Radiofrequency Volumetric Thermal Ablation of Fibroids and Laparoscopic Myomectomy: Long-Term Follow-up From a Randomized Trial.

! Aims: Laparoscopic myomectomy (LM) has been the gold standard treatment for uterine fibroids in women desiring uterine conservation. To eval- uate a new fibroid treatment modality – radiofre- quency volumetric thermal ablation (RFVTA) – we compare 12-month results in women who had symptomatic uterine fibroids and who were randomized to laparoscopic ultrasound-guided RFVTA or LM.

Our study is a 1 : 1 paral- lel, randomized, prospective, single-center, longi- tudinal, comparative analysis of RFVTA to LM for fibroid treatment in women ≥ 18 years of age who desired uterine conservation. Fifty women were randomized intraoperatively to RFVTA (n = 25) or to LM (n = 25) after laparoscopic ultra- sound mapping of the uterus.

Post surgery, ablation and myomectomy subjects took pain medications for 4 days (range: 1– 46) and 7 days (range: 1 – 83 days) respectively (p = 0.60). Ablation and myomectomy subjects missed 10.0 workdays (range: 2 – 86 days) and 17.0 workdays (range: 7 – 30 days) (p = 0.28), re- sumed normal activities in 20.5 days (range: 5 – 103 days) versus 28.0 days (range: 10 – 42 days) (p = 0.86) respectively. Mean symptom severity scores decreased (improved) by − 7.8 for the abla- tion subjects and by − 17.9 for the myomectomy subjects (p = 0.16). Health-related quality of life improved (increased) by 7.5 and 13.1, respectively, for the two groups (p = 0.46). Two myomectomy subjects had pregnancies that ended in a Cesarean delivery and a vaginal delivery of healthy infants. Two pregnancies in the RFVTA group ended in full-term vaginal deliveries of healthy infants.

Early postoperative recovery and twelve-month results attest to similar clinical benefits from RFVTA and LM. Zusammenfassung ! Zielsetzung: Die laparoskopische Enukleation von Myomen (LM) war bislang der Goldstandard bei Frauen mit Wunsch nach Uteruserhalt. Wir evaluieren die ultraschallgesteuerte thermale vo- lumetrische Radiofrequenzablation (RFVTA) als eine neue Therapieoption: die 12-Monats-Ergeb- nisse von Patientinnen, die aufgrund symptoma- tischer Uterusmyome in die Therapiearme RFVTA oder LM randomisiert wurden, werden vergli- chen.

und Methoden: Es handelt sich um eine 1 : 1 parallele, longitudinale, randomisiert pro- spektive Single-Center-Vergleichsanalyse zwi- schen RFVTA und LM bei Frauen ≥ 18 Jahren mit Wunsch nach Uteruserhalt. Nach laparoskopisch gesteuertem Ultraschall-Mapping des Uterus wurden insgesamt 50 Frauen intraoperativ in die beiden Arme RFVTA (n = 25) oder LM (n = 25) ran- domisiert. Ergebnisse: Nach Ablation und Myomektomie nahmen die Patientinnen für 4 (1 – 46 d) bzw. 7 Tage (1– 83 d) Schmerzmittel ein (p = 0,60), fehl- ten 10 (2 – 86 d) bzw. 17 Arbeitstage (7 – 30 d) (p = 0,28) und kehrten nach 20,5 (5 – 103 d) vs. 28,0 Tagen (10 – 42 d) (p = 0,86) wieder zu ihren normalen Aktivitäten zurück. Im Mittel sank der Schweregrad der Symptome um − 7,8 (RFVTA) und um − 17,9 (LM) (p = 0,16). Die gesundheits- bezogene Lebensqualität verbesserte sich um 7,5 bzw 13,1 (p = 0,46). Zwei Schwangerschaften tra- ten nach Myomektomie ein und resultierten in einer Sectio und einer vaginalen Entbindung mit unauffälligen Kindern. Zwei Schwangerschaften im RFVTA ‑Arm führten zu vaginalen Spontanpar- tus ebenfalls unauffälliger Neugeborener. Conclusio: Die rasche postoperative Erholungs- phase und die 12-Monats-Ergebnisse lassen auf einen ähnlichen klinischen Nutzen der neuen RFVTA-Methode im Vergleich zur LM schließen. * Joint senior author. Radiofrequency Volumetric Thermal Ablation of Fibroids and Laparoscopic Myomectomy: Long-Term Follow-up From a Randomized Trial Radiofrequenz-volumetrische Thermoablation von Myomen und Laparo- skopische Myomektomie: Langzeit-Follow-up einer randomisierten Studie Authors M. Hahn 1, S. Brucker 1, D. Kraemer 1, M. Wallwiener 2, F.