Obstetrics & Gynecology:
Outpatient Procedure for the Treatment and Relief of Symptomatic Uterine Myomas
Chudnoff, Scott G. MD, MS; Berman, Jay M. MD; Levine, David J. MD; Harris, Micah MD; Guido, Richard S. MD; Banks, Erika MD
Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center, Einstein and Moses Divisions, Albert Einstein College of Medicine, New York, New York; the Department of Obstetrics and Gynecology, Division of Gynecology, Wayne State University School of Medicine, Detroit, Michigan; St John's Mercy Hospital, St. Louis, Missouri; Women's Health Research, Phoenix, Arizona; and the University of Pittsburgh Medical School, Magee-Women's Hospital, Pittsburgh, Pennsylvania.
Corresponding author: Scott G. Chudnoff, MD, MS, Centennial Women's Center, Montefiore Medical Center, 3332 Rochambeau Avenue, New York, NY 10467; e-mail: firstname.lastname@example.org.
Supported by Halt Medical, Brentwood, California. Drs. Chudnoff, Berman, Levine, Harris, Guido, and Banks are investigators in the ongoing study: Laparoscopic Radiofrequency Ablation of Symptomatic Uterine Myomas, which is sponsored by Halt Medical. The authors received only materials and administrative support from the sponsor to conduct the study. For a list of other members of the Halt Study Group, see the Appendix online at http://links.lww.com/AOG/A366.
Financial Disclosure All authors' institutions received clinical research support from Halt Medical. Dr. Berman is on the speaker's bureau for Merck and is a consultant for Halt Medical, receives clinical research support from, and is on the Scientific Advisory Board and speaker's bureau for Boston Scientific. Dr. Levine receives clinical research support from Idoman, Ltd. Dr. Guido receives clinical research support from Dysplasia Research and is a board member of the American Society of Colposcopy and Cervical Pathology.
The authors thank Fredrick S. Whaley, PhD, of Innovative Analytics for statistical analysis and Mimi Wainwright for research and editorial support. Halt Medical paid Innovative Analytics and Wainwright Medical Communications for their work.
Presented at the American Association of Gynecologic Laparoscopists 41st Global Congress of Minimally Invasive Gynecology, November 5-9, 2012, Las Vegas, Nevada.
OBJECTIVE: To estimate the safety and efficacy of laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of uterine myomas in symptomatic women.
METHODS: A cohort of 135 premenopausal symptomatic women with uterine myomas, uteri 14 weeks of gestation-sized or less with no single myoma exceeding 7 cm, and objectively confirmed heavy menstrual bleeding participated in this prospective, international trial of outpatient laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation. Bleeding outcomes were measured by alkaline hematin analysis at baseline and again at 3, 6, and 12 months posttreatment. Validated quality-of-life and patient satisfaction scales and objective measurements of uterine and myoma volume were conducted at 3, 6, and 12 months.
RESULTS: The mean baseline menstrual blood loss of women in the full analysis set (n=127) was 272.7±82.3 mL. At 3-, 6-, and 12-month follow-ups, mean alkaline hematin and associated menstrual blood loss decreased from baseline levels by 31.8%, 40.7%, and 38.3%, respectively (P<.001, paired t test). Symptom severity decreased from a baseline mean transformed score of 61.1 to 26.6 at 12 months postprocedure (P<.001, paired t test). Health-related quality of life improved from a mean transformed score of 37.3 at baseline to 79.5 at 12 months (P<.001, paired t test). At 12 months postprocedure, total mean myoma volume decreased from baseline by 45.1% (measured by magnetic resonance imaging). There was one serious adverse event (one of 135 [0.7%]) requiring readmission 5 weeks postprocedure and one surgical reintervention for persistent bleeding. Ninety-four percent of the women reported satisfaction with the treatment.
CONCLUSION: Radiofrequency volumetric thermal ablation of myomas is well tolerated and results in rapid recovery, high patient satisfaction, improved quality of life, and effective symptom relief.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00874029.
