultrasound surgery of uterine leiomyomas. Acad Radiol 2005;12(9):1158–66. [16] Hindley J, Gedroyc WM, Regan L, et al. MRI guidance of focused ultrasound therapy of uterine fibroids: early results. AJR Am J Roentgenol 2004;183(6):1713–9.
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[17] Jacobs MA, Herskovits EH, Kim HS. Uterine fibroids: diffusionweighted MR imaging for monitoring therapy with focused ultrasound surgery—preliminary study. Radiology 2005;236(1):196–203. [18] Stewart EA, Gedroyc WM, Tempany CM, et al. Focused ultrasound treatment of uterine fibroid tumors: safety and feasibility of a noninvasive thermoablative technique. Am J Obstet Gynecol 2003;189(1): 48–54. [19] Fennessy F, Tempany C, McDannold N. Uterine leiomyomas: MR imaging-guided focused ultrasound surgery—results of different treatment protocols. Radiology 2007;243:885–93. [20] Stewart EA. Magnetic resonance imaging-guided focused ultrasound: no panacea, but nevertheless a safe step forward. Fertil Steril 2006;85(1):49. [21] Funaki K, Fukunishi H, Funaki T, et al. Magnetic resonance-guided focused ultrasound surgery for uterine fibroids: relationship between the therapeutic effects and signal intensity of preexisting T2-weighted MFR images. Am J Obstet Gynecol 2007;196. 184.e 1–6. [22] Morita Y, Ito N, Ohashi H. Pregnancy following MR-guided focused ultrasound surgery for a uterine fibroid. Int J Gynaecol Obstet 2007;99:56–7. [23] Marret H, Cottier JP, Alonso AM, et al. Predictive factors for fibroids recurrence after uterine artery embolisation. BJOG 2005;112: 461–5. [24] Volkers NA, Hehenkamp WJ, Birnie E, Ankum WM, Reekers JA. Uterine artery embolization versus hysterectomy in the treatment of symptomatic uterine fibroids: 2 years’ outcome from the randomized EMMY trial. Am J Obstet Gynecol 2007;196(6):519.e1–519.e11. [25] Spies JB, Bruno J, Czeyda-Pommersheim F, et al. Long-term outcome of uterine artery embolization of leiomyomata. Obstet Gynecol 2005;106:933–9.
Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids – early experience Yutaka Morita a,*, Naoki Ito b, Hiromi Hikida a, Sawako Takeuchi a, Kouji Nakamura a, Hirofumi Ohashi a a
Department of Obstetrics & Gynecology, Itabashi Chuo Medical Center, 2-12-7 Azusawa, Itabashi-ku, Tokyo 174-0051, Japan b Department of Radiology, Itabashi Chuo Medical Center, Tokyo, Japan Received 8 May 2007; received in revised form 14 August 2007; accepted 25 October 2007
Abstract Objective: To describe early results regarding efficacy and safety of magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) for the treatment of uterine leiomyomas among a population of Japanese women. Study design: In this single site study, 48 Japanese women, over 18 years of age, who were candidates for surgical intervention due to symptomatic fibroids, were recruited. Fifty-five uterine fibroids were treated by MRgFUS and followed up for 12 months. Results: During the 12-month follow-up period, two patients (4%) required surgical interventions, and two patients required additional drug treatment for fibroids. The average reduction in fibroid volume determined by MR imaging at 6 months after treatment was 33%. This volume reduction is correlated with the fibroid’s treated volume. No serious complications were recorded during the treatments or follow-up period. Conclusion: MRgFUS can safely be used to non-invasively treat symptomatic uterine fibroids and avoid the need for surgical intervention in the short term. With large treatment volumes, MRgFUS also results in significant fibroid shrinkage in a relatively short time. Additional follow-up is needed to determine the long-term durability of this promising non-invasive approach. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Focused ultrasound; Leiomyoma; Magnetic resonance guided focused ultrasound; Uterine fibroids
1. Introduction Uterine leiomyomas are the most common benign tumor found in women of childbearing age [1,2] with symptoms appearing in 25% of women 30–50 years of age [1,3]. Symptoms include heavy and prolonged menstrual flow, pelvic pain and pressure, pain in the legs and back, pain during sexual intercourse, frequent urination, constipation, abnormally enlarged abdomen, and infertility [1,3–5]. In light of the morbidity posed by both uterine fibroids and by hysterectomy, which is the sole definitive treatment [6], and given the growing tendency of women to postpone pregnancy into the late thirties [7], less-invasive treatment alternatives with
* Corresponding author. Tel.: +81 3 3967 1181x555; fax: +81 3 3967 4941. E-mail address: [email protected] (Y. Morita).