-A. Taran 1, C. W. Wallwiener 1*, B. Krämer 1* Affiliations 1 Department of Obstetrics and Gynecology, University of Tübingen, Tübingen 2 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg Key words l" radiofrequency volumetric thermal ablation l " laparoscopic myomectomy l" fibroids l" laparoscopic ultrasound l" Acessa Schlüsselwörter l" Radiofrequenz‑volu- metrische Thermoablation l" laparoskopische Myomektomie l " Myome l" laparoskopischer Ultraschall l" Acessa received 19. 1. 2015 revised 20. 3. 2015 accepted 20. 3. 2015

DOI http://dx.doi.org/ 10.1055/s-0035-1545931 Geburtsh Frauenheilk 2015; 75: 442–449 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0016‑5751 Correspondence Prof. Dr. Markus Hahn University Hospital Tübingen Obstetrics and Gynecology Calwerstraße 7 72076 Tübingen markus.hahn@ med.uni-tuebingen.de 442 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 GebFra Science Précis ! Twelve-month qualitative results indicate similar efficacy, quality of life, and safety for both laparoscopic ultrasound-guided radio- frequency volumetric thermal ablation of fibroids and laparo- scopic myomectomy.

! Hysterectomy for symptomatic fibroid treatment is prevalent in parts of Europe and in the United States [1]. However, European and U. S. patients are increasingly seeking uterine-sparing ther- apy and fertility conservation [2]. Minimally invasive options – such as ultrasound-guided laparoscopic myomectomy, uterine artery embolization, and magnetic resonance-guided focused ul- trasound – are becoming popular among patients and their gyne- cologists [3]. Laparoscopic myomectomy (LM) has long been con- sidered the gold standard treatment of symptomatic uterine fi- broids in women desiring uterine conservation and fertility [4 – 6]. Advantages of LM over abdominal myomectomy include re- duced blood loss, decreased postoperative pain, shorter hospital stay, and more rapid recovery [7]. However, the technical chal- lenges of multilayer laparoscopic suturing require skill and expe- rience, as well as extirpation of any deep intramural fibroids or fibroids located near the fallopian tubes with consequent uterot- omy and myometrial scars. A newer minimally invasive, outpatient, uterine-sparing ap- proach to fibroid treatment has been described in the literature: laparoscopic radiofrequency volumetric thermal ablation (RFVTA, the Acessa ™ Procedure, Halt Medical, Inc., Brentwood, California USA) [8– 10]. Previously reported 3-month results from a large, multicenter trial of RFVTA were predictive of near- and long-term clinical outcomes [9]. Brucker et al. recently reported mean times to discharge from the hospital following RFVTA and LM (ClinicalTrials.gov Identifier: NCT01750008) [11]. Their study confirmed significantly shorter mean hospitalization for subjects undergoing RFVTA compared to those undergoing LM. The purpose of this follow-up to Brucker et al.ʼs earlier report [11] is to analyze, compare and describe that study ʼs 3-, 6-, and 12- month outcomes in terms of pain medication use, recovery from surgery, and subjectsʼ subjective responses to validated question- naires.

