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New Treatments for Uterine Fibroids
New Treatments for Uterine Fibroids Gary Siskin, MD Since the introduction of uterine artery embolization as a minimally invasive treatment option for uterine fibroids, there has been a great deal of effort made toward developing other options for these patients. These options approach the problem differently, either with direct targeting of individual fibroids, organ-wide targeting of multiple fibroids, and systemic therapy to address the problem of fibroids using a hormonal approach. This review will focus on the different techniques and different philosophies that have been applied to the treatment of fibroids during the past decade. Tech Vasc Interventional Rad 9:12-18 © 2006 Elsevier Inc. All rights reserved. KEYWORDS uterine fibroids, tumor ablation, cryoablation, ultrasound
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or decades, there was very little innovation in the treatment of uterine fibroids.1 During that time, the standard treatment for fibroids has been surgical excision and hysterectomy, primarily because it works and offers a complete solution to this problem. There have been significant advances in surgical technique to avoid the morbidity associated with laparotomy,2 including laparoscopic and hysteroscopic resection of subserosal and submucosal fibroids, respectively. However, these approaches are often not appropriate for many patients, which has prompted the search for novel treatment options for these patients.1 With the success of UAE has an alternative to surgery, it now appears that a multitude of different approaches to treat these patients have been introduced into both the literature and into current medical practice. The purpose of this article is to review the different approaches to fibroid therapy and the data supporting the use of the different techniques described.
Lesion Based Therapy The fundamental concept behind lesion-based treatment options for uterine fibroids is that fibroids represent a focal problem within the uterus that can potentially be treated by directing therapy toward one lesion at a time. The most invasive form of this therapy is myomectomy since conceptually, this procedure involves removing specific lesions and leaving the remaining portions of the uterus intact. If a less invasive approach is desired, then nonsurgical lesion-based therapy will require accurate imaging guidance to be certain that therapy is being directed at abnormal tissue with the intention of sparing as much normal uterine tissue as possible. This concept is one that is familiar to most interventional Department of Radiology, Albany Medical Center, Albany, NY. Address reprint requests to Department of Radiology, Albany Medical Center, 47 New Scotland Avenue, MC-113, Albany, NY 12208. E-mail: [email protected].
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1089-2516/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2006.08.004
radiologists who are involved with using procedures such as radiofrequency ablation, cryoablation, microwave ablation, and so forth, to treat hepatic, renal, and pulmonary malignancies. In fact, many of these interventions have been applied in limited fashion toward the treatment of uterine fibroids and the results in patients with fibroids will be reviewed in this section. The use of magnetic resonance (MR) guided, high frequency ultrasound as a treatment option for fibroids represents an exciting step forward in the area of lesion-based therapy because it has shown promise and is completely noninvasive. This procedure will be reviewed in this section as well.
Thermal Ablation A variety of thermal ablation techniques have been applied to the treatment of uterine fibroids. This includes radiofrequency ablation, cryoablation, and laser ablation. The use of radiofrequency ablation (RFA) to achieve local control of a wide variety of tumors in many locations has become more accepted in recent years. Bergamini and co-workers were the first to report the use of RFA to treat symptomatic uterine fibroids.3 In this study, 18 patients, all of whom were older than age 40 and premenopausal with fewer than 3 fibroids were treated with RFA. All of the procedures were performed under general anesthesia using the system manufactured by Rita Medical Systems (Mountain View, CA) under laparoscopic guidance. The depth of probe insertion was determined on the basis of a preoperative ultrasound examination. The operative time ranged from 20 to 40 minutes and there were no intraoperative or postoperative complications were reported. Only two patients complained of mild abdominal pain, both of who did not require analgesic drugs. All patients were observed overnight and discharged on the first postoperative day. Nine patients were available for 12-month follow-up, which demonstrated a mean fibroid volume re-
New treatments for uterine fibroids duction of 85%. The Uterine Fibroids Symptom and Quality of Life (UFS-QOL) questionnaire was used to assess clinical outcome after ablation. At 12-month follow-up the mean symptom score decreased from 43.7 to 0 and the mean QOL score increased from 66.7 to 100. Milic and co-workers reported on the outcomes of four patients undergoing RFA to treat fibroids measuring ⬍6 cm in diameter.4 In this study, the procedures were performed under general anesthesia using both laparoscopy and intraoperative ultrasound for guidance. In this study, the LeVeen Needle Electrode (Boston Scientific Corp, Natick, MA) system was used for ablation. The patients were observed for 6 hours and discharged home the same day. The procedure was technically successful in three of four patients: one patient had a firm, mobile, posterior fibroid in the lower uterine segment that could not be treated. Symptomatic relief was achieved in two of the three treated patients: the one patient with persistent postprocedure pain was later found to have adenomyosis in addition to fibroids. An MRI performed at 3 months in the three treated patients revealed lack of fibroid enhancement in all three patients. However, at 7 months, a focal area of enhancement within a treated fibroid was seen in one patient and this particular patient experienced recurrence of pain and bleeding within 9 months of the procedure. Laser myolysis was first described in 1989 by Nisolle using laparoscopic or hysteroscopic technique.5 In 1999, Law and co-workers reported on the use of MR-guided percutaneous laser ablation of uterine fibroids.6,7 In this report, 12 patients who were awaiting hysterectomy underwent this procedure. Four MR-compatible 18 g needles were placed within the fibroid under MR guidance while the patients received IV sedation. Laser fibers were then advanced into the needles and the needles were withdrawn to expose the tip of the laser fiber. Laser light at a wavelength of 810 nm was then delivered to the fibroid tissue via each laser fiber. Real-time monitoring of the thermal ablation was performed using MRI.8 The mean ablation time was 15 minutes (range, 10 –25 minutes). Eleven of the 12 patients went home on the same day: one patient chose to remain in the hospital overnight. Of the 12 treated patients, four underwent hysterectomy with well defined areas of coagulative necrosis seen within the excised fibroids. The remaining eight patients declined surgery after laser ablation and were found to have a fibroid volume reduction of 37.5% on MRI exams performed 3 months after the procedure. Law and co-workers subsequently reported their experience in their first 30 patients.9 Treatment in 29 of 30 patients was considered technically successful: one patient terminated the procedure after 12 minutes because of abdominal pain. All but one patient was discharged on the day of the procedure. Of the 30 patients treated, 26 patients declined their planned surgery with all but one of them followed with serial MRI examinations. After 3 months, the mean fibroid volume reduction was 37.5% (range, 25– 49%). All of these women reported significant symptomatic improvement. As this pilot study continued, Hindley and co-workers reported on a total of 66 patients.10 Forty-seven of these patients were followed at 3 months with an MRI, which revealed a mean fibroid volume reduction of 31% (range, 21% increase to 76% decrease). Twenty-four patients had an MRI at 12 months, which revealed a mean volume reduction of 41%.
