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Vascular and Interventional Radiology |
1 From the Departments of Radiology (F.M.F., C.M.T., N.J.M., M.J.S., K.H., F.A.J.) and Obstetrics and Gynecology (E.A.S.), Harvard Medical School/Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; Departments of Radiology (G.H.) and Obstetrics and Gynecology (B.G.), Mayo Clinic, Rochester, Minn; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Md (H.S.K.); Department of Radiology, Lahey Clinic, Burlington, Mass (G.A.H.); and Radnet Management, Los Angeles, Calif (D.A.S.). From the 2005 RSNA Annual Meeting. Received February 10, 2006; revision requested April 12; revision received July 17; accepted August 23; final version accepted October 4. Supported by InSightec, Haifa, Israel. Supported by National Institutes of Health grants 5R25CA089017-05 (F.A.J., M.J.S.), 5P01CA067165-08 (F.A.J.), and 1U41RR019703-01A2 (F.A.J.). F.M.F. supported by GE AUR Radiology Research Academic Fellowship. Address correspondence to F.M.F. (e-mail: ffennessy{at}partners.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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Materials and Methods: This prospective clinical trial was approved by institutional review boards and was HIPAA compliant. After giving informed consent, patients with symptomatic leiomyomas were consecutively enrolled and treated at one of five U.S. centers by using an original or a modified protocol. Outcomes were assessed with the symptom severity score (SSS) obtained at baseline and 3, 6, and 12 months after treatment. Adverse events (AEs) were recorded. Statistical analysis included Student t test, Fisher exact test, analysis of covariance, Spearman correlation, and logistic regression.
Results: One hundred sixty patients had a mean SSS of 62.1 ± 16.3 (standard deviation) at baseline, which decreased to 35.5 ± 19.5 at 3 months (P < .001) and to 32.3 ± 19.8 at 6 months (P < .001) and was 32.7 ± 21.0 at 12 months (P < .001). Ninety-six patients (mean age, 46.0 years ± 4.6) were treated with an original protocol, and 64 (mean age, 45.9 years ± 3.9) were treated with a modified protocol. Patients in the modified group had a significantly greater SSS decrease at 3 months (P = .037) than those in the original group, and 73% of those in the original group and 91% of those in the modified group reported a significant decrease in SSS (of 10 points or greater) at 12 months. No serious AEs were recorded. Fewer AEs were reported in the modified group than in the original group (25% vs 13% reporting no event). Of evaluable patients, fewer in the modified group chose alternative treatment (28%) than in the original group (37%).
Conclusion: MR imaging–guided focused ultrasound surgery results in symptomatic improvement, sustained to 12 months after treatment. Treatment with a modified protocol results in greater clinical effectiveness and fewer AEs.
© RSNA, 2007
Clinical trial registration no. IDE G020001-Protocol UF005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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As a noninvasive technique for treatment of uterine leiomyomas, MR imaging–guided focused ultrasound surgery has been shown to result in focal well-defined areas of protein denaturation and coagulative necrosis while sparing overlying and surrounding tissues (10,11). This technique provides precise targeting of the beam and has been demonstrated to be well tolerated, feasible, and safe (10,11). Results of initial studies have demonstrated substantial fibroid-related symptom reduction at 6 months, with more than 70% of women reporting improvement in their symptoms (12,13), which was sustained in 51% of women at 12 months (13). The purpose of our study was to prospectively assess patient response (after 12 months) to MR imaging–guided focused ultrasound surgery in the treatment of uterine leiomyomas by using two different treatment protocols.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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This was a prospective phase III multicenter clinical trial, which was approved by all local institutional review boards. All patients gave informed consent after the nature of the MR imaging–guided focused ultrasound surgery procedure and our study was explained to them. All patients treated were part of a continued access study, which was an extension of a pivotal trial (to determine treatment effectiveness and to monitor for complications) of MR imaging–guided focused ultrasound surgery in the treatment of uterine fibroids, once preliminary evidence from the pivotal study showed this technique to be likely effective and without important safety concerns. In this study, some patients were treated according to the original treatment guidelines used in the pivotal trial, and some were treated according to modified guidelines. This study was Health Insurance Portability and Accountability Act compliant.