shorter recovery times and the retention of childbearing potential have recently garnered much attention. Uterine-sparing treatments, such as myomectomy and uterine artery embolization (UAE), have recently become significant treatment options for uterine fibroids. The advantages of these treatment modalities are lower morbidity and shorter recovery times when compared with hysterectomy. However, these procedures remain associated with treatment-specific limitations on fibroid size and location (myomectomy), the probability of postoperative fever and pain (UAE), intraoperative blood loss, posttreatment hospital stay, lengthy time off work and suspension of normal activities during recovery [8]. Focused ultrasound (FUS) was originally proposed as a potential surgical tool in the early 1940s [9]. The ability to concentrate ultrasound energy at high power has given rise to surgical FUS—a powerful tissue-ablation technique that maintains precise, tightly focused temperatures required to
0301-2115/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2007.10.018
200
Y. Morita et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203
produce protein denaturation, cell death and coagulative necrosis of pathological tissues while leaving tissues outside the target region preserved and unaffected [10,11]. Only recently has FUS been complemented with magnetic resonance (MR) real-time imaging, allowing physicians a high degree of accurate tumor localization, temperature monitoring, and tissue-destruction assessment [6,12–21]. The ExAblate1 2000 System (InSightec, Haifa, Israel) is FDA-approved for the ablation of uterine fibroid tissue in pre- or perimenopausal women who have completed their family [6,15–21]. Recent long-term (12-month) follow-up data from women treated with this system have shown significant long-term improvements in quality-of-life parameters (primary outcome) and an excellent safety profile [6,19]. At Itabashi Chuo Medical Center in Tokyo, MRgFUS has recently been added to the uterine-fibroid-treatment repertoire because it is non-invasive, and because it does not require anesthesia, and thus is suitable as an outpatient treatment. Women undergoing this treatment do not require a hospital stay, and can usually return to work and full resumption of normal activities within a day or two of the procedure. This paper describes the experience with the first 48 patients treated with MRgFUS at Itabashi Chuo Medical Center. The effects of MRgFUS are evaluated by measurements of uterine fibroid size reduction and non-perfused volume (NPV) ratio which is defined below.
2. Materials and methods Fifty-one pre-menopausal Japanese women with symptomatic uterine fibroids, diagnosed by clinical examination and ultrasound imaging, met the initial screening criteria for MRgFUS suitability, and were prepared to undergo
treatment at the Itabashi Chuo Medical Center in Tokyo between January 2005 and February 2006. The local institutional review board has approved MRgFUS for treating fibroids and all patients provided written, informed consent after the nature of the procedure was explained to them. The patients were screened for treatment eligibility as described according to the approved indication [16]. Before treatment, the bowels of two women were located between the fibroid and the abdominal wall, potentially compromising the beam path. A third woman was diagnosed as having adenomyosis. These three patients were not treated and therefore not further analyzed. The ExAblate 2000 is integrated with a 1.5-T MRI scanner (GE Medical Systems, Milwaukee, WI), and provides real-time thermal imaging during the treatment phase of the procedure. Prior to treatment, hair is shaved from the umbilicus to the pubis to ensure acoustic coupling. The patient lies prone on the treatment table, with her abdomen lying on a gel pad situated directly above the ultrasound transducer. The patient is pre-medicated with light conscious sedation (diazepam 5 mg PO, pentazocine 15 mg IV, and hydroxyzine hydrochloride 25 mg IV) to relieve anxiety, prevent movement, and to minimize discomfort. Light sedation allows patients to communicate with the medical staff throughout the procedure. In addition, patients are given a ‘‘stop button’’ so that they can immediately stop the energy pulse in the event of pain or discomfort. To identify and measure the target lesion(s) and to evaluate the surrounding pelvic anatomy during treatment, the patient goes through an initial MR scan using T2 weighted sequences (Fig. 1A) and a pre-treatment plan is initiated by a team including a gynecologist and a radiologist. Contours of the entire targeted fibroid(s) are drawn on the MR image by the treating physician using
Fig. 1. Intramural fibroid 7 cm in diameter with associated heavy bleeding in a 44-year-old patient. MRgFUS treatment comprised 60 sonications, resulting in a %NPV of almost 100%. Fibroid was reduced by 46.6% at month 6. A and B: MR image (T2W) before and at 6 months post-treatment.