13 All patients were noted to have a decrease in mean menstrual blood loss after treatment. In addition, the Menorrhagia Outcomes Questionnaire (MOQ), which was used to assess clinical outcomes, revealed that outcomes were not as good as those seen after hysterectomy in a historical control group but that there were no significant differences in quality of life and satisfaction between the two groups of patients. Cryoablation appears to be the lesion-based approach that has the most literature supporting its use in patients with symptomatic uterine fibroids. It is thought that cryoablation destroys tissue by several mechanisms by cooling the target tissue to ⫺20°C, which results in intracellular freezing, extracellular crystallization of interstitial water followed by cellular dehydration, thrombosis of small blood vessels, mechanical damage to cellular integrity by expansion of large ice crystals within the interstitial space.11-15 Olive and co-workers were the first to report the use of cryoablation to treat uterine fibroids.16-17 In this early report, cryoablation was performed using laparoscopic guidance on 14 patients and the authors subsequently reported a 10% fibroid volume reduction on follow-up imaging. Since then, other studies have been performed evaluating the use of laparoscopic-guided cryoablation to treat uterine fibroids. Ciavattini and co-workers treated 76 fibroids in 61 patients.18 All procedures were performed under general anesthesia and the procedure time ranged from 20 to 60 minutes. During immediate follow-up, 8.3% of patients complained of pain and 5% had a postoperative fever. There was 83.6% of patients who reported symptomatic relief after the procedure with the remaining patients reporting worsening or no change. Based on transabdominal and transvaginal ultrasound examinations performed during follow-up, the mean fibroid volume reduction was 60.3% at 12 months and 69.8% at 24 months. Importantly, none of the treated fibroids demonstrated a volume increase during follow-up. Zupi and co-workers subsequently treated 20 patients using this technique.19 All procedures were performed with general anesthesia and all patients were discharged within 24 hours. No postprocedure analgesia was required and no procedural complications were reported. During follow-up, 95% of patients reported elimination or improvement of their presenting symptoms. Using ultrasound for imaging, there was a 24.9% fibroid volume reduction at 1 month, which improved to 60% at 12 months.20 The ultrasound findings were further evaluated in 10 of these patients by Exacoustos and co-workers, who found decreased blood flow in all treated fibroids, even when peripheral surrounding vessels remained intact.21 This could be seen 1 month after treatment and remained unchanged 3 to 6 months after treatment. In addition, a hyperechoic avascular central zone was seen in 80% of treated fibroids that persisted (although reduced in size) 6 months after treatment. The first report on MR-guided cryoablation was by Sewell and co-workers who treated two patients with large symptomatic fibroids.22 Under MR guidance, a percutaneous approach was utilized to place a 10F access sheath into the targeted fibroid. A 6F cryoablation probe was then advanced through the sheath into the fibroid. Cryoablation was then performed so that the “iceball” would encompass the fibroid with minimal overlap of the surrounding myometrium. Once the cryoprobe was removed, the access sheath was filled with
14 Surgiseal for hemostasis. After 2 and 3 months, MR revealed fibroid volume reductions of 65% and 53%, respectively. Cowan and co-workers later reported a similar mean fibroid volume reduction of 65% when 9 patients were treated using similar technique.23 In this series, complications were reported including nausea requiring an overnight admission, mild foot drop because of a peroneal nerve defect that resolved after 4 months, and laceration of a vessel coursing over the serosal surface of a fibroid that led to bleeding requiring laparotomy and myomectomy. Importantly, they did note that one patient had a second large fibroid that was not initially treated but ultimately grew and required a hysterectomy, despite the fact that the treated fibroid had undergone a significant volume reduction. Sakuhara and co-workers also reported on their experience with six patients undergoing MR-guided cryoablation.24 All of these patients experienced a fever after treatment with one patient requiring surgical drainage of an abscess in the probe channel. The mean fibroid-volume reduction rate in these patients in these patients was 79.4% at 9 to 12 months. Dohi and co-workers were the first to report the use of cryoablation from a transvaginal approach to treat eight patients with symptomatic fibroids.11 Cryoprobes were introduced utilizing MR fluoroscopy for guidance under epidural and local anesthesia into the targeted fibroids using a transvaginal approach. Lower abdominal pain occurred after the procedure in three patients, which was addressed with analgesic medication. All patients were discharged on the day after the procedure. Clinically, the menstrual score improved in 75% of the patients with pain and anemia successfully addressed in all patients with these symptoms. At 6 to 7 weeks after the procedure, the mean fibroid volume reduction was 59% while at 9 to 12 months, it was 67.7% (in five patients). When evaluating this data together, irrespective of the actual technique used (laser ablation, radiofrequency ablation, or cryoablation) and the imaging modality used for guidance (laparoscopy or MRI), it appears that the short-term data are promising in terms of the ability of these procedures to improve symptoms and reduce the volume of the treated fibroids. An additional benefit of these procedures is the clear absence of significant postprocedure pain, a finding that differentiates these procedures from uterine artery embolization. This may be because of the fact that these targeted therapies are successful in limiting treatment to the fibroids and limiting the inclusion of normal myometrium in the treated area. This is therefore an advantage of this type of therapy when compared with a more organ-based treatment such as uterine artery embolization. A lesion-based approach using imaging guidance also has the additional benefit of providing an opportunity for interventional radiologists to remain involved or increase their level of involvement in the care of patients with fibroids. However, a lesion-based approach has limitations. Because each fibroid requires individually targeted therapy, there are restrictions to the number of fibroids that can be present before this would be considered an unreasonable approach. If multiple procedures are required to treat multiple fibroids, then the overall risk of utilizing this approach would be increased as well. In addition, if small fibroids are left untreated, then symptom recurrence may become a potential
Gary Siskin long-term issue. Multiple fibroids were therefore a limitation that was mentioned in many of the above-quoted studies and was often used as selection criteria for deciding which patients would be eligible for participation. Given the fact that many patients present with multiple fibroids, thermal ablation procedures may not be applicable to many of the patients with symptomatic fibroids. An additional limitation is that at this time, all of the patients described above were not evaluated with contrast-enhanced MRI. Our global experience with uterine artery embolization has emphasized the importance of utilizing contrast-enhanced MRI as the imaging modality of choice after UAE to confirm that fibroid infarction has been induced by the procedure.25 Without this information, it is not possible to know if these targeted ablation techniques result in tissue infarction. While this may open up the possibility of future recurrence it also may help explain why these patients experienced less postprocedure pain than typically seen after UAE. Therefore, additional studies with contrast enhanced MRI as the follow-up imaging modality would be required to better characterize the tissue changes induced by these procedures.
High-Frequency Ultrasound The use of MR-guided high frequency ultrasound (HIFU) to treat patients with symptomatic uterine fibroids is an exciting step forward in lesion-based therapy because it truly defines minimally invasive medicine. HIFU has been studied for over six decades and works by bringing a high-energy ultrasound beam into tight focus within a focal volume of tissue without any incisions, catheters, or other invasive techniques.26 When directed toward the target tissue, this can result in a local rise in temperature above a threshold of 56°C, which can cause thermal toxicity and coagulative necrosis leading to irreversible cell death.27 Imaging guidance during focused ultrasound surgery is important for precise target definition and control of the focal spot position.28 MRI guidance has been successful at meeting these requirements because it has excellent anatomic resolution, high sensitivity for localizing tumors, and temperature sensitivity for treatment monitoring.28 This is because several MRI parameters are temperature sensitive, allowing relatively small temperature elevations to be detected before any irreversible tissue damage.28,29 If sequential phase-shift MRIs are obtained during the procedure, these images can be compared with preprocedure images and the changes can be used to create a real-time thermal map of the increasing temperature at and close to the target.30 During these procedures, patients are placed prone on the table, on top of a water tank which contains the transducer. A coil is then wrapped around the pelvis of the patient. A gel pad placed between the patient and the water tank acts to achieve acoustic coupling. At that point, pretreatment MRI is performed to identify the volume of tissue to be treated. A path for the beam to travel toward the target volume must then be mapped out to evaluate what the beam must pass through to treat the target tissue. Low-energy test pulses, which are below the level for thermal tissue damage, are then aimed toward the target volume, to be certain that they are visible on temperature-sensitive MRI and to align the focused ultrasound system with the MRI. At this point, higher power
New treatments for uterine fibroids pulses are used to achieve the desired temperature (60 –70°C) and thermal dose within the target volume. Once this technology was shown to effectively reduce uterine fibroid tumor size in a nude mouse model,31 trials began in humans. Tempany and co-workers reported the initial feasibility data obtained on patients with symptomatic uterine fibroids.28 In this study, nine patients were treated with HIFU before a planned hysterectomy. Six of these nine patients received the entire planned thermal dose to their target fibroid. One of the remaining patients began treatment but needed it to be stopped because of pain within a scar located on her anterior abdominal wall. Another patient did not receive treatment because multiple loops of bowel were interposed between the target fibroid and the anterior abdominal wall. The third patient had their procedure stopped because the initial low-power sonications could not be detected on MRI. During the procedure, seven patients received intravenous conscious sedation and two utilized oral sedation. The room times ranged from 3 hours and 19 minutes to 4 hours and 55 minutes and the overall treatment times ranged from 1 hour to 2 hours and 32 minutes. All patients were discharged home on the day of the procedure after a short observation stay. Two patients experienced minor skin burns after the procedures (one of which had an abdominal scar). MRI performed after treatment revealed discrete areas of decreased contrast enhancement in the treated fibroids were felt to represent tissue devascularization and necrosis, findings that were confirmed after hysterectomy. Stewart and co-workers then reported on an initial multicenter experience treating 55 patients with clinically significant uterine fibroids.32 For each of these patients, one myoma was targeted for treatment. The goal of treatment was to induce coagulative necrosis within an operator-defined portion of the targeted tumor and not to cause necrosis within the entire fibroid. The median treatment time was 1 hour and 45 minutes with the mean total time in the scanner equal to 3 hours. There were 76% of patients enrolled the were able to undergo adequate FUS; some patients received no sonication because of the presence of bowel or bladder in the path of the beam and some patients received limited sonications because of an inability to visualize the low energy test pulse. Most patients reported only limited pain and discomfort after the procedure and all were treated as outpatients. Of the patients, 25% reported generalize discomfort after the procedure with most describing this as mild. Other postprocedure complaints included nausea and pain at the treatment site in 10% of patients. Posttreatment MRI scans revealed areas of nonperfusion within the treated fibroids, often times larger than expected based on treatment volumes. Hindley and co-workers and Stewart and co-workers both reported on the results from the phase III clinical trial to evaluate the MR-guided focused ultrasound therapy system known as the ExAblate 2000 (Insightec, Haifa, Israel).33,34 In this study, 176 patients were enrolled and screened and 62% (109) of these women underwent treatment at seven sites. Reasons for exclusion included failure to meet all of the inclusion and exclusion criterion including findings on the MRI such as location, size, position, or lack of contrast enhancement. For patients enrolled in this study, limitations were placed on the amount of tissue that could be treated. Margins of 1.5 cm were maintained at both the serosal and