! Study design This 1 : 1 parallel randomized, prospective, single-center, longitu- dinal, comparative study of clinical and safety outcomes after lap- aroscopic ultrasound-guided RFVTA and ultrasound-guided lap- aroscopic myomectomy was designed for women ≥ 18 years of age with uterine sizes of < 16 gestational weeks, who had symp- tomatic fibroids (< 10 cm in any diameter) detected by transvagi- nal ultrasound, and who desired uterine conservation and pres- ervation of fertility [11]. Exclusion criteria applied to those wom- en who: were contraindicated for laparoscopic surgery and/or general surgery, were known to have significant intra-abdominal adhesions, had an implanted intrauterine or fallopian tube con- traceptive device, had chronic pelvic pain not due to fibroids, had known or suspected endometriosis or adenomyosis, had ac- tive (or a history of) pelvic inflammatory disease, had a history of (or evidence of) gynecologic malignancy or premalignancy with- in the past 5 years, had a cervical myoma, or had one or more completely intracavitary submucous fibroids or only type 0/1 submucous fibroids that are better treated via hysteroscopic

[11]. Subjects were recruited from referral gynecologists beginning in mid-2012 in Germany, and study subjects were enrolled at the Womenʼs Hospital at the University of Tübingen between No- vember 1, 2012 and June 30, 2013. The University of Tübingen Local Ethics Committee approved the protocol. An independent third party (CenTrial GmbH, Tübingen, Germany) monitored the data and an independent biostatistics company (Innovative Ana- lytics, Kalamazoo, Michigan USA) analyzed all monitored data. The 50 enrolled women were informed of the purpose of the study, study testing, expected duration of 60 months of follow- up, and potential risks and benefits of participation. They were treated at Tübingen University Women ʼs Hospital in Tübingen, Germany. Intraoperative treatment randomization and operative technique Randomization occurred as an intraoperative step following con- tact laparoscopic ultrasound mapping of the uterus; the latter provided classification, size, and location of all fibroids within the uterus. Once each subject ʼs fibroids were mapped and re- corded on the treatment case report form, the surgeon, who up to this point was blinded as to which treatment method would be assigned – RFVTA or LM – drew an envelope containing the subjectʼs treatment assignment ( l " Fig. 1). The assignments were computer-generated in blocks of 6 or 4 by an independent bio- statistics company (Innovative Analytics, Kalamazoo, Michigan USA). Brucker et al. have described the treatment approaches in detail [11]. Briefly, subjects randomized to LM received the standard surgical procedure in the lithotomy position. Two-layer suturing was used, as a standard of care, only for deep intramural fibroids or for those without endometrial or serosal distortion ( l " Fig. 2 a). Though not a protocol exclusion, surgeons performing LM chose not to excise small (1.0 – 1.5-cm diameter) deep intramural fi- broids. Subjects undergoing RFVTA first had 3 – 5 core tissue needle biop- sies from their largest fibroid and the samples were sent to pa- thology for routine analysis. The tip of the Acessa handpiece (3.4 mm in diameter) was then inserted and advanced into the fi- broid via the same tract as the biopsy needle. The needle elec- trodes were deployed depending on the size of the fibroid, the ablation was carried out, and the tract was coagulated upon handpiece tip removal, therein providing