LEVEL OF EVIDENCE: II
In reproductive-aged women with myomas, patients commonly present with heavy menstrual bleeding, pelvic pain or pressure, dyspareunia, and urinary symptoms. In 2002, Lee1 first reported the novel use of radiofrequency ablation under laparoscopic and intraabdominal ultrasound guidance to treat patients with symptomatic myomas. Since then, several authors have reported series of both percutaneous and laparoscopic-guided radiofrequency ablation to treat symptomatic myomas.2–6 Difficulties encountered with available radiofrequency ablation devices in the ablation of myomas (principally, limited uterine myoma detection and penetration) prompted the development of the study device (Acessa) specifically for the treatment of symptomatic uterine myomas.
The purpose of this U.S. Food and Drug Administration (FDA)–approved study was to estimate the efficacy and safety of laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of uterine myomas using the study device in women with heavy menstrual bleeding. Study objectives were to compare the baseline with 12-month posttreatment measures of myoma symptom severity and quality-of-life scores (Uterine Fibroid Symptom and Quality-of-Life Questionnaire),7 uterine and myoma volume, general health outcome assessments (EuroQOL-5D Health State Index8 and Overall Treatment Evaluation survey9), and menstrual blood loss as measured by alkaline hematin analysis of women's catamenial products (pads, liners, and tampons). In addition, the incidence of device-related adverse events and surgical reintervention for heavy menstrual bleeding was analyzed.
MATERIALS AND METHODS
This study was designed as a prospective, multicenter, interventional clinical trial with primary outcome measures of change from baseline to 12 months and ongoing qualitative follow-up of women for 3 years posttreatment. Recruitment began in February 2009 with enrollment of the last patient in February 2011. All women signed informed consent and were enrolled at nine clinical sites throughout the U.S. and two clinical sites in Latin America.
All sites were required to obtain local institutional review board or independent ethics committee approval of the protocol. In addition, the FDA, the Guatemalan Ministry of Health, and the Mexican Health Ministry granted approval to conduct this study. The study (ClinicalTrials.gov Identifier: NCT00874029) was, and continues to be, conducted in accordance with general ethical principles enunciated in the Declaration of Helsinki and in conformance with applicable guidelines for Good Clinical Practices, the U.S. Code of Federal Regulations for conducting clinical studies, International Organization for Standardization 14155, and other applicable local or international regulations related to the rights and welfare of human subjects who participate in medical research, whichever provided the greater protection of the participants.
Potential women, who were self-referred or sent directly by their health care providers, were identified through a phone or in-person screening process in which information related to their age, medical history, menstrual status, and primary myoma-related complaints was recorded. Study eligibility required the following: premenopausal women, 25 years of age or older; presence of symptomatic uterine myomas, uterine size of 14 weeks of gestation or less by pelvic examination, and six or fewer treatable myomas with no single myoma exceeding 7 cm in any diameter as measured by transvaginal ultrasound; total myoma volume of 300 cm3 or less; cyclic menstrual blood loss of 160 mL or more to 500 mL or less as measured by the alkaline hematin method; a minimum of a 3-month history of menorrhagia (menstrual blood loss more than 80 mL) within the last 6 months; the desire for uterine preservation but not for future childbearing; normal coagulation profile and normal Pap test result in the last year; and hemoglobin level of 10.0 g/dL or more at the time of treatment. Women were excluded for the following: radiologic evidence by magnetic resonance imaging of adenomyosis (n=127), pedunculated subserosal or intracavitary myomas (n=43), a history of pelvic malignancy, cervical dysplasia, a prior procedure to treat or remove myomas (n=22), and contraindications to anesthesia or abdominal surgery (n=12).
Validated questionnaires (the Uterine Fibroid Symptom and Quality-of-Life Questionnaire and the EuroQol-5D) were administered at baseline and at 3, 6, and 12 months posttreatment. The Overall Treatment Evaluation questionnaire was also administered at 3, 6, and 12 months posttreatment. In addition, all women had baseline and follow-up myoma and uterine size assessments at 3-month intervals by ultrasound and 3- and 12-month contrast-enhanced magnetic resonance imaging. Collection of women's catamenial products for alkaline hematin analysis occurred at baseline, 3, 6, and 12 months posttreatment.