15 mucosal borders of the uterus and coagulation volume was limited to a maximum of 100 cm3 per myoma and 150 cm3 per treatment.34 In total, 10 to 11% of the fibroid volume was treated using this protocol.32 The mean time that the patients were in the MR scanner was 202 minutes (range, 90 –370 minutes). There was 82% of patients who reported pain during the procedure although only 16% reported severe pain during the procedure. After the procedure, only 1% reported severe pain and 7% reported moderate pain. Only one patient required admission because of nausea and this was felt to be possibly related to the use of opioid analgesia rather than to the procedure itself. During follow-up, one patient complained of leg and buttock pain that was attributed to sciatic nerve palsy secondary to exposure of the sciatic nerve to the high-frequency ultrasound beam; this complication resolved by the time of her 12-month follow-up visit. Clinically, 79.3% of patients achieved a ⬎10 point reduction in the UFS-QOL questionnaire score with a mean reduction of 27.3 points. At 6 months, the mean fibroid volume reduction was 13.5% with a mean nonperfused volume of approximately 25% (that was greater than the target for treatment). It would appear that MR-guided high frequency ultrasound represents an idealized form of lesion-based therapy. To be able to target well defined areas of tissue and address them in a completely noninvasive manner while sparing a maximum amount of normal tissue should be the goal of any form of lesion-based therapy. However, as a form, albeit advanced form of lesion-based therapy, many of the same limitations that were described previously in the context of radiofrequency ablation, laser ablation, and cryoablation, can be applied to this procedure as well. The ability of this treatment to address patients with multiple fibroids may represent a significant limitation to widespread applicability. While multiple treatments are certainly possible, especially given the noninvasive nature of this therapy, the procedure times that have been required to date may be seen as a limitation, both from a patient perspective and an economic perspective when one focuses on throughput on an expensive piece of capital equipment. A second important limitation concerns the ability of this therapy to induce fibroid infarction. At the present time, only a small percentage of tissue within the targeted fibroids have been treated which means that we do not yet know how feasible it is to actually treat fibroids in their entirety and induce infarction within a completely treated fibroid. Therefore, we can only presume that with treatment times over 2 hours to treat 10% of the target fibroid, targeting fibroids in their entirety may be prohibitive and if infarction is not induced within the entire fibroid, then data obtained in the context of UAE indicates that these patients may be at risk for fibroid regrowth and symptom recurrence. That said, if nonperfused volume on MRI continues to exceed treated volume, then treating entire fibroids may not be necessary and we do also know that inducing fibroid infarction is not always necessary to achieve symptomatic relief in these patients. There is no doubt that results are extremely promising, given the completely noninvasive nature of this treatment, but future study should continue in an effort to answer these questions (that are in essence the same questions that are facing providers of UAE as well).
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Organ-Based Therapy The fundamental concept behind organ-based treatment options for uterine fibroids is that fibroids represent a diffuse problem within the uterus that can potentially be treated by directing therapy toward the entire uterus. This concept forms the basis for hysterectomy, which can be seen as the ultimate form of organ-based therapy: remove the organ and the problem is solved. This concept also forms the basis for uterine artery embolization, because embolizing both uterine arteries appears to creates an ischemic environment within the uterus that ultimately leads to fibroid infarction and symptomatic relief. The procedures that fall under the heading of organ-based therapy have to date utilized this philosophy to come up with alternative methods of reducing blood flow within the uterus arteries to induce an effect similar to UAE. In some way, this has validated the methodology that interventional radiologists have long-perceived as being an effective way to treat uterine fibroids and other tumors throughout the body. Besides uterine artery embolization, the procedures in this section include laparoscopic occlusion of the uterine arteries, laparoscopic bipolar coagulation of the uterine arteries, and transvaginal clamping of the uterine arteries. Hald and co-workers studied 46 patients undergoing either uterine artery embolization (n ⫽ 24) or laparoscopic closure of the uterine arteries (n ⫽ 22) to treat symptomatic uterine fibroids.35 The laparoscopic procedure involved identification of the uterine arteries and placement of an endoclip at the level of the internal iliac artery. The collateral arteries between the ovaries and uterus were then coagulated using bipolar forceps. Three patients undergoing laparoscopic uterine artery occlusion complained of skin sensation abnormalities and reduction of leg adduction because of the procedure affecting the obturator nerve, which was ultimately self-limited in all patients. Six months after therapy the group undergoing laparoscopic uterine artery occlusion experienced a mean fibroid volume reduction of 36.2% and a mean uterine volume reduction of 36.7% while the group undergoing UAE experienced a mean fibroid volume reduction of 45.1% and a mean uterine volume reduction of 40.1%. Postoperative pain was found to be more severe in the UAE group. Of the 16 patients available for follow-up in the laparoscopy group, 14 experienced a reduction in bleeding and were satisfied with their clinical outcome. Liu and co-workers reported on their experience with treating 87 patients with symptomatic uterine fibroids using laparoscopic bipolar coagulation of the uterine arteries.36 In these patients, laparoscopy was performed under general anesthesia. Once the uterine artery was visualized and separated from the ureter, it was desiccated using bipolar forceps under direct vision. The anastomotic sites of the uterine and ovarian arteries were coagulated as well. The procedure was technically successful in 97.7%. After the procedure, 27.6% of patients experienced lower abdominal pain that persisted for approximately 2 weeks with NSAID treatment. Symptomatic improvement was found in most patients: 93.1% of patients with menorrhagia reported improvement, 87% of patients with bladder compressive symptoms reported improvement, and 81.1% of patients with dysmenorrheal reported improvement. Of note, two patients conceived after
Gary Siskin the procedure but underwent elective termination of pregnancy at their request. Using ultrasound for imaging followup, it was found that the mean fibroid volume reduction was 76%, with greater decreases seen in fibroids ⬎5 cm in diameter compared with fibroids ⬍5 cm in diameter. Istre and co-workers presented a case report in 2004 describing the use of a Doppler-directed, transvaginal uterine artery clamp to treat a patient with symptomatic uterine fibroids.37 The system utilized consisted of a guiding cervical tenaculum, a transvaginal vascular clamp with integrated Doppler ultrasound, and a small transceiver that generates audible Doppler sound. After pretreatment with benzodiazepines, a paracervical block was performed. With the patient in the lithotomy position, a guiding cervical tenaculum was placed in the cervix and the vascular clamp was attached to this tenaculum. The clamp was then slid along the tenaculum to the level of the lateral vaginal fornices. At that point, Doppler signals from the uterine arteries were detected. When advancing the clamp further along the tenaculum displaced the arteries, the clamp was closed, occluding the uterine arteries by squeezing them along the lateral borders of the uterus. The clamp remained in place for 6 hours and was then released, with immediate return of Doppler signal from each uterine artery. This treatment resulted in an improved bleeding pattern, a 77.2% fibroid volume reduction, and a 48.9% uterine volume reduction at 3 months. Each of these procedures, in addition to uterine artery embolization, demonstrates the potential role that arterial occlusive therapy and subsequent tissue ischemia can potentially play in the treatment of patients with symptomatic uterine fibroids. However, from the perspective of an interventional radiologist, these alternative procedures are troubling in that they appear to disregard what is perceived as a fundamental understanding of tissue perfusion and ischemia induction that has been gained through more than three decades of experience with transcatheter embolization procedures. The premise is that when the level of occlusion produced during an embolization procedure within the vasculature of a target organ is distal, the potential for true tissue infarction is higher than when the level of occlusion is proximal, primarily because proximal occlusions tend to leave open the possibility of collateral flow bypassing the occlusion induced by the embolization procedure. UAE is based on this through its use of flow-directed particles that presumably occlude the uterine vasculature beyond the point where significant collaterals can become an issue. All of the procedures described produce a proximal uterine artery occlusion, and therefore leave open the possibility of collateral flow and continued perfusion. Therefore, while each of these alternative therapies presents promising data, the absence of follow-up imaging using contrast enhanced MRI is a limitation since there is no documentation that any of these procedures resulted in true fibroid infarction. It is known that fibroid ischemia, even in the absence of tissue infarction, can lead to symptomatic improvement and even uterine and fibroid volume reduction after UAE. However, it has been demonstrated that the lack of tissue infarction can predispose patients to incomplete treatment and symptomatic recurrence.25 Therefore, MRI will be needed to demonstrate tissue infarction to support the premise that a proximal uterine
New treatments for uterine fibroids artery occlusion will lead to permanent changes within the treated fibroids.