Patients
Patients seeking treatment for symptomatic leiomyomas at one of five U.S. clinical centers (in Boston, Mass; Rochester, Minn; Baltimore, Md; Los Angeles, Calif; Burlington, Mass) were considered. The eligibility criteria for enrollment in this study have been previously described (12,13) and included adult premenopausal women with no future childbearing plans. Pregnant women, postmenopausal women, and those with MR imaging contraindications were excluded. The anterior abdominal wall of women who had previously undergone abdominal surgery was examined for scars, and if these were extensive or thought to be in the path of the ultrasound beam, these patients were excluded because of increased risk of skin burns (14).
Clinical Selection
Suitable candidates were asked to complete an eight-item section of a uterine fibroid symptom and quality of life (UFSQOL) questionnaire (15) to determine a symptom severity score (SSS). Components were scored on a five-point Likert scale, with responses ranging from "not at all" to "a very great deal." An SSS score of 21 of 40 possible points, as a reflection of substantial fibroid-related symptoms at enrollment, was required for entry into the clinical trial. Age, body mass index, hormonal (pre- or postmenopausal) status, and the presence of chronic medical disease were recorded for each patient. These demographics were compared between patients treated according to original guidelines and those treated according to modified guidelines.
Pretreatment Imaging
After documentation of a negative pregnancy test result, all patients were evaluated with MR imaging performed by using a standard imaging protocol. Imaging was performed with a 1.5-T MR system (Signa; GE Healthcare, Milwaukee, Wis) with an LX computer platform with version 8.3 or higher software, by using a receive-only pelvic coil (USA Instruments, Aurora, Ohio). Initial three-plane localizer images with a large field of view were obtained first. Standard T2-weighted fast spin-echo images, T1-weighted spin-echo images, and multiphase fat-suppressed T1-weighted spoiled gradient-recalled-echo images were obtained before and after intravenous injection of gadopentetate dimeglumine (0.1 mmol per kilogram of body weight) (Magnevist; Berlex Laboratories, Wayne, NJ). Parameters for the T1- and T2-weighted and spoiled gradient-recalled-echo MR images have been previously described (10). All MR images were obtained at 1.5 T by using the same protocol.
MR images were analyzed to determine the number, size, and location of uterine leiomyomas, to evaluate for contrast enhancement within the leiomyomas, and to exclude other causes of reported symptoms such as adenomyosis. Patients without MR evidence of fibroids or with extensive abdominal wall scarring were not deemed eligible. Image analysis of the ultrasound beam path was performed in all patients to evaluate for possible obstructions to treatment, such as bowel loops anterior to the uterus at the level of the uterine fibroid. Pretreatment MR images were also used to select leiomyoma(s) to be treated. If there were multiple leiomyomas, clinical symptoms and accessibility of target leiomyomas were reviewed in detail and target leiomyoma(s) were selected. We attempted to select the leiomyoma that was most likely to explain the dominant symptom.
Treatment Protocols
Consecutive patients were treated in the continued access study from April 2003 to December 2004. Prior to April 30, 2004, they were treated according to original treatment guidelines, and after April 30, 2004, they were treated according to modified treatment guidelines (Table 1), subsequent to Food and Drug Administration satisfaction with results in those treated by using original guidelines and Food and Drug Administration approval of less restrictive treatment guidelines. The goal of treatment was to deliver therapeutic sonications to as large an area as possible according to treatment guidelines to induce a subsequent large area of nonperfusion. In patients treated according to modified guidelines, it was recorded if a second treatment was deemed necessary, and treatment was performed within guidelines.
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Patient Preparation
All patients were instructed to shave the hair of the anterior abdominal wall from the umbilicus to the superior aspect of the pubic bone and were asked not to use creams on the skin to allow maximal skin coupling with the ultrasound beam. Women arrived at the radiology department in a fasting state and with a companion to escort them home. On arrival, a urine-based pregnancy test was performed, and an intravenous line and Foley catheter were inserted. Informed consent was obtained for use of intravenous conscious sedation (fentanyl citrate and midazolam hydrochloride), per hospital guidelines. Patient preparation and monitoring during treatment was performed (10–13). A registered nurse was in the room with the patient at all times. The patient could press an emergency stop button during the treatment, which allowed her to terminate any single sonication should she be required to do so. Radiologists (F.M.F., C.M.T., M.J.S., G.H., G.A.H., D.A.S.) supervised the procedures and anesthesia administration.