The study device system is comprised of a dual-function radiofrequency generator, a disposable radiofrequency 3.4-mm diameter handpiece with a deployable seven-needle electrode array and two control buttons for inputting data and modifying generator parameters, two dispersive electrode pads, extension cables, and a foot pedal.10 Each needle electrode of the array contains a thermocouple allowing continuous, real-time temperature feedback. Two side-by-side video monitors displayed the laparoscopic and ultrasonographic images.
All procedures were performed in a standardized fashion using a 5-mm or 10-mm laparoscope placed through a 5-mm or 10-mm umbilical trocar. Using a laparoscopic ultrasound transducer (Aloka) placed through a standard 10-mm or 12-mm suprapubic trocar, systematic ultrasonographic mapping of the uterus identified the location, size, and number of all myomas. The handpiece was inserted percutaneously (directly through the skin without a trocar) under laparoscopic visualization and was introduced into each myoma using ultrasonographic guidance. Based on the dimensions of the target myoma, the surgeon selected the proper deployment of the needle array, time of treatment, and generator settings as indicated by a treatment algorithm. With each deployment, ultrasonographic imaging verified that the electrode array was entirely within the capsule and at a minimum distance of 1 cm from the myoma capsule (Fig. 1A–B) in all three planes, ensuring preservation of the surrounding myometrium (Video 1 available online at http://links.lww.com/AOG/A367). For myomas measuring less than 1.5 cm in diameter, deployment of the needle array was not required. The surgeons were proficient at basic gynecologic ultrasonography but had no advanced training. They received brief preoperative simulation training in intraoperative ultrasound from the sponsor. Surgeons learned the elements of laparoscopic ultrasound and radiofrequency volumetric thermal ablation before initial surgeries and generally felt proficient in two to three procedures. No sonographers or radiologists were needed or used at any of the procedures.
A. Radiofrequency ab...Image Tools
Radiofrequency volumetric thermal ablation of myomas was carried out using a continuous, alternating current at 460 kHz with a maximum output of 200 W. After a 35- to 45-second ramp-up period, the tissue temperature reached the target of 100°C and the generator power output automatically adjusted to maintain target temperature. Once the required time at target temperature was completed, the surgeon terminated the ablation, retracted the electrode array into the probe shaft, and performed monopolar coagulation of the probe track during probe withdrawal. Visual confirmation of hemostasis was performed after each ablation. No suturing was required or performed. In cases of irregularly shaped myomas, side-by-side or overlapping ablations were performed at the surgeon's discretion. Often, multiple myomas were ablated through a single serosal puncture, and most leiomyomas less than 1 cm in greatest diameter were left untreated, as specified in the protocol. At the conclusion of the procedure, the trocar skin and fascial sites were repaired per standard surgical practice. After completion of the procedure and standard postoperative care, women were discharged on the day of treatment with instructions to return to work and normal activities as they felt able and to refrain from sexual activity (pelvic rest) for 4–6 weeks. Ibuprofen, naproxen, or celecoxib was prescribed for pain as needed.
Overview of laparosc...Image Tools
Two potential sources of bias were the collection of alkaline hematin by the women and the qualitative questions posed to the patients. The former was minimized by the evaluation of the catamenial products by a central laboratory that had no pecuniary interest in the study and the latter was minimized through the administration of standardized questionnaires by study coordinators rather than investigators.
The coprimary efficacy end points of the study were volume of menstrual bleeding and surgical reintervention at 12 months posttreatment. A sample size calculation was based on the null hypothesis of an aggressive clinical efficacy assumption of a 50% or greater menstrual blood loss reduction based on alkaline hematin levels in at least 45% of the participant population (as mandated by the FDA). Setting the α level equal to 0.05, we determined that a sample size of 135 would yield a power of 94% given the alternative hypothesis of 50% blood loss reduction in 60% of the study population. Assuming a surgical reintervention rate of no more than 25% as the null hypothesis and setting the α level equal to 0.05, a sample of 87 women would yield a power of 90% under the alternative hypothesis of a surgical reintervention rate of 11.5%. Based on these assumptions, we planned to enroll at least 135 and up to 150 women in the study. Missing data that were the result of either missed visits or loss to follow-up were not imputed.