Systemic Therapy Any practitioner performing any of the above procedures must be made aware of the fact that long-term, medical management of uterine fibroids and their associated symptoms is an impending reality.2 Mifepristone (RU-486), a progesterone receptor antagonist, has shown promise in low doses at reducing both fibroid volume (40 –70%) and the incidence of abnormal uterine bleeding associated with fibroids.38,39 These effects have been shown to be accompanied by a reduction in uterine blood flow, suggesting that progesterone plays an important role in the regulation of uterine perfusion.40,41 At higher doses, unopposed estrogenic effects including a high rate of endometrial hyperplasia have been reported in association with the use of Mifepristone.41-43 Interestingly, regrowth of the fibroids has been shown to occur slowly after cessation of the medication.39 Selective progesterone receptor modulators have the potential to exert clinically relevant, tissue-selective progesterone agonist, antagonist, or partial agonist/antagonist effects on various progesterone target tissues.41 It has been shown that they can maintain estrogen secretion, decrease or not change progesterone secretion, and cause amenorrhea via a direct effect on the endometrium.41 Traditionally, estrogen has been considered essential to the development and continued viability of uterine fibroids. However, there is growing evidence that progesterone plays a key role in uterine fibroid growth and development.44-47 Asoprisnil is one example of a selective progesterone receptor modulator that has shown promise in the treatment of uterine fibroids.48 This agent has been shown to inhibit the expression of growth factors and growth factor-induced proliferation of uterine leiomyomata.49 In a phase 1 study on healthy volunteers having regular menstrual cycles, Asoprisnil suppressed menstruation in a dose-dependent manner.50,51 The dose-dependent induction of amenorrhea by Asoprisnil was then confirmed in a phase II study in patients with uterine fibroids.52 In these patients, Asoprisnil was effective in shrinking fibroids, reducing pressure symptoms, and suppressing both normal and abnormal uterine bleeding and is therefore positioned to be offered as an orally administered treatment for fibroids in the near future. While outside the scope of this article, Young and co-workers prepared a comprehensive review of potential nonhormonal therapy for fibroids and again demonstrates the work being done to seek a medical option for this patient population.53
Conclusions In conclusion, the introduction of UAE as a treatment option for patients with symptomatic fibroids has changed the landscape of fibroid therapy. It was not very long ago that articles were being written and lectures were being delivered to encourage patients and physicians to consider UAE as an alternative to surgery for uterine fibroids. With the success of UAE, others have now been seeking additional, “nonsurgical” options for these patients and the innovative attempts that have been reported during the past decade have given an
17 unprecedented amount of attention to this condition and these patients. Now, working under the premise that UAE has become an accepted treatment option for uterine fibroids, all of the procedures described in this article have all been touted as “alternatives to UAE.” Things have changed! Because of the potential for success demonstrated by many of these techniques, it is important that any interventional radiologist offering UAE be familiar with these procedures, for their own education and eye toward the future, but also to enable them to have appropriate discussions with their patients regarding the best available treatment options on a patient-by-patient basis.
References 1. Walker CL, Stewart EA: Uterine fibroids: The elephant in the room. Science 308:1589-1592, 2005 2. Munro MG: Management of leiomyomas: Is there a panacea in Pandora’s box? Fertil Steril 85:40-43, 2006 3. Bergamini V, Ghezzi F, Cromi A, et al: Laparoscopic radiofrequency thermal ablation: A new approach to symptomatic uterine myomas. Am J Obstet Gynecol 192:768-773, 2005 4. Milic A, Asch MR, Hawrylyshyn PA, et al: Laparoscopic ultrasoundguided radiofrequency ablation of uterine fibroids. Cardiovasc Intervent Radiol 29:694-698, 2006 5. Nisolle M, Smets M, Malvaux V, et al: Laparoscopic myolysis with the neodymium-ytrium aluminum garnet laser. Int J Gynaecol Surg 9: 95-99, 1993 6. Law P, Gedroyc WMW, Regan L: Magnetic-resonance guided percutaneous laser ablation of uterine fibroids. Lancet 354:2049-2050, 1999 7. Law P, Gedroyc WMW, Regan L: Magnetic resonance-guided percutaneous laser ablation of uterine fibroids. J Magn Reson Imaging 12:565570, 2000 8. Parker DL, Smith V, Sheldon P, et al: Temperature distribution measurements in two dimensional NMR imaging. Med Phys 10:321-325, 1983 9. Law P, Regan L: Interstitial thermo-ablation under MRI guidance for the treatment of fibroids. Curr Opin Obstet Gynecol 12:277-282, 2000 10. Hindley JT, Law PA, Hickey M, et al: Clinical outcomes following percutaneous magnetic resonance image guided laser ablation of symptomatic uterine fibroids. Hum Reprod 17:2737-2741, 2002 11. Dohi M, Harada J, Mogami T, et al: MR-guided transvaginal cryotherapy of uterine fibroids with a horizontal open MRI system: Initial experience. Radiat Med 22:391-397, 2004 12. Tacke J, Adam G, Haage P, et al: MR-guided percutaneous cryotherapy of the liver: In-vivo evaluation with histologic correlation in an animal model. J Magn Reson Imaging 13:50-56, 2001 13. Rubinsky B, Lee CY, Bastacky J, et al: The process of freezing and the mechanism of damage during hepatic cryosurgery. Cryobiology 27: 85-97, 1990 14. Bischof JC, Fahssi WM, Smith D, et al: A parametric study of freezing injury in ELT-3 uterine leiomyoma tumour cells. Hum Reprod 16:340348, 2001 15. Rupp CC, Nagel TC, Swanlund DK, et al: Cryothermic and hyperthermic treatments of human leiomyoma and adjacent myometrium and their implications for laparoscopic surgery. J Am Assoc Gynecol Laparosc 10:90-98, 2003 16. Olive DL, Rutherford T, Zreik T, et al: Cryomyolysis in the conservative treatment of uterine fibroids. J Am Assoc Gynecol Laparosc 3(suppl): S36, 1996 17. Zreik TG, Rutherford TJ, Palter SF, et al: Cryomyolysis, a new procedure for the conservative treatment of uterine fibroids. J Am Assoc Gynecol Laparosc 5:33-38, 1998 18. Ciavattini A, Tsiroglou D, Piccioni M, et al: Laparoscopic cryomyolysis. An alternative to myomectomy in patients with symptomatic fibroids. Surg Endosc 18:1785-1788, 2004 19. Zupi E, Piredda A, Marconi D, et al: Directed laparoscopic cryomyolysis: A possible alterantive to myomectomy and/or hysterectomy for symptomatic leiomyomas. Am J Obstet Gynecol 190:639-643, 2004