The patient was in the magnet in the prone position, and the anterior abdominal wall was placed over the transducer-containing water tank. The pelvic coil was mounted on the water tank (5,10). The relationship between the fibroid and the transducer was checked by using three-plane localizer images with a large field of view, and the patient was repositioned if necessary. The pelvis was imaged by using T2-weighted fast spin-echo images in transverse, coronal, and sagittal planes, which were transferred to the system workstation.
Treatment
The volume to be ablated was delineated by one of seven radiologists (F.M.F., C.M.T., M.J.S., G.H., H.S.K., G.A.H., D.A.S.) on a selected coronal T2-weighted image by using the system software. The years of experience of these radiologists with MR procedures ranged from 3 to 15 years. Equally spaced individual sonications were then placed such that the entire target volume was covered. The system software allowed display of all the individual sonications superimposed on all tissues through which it would pass, in three orthogonal planes. The beam path was reviewed, and care was taken to ensure safe passage to avoid any contact with bowel loops and remain a safe distance from the sacrum. If necessary, the transducer beam could be tilted up to 20° to provide a suitable pathway. The sonication spot size could be altered in power, frequency, diameter, and length to ablate the outlined volume in as few sonications as possible. Locations of the planned sonications could be changed if any patient motion occurred during the procedure.
Once planning was complete, low-energy sonications were delivered to confirm correct anatomic location (5,10). The power was then increased until the temperature-sensitive images displayed a therapeutic focus. Sonications were typically all delivered in the same coronal plane. Sonication duration was typically 16–20 seconds, followed by 90–120 seconds of cooling time. The patient gave constant feedback regarding any symptoms after each sonication. This, in addition to image-based feedback, was routinely used to modify the sonication parameters so that each sonication achieved a sufficient thermal dose without causing discomfort. Thermometric results provided immediate measurement of thermal dose, and repeated sonications could be performed as necessary.
Thermal Map Acquisition
Phase-subtraction fast spoiled gradient-recalled-echo imaging was used to monitor temperature elevations and construct temperature maps (2) during treatment sonications. Each sonication was monitored with MR imaging, which was timed to coincide with the deposition of thermal energy (5,10). The first image was triggered 5 seconds before the sonication to create a baseline image. During the heating and early cooling phase, multiple images were created every few seconds in a single imaging plane. The MR imaging unit was programmed to construct the magnitude, real, and imaginary images for each imaging time point, which were used to calculate phase subtraction between two imaging time points (6). If MR thermometric results indicated that the thermal dose delivered was insufficient or that temperatures were too low, the power was increased. The sonication frequency was altered as deemed necessary, according to patient anatomy and/or reported pain during sonications.
Posttreatment Follow-up
Immediately after completion of treatment, MR imaging with administration of intravenous gadopentetate dimeglumine was performed to assess the therapeutic effect, or nonperfused volume (NPV). Patients were evaluated and released from the medical center and returned within 1 week for clinical evaluation. At 3 months after the procedure, a phone interview was conducted with patients. At 6 and 12 months after the procedure, patients returned for clinical evaluation (E.A.S.) and underwent repeat MR imaging examination. At all three time points (3, 6, and 12 months), the effect of treatment on leiomyoma-related symptoms was assessed by completion of a self-assessment UFSQOL questionnaire. The 3-month questionnaire was completed at home, and the patient called in her answers to the clinic by telephone. The 6- and 12-month questionnaires were completed at the clinic. If data for a time point were acquired outside a protocol-specified allowance, the patient was considered nonevaluable and their data for that specific time point were not used for this study. Patients did, however, remain in the study for data collection at future time points. There was a 2-week window allowance for the 3-month follow-up, a 3-week window allowance for the 6-month follow-up, and a 6-week window allowance for the 12-month follow-up. The number of patients in the study population who were followed up to all time points was recorded. In addition, the numbers of patients whose data were obtained but were obtained outside the window allowance for follow-up, who were overdue or not yet due for follow-up, who were lost to follow-up, and who had chosen alternative treatment for their uterine fibroids at each specific time point were recorded.