All analyses were performed using SAS 9.2. Continuous variables for these analyses were summarized using descriptive statistics (mean, standard deviation, median, minimum, and maximum) and categorical variables were summarized by frequencies and percentages. P values <.05 were considered significant. For continuous data, P values were based on the t test, paired t test, and signed-rank test and were not adjusted for multiple comparisons. Categorical variables were analyzed using the χ2 test. Treatment-emergent adverse events were recorded starting with the induction of anesthesia and coded using MedDRA. Frequencies and percentages of the number of women reporting at least one treatment-emergent device-related adverse event were summarized. In terms of safety, the study would be successful if the device-related adverse event rate was 10% or less, a rate considered acceptable by the investigators and the scientific advisors to the sponsor.
A total of 135 women met all inclusion criteria, were enrolled, and underwent the ablation procedure. There were no cases of intraoperative exclusion; leiomyomas ranging from 0.7 to 9.7 cm in the largest diameter were treated, and insertion of the device in firm, calcified myomas was not problematic. Of the enrolled women, four were excluded from final analysis because they were unable to provide catamenial products at the 12-month follow-up visit; three women were excluded because they became pregnant; and one women was excluded after she was diagnosed with Hashimoto's disease, which could have affected her menstrual bleeding volume. Demographics of study women (n=127) are provided in Table 1. Intraoperative findings, outpatient status, and surgical reintervention over the first 12-month cycle of the study are presented in Table 2.
The objectively measured effects of laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation were seen by 3 months posttreatment followed by continued improvement to 12 months. The majority of women (81.9% [104 of 127]) showed a decrease in menstrual blood loss from baseline to 12 months posttreatment. Of the 127 women, 40.2% (95% confidence interval [CI] 31.6–48.7%) experienced at least a 50% reduction from baseline to 12 months posttreatment in their menstrual blood flow; 48.8% (95% CI 40.1–57.5%) of women experienced at least a 40% reduction; 59.1% (95% CI 50.5–67.6%) experienced at least a 30% reduction; and 67.7% (95% CI 59.6–75.8%) experienced at least a 22% reduction. Collection and changes in menstrual blood loss are presented in Table 3.
The reduction in total uterine and myoma volumes over time for each participant as determined by pretreatment and posttreatment magnetic resonance imaging was evident at the initial 3-month follow-up with continued decrease in volumes during the 9 months of subsequent follow-up visits. Total mean uterine volume decreased by 15.7% (95% CI; −20.4% to −11.0%; P<.001) at 3 months (n=119) and by 24.3% (95% CI −30.0% to −18.7%; P<.001) at 12 months (n=122). The mean myoma volume at baseline (n=124) was 80.4±84.4 cm3. At 3 months (n=114), total mean myoma volume decreased from baseline by 39.8% (95% CI −44.1% to −35.6%; P<.001) to 50.2±57.0 cm3. At 12 months (n=113), total mean myoma volume decreased by 45.1% (95% CI −51.6% to −38.6%; P<.001) to 44.9±53.5 cm3. Total uterine volume was also measured by preoperative and postoperative ultrasound. Mean decreases in total uterine volume from baseline (n=126) to 3, 6, and 12 months were observed: by 14.9% (95% CI −19.5% to −10.4%; P<.001) at 3 months (n=121), 20.6% (95% CI −26.1% to −15.0%; P<.001) at 6 months (n=122), and 24.7% (95% CI −30.4% to −19.0%; P<.001) at 12 months (n=122).
Patient-reported outcomes showed improvement at 3 months posttreatment with continued improvement through 12 months of follow-up. Symptom severity decreased from the mean transformed baseline score of 61.1±18.6 to 29.1±18.9 at 3 months (n=124), a change of −32.0 (95% CI −36.1 to −27.9; P<.001) for those women with 3-month scores and continued improving to 12 months. Health-related quality of life improved over the mean baseline value of 37.3±19.1 to 75.1±22.1 at 3 months (n=124), a change of 37.7 (95% CI 33.5–42.9; P<.001) for those women with 3-month scores and continued to improve over 12 months. Improvement in Uterine Fibroid Symptom and Quality-of-Life Questionnaire mean transformed symptom severity and health-related quality-of-life scores over time is presented in Figure 2.