18 20. Zupi E, Marconi D, Sbracia M, et al: Directed laparoscopic cryomyolysis for symptomatic leiomyomata: One-year follow-up. J Min Inv Gynecol 12:343-346, 2005 21. Exacoustos C, Zupi E, Marconi D, et al: Ultrasound-assisted, laparoscopic cryomyolysis: Two- and three-dimensional findings before, during and after treatment. Ultrasound Obstet Gynecol 25: 393-400, 2005 22. Sewell PE, Arriola RM, Robinette L, et al: Real-time I-MR-guided cryoablation of uterine fibroids. J Vasc Interv Radiol 12:891-893, 2001 23. Cowan BD, Sewell PE, Howard JC, et al: Interventional magnetic resonance imaging cryotherapy of uterine fibroid tumors: Preliminary observation. Am J Obstet Gynecol 186:1183-1187, 2002 24. Sakuhara Y, Shimizu T, Kodama Y, et al: Magnetic resonance-guided percutaneous cryoablation of uterine fibroids: Early clinical experiences. Cardiovasc Intervent Radiol 29:552-558, 2006 25. Pelage JP, Guaou NG, Jha RC, et al: Uterine fibroid tumors: Long-term MR imaging outcome after embolization. Radiology 230:803-809, 2004 26. Lynn JG, Zwemer RL, Chick AJ, et al: A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol 26:179-183, 1942 27. Kennedy JE, Haar GR, Cranston D: High intensity focused ultrasound: Surgery of the future? Br J Radiol 76:590-599, 2003 28. Tempany CMC, Stewart EA, McDannold N, et al: MR-imaging-guided focused ultrasound surgery of uterine leiomyomas: A feasibility study. Radiology 226:897-905, 2003 29. Hynynen K, Vykhodtseva NI, Chung A, et al: Thermal effects of focused ultrasound on the brain: Determination with MR imaging. Radiology 204:247-253, 1997 30. Chung A, Jolesz FA, Hynynen K: Thermal dosimetry of a focused ultrasound beam in vivo by MRI. Med Phys 26:2017-2026, 1999 31. Vaezy S, Fujimoto VY, Walker C, et al: Treatment of uterine fibroid tumors in a nude mouse model using high-intensity focused ultrasound. Am J Obstet Gynecol 183:6-11, 2000 32. Stewart EA, Gedroyc WMW, Tempany CMC, et al: Focused ultrasound treatment of uterine fibroid tumors: Safety and feasibility of a noninvasive thermoablative technique. Am J Obstet Gynecol 189: 48-54, 2003 33. Hindley J, Gedroyc WMW, Regan L, et al: MRI guidance of focused ultrasound therapy of uterine fibroids: Early results. AJR 183:17131719, 2004 34. Stwart EA, Rabinovici J, Tempany CMC, et al: Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids. Fertil Steril 85:22-29, 2004 35. Hald K, Langebrekke A, Klow NE, et al: Laparoscopic occlusion of uterine vessels for the treatment of symptomatic uterine fibroids: Initial experience and comparison to uterine artery embolization. Am J Obstet Gynecol 190:37-43, 2004 36. Liu WM, Ng HT, Wu YC, et al: Laparoscopic bipolar coagulation of uterine vessels: A new method for treating symptomatic uterine fibroids. Fertil Steril 75:417-422, 2001
Gary Siskin 37. Istre O, Hald K, Qvigstad E: Multiple myomas treated with a temporary, noninvasive Doppler-directed transvaginal uterine artery clamp. J Am Assoc Gynecol Laparosc 11:273-276, 2004 38. Murphy AA, Kettel LM, Morales AJ, et al: Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab 76:513-517, 1993 39. Eisinger SH, Bonfiglio T, Fiscella K, et al: Twelve month safety and efficacy of low-dose mifepristone for uterine myomas. J Minim Invasive Gynecol 12:227-233, 2005 40. Reinsch RC, Murphy AA, Morales AJ, et al: The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: A prospective, randomized study. Am J Obstet Gynecol 170:1623-1628, 1994 41. Chwalisz K, Perez MC, DeManno D, et al: Selective progresterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocrine Reviews 26:423-438, 2005 42. Murphy AA, Kettel LM, Morales AJ, et al: Endometrial effects of longterm low-dose administration of RU-486. Fertil Steril 63:761-766, 1995 43. Eisinger SH, Meldrum S, Fiscella K, et al: Low-dose mifepristone for uterine leiomyomata. Obstet Gynecol 101:243-250, 2003 44. Brandon DD, Bethea CL, Strawn EY, et al: Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas. Am J Obstet Gyncol 169:78-85, 1993 45. Harrison-Woolrych ML, Charnock-Jones DS, Smith SK: Quantification of messenger ribonucleic acid for epidermal growth factor in human myometrium and leiomyomata using reverse transcriptase polymerase chain reaction. J Clin Endocrinol Metab 78:1179-1184, 1994 46. Maruo T, Matsuo H, Samoto T, et al: Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 65:585-592, 2000 47. Maruo T, Matsuo H, Shimomura Y, et al: Effects of progesterone on growth factor expression in human uterine leiomyoma. Steroids 68: 817-824, 2003 48. Bachmann G: Expanding treatment options for women with symptomatic uterine leiomyomas: Timely medical breakthroughs. Fertil Steril 85:46-47, 2006 49. Wang J, Ohara N, Wang Z, et al: A novel selective progesterone receptor modulator asoprisnil (J867) downregulates the expression of EGF, IGF-I, TGFbeta3, and their receptors in cultured uterine leiomyoma cells. Hum Reprod 21:1869-1877, 2006 50. Chwalisz K, DeManno D, Garg R, et al: Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata. Semin Reprod Med 22:113-119, 2004 51. Chwalisz K, Elger W, McCrary K, et al: Reversible suppression of menstruation in normal women irrespective of the effect on ovulation with the noval selective progesterone receptor modulator (SPRM) J867. J Soc Gynecol Investig 9(suppl):abstract 49, 2002 52. Chwalisz K, Parker L, Williamson S: Treatment of uterine leiomyomas with the novel selective progesterone receptor modulator (SPRM). J Soc Gynecol Investig 10:abstract 301A, 2003 53. Young SL, Al-Hendy A, Copland JA: Potential nonhormonal therapeutics for medical treatment of leiomyomas. Semin Reprod Med 22:121130, 2004
F
or decades, there was very little innovation in the treatment of uterine fibroids.1 During that time, the standard treatment for fibroids has been surgical excision and hysterectomy, primarily because it works and offers a complete solution to this problem. There have been significant advances in surgical technique to avoid the morbidity associated with laparotomy,2 including laparoscopic and hysteroscopic resection of subserosal and submucosal fibroids, respectively. However, these approaches are often not appropriate for many patients, which has prompted the search for novel treatment options for these patients.1 With the success of UAE has an alternative to surgery, it now appears that a multitude of different approaches to treat these patients have been introduced into both the literature and into current medical practice. The purpose of this article is to review the different approaches to fibroid therapy and the data supporting the use of the different techniques described.
Lesion Based Therapy The fundamental concept behind lesion-based treatment options for uterine fibroids is that fibroids represent a focal problem within the uterus that can potentially be treated by directing therapy toward one lesion at a time. The most invasive form of this therapy is myomectomy since conceptually, this procedure involves removing specific lesions and leaving the remaining portions of the uterus intact. If a less invasive approach is desired, then nonsurgical lesion-based therapy will require accurate imaging guidance to be certain that therapy is being directed at abnormal tissue with the intention of sparing as much normal uterine tissue as possible. This concept is one that is familiar to most interventional Department of Radiology, Albany Medical Center, Albany, NY. Address reprint requests to Department of Radiology, Albany Medical Center, 47 New Scotland Avenue, MC-113, Albany, NY 12208. E-mail: [email protected].
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1089-2516/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2006.08.004
radiologists who are involved with using procedures such as radiofrequency ablation, cryoablation, microwave ablation, and so forth, to treat hepatic, renal, and pulmonary malignancies. In fact, many of these interventions have been applied in limited fashion toward the treatment of uterine fibroids and the results in patients with fibroids will be reviewed in this section. The use of magnetic resonance (MR) guided, high frequency ultrasound as a treatment option for fibroids represents an exciting step forward in the area of lesion-based therapy because it has shown promise and is completely noninvasive. This procedure will be reviewed in this section as well.