hemostasis ( l " Fig. 2 b). For both LM and RFVTA, the port sites were closed per standard procedure. Subjects were followed via phone, mail, and/or an in- person interview at 3, 6, and 12 months post procedure. Outcome measures The primary outcome measure of the study (hospitalization time) has been reported in the literature [11]. In this longer term follow-up of the same study, we report on qualitative outcomes through one year post treatment: subjects ʼ subjective responses to validated questionnaires (Uterine Fibroid Symptom and Qual- ity-of-Life (UFS ‑QOL), EQ-5D, Overall Treatment Effect Survey (OTE), and menstrual impact (MIQ) questionnaires [12 – 15]), their use of pain medication, procedure-related complications, re-interventions for fibroid symptoms, and pregnancy outcomes. 443 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 Original Article Assessed for eligibility (n = 110) Intraoperative mapping (n 56)= Randomized (n 51)= Excluded (n = 54) Excluded (n = 5) A l l o c a t e dt oL M( n=2 5 ) Analyzed at 6 months (n 23) Excluded from analysis: m i s s i n gd a t a( n 2 ) = = Analyzed at 12 months (n 22) Excluded from analysis: m i s s i n gd a t a( n 1 ) = = Allocated to RFVTA (n = 26) Analyzed at 6 months (n 23) Excluded from analysis: hysterectomy (n 2) = = Analyzed at 12 months (n 21) Excluded from analysis: = m i s s i n gd a t a( n=1 ) ; myomectomy (n = 1) N o tm e e t i n gi n c l u s i o nc r i t e r i a( n 5 4 )= 1 subject had a fibroid > 10 cm and a nI U Di np l a c e ; 2 subjects had many fibroids, and if randomized to laparoscopic myomectomy, would have had a hysterectomy; 1 subject had no fibroids; 1 subject had only 1 large pedunculated fibroid Received allocated intervention and followed through 3 months (n 25)= Received allocated intervention and followed through 3 months (n 25) Did not receive allocated intervention (n 1), procedure was terminated because of an unrelated operating room emergency = = Fig. 1 Disposition of subjects throughout study. Flow of subjects through 12 months of follow-up (modified from Figure 1, reference [11]). Fig. 2 a and ba Laparoscopic myomectomy. Intraoperative view of sutured uterus after laparoscopic myomectomy. Hemostasis achieved. b Radiofre- quency volumetric thermal ablation (RFVTA). Intraoperative view of uterus during RFVTA of an intramural fibroid with handpiece (left) and transducer (right). Hemostasis via tract coagulation is achieved upon withdrawal of the handpiece. 444 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 GebFra Science Sample size and statistical analyses The determination of the sample size has been reported in detail [8]. In brief, the sample size required for comparison of RFVTA and LM was based on assumptions with regard to hospitalization time. The null hypothesis was that RFVTA is more than 10 % worse than LM concerning hospital stay and the alternative hy- pothesis was that this is not the case. The sample size required to reject the null hypothesis with a power of 0.80 was 50 (25 in each surgical group). Analyses were performed using SAS version 9.3 (SAS Institute, Cary, North Carolina, USA). Continuous variables for the analyses performed for this study were summarized using descriptive sta- tistics, whereas categorical variables were summarized in terms of frequencies and percentages. The precision of selected ques- tionnaire outcomes for each treatment group is presented using 95 % confidence intervals. Statistical tests comparing the two treatment groups were performed using the t-test, unless other- wise noted.