Improvement in sympt...Image Tools
We observed a mean increase (improvement) in the women's EuroQol-5D Health Status score from baseline to 3, 6, and 12 months of follow-up. Respective mean EuroQol-5D scores and percent change from baseline were: baseline (n=126), 71.1±18.9; 3 months (n=122), 85.0±12.6 (Δ 14.3, 95% CI 10.3–18.2; P<.001); 6 months (n=124), 84.8±13.0 (Δ 13.7, 95% CI 10.1–17.2; P<.001); and 12 months (n=123), 85.8±14.1 (Δ 15.0, 95% CI 11.4–18.6, P<.001). The results of the Overall Treatment Evaluation surveys at 12 months (n=124) were as follows: when asked, “Overall, how satisfied were you with your uterine fibroid treatment?” 12.1% of the respondents were somewhat satisfied, 21.0% were moderately satisfied, and 61.3% were very satisfied with the treatment for a total satisfaction response of 94.4%. When asked, “In your opinion, how effective was this treatment in eliminating your symptoms?,” 94.4% of the women responded that the treatment had been somewhat (14.5%), moderately (29.8%), or very effective (50.0%) in eliminating their symptoms. Furthermore, 98% of the study women responded that they would recommend the treatment to a friend with the same health problem: 76.6% would definitely recommend the treatment and 21.0% would probably recommend the treatment. Median time to return to normal activities (excluding sexual activity, n=133) was 9 days (range 2–60 days). Those study women who reported that they were employed (n=88) missed a median of 5 days (range 0–29 days) of work postprocedure. Treated women used their own discretion for returning to work.
Device-related adverse events were reported in five women (five of 135 [3.7%], 95% CI 1.2–8.4%): a postoperative pelvic abscess in the posterior cul de sac, which required rehospitalization 5 weeks after the procedure for antibiotic treatment and a posterior colpotomy for drainage; a 2-cm laceration of the sigmoid colon serosa caused by the ultrasonographic probe, which was treated prophylactically with sutures; postprocedural vaginal bleeding treated with intravenous iron supplement; severe lower abdominal pain treated with ibuprofen; and a mild superficial uterine serosal burn, which was not treated and resolved without sequelae. One participant was lost to follow-up at 6 months and not monitored within the study; she pursued reintervention by uterine artery embolization at approximately 10 months after radiofrequency volumetric thermal ablation (one of 135 [0.7%], 95% CI <0.1–4.1%). We considered this participant a treatment failure.
The study results confirmed the hypothesis that outpatient, laparoscopic, ultrasound-guided radiofrequency volumetric thermal ablation of myomas was safe and effective in reducing uterine and myoma volumes, reducing severity of symptoms, and improving quality of life through 12 months follow-up. The posttreatment menstrual blood loss changes showed clinically and statistically significant menstrual blood loss reduction in women with heavy menstrual bleeding.
The number and variety of types of study sites—ranging from community outpatient ambulatory surgery centers to major urban teaching hospitals—as well as a geographically and ethnically diverse population with menorrhagia documented by alkaline hematin testing provided strong external factors, which validated the appropriateness of a heterogeneous participant profile and minimized potential bias of any single site. The screening process leading to enrollment was rigorous. The evaluation of both patient-reported (Uterine Fibroid Symptom and Quality-of-Life Questionnaire, EuroQOL-5D, and Overall Treatment Evaluation survey) outcomes and objective data (safety data, reinterventions, adverse events, uterine and leiomyoma volumes, and menstrual bleeding by alkaline hematin) satisfied the researchers' need for thorough evaluation of treatment outcomes of highly symptomatic patients. That favorable results were obtained from 11 sites with diverse populations and by 13 surgeons—all of whom were new to the procedure—suggests external validity and the potential for use by the general gynecologic surgeon. Potential weaknesses of the study were the uterine size limitation and the exclusion of small myomas (less than 1 cm) and women with menstrual blood loss greater than 500 mL. The effectiveness has not been tested in women with uteri larger than 14 weeks of gestation nor in women with menstrual blood loss greater than 500 mL. The protocol-specified minimum preoperative hemoglobin and hematocrit levels of 10.0 g/dL and 30%, respectively, required that some women be administered iron therapy or blood transfusions preoperatively for anemia. Thus, these measurements were not used as an indication of efficacy. This FDA-approved study was an efficacy and safety trial, was designed as a single-arm cohort, and was not randomized with a comparative arm. Because this was a population of women who did not desire future childbearing, this study was not designed to evaluate pregnancy outcomes.