Thermal Ablation A variety of thermal ablation techniques have been applied to the treatment of uterine fibroids. This includes radiofrequency ablation, cryoablation, and laser ablation. The use of radiofrequency ablation (RFA) to achieve local control of a wide variety of tumors in many locations has become more accepted in recent years. Bergamini and co-workers were the first to report the use of RFA to treat symptomatic uterine fibroids.3 In this study, 18 patients, all of whom were older than age 40 and premenopausal with fewer than 3 fibroids were treated with RFA. All of the procedures were performed under general anesthesia using the system manufactured by Rita Medical Systems (Mountain View, CA) under laparoscopic guidance. The depth of probe insertion was determined on the basis of a preoperative ultrasound examination. The operative time ranged from 20 to 40 minutes and there were no intraoperative or postoperative complications were reported. Only two patients complained of mild abdominal pain, both of who did not require analgesic drugs. All patients were observed overnight and discharged on the first postoperative day. Nine patients were available for 12-month follow-up, which demonstrated a mean fibroid volume re-
New treatments for uterine fibroids duction of 85%. The Uterine Fibroids Symptom and Quality of Life (UFS-QOL) questionnaire was used to assess clinical outcome after ablation. At 12-month follow-up the mean symptom score decreased from 43.7 to 0 and the mean QOL score increased from 66.7 to 100. Milic and co-workers reported on the outcomes of four patients undergoing RFA to treat fibroids measuring ⬍6 cm in diameter.4 In this study, the procedures were performed under general anesthesia using both laparoscopy and intraoperative ultrasound for guidance. In this study, the LeVeen Needle Electrode (Boston Scientific Corp, Natick, MA) system was used for ablation. The patients were observed for 6 hours and discharged home the same day. The procedure was technically successful in three of four patients: one patient had a firm, mobile, posterior fibroid in the lower uterine segment that could not be treated. Symptomatic relief was achieved in two of the three treated patients: the one patient with persistent postprocedure pain was later found to have adenomyosis in addition to fibroids. An MRI performed at 3 months in the three treated patients revealed lack of fibroid enhancement in all three patients. However, at 7 months, a focal area of enhancement within a treated fibroid was seen in one patient and this particular patient experienced recurrence of pain and bleeding within 9 months of the procedure. Laser myolysis was first described in 1989 by Nisolle using laparoscopic or hysteroscopic technique.5 In 1999, Law and co-workers reported on the use of MR-guided percutaneous laser ablation of uterine fibroids.6,7 In this report, 12 patients who were awaiting hysterectomy underwent this procedure. Four MR-compatible 18 g needles were placed within the fibroid under MR guidance while the patients received IV sedation. Laser fibers were then advanced into the needles and the needles were withdrawn to expose the tip of the laser fiber. Laser light at a wavelength of 810 nm was then delivered to the fibroid tissue via each laser fiber. Real-time monitoring of the thermal ablation was performed using MRI.8 The mean ablation time was 15 minutes (range, 10 –25 minutes). Eleven of the 12 patients went home on the same day: one patient chose to remain in the hospital overnight. Of the 12 treated patients, four underwent hysterectomy with well defined areas of coagulative necrosis seen within the excised fibroids. The remaining eight patients declined surgery after laser ablation and were found to have a fibroid volume reduction of 37.5% on MRI exams performed 3 months after the procedure. Law and co-workers subsequently reported their experience in their first 30 patients.9 Treatment in 29 of 30 patients was considered technically successful: one patient terminated the procedure after 12 minutes because of abdominal pain. All but one patient was discharged on the day of the procedure. Of the 30 patients treated, 26 patients declined their planned surgery with all but one of them followed with serial MRI examinations. After 3 months, the mean fibroid volume reduction was 37.5% (range, 25– 49%). All of these women reported significant symptomatic improvement. As this pilot study continued, Hindley and co-workers reported on a total of 66 patients.10 Forty-seven of these patients were followed at 3 months with an MRI, which revealed a mean fibroid volume reduction of 31% (range, 21% increase to 76% decrease). Twenty-four patients had an MRI at 12 months, which revealed a mean volume reduction of 41%.
13 All patients were noted to have a decrease in mean menstrual blood loss after treatment. In addition, the Menorrhagia Outcomes Questionnaire (MOQ), which was used to assess clinical outcomes, revealed that outcomes were not as good as those seen after hysterectomy in a historical control group but that there were no significant differences in quality of life and satisfaction between the two groups of patients. Cryoablation appears to be the lesion-based approach that has the most literature supporting its use in patients with symptomatic uterine fibroids. It is thought that cryoablation destroys tissue by several mechanisms by cooling the target tissue to ⫺20°C, which results in intracellular freezing, extracellular crystallization of interstitial water followed by cellular dehydration, thrombosis of small blood vessels, mechanical damage to cellular integrity by expansion of large ice crystals within the interstitial space.11-15 Olive and co-workers were the first to report the use of cryoablation to treat uterine fibroids.16-17 In this early report, cryoablation was performed using laparoscopic guidance on 14 patients and the authors subsequently reported a 10% fibroid volume reduction on follow-up imaging. Since then, other studies have been performed evaluating the use of laparoscopic-guided cryoablation to treat uterine fibroids. Ciavattini and co-workers treated 76 fibroids in 61 patients.18 All procedures were performed under general anesthesia and the procedure time ranged from 20 to 60 minutes. During immediate follow-up, 8.3% of patients complained of pain and 5% had a postoperative fever. There was 83.6% of patients who reported symptomatic relief after the procedure with the remaining patients reporting worsening or no change. Based on transabdominal and transvaginal ultrasound examinations performed during follow-up, the mean fibroid volume reduction was 60.3% at 12 months and 69.8% at 24 months. Importantly, none of the treated fibroids demonstrated a volume increase during follow-up. Zupi and co-workers subsequently treated 20 patients using this technique.19 All procedures were performed with general anesthesia and all patients were discharged within 24 hours. No postprocedure analgesia was required and no procedural complications were reported. During follow-up, 95% of patients reported elimination or improvement of their presenting symptoms. Using ultrasound for imaging, there was a 24.9% fibroid volume reduction at 1 month, which improved to 60% at 12 months.20 The ultrasound findings were further evaluated in 10 of these patients by Exacoustos and co-workers, who found decreased blood flow in all treated fibroids, even when peripheral surrounding vessels remained intact.21 This could be seen 1 month after treatment and remained unchanged 3 to 6 months after treatment. In addition, a hyperechoic avascular central zone was seen in 80% of treated fibroids that persisted (although reduced in size) 6 months after treatment. The first report on MR-guided cryoablation was by Sewell and co-workers who treated two patients with large symptomatic fibroids.22 Under MR guidance, a percutaneous approach was utilized to place a 10F access sheath into the targeted fibroid. A 6F cryoablation probe was then advanced through the sheath into the fibroid. Cryoablation was then performed so that the “iceball” would encompass the fibroid with minimal overlap of the surrounding myometrium. Once the cryoprobe was removed, the access sheath was filled with
14 Surgiseal for hemostasis. After 2 and 3 months, MR revealed fibroid volume reductions of 65% and 53%, respectively. Cowan and co-workers later reported a similar mean fibroid volume reduction of 65% when 9 patients were treated using similar technique.23 In this series, complications were reported including nausea requiring an overnight admission, mild foot drop because of a peroneal nerve defect that resolved after 4 months, and laceration of a vessel coursing over the serosal surface of a fibroid that led to bleeding requiring laparotomy and myomectomy. Importantly, they did note that one patient had a second large fibroid that was not initially treated but ultimately grew and required a hysterectomy, despite the fact that the treated fibroid had undergone a significant volume reduction. Sakuhara and co-workers also reported on their experience with six patients undergoing MR-guided cryoablation.24 All of these patients experienced a fever after treatment with one patient requiring surgical drainage of an abscess in the probe channel. The mean fibroid-volume reduction rate in these patients in these patients was 79.4% at 9 to 12 months. Dohi and co-workers were the first to report the use of cryoablation from a transvaginal approach to treat eight patients with symptomatic fibroids.11 Cryoprobes were introduced utilizing MR fluoroscopy for guidance under epidural and local anesthesia into the targeted fibroids using a transvaginal approach. Lower abdominal pain occurred after the procedure in three patients, which was addressed with analgesic medication. All patients were discharged on the day after the procedure. Clinically, the menstrual score improved in 75% of the patients with pain and anemia successfully addressed in all patients with these symptoms. At 6 to 7 weeks after the procedure, the mean fibroid volume reduction was 59% while at 9 to 12 months, it was 67.7% (in five patients). When evaluating this data together, irrespective of the actual technique used (laser ablation, radiofrequency ablation, or cryoablation) and the imaging modality used for guidance (laparoscopy or MRI), it appears that the short-term data are promising in terms of the ability of these procedures to improve symptoms and reduce the volume of the treated fibroids. An additional benefit of these procedures is the clear absence of significant postprocedure pain, a finding that differentiates these procedures from uterine artery embolization. This may be because of the fact that these targeted therapies are successful in limiting treatment to the fibroids and limiting the inclusion of normal myometrium in the treated area. This is therefore an advantage of this type of therapy when compared with a more organ-based treatment such as uterine artery embolization. A lesion-based approach using imaging guidance also has the additional benefit of providing an opportunity for interventional radiologists to remain involved or increase their level of involvement in the care of patients with fibroids. However, a lesion-based approach has limitations. Because each fibroid requires individually targeted therapy, there are restrictions to the number of fibroids that can be present before this would be considered an unreasonable approach. If multiple procedures are required to treat multiple fibroids, then the overall risk of utilizing this approach would be increased as well. In addition, if small fibroids are left untreated, then symptom recurrence may become a potential
Gary Siskin long-term issue. Multiple fibroids were therefore a limitation that was mentioned in many of the above-quoted studies and was often used as selection criteria for deciding which patients would be eligible for participation. Given the fact that many patients present with multiple fibroids, thermal ablation procedures may not be applicable to many of the patients with symptomatic fibroids. An additional limitation is that at this time, all of the patients described above were not evaluated with contrast-enhanced MRI. Our global experience with uterine artery embolization has emphasized the importance of utilizing contrast-enhanced MRI as the imaging modality of choice after UAE to confirm that fibroid infarction has been induced by the procedure.25 Without this information, it is not possible to know if these targeted ablation techniques result in tissue infarction. While this may open up the possibility of future recurrence it also may help explain why these patients experienced less postprocedure pain than typically seen after UAE. Therefore, additional studies with contrast enhanced MRI as the follow-up imaging modality would be required to better characterize the tissue changes induced by these procedures.