! Demographics, fibroid dimensions, and symptomatology Demographic and baseline symptomatology summaries for sub- jects in each of the two treatment groups are presented in l" Ta- bles 1 and 2, respectively. Subjects in the RFVTA and LM groups were similar with regard to height and weight, although the RFVTA subjects were several years older (p = 0.006). At baseline, symptomatology was similar between the two groups (p = 0.19 to 1.00, χ 2 or Fisherʼs exact test). The surgeons incorporated intraoperative laparoscopic ultra- sound not only to detect the uterine fibroids, but to measure the sum of their major diameters. For those women in the ablation group, the mean sum at baseline was 7.7 ± 4.2 cm; for those women randomized to myomectomy, the mean sum was 6.6 ± 3.2 cm. For those fibroids that were present and measurable at 12 months in the 19 subjects in each group, the mean sum of Table 1 Demographics of study participants and intraoperative myoma characteristics at baseline (modified from Table 2, reference [11]) a, b. Variable Baseline RFVTA (n = 25) LM (n = 25) p-value c Mean age, years (SD) 40.0 (7.8) 34.4 (6.1) 0.006 Mean height, cm (SD) 166.0 (5.8) 164.4 (5.9) 0.33 Mean weight, kg (SD) 62.4 (8.9) 64.9 (13.5) 0.43 Race, n (%) " White/Caucasian 25 (100) 25 (100) Intraoperative myoma characteristics " Total fibroids, n 72 61 " Mean number of fibroids per subject (SD; median: range) 2.9 (2.6; 2 : 1 –9) 2.4 (1.6; 2 : 1 –6) 0.99 " Submucosal, N (%) 0 (0.0) 2 (3.3) 0.17 " Transmural, N (%) 0 (0.0) 3 (4.9) 0.17 " Intramural, N (%) 33 (45.8) 26 (42.6) 0.45 " IMAE, N (%) 2 (2.8) 0 (0.0) 0.17 " Subserosal, N (%) 37 (51.4) 34 (55.7) 0.21 " Pedunculated subserosal, N (%) 0 (0.0) 2 (3.3) 0.17 a RFVTA = radiofrequency volumetric thermal ablation; LM = laparoscopic myomectomy; SD = standard deviation; IMAE = intramural abutting the endometr ium b Intraoperative myoma characteristics were evaluated by laparoscopic ultrasound mapping of the uterus prior to treatment/excision. c P-values based on t-test for age, height, and weight; p-values were based on Wilcoxon test for fibroids. Table 2 Number and percentage of subjects reporting symptoms at baseline and at 12 months. Symptom Baseline 12 months RFVTA (n = 25) n( % ) LM (n = 25) n( % ) p-value RFVTA (n = 21) n( % ) LM (n = 22) n( % ) p-value Heavy menstrual bleeding 21 (84.0) 18 (72.0) 0.31 a 7 (33.3) 2 (9.1) 0.069 b Increased abdominal girth 7 (28.0) 5 (20.0) 0.51 a 3 (14.3) 1 (4.5) 0.34 Dyspareunia 3 (12.0) 6 (24.0) 0.46 0 (0.0) 0 (0.0) Pelvic discomfort/pain 10 (40.0) 11 (44.0) 0.77 a 1 (4.8) 2 (9.1) 1.00 Dysmenorrhea 7 (28.0) 8 (32.0) 0.78 a 2 (9.5) 2 (9.1) 1.00 Urinary frequency 13 (52.0) 9 (36.0) 0.25 a 3 (14.3) 1 (4.5) 0.34 Urinary retention 4 (16.0) 8 (32.0) 0.19 a 0 (0.0) 0 (0.0) Sleep disturbance 0 (0.0) 1 (4.0) 1.00 0 (0.0) 0 (0.0) Uterine pain 3 (12.0) 1 (4.0) 0.61 0 (0.0) 0 (0.0) Backache 7 (28.0) 6 (24.0) 0.75 a 1 (4.8) 2 (9.1) 1.00 Localized pain 5 (20.0) 5 (20.0) 1.00 a 0 (0.0) 1 (4.5) 1.00 Other 0 (0.0) 1 (4.0) 1.00 2 (9.5) 0 (0.0) 0.23 a P-value based on χ2 test, otherwise based on Fisher ʼs exact test. b P-value is 0.088 based on logistic regression controlling for baseline heavy menstrual bleeding. 445 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 Original Article the major diameters was 4.8 ± 2.8 cm for the 15 fibroids detected in those women in the ablation group and 4.2 ± 2.6 cm for the 3 residual fibroids detected in those women in the myomectomy group. At 12 months, heavy menstrual bleeding was the symptom with the greatest numerical difference between the two groups and the smallest associated p-value: 7 of 21 subjects (33.3 %) in the RFVTA group and 2 of 22 subjects (9.1 %) in the LM group (p = 0.088, logistic regression, controlling for baseline heavy menstrual bleeding) ( l " Table 2 ). All patients provided binary (yes/no) responses regarding the