Y. Morita et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203
ExAblate System software. Based on tumor volume and depth, the system computes the energy and the number of focal energy deliveries (‘‘sonications’’) required to completely treat the defined region. The treating physician manually optimizes the plan to cover as much fibroid volume as possible to achieve maximum tumor ablation. A low-energy test sonication is first delivered to ensure the accuracy of its location. Following confirmation of the test sonication and treatment plan, the treatment phase commences with multiple sonications of approximately 20 s each, followed by an approximately 90 s cool-down. After a sonication, the patient is asked to provide verbal feedback. When sufficient portion of the tumor has been treated, T1 weighted contrast enhanced (T1W CE) images are acquired to evaluate the ratio (%) of the treated areas of the fibroid to the untreated parts by measuring the nonenhanced regions. These non-enhanced regions represent non-perfusion, where the blood supply has been cut-off due to treatment, causing tissue ablation. These slice-by-slice measurements are then converted into volumetric results, and used later to assess treatment effectiveness [16,19]. The patients were asked about subjective relief of symptoms and whether they had sought additional treatments to deal with them at 1, 3, 6 and 12 months posttreatment. In addition, T2 and T1 (with and without contrast) weighted images were acquired at 6 months of follow-up and used to determine treatment outcome (fibroid size and NPV) (see Fig. 1B). Fibroid volume and NPV during treatment and at 6 months thereafter were calculated as the mean of all 8 mm fibroid slices in three axes with visible fibroid or NPV. NPV ratio was determined as the non-perfused volume divided by the fibroid volume. Fibroid shrinkage was calculated as volume change in a fibroid between the treatment day and at the 6-month follow-up, divided by the volume at treatment day. Student’s one-sample t-test was used for statistical comparisons of mean fibroid volume between baseline and that reported at 6 months. Correspondence between fibroid shrinkage and non-perfused volume was evaluated by linear regression. The stratification of the group of patients, for which shrinkage data is available, based on NPV ratio into two statistically significant sub-groups was performed using a two-sample t-test assuming equal variance. A p value below 0.05 was considered to indicate a significant difference.
3. Results Forty-eight Japanese women aged 42.6 5.8 years (mean S.D.; range, 24–51) (Table 1) were treated using MRgFUS. Symptomology demonstrated by this patient population included heavy menstrual bleeding (30 patients, 63%), abdominal discomfort (21 patients, 44%), anemia (determined from laboratory testing: 9 patients, 19%), frequent urination (16 patients, 33%), and menstrual pain (5
201
Table 1 Baseline characteristics of treatment group Baseline demographics
All patients (n = 48)
Age (years); mean S.D. (minimum, maximum) Body mass index (kg/m2); mean S.D. (minimum, maximum) Nationality
42.6 5.8 (24, 51) 21.6 3.0 (n = 41) (17, 35)
Japanese
patients, 10%). We treated 55 fibroids with a mean (S.D.) diameter of 80.4 19.1 mm (range: 35–115 mm). In an attempt to treat the complete volume of each fibroid, five patients with large fibroids (mean S.D., 94 8 mm) required a second procedure. No serious or unexpected adverse events arose during the study. Four patients (8.3%) developed skin redness, which was considered to be related to the MRgFUS procedure. Dimethyl isopropyl azulene ointment (10 g) resolved this symptom in three of the patients within 3 days, and in the other within 1 week. One patient developed transitory sciatic neuralgia because of disc herniation at L4-L5 and L5-S1, which was confirmed by anteroposterior radiography and MRI. This was caused by an underlying disease and was not a complication of MRgFUS. It took about a month for the symptoms related to that disease to cease. Three patients (6%) had occasional severe pain during the procedure, which was managed by changing treatment parameters and an additional dose of sedation (pentazocine 15 mg IV, and hydroxyzine hydrochloride 25 mg IV) so that none of the patients aborted the treatment due to pain. All patients were followed up for the duration of 12 months, and throughout this period no additional procedure-related complications were recorded. The mean (S.D.) non-perfused volume ratio (NPV%) was 60 18% (n = 48, range, 22–100%) immediately upon completion of MRgFUS treatment. Thirty-nine patients underwent MR imaging at the 6-month follow-up visit. For these patients, the mean (S.D.) fibroid size had been reduced from baseline by 33% 19% (n = 39). This decrease was statistically significant ( p < 0.0001). The population of patients, for which shrinkage data was available at the 6-month follow-up visit, was further stratified into similar size groups, based on NPV ratio values. This additional stratification of the shrinkage data at 6 months revealed that when the NPV ratio at the end of the treatment was above 60%, the mean (S.D.) shrinkage value was 39 16% (n = 18), while that of the lower NPV group was only 27 20% (n = 21). This difference was statistically significant ( p = 0.05). Linear regression of the data regarding fibroid shrinkage at 6 months of follow-up showed that a larger treatment NPV ratio resulted in more fibroid shrinkage by 6 months ( p = 0.037; Fig. 2). The treating physician used a subjective questionnaire for patients returning for follow-up appointments. Patients were asked whether their symptoms had improved or not in the period following treatment. Seven patients (14.6%) were not
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Y. Morita et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 139 (2008) 199–203
Fig. 2. Relationship between 6 months fibroid shrinkage and treatment nonperfused volume ratio (n = 39). The points describe the patients data and the line is the linear regression ( p = 0.037).