High-Frequency Ultrasound The use of MR-guided high frequency ultrasound (HIFU) to treat patients with symptomatic uterine fibroids is an exciting step forward in lesion-based therapy because it truly defines minimally invasive medicine. HIFU has been studied for over six decades and works by bringing a high-energy ultrasound beam into tight focus within a focal volume of tissue without any incisions, catheters, or other invasive techniques.26 When directed toward the target tissue, this can result in a local rise in temperature above a threshold of 56°C, which can cause thermal toxicity and coagulative necrosis leading to irreversible cell death.27 Imaging guidance during focused ultrasound surgery is important for precise target definition and control of the focal spot position.28 MRI guidance has been successful at meeting these requirements because it has excellent anatomic resolution, high sensitivity for localizing tumors, and temperature sensitivity for treatment monitoring.28 This is because several MRI parameters are temperature sensitive, allowing relatively small temperature elevations to be detected before any irreversible tissue damage.28,29 If sequential phase-shift MRIs are obtained during the procedure, these images can be compared with preprocedure images and the changes can be used to create a real-time thermal map of the increasing temperature at and close to the target.30 During these procedures, patients are placed prone on the table, on top of a water tank which contains the transducer. A coil is then wrapped around the pelvis of the patient. A gel pad placed between the patient and the water tank acts to achieve acoustic coupling. At that point, pretreatment MRI is performed to identify the volume of tissue to be treated. A path for the beam to travel toward the target volume must then be mapped out to evaluate what the beam must pass through to treat the target tissue. Low-energy test pulses, which are below the level for thermal tissue damage, are then aimed toward the target volume, to be certain that they are visible on temperature-sensitive MRI and to align the focused ultrasound system with the MRI. At this point, higher power
New treatments for uterine fibroids pulses are used to achieve the desired temperature (60 –70°C) and thermal dose within the target volume. Once this technology was shown to effectively reduce uterine fibroid tumor size in a nude mouse model,31 trials began in humans. Tempany and co-workers reported the initial feasibility data obtained on patients with symptomatic uterine fibroids.28 In this study, nine patients were treated with HIFU before a planned hysterectomy. Six of these nine patients received the entire planned thermal dose to their target fibroid. One of the remaining patients began treatment but needed it to be stopped because of pain within a scar located on her anterior abdominal wall. Another patient did not receive treatment because multiple loops of bowel were interposed between the target fibroid and the anterior abdominal wall. The third patient had their procedure stopped because the initial low-power sonications could not be detected on MRI. During the procedure, seven patients received intravenous conscious sedation and two utilized oral sedation. The room times ranged from 3 hours and 19 minutes to 4 hours and 55 minutes and the overall treatment times ranged from 1 hour to 2 hours and 32 minutes. All patients were discharged home on the day of the procedure after a short observation stay. Two patients experienced minor skin burns after the procedures (one of which had an abdominal scar). MRI performed after treatment revealed discrete areas of decreased contrast enhancement in the treated fibroids were felt to represent tissue devascularization and necrosis, findings that were confirmed after hysterectomy. Stewart and co-workers then reported on an initial multicenter experience treating 55 patients with clinically significant uterine fibroids.32 For each of these patients, one myoma was targeted for treatment. The goal of treatment was to induce coagulative necrosis within an operator-defined portion of the targeted tumor and not to cause necrosis within the entire fibroid. The median treatment time was 1 hour and 45 minutes with the mean total time in the scanner equal to 3 hours. There were 76% of patients enrolled the were able to undergo adequate FUS; some patients received no sonication because of the presence of bowel or bladder in the path of the beam and some patients received limited sonications because of an inability to visualize the low energy test pulse. Most patients reported only limited pain and discomfort after the procedure and all were treated as outpatients. Of the patients, 25% reported generalize discomfort after the procedure with most describing this as mild. Other postprocedure complaints included nausea and pain at the treatment site in 10% of patients. Posttreatment MRI scans revealed areas of nonperfusion within the treated fibroids, often times larger than expected based on treatment volumes. Hindley and co-workers and Stewart and co-workers both reported on the results from the phase III clinical trial to evaluate the MR-guided focused ultrasound therapy system known as the ExAblate 2000 (Insightec, Haifa, Israel).33,34 In this study, 176 patients were enrolled and screened and 62% (109) of these women underwent treatment at seven sites. Reasons for exclusion included failure to meet all of the inclusion and exclusion criterion including findings on the MRI such as location, size, position, or lack of contrast enhancement. For patients enrolled in this study, limitations were placed on the amount of tissue that could be treated. Margins of 1.5 cm were maintained at both the serosal and
15 mucosal borders of the uterus and coagulation volume was limited to a maximum of 100 cm3 per myoma and 150 cm3 per treatment.34 In total, 10 to 11% of the fibroid volume was treated using this protocol.32 The mean time that the patients were in the MR scanner was 202 minutes (range, 90 –370 minutes). There was 82% of patients who reported pain during the procedure although only 16% reported severe pain during the procedure. After the procedure, only 1% reported severe pain and 7% reported moderate pain. Only one patient required admission because of nausea and this was felt to be possibly related to the use of opioid analgesia rather than to the procedure itself. During follow-up, one patient complained of leg and buttock pain that was attributed to sciatic nerve palsy secondary to exposure of the sciatic nerve to the high-frequency ultrasound beam; this complication resolved by the time of her 12-month follow-up visit. Clinically, 79.3% of patients achieved a ⬎10 point reduction in the UFS-QOL questionnaire score with a mean reduction of 27.3 points. At 6 months, the mean fibroid volume reduction was 13.5% with a mean nonperfused volume of approximately 25% (that was greater than the target for treatment). It would appear that MR-guided high frequency ultrasound represents an idealized form of lesion-based therapy. To be able to target well defined areas of tissue and address them in a completely noninvasive manner while sparing a maximum amount of normal tissue should be the goal of any form of lesion-based therapy. However, as a form, albeit advanced form of lesion-based therapy, many of the same limitations that were described previously in the context of radiofrequency ablation, laser ablation, and cryoablation, can be applied to this procedure as well. The ability of this treatment to address patients with multiple fibroids may represent a significant limitation to widespread applicability. While multiple treatments are certainly possible, especially given the noninvasive nature of this therapy, the procedure times that have been required to date may be seen as a limitation, both from a patient perspective and an economic perspective when one focuses on throughput on an expensive piece of capital equipment. A second important limitation concerns the ability of this therapy to induce fibroid infarction. At the present time, only a small percentage of tissue within the targeted fibroids have been treated which means that we do not yet know how feasible it is to actually treat fibroids in their entirety and induce infarction within a completely treated fibroid. Therefore, we can only presume that with treatment times over 2 hours to treat 10% of the target fibroid, targeting fibroids in their entirety may be prohibitive and if infarction is not induced within the entire fibroid, then data obtained in the context of UAE indicates that these patients may be at risk for fibroid regrowth and symptom recurrence. That said, if nonperfused volume on MRI continues to exceed treated volume, then treating entire fibroids may not be necessary and we do also know that inducing fibroid infarction is not always necessary to achieve symptomatic relief in these patients. There is no doubt that results are extremely promising, given the completely noninvasive nature of this treatment, but future study should continue in an effort to answer these questions (that are in essence the same questions that are facing providers of UAE as well).