presence of heavy menstrual bleeding. Twelve (12/18; 66.7 %) of the ablation subjects who had reported heavy menstrual bleeding at baseline did not have heavy menstrual bleeding at 12 months. This compares with 13 (13/15; 86.7 %) of the myomectomy subjects who had heavy menstrual bleeding at baseline but not at 12 months. One of the 3 ablation subjects who reported no heavy menstrual bleeding at baseline reported heavy menstrual bleeding at 12 months; all of the 7 LM subjects reporting no heavy menstrual bleeding at base- line continued to report absence of this symptom at 12 months. Postoperative use of pain medication and recovery Subjects were followed postoperatively for 3 months with regard to their medication use and their return to day-to-day and work activities. During this period, ablation subjects (n = 25) took pain relievers for a median of 4.0 days (range: 1 – 46 days), whereas myomectomy subjects (n = 25) took pain medications for a me- dian of 7.0 days (range: 1 – 83 days) (p = 0.60). Twenty-four abla- tion subjects reported that they returned to normal activities in a median of 20.5 days (range: 5– 103 days); 24 myomectomy sub- jects reported that they returned to normal activities in a median of 28.0 days (range: 10 – 42 days) (p = 0.86). Of the 24 ablation subjects who reported that they worked outside the home, 23 re- turned to work having missed a median of 10.0 workdays (range, 2– 86 days) including the procedure day. Of the 18 myomectomy subjects who worked outside the home, 17 returned to work and missed a median of 17.0 workdays (range, 7 – 30 days) (p = 0.28). Uterine Fibroid Symptom Severity and Quality-of-Life (UFS ‑QOL) outcomes Uterine Fibroid Symptom Severity and Health Related Quality-of- Life (HRQL) scores over time are presented in l" Figs. 3 and 4. The mean symptom severity score (the higher the score, the worse the severity) at baseline was 41.8 for the LM group and 39.9 for the RFVTA group, while the mean HRQL score (the lower the score, the worse the quality of life) was 70.2 for the myomectomy group and 77.2 for the ablation group. For the 18 ablation subjects with both baseline and 12-month symptom severity data, mean transformed symptom severity scores decreased (improved) from baseline to 12 months by − 7.8 to 26.2, whereas the corresponding 20 myomectomy subjects achieved a reduction of − 17.9 to 23.4 over the same period (mean difference of 10.1 ± 21.6; 95 % CI: − 4.1, 24.3; p = 0.16). HRQL increased (improved) for both groups over 12 months of follow-up, with mean increases of 7.5 to 86.4 and 13.1 to 83.2 for the ablation and myomectomy subjects, respectively, with both baseline and 12 month HRQL data (mean difference of − 5.6 ± 24.1; 95 % CI: − 20.8, 9.7, p = 0.46). The mean 12-month HRQL subscale scores (describing patient-reported concern, ac- tivities, energy/mood, control, self-consciousness, and sexual function) were similar between both treatment groups ( l " Fig. 5). Health state (EQ-5D) outcomes The mean health state (EQ-5D) scores (the lower the score, the worse the health state) at baseline through 12 months are pre- sented in l " Fig. 6. The mean EQ-5D score at baseline was 72.3 for the myomectomy subjects and 81.7 for the ablation subjects. Both groups reached their highest score at 6 months. Ablation Mean Transformed Symptom Severity Scores 100 80 60 40 20 0 Baseline 3 6 Months RFVTA LM 12 41.8 30 27.9 23.4 39.9 25.3 21.9 26.2 Fig. 3 Mean transformed uterine fibroid symptom severity scores. Symp- tom Severity scores for both radiofrequency volumetric thermal ablation (RFVTA) and laparoscopic myomectomy (LM) subjects. Note: The sample sizes at baseline, 3 months, 6 months, and 12 months are 25, 24, 23, and 18 for the RFVTA group; 25, 25, 22, and 20 for the LM group. Mean Transformed He alth-Related Quality-of-Life Scores 100 80 60 40 20 0 Baseline 3 6 Months RFVTA LM 12 70.2 77.7 80.3 83.2 77.2 77.9 85.2 86.4 Fig. 4 Mean transformed uterine fibroid health-related quality-of-life scores. Health-Related Quality of Life scores for both RFVTA and LM sub- jects. Note: The sample sizes at baseline, 3 month, and 6 months are 25, 24, 23, and 20 for the RFVTA group; 25, 24, 23, and 21 for the LM group. 