satisfied with the outcome of the MRgFUS procedure. Three of these patients have decided not to pursue alternative forms of treatments; one resumed usage of painkillers, another continued her treatment for anemia, while the third patient was not prescribed with therapy. Regarding the other four, patients were followed up for having alternative treatments for their fibroids; two were referred to alternative forms of surgical treatments: one patient was treated with UAE, and another one with myomectomy. Two additional patients were prescribed GnRH until the onset of natural menopause. Although women seeking future pregnancies were excluded, one patient became pregnant after treatment. A 29-year-old with no previous pregnancies was treated for one intramural fibroid with a total volume of 215 cc. The estimated conception date was 4 months after the ExAblate treatment. Her pregnancy course was uneventful and on the 39th week, she vaginally delivered a normal boy weighing 3212 g with Apgar scores of 8/9. The postpartum course was uneventful [22].
4. Comments Hysterectomy has been the definitive curative option available to women with uterine fibroids for many years. This procedure is widely effective, but not without limitations. Hysterectomy is an irreversible open surgical technique with an established history of effectiveness that is tarnished predominantly by its associated morbidity. Cost, blood loss, pain, lengthy hospitalization and recovery time, and the psychological distress caused to some women due to the loss of the uterus, are some of the negative features of this procedure. Patients were followed up at 6 months for MR imaging to visualize fibroid changes. Persistent fibroid shrinkage was evident at 6 months and the amount of shrinkage closely correlated with the NPV ratio achieved during treatment. This indicates that the ablated fibroid tissue is absorbed by
the body over time, and thus translates into fibroid shrinkage. In other words, more fibroid ablation during treatment generates better outcomes. If a benchmark NPV ratio of 60% at treatment is presumed, fibroids with values higher than this will shrink by about 39% at 6 months. If an NPV ratio of 60% is not achieved during treatment (e.g. due to technical limitations), then the linear regression results imply that a larger NPV at the end of treatment will also indicate more fibroid shrinkage. At the 12-month follow-up, seven women (15%) were not satisfied with the treatment. The satisfaction feedback form used is not of a quantitative nature. However, all patients were followed up for having any additional fibroid treatment. Since all patients were seeking a treatment for their symptomatic uterine fibroids, recording their decision to get another intervention serves as a quantitative measure of efficacy, as often used to describe outcomes of minimally invasive treatment techniques [23,24]. Two patients (4%) underwent an alternative form of surgical intervention, and two more required additional non-invasive drug therapy. Albeit reporting on a small sample in this study, these results seem to be comparable to the outcome of uterine artery embolization treatments, whose interim value of 7% treatment failures is reported 1 year post-treatment [25]. Patients will be followed up for a longer term to examine the option of symptom recurrence, but these are promising results. Four cases of adverse events were reported following the treatment and all were resolved within 1 week. Three patients developed mild skin redness, which might be caused by a reaction to the gel pad interface or imperfect acoustic coupling at the skin (e.g., presence of air or hair). One patient had neuralgia that was part of an underlying condition, which was possibly exacerbated due to remaining prone for a prolonged period during the procedure. These are known adverse events that can occur after MRgFUS, and are similar to those observed in previous studies [6,19]. In conclusion, MRgFUS is an effective and safe treatment for Japanese women with uterine fibroids. The procedure has an excellent safety record and patient satisfaction is high. Fibroids significantly shrink by 6 months after treatment, and the amount of shrinkage depends on the fibroid volume treated.
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