16
Organ-Based Therapy The fundamental concept behind organ-based treatment options for uterine fibroids is that fibroids represent a diffuse problem within the uterus that can potentially be treated by directing therapy toward the entire uterus. This concept forms the basis for hysterectomy, which can be seen as the ultimate form of organ-based therapy: remove the organ and the problem is solved. This concept also forms the basis for uterine artery embolization, because embolizing both uterine arteries appears to creates an ischemic environment within the uterus that ultimately leads to fibroid infarction and symptomatic relief. The procedures that fall under the heading of organ-based therapy have to date utilized this philosophy to come up with alternative methods of reducing blood flow within the uterus arteries to induce an effect similar to UAE. In some way, this has validated the methodology that interventional radiologists have long-perceived as being an effective way to treat uterine fibroids and other tumors throughout the body. Besides uterine artery embolization, the procedures in this section include laparoscopic occlusion of the uterine arteries, laparoscopic bipolar coagulation of the uterine arteries, and transvaginal clamping of the uterine arteries. Hald and co-workers studied 46 patients undergoing either uterine artery embolization (n ⫽ 24) or laparoscopic closure of the uterine arteries (n ⫽ 22) to treat symptomatic uterine fibroids.35 The laparoscopic procedure involved identification of the uterine arteries and placement of an endoclip at the level of the internal iliac artery. The collateral arteries between the ovaries and uterus were then coagulated using bipolar forceps. Three patients undergoing laparoscopic uterine artery occlusion complained of skin sensation abnormalities and reduction of leg adduction because of the procedure affecting the obturator nerve, which was ultimately self-limited in all patients. Six months after therapy the group undergoing laparoscopic uterine artery occlusion experienced a mean fibroid volume reduction of 36.2% and a mean uterine volume reduction of 36.7% while the group undergoing UAE experienced a mean fibroid volume reduction of 45.1% and a mean uterine volume reduction of 40.1%. Postoperative pain was found to be more severe in the UAE group. Of the 16 patients available for follow-up in the laparoscopy group, 14 experienced a reduction in bleeding and were satisfied with their clinical outcome. Liu and co-workers reported on their experience with treating 87 patients with symptomatic uterine fibroids using laparoscopic bipolar coagulation of the uterine arteries.36 In these patients, laparoscopy was performed under general anesthesia. Once the uterine artery was visualized and separated from the ureter, it was desiccated using bipolar forceps under direct vision. The anastomotic sites of the uterine and ovarian arteries were coagulated as well. The procedure was technically successful in 97.7%. After the procedure, 27.6% of patients experienced lower abdominal pain that persisted for approximately 2 weeks with NSAID treatment. Symptomatic improvement was found in most patients: 93.1% of patients with menorrhagia reported improvement, 87% of patients with bladder compressive symptoms reported improvement, and 81.1% of patients with dysmenorrheal reported improvement. Of note, two patients conceived after
Gary Siskin the procedure but underwent elective termination of pregnancy at their request. Using ultrasound for imaging followup, it was found that the mean fibroid volume reduction was 76%, with greater decreases seen in fibroids ⬎5 cm in diameter compared with fibroids ⬍5 cm in diameter. Istre and co-workers presented a case report in 2004 describing the use of a Doppler-directed, transvaginal uterine artery clamp to treat a patient with symptomatic uterine fibroids.37 The system utilized consisted of a guiding cervical tenaculum, a transvaginal vascular clamp with integrated Doppler ultrasound, and a small transceiver that generates audible Doppler sound. After pretreatment with benzodiazepines, a paracervical block was performed. With the patient in the lithotomy position, a guiding cervical tenaculum was placed in the cervix and the vascular clamp was attached to this tenaculum. The clamp was then slid along the tenaculum to the level of the lateral vaginal fornices. At that point, Doppler signals from the uterine arteries were detected. When advancing the clamp further along the tenaculum displaced the arteries, the clamp was closed, occluding the uterine arteries by squeezing them along the lateral borders of the uterus. The clamp remained in place for 6 hours and was then released, with immediate return of Doppler signal from each uterine artery. This treatment resulted in an improved bleeding pattern, a 77.2% fibroid volume reduction, and a 48.9% uterine volume reduction at 3 months. Each of these procedures, in addition to uterine artery embolization, demonstrates the potential role that arterial occlusive therapy and subsequent tissue ischemia can potentially play in the treatment of patients with symptomatic uterine fibroids. However, from the perspective of an interventional radiologist, these alternative procedures are troubling in that they appear to disregard what is perceived as a fundamental understanding of tissue perfusion and ischemia induction that has been gained through more than three decades of experience with transcatheter embolization procedures. The premise is that when the level of occlusion produced during an embolization procedure within the vasculature of a target organ is distal, the potential for true tissue infarction is higher than when the level of occlusion is proximal, primarily because proximal occlusions tend to leave open the possibility of collateral flow bypassing the occlusion induced by the embolization procedure. UAE is based on this through its use of flow-directed particles that presumably occlude the uterine vasculature beyond the point where significant collaterals can become an issue. All of the procedures described produce a proximal uterine artery occlusion, and therefore leave open the possibility of collateral flow and continued perfusion. Therefore, while each of these alternative therapies presents promising data, the absence of follow-up imaging using contrast enhanced MRI is a limitation since there is no documentation that any of these procedures resulted in true fibroid infarction. It is known that fibroid ischemia, even in the absence of tissue infarction, can lead to symptomatic improvement and even uterine and fibroid volume reduction after UAE. However, it has been demonstrated that the lack of tissue infarction can predispose patients to incomplete treatment and symptomatic recurrence.25 Therefore, MRI will be needed to demonstrate tissue infarction to support the premise that a proximal uterine
New treatments for uterine fibroids artery occlusion will lead to permanent changes within the treated fibroids.
Systemic Therapy Any practitioner performing any of the above procedures must be made aware of the fact that long-term, medical management of uterine fibroids and their associated symptoms is an impending reality.2 Mifepristone (RU-486), a progesterone receptor antagonist, has shown promise in low doses at reducing both fibroid volume (40 –70%) and the incidence of abnormal uterine bleeding associated with fibroids.38,39 These effects have been shown to be accompanied by a reduction in uterine blood flow, suggesting that progesterone plays an important role in the regulation of uterine perfusion.40,41 At higher doses, unopposed estrogenic effects including a high rate of endometrial hyperplasia have been reported in association with the use of Mifepristone.41-43 Interestingly, regrowth of the fibroids has been shown to occur slowly after cessation of the medication.39 Selective progesterone receptor modulators have the potential to exert clinically relevant, tissue-selective progesterone agonist, antagonist, or partial agonist/antagonist effects on various progesterone target tissues.41 It has been shown that they can maintain estrogen secretion, decrease or not change progesterone secretion, and cause amenorrhea via a direct effect on the endometrium.41 Traditionally, estrogen has been considered essential to the development and continued viability of uterine fibroids. However, there is growing evidence that progesterone plays a key role in uterine fibroid growth and development.44-47 Asoprisnil is one example of a selective progesterone receptor modulator that has shown promise in the treatment of uterine fibroids.48 This agent has been shown to inhibit the expression of growth factors and growth factor-induced proliferation of uterine leiomyomata.49 In a phase 1 study on healthy volunteers having regular menstrual cycles, Asoprisnil suppressed menstruation in a dose-dependent manner.50,51 The dose-dependent induction of amenorrhea by Asoprisnil was then confirmed in a phase II study in patients with uterine fibroids.52 In these patients, Asoprisnil was effective in shrinking fibroids, reducing pressure symptoms, and suppressing both normal and abnormal uterine bleeding and is therefore positioned to be offered as an orally administered treatment for fibroids in the near future. While outside the scope of this article, Young and co-workers prepared a comprehensive review of potential nonhormonal therapy for fibroids and again demonstrates the work being done to seek a medical option for this patient population.53
Conclusions In conclusion, the introduction of UAE as a treatment option for patients with symptomatic fibroids has changed the landscape of fibroid therapy. It was not very long ago that articles were being written and lectures were being delivered to encourage patients and physicians to consider UAE as an alternative to surgery for uterine fibroids. With the success of UAE, others have now been seeking additional, “nonsurgical” options for these patients and the innovative attempts that have been reported during the past decade have given an
17 unprecedented amount of attention to this condition and these patients. Now, working under the premise that UAE has become an accepted treatment option for uterine fibroids, all of the procedures described in this article have all been touted as “alternatives to UAE.” Things have changed! Because of the potential for success demonstrated by many of these techniques, it is important that any interventional radiologist offering UAE be familiar with these procedures, for their own education and eye toward the future, but also to enable them to have appropriate discussions with their patients regarding the best available treatment options on a patient-by-patient basis.
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