446 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 GebFra Science subjects with both baseline and 12-month data achieved a mean change from baseline to 12 months of 2.0, compared with a mean change of 8.9 for the myomectomy subjects. The mean difference in the increase in scores between the ablation and myomectomy treatment groups was − 6.8 ± 18.8 (95 % CI: − 18.4, 4.7; p = 0.24). Menstrual Impact Questionnaire The Menstrual Impact Questionnaire (MIQ) was used to gauge subjectsʼ perceptions of blood loss from the previous period. At 12 months follow-up, 94.4 % of ablation respondents reported “better” or “about the same ” compared to their previous period. At the same follow-up period, 84.3 % of the LM subjects reported that their bleeding was “better” or “about the same ” (p = 0.12, Wilcoxon test). Overall Treatment Effect (OTE) In terms of subject responses regarding overall treatment satis- faction at 12 months based on the Overall Treatment Effect (OTE) Survey, 42.9 % (9/21) of the ablation respondents reported being very satisfied with the treatment, 42.9 % (n = 9) were mod- erately satisfied, 9.5 % (n = 2) were somewhat satisfied, and 4.8 % (n = 1) were moderately dissatisfied with the treatment due to the presence of hypermenorrhea at 4 weeks follow-up. Also at 12 months, 86.5 % (n = 19) myomectomy subjects reported being very satisfied with the treatment, whereas 13.6 % (n = 3) reported being moderately satisfied (p = 0.004, Wilcoxon test). No subject in either group reported being very dissatisfied with her treat- ment. Mean Health-Related Quality-of-Life Subscale Scores 100 80 60 40 20 0 Concern Activities Energy/mood RFVTA LM 85.6 90.2 91.5 87.2 83.8 75.9 85.7 81.8 86.383.9 85.7 77.8 Control Self-consciousness Sexual function Fig. 5 Mean transformed health-related quality-of-life subscale scores. Health-related quality-of-life subscale scores at 12 months of follow-up for R FVTA and LM subjects. Mean General Health-State Scores (EQ-SD) 100 80 60 40 20 0 Baseline 3 6 Months RFVTA LM 81.7 72.3 86 81.6 88.9 85.3 85.3 80.9 12 Fig. 6 Mean health state (EQ-5D) scores. Mean health state (EQ-5D) scores over time for both RFVTA and LM subjects. 447 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 Original Article In terms of responses to the question, “Would you recommend this treatment to a friend with the same health problem? ” 33.3 % of the ablation respondents reported that they would definitely recommend RFVTA, 61.9 % would probably recommend RFVTA, and 4.8 % would probably not. In the myomectomy group, 54.5 % would definitely recommend LM, whereas 45.5 % would probably recommend LM (p = 0.14, Wilcoxon test). In response to the question “How effective was the treatment in eliminating symptoms?” 23.8 % of the ablation group found that the treatment was very effective, 57.1 % found it moderately ef- fective, 9.5 % found it somewhat effective, 4.8 % regarded it as somewhat ineffective, and 4.8 % found it very ineffective. Of the myomectomy respondents, 45.5 % found the treatment very ef- fective, 31.8 % found it to be moderately effective, and 22.7 % found it to be somewhat effective (p = 0.32, Wilcoxon test). Procedure-related complications and re-interventions There was one serious complication that occurred during the early postoperative follow-up period in a subject who had under- gone RFVTA and was experiencing hypermenorrhea. Dilation and curettage resulted in uterine perforation and subsequent hysterectomy. Another ablation subject underwent a preemptive hysterectomy after a biopsy revealed