The primary end point of the study was improvement in SSS, according to the UFSQOL questionnaire, from baseline. SSSs were obtained and transformed to create a summed comparable score (15). The SSS assesses menorrhagia and bulk-related symptoms on a single 100-point scale, with higher scores indicating worse symptoms. In the initial validation UFSQOL questionnaire, patients with uterine fibroids had a mean score of 44.0, while a reference control population had a mean score of 22.5 (15). The SSS will, however, vary depending on the severity of fibroids in the population in question. SSS at baseline and at 3, 6, and 12 months after treatment was obtained. The rate of improvement in SSS from baseline to 3, 6, and 12 months after treatment was calculated and compared between patients treated according to original and those treated according to modified guidelines by using analysis of covariance. In addition, the percentage of patients with a 10-point improvement in the transformed SSS was calculated. A 10-point improvement is consistent with a clinical improvement and was the primary end point of the pivotal study of the evaluation of MR imaging–guided focused ultrasound surgery on uterine fibroids (12,13). The odds of a 10-point improvement in SSS in those with a greater NPV (
30% vs <30%) were calculated.
At each time point, all adverse events (AEs) were documented. Serious AEs were defined according to Standard Code of Federal Regulation definitions for use of an investigational product (17). AEs were reported to the institutional review board and the Food and Drug Administration as required. AEs were classified as not important or important (lasting more than 14 days). Important AEs were classified according to severity (mild, moderate, or severe).
MR Data Analyses
MR images from all five medical centers were sent to a core laboratory, where baseline total fibroid volume load (ie, total volume of all fibroids per patient at baseline) and NPV were measured. Fibroid volume load and NPV were outlined by an independent MR radiologist (with 20 years of experience in genitourinary MR imaging) in a core laboratory. The fibroid volume load was calculated on standard T2-weighted fast spin-echo images. NPV immediately after treatment was calculated on coronal spoiled gradient-recalled-echo images after administration of gadopentetate dimeglumine and was defined as the area of nonenhancement within the uterine fibroid. Commercially available software (ProVision; Algotec, Rochester, NY) was used to calculate volume. The outlines of the leiomyomas and nonenhancing treated areas were contoured with electronic calipers to compute the area per section. The volume was computed by multiplying the sum of the measured areas by the distance between the centers of two consecutive images. NPV as a percentage of fibroid load at treatment was also calculated.
Statistical Analysis
Baseline age, body mass index, and total fibroid volume load were compared by using a two-sample t test assuming unequal variance. Race (white vs nonwhite), hormonal status, and history of chronic medical disease were compared by using the Fisher exact test. The number of patients who did not report any AEs in each treatment group was also compared by using the Fisher exact test. The transformed SSS was expressed as mean ± standard deviation. Student one-sample t tests were used for statistical comparisons of mean SSS at baseline and that reported at 3, 6, and 12 months for both protocol groups. Analysis of covariance was used to compare the mean change in SSS at 3, 6, and 12 months between patients treated according to the original protocol and those treated according to the modified protocol. Linear regression analysis and Spearman correlation were used to evaluate for a correlation between SSS change and treatment NPV. Software (SAS; SAS Institute, Cary, NC) was used for all data analysis. A P value of less than .05 was considered to indicate a significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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There was no significant difference in age (P = .84), body mass index (P = .12), race (P = .59), hormonal status (P > .999), or underlying chronic medical disease status (P = .8) between the two treatment groups (Table 4). There was no significant difference (P = .1) in total fibroid volume load between those treated according to original guidelines (385.0 cm3 ± 284.1 [mean ± standard deviation]; range, 41.6–1588.8 cm3) and those treated according to the modified protocol (498.4 cm3 ± 345.0; range, 18.1–1351.0 cm3).
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Safety: AEs
No serious AEs were reported. A total of 290 AEs was recorded (mean, 1.8 AEs per patient) in the entire study population. In the original treatment group, 13% of patients reported no AE, which increased to 25% in the modified treatment group. This difference was not significant (P = .06).
In the original treatment group, two important AEs (ie, ones that did not resolve without sequelae within 14 days) were reported. One patient reported paresthesia at the site of the intravenous cannula that resolved within 6 weeks. A second patient reported mild sonication-related leg pain, which resolved within 2 days, but was nonetheless considered important for Food and Drug Administration reporting. No important events were reported in the modified treatment group.
All other AEs were not important, the most common being pain or discomfort related either to position within the magnet or uterine discomfort due to sonications; these AEs occurred in 54% and 47% of patients treated according to the original and modified protocols, respectively (Table 6).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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In the total population evaluable in this continued access study, 79.2% and 78% of patients treated reported a 10-point or greater improvement in SSS at 6 and 12 months after treatment, respectively. This result demonstrates a sustained response in a far greater number of patients in comparison to that in the pivotal study (13), in which only 51% of patients were reported to have a significant clinical response at 12 months.