It has been recommended that the clinical management of heavy menstrual bleeding be guided by subjective, patient-centered measures.11–13 Lukes et al correlated the objective and subjective outcomes of treatment with tranexamic acid (Lysteda tablets) in patients with heavy menstrual bleeding using receiver operator characteristic curve analysis as well as alkaline hematin measures.11,14 They identified the minimum change in menstrual blood loss (objectively measured by alkaline hematin) that would be meaningful to women who were assessed using the Menorrhagia Impact Questionnaire, a validated patient-reported outcome measure. The authors concluded that a reduction in menstrual blood loss of 36 mL per cycle, or a bleeding reduction of approximately 22%, was a meaningful improvement for the majority of women. Based on the findings reported by Lukes, 67.7% of our population achieved a clinically meaningful reduction in menstrual bleeding. Furthermore, patient-reported outcomes in the present study demonstrated 94% of the study population was satisfied with the treatment received.
Radiofrequency volumetric thermal ablation as described here uses laparoscopic ultrasound. The key feature to laparoscopic ultrasound lies in the inherent and immediate proximity of the transducer to the target, allowing the use of higher frequencies with significantly increased resolution.15 In addition, the versatility and mobility of laparoscopic ultrasound permits direct imaging from multiple directions and angles. The short learning curve (two to three procedures) required to manipulate the transducer while interpreting image orientation and position of the treatment probe seems within the capabilities of the gynecologic surgeon. Laparoscopic ultrasound has been evaluated in combination with myomectomy because of its high sensitivity and high resolution.16,17
The Uterine Fibroid Symptom and Quality-of-Life questionnaire has been used extensively as a validated measure of myoma treatment outcome, and results from the questionnaire are considered effective measurements of outcome even when not evaluating menstrual blood loss by alkaline hematin.18–21 None of our study women experienced symptoms similar to postuterine artery embolization syndrome (usually consisting of fever, abdominal pain, nausea, vomiting, or elevated white blood cell count, or all of these) and no women experienced delayed cervical passage of myomas or vascular compromise to other organs.
Concerns exist regarding adhesion formation, uterine integrity, and intraoperative blood loss with techniques that require myometrial suturing.22 Radiofrequency volumetric thermal ablation does not involve myometrial suturing, estimated blood loss was minimal, and surgeons were able to treat several myomas in a single serosal puncture. The decreased serosal and myometrial trauma and improved hemostasis associated with radiofrequency volumetric thermal ablation could theoretically be positive factors in minimizing the incidence of postprocedural pelvic adhesions. Ongoing evaluation and continued study of the safety of this device are important in two populations: those with larger uteri and heavier menses and those with infrequent complications. Despite the entry criteria that required all women to have completed childbearing, four women in this trial have conceived with two pregnancies ending in full-term births of healthy neonates, one pregnancy progressing uneventfully at 7 months, and one pregnancy ending in miscarriage. We are following all pregnancies in the study women; however, we do not have sufficient safety data to evaluate the use of the device in women desiring future childbearing.
A search of PubMed, PLoS, Medscape, and ClinicalTrials.gov with search terms fibroids, myomas, radiofrequency ablation, radiofrequency ablation fibroids, radiofrequency ablation myomas, radiofrequency ablation leiomyomata; English articles; from January 1990 to November 2012 showed that this is the largest trial conducted to date addressing radiofrequency volumetric thermal ablation of uterine myomas. Based on the results demonstrated in our diverse population, radiofrequency volumetric thermal ablation of uterine myomas safely achieved a high rate of patient satisfaction, a low reintervention rate, and significant improvements in menstrual blood loss, symptom severity, and quality of life through 12 months of follow-up. Both patients and the health care system share the burden of symptomatic myomas; a technology, that is safe and effective and can be administered by gynecologists is needed. Radiofrequency volumetric thermal ablation meets these needs and therefore may play a significant role in the treatment of uterine myomas.
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