The overall significant decrease in mean SSS from 62.1 at baseline to 32.7 at 12 months after treatment also confirms the durability of response. We do, however, recognize that longer-term follow-up and evaluation are indicated. These processes are currently underway, and data collection at 24 and 36 months is in progress.
Optimization of treatment protocol by expansion of treatment guidelines resulted in a far greater number of evaluable patients (91%) reporting a significant clinical response at 12 months after treatment. Symptom reduction occurred early, with a significant decrease seen at 3 months after treatment. A significantly greater reduction in symptom score at 3 months was seen in patients treated according to the modified treatment protocol than in those treated according to the original protocol. While this difference in symptom reduction was not significantly greater at 6 and 12 months, this may reflect the smaller number of patients in each group at the later time points, and continued follow-up is warranted. The apparent trend is for those treated according to the modified protocol to maintain a greater symptom reduction.
Assuming treatment failure in those lost to follow-up, there was a smaller percentage of patients seeking alternative treatment at 6 and 12 months after MR imaging–guided focused ultrasound surgery performed according to the modified protocol than after MR imaging–guided focused ultrasound surgery performed according to the original protocol. Although the number of women followed up to 12 months is small (particularly in the modified protocol group) and longer-term follow-up is essential, these findings point toward a trend for better clinical outcome and increased patient satisfaction when larger volumes of tissue are ablated.
This conclusion is further supported by the relationship between SSS change at 6 months and NPV after treatment. The correlation is stronger in patients with larger volumes treated according to the modified protocol. The implication of this finding is that greater clinical symptom reduction is likely achieved with maximal NPV. Therefore, we believe that it is an important goal to treat as much tissue as feasible and as safely as possible in each woman.
We recognize that the decrease in SSS 12 months after uterine artery embolization is greater (from 58.61 to 19.23) (19) than that after MR imaging–guided focused ultrasound surgery. However, treatment guideline limitations with MR imaging–guided focused ultrasound surgery (and subsequent relatively small NPV as a percentage of total fibroid volume load) should be taken into account when the difference in the decrease in SSS with MR imaging–guided focused ultrasound surgery is being weighed against that with uterine artery embolization. Future technical improvements in MR imaging–guided focused ultrasound surgery, which would allow for a greater NPV, may provide greater SSS decrease.
While the modified guidelines may explain our results, there may be factors such as experience, familiarity with the device, and better patient preparation and education that play a role. The number of AEs reported in the entire population was 290 (mean, 1.8 AE per patient). This number is decreased when compared with that in the pivotal trial, in which 271 AEs were recorded in 109 treated patients (mean, 2.5 AEs per patient) (20). Improved patient selection, enhanced explanation of the procedure to the patient, continuous communication with the patient and the treating physician during the procedure, and optimization of fibroid targeting and thermometry all likely contributed to the reduction of AEs.
An important limitation of this study was that this was a single treatment-arm trial. Patients were not randomly assigned into treatment with MR imaging–guided focused ultrasound surgery or accepted alternatives, such as hysterectomy or uterine artery embolization; therefore, direct comparison with these accepted forms of therapy cannot be done. We also do not have a no-treatment control arm to confirm lack of symptom change in those not receiving treatment. Although we are continuing to follow up patients to 12 months and beyond to 24 and 36 months, another important limitation was the small number of patients currently evaluable at 12 months and the reporting of outcomes in symptom relief on the basis of data in the evaluable population. Longer-term follow-up and use of an intent-to-treat population to report sustainability of response to treatment and the number of patients seeking alternative treatments is required.
In summary, in this study, we demonstrate sustained symptom improvement at 12 months, confirm the reproducibility of MR imaging–guided focused ultrasound surgery for uterine leiomyomas, and demonstrate that treatment according to a modified protocol results in a greater clinical response and a decrease in the number of patients seeking alternative treatment and the number of AEs reported.
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ADVANCES IN KNOWLEDGE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: AE = adverse event • NPV = nonperfused volume • SSS = symptom severity score • UFSQOL = uterine fibroid symptom and quality of life
See Materials and Methods for pertinent disclosures.
Author contributions: Guarantor of integrity of entire study, F.M.F.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, F.M.F., C.M.T., E.A.S.; clinical studies, all authors; statistical analysis, F.M.F., C.M.T., E.A.S.; and manuscript editing, F.M.F., C.M.T., N.J.M., G.H., H.S.K., K.H., F.A.J., E.A.S.
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References |
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