a fibroid of smooth muscle tumor of uncertain malignant potential (STUMP) [11]. Histopath- ologic analysis of the uterus and fibroids confirmed no malignan- cy. One myomectomy subject had a hematoma at the trocar site, which resolved without sequelae. There was one elective surgical re-intervention in the ablation group. A 30-year-old subject presented with a single 6.3-cm in- tramural fibroid at baseline, and the fibroid had decreased to 2.5 cm by 6 months. Though she reported to be asymptomatic at the 6-month visit, she desired pregnancy in the near future. Transvaginal ultrasound at 9 months showed an increase in the fibroidʼs diameter to 4 cm; therefore, she sought myomectomy prior to attempting pregnancy. Pregnancy outcomes There were 5 pregnancies in 4 subjects within the first 9 months of follow-up: a myomectomy subject (G0P0) conceived; however, the fetus was anacephalic and was aborted. The same woman conceived again after excision of 5 fibroids measuring 0.7 to 2.0 cm; she had a full-term pregnancy with Cesarean delivery (adhesions were noted) of a healthy male infant weighing 3310 g (Apgars 1 minute/5 minutes, 10/10). Another myomec- tomy patient (G1P0), who had a spontaneous abortion in 2012 before the trial began, conceived after excision of a 1.5-cm intra- mural fibroid and a 0.9 subserosal fibroid. This pregnancy con- cluded with a spontaneous vaginal delivery at 39 weeks of a healthy female (Apgars 1 minute/5 minutes, 5/8) weighing 3280 g. A third patient (G3P1), who was 31 years old, underwent RFVTA of a 5.7-cm intramural fibroid, conceived at 8.5 months post ablation, and vaginally delivered a healthy male infant at 40 weeks (Apgars 1 minute/5 minutes, 8/8; weight, 3880 g). Last, a 31 year-old G0P0 woman underwent RFVTA of a 3.3-cm intra- mural fibroid abutting the endometrium for heavy menstrual bleeding symptoms. There were no complications intra- or post- operatively, and the subject was free of fibroid symptoms by 3 months post ablation. She conceived 7 months post surgery and spontaneously delivered a healthy female baby (Apgars 1 minute/5 minutes, 10/10; weight, 3260 g) at 39 weeks gestation. All 4 subjects will remain in the study.

! Management of fibroid symptoms ranges from medical therapy to the most definitive approach, hysterectomy. Along this range of care, fibroid ablation and laparoscopic myomectomy offer uterine-conserving therapies that can be considered when med- ical treatment fails, is inappropriate, or is not well tolerated. This study provides the first description of 12-month outcomes in women with symptomatic fibroids who were randomized to lap- aroscopic myomectomy and to radiofrequency volumetric ther- mal ablation for treatment of their fibroid symptoms. Both treat- ment groups improved in terms of their reported symptom se- verity, health-related quality of life, and EQ-5D health state at 12 months. However, the differences in improvements between both groups were not statistically significant. The only significant difference detected between the two groups was in the degree of treatment satisfaction (very vs. moderately satisfied) favoring the myomectomy group. The perception of blood loss from the previous period as mea- sured by the MIQ indicated that RFVTA subjects had a more fa- vorable perception, in contrast to the higher proportion of sub- jects in the RFVTA group who reported having heavy menstrual bleeding at 12 months. These somewhat contradictory results could have to do with the magnitude of the blood loss both at 12 months and at the preceding period for subjects in each group. The relationships between perception of blood loss and treat- ment, as well as between heavy menstrual bleeding and treat- ment, were not very strong. It is interesting to note that the loca- tion of the fibroids in both groups were almost entirely intra- mural and subserosal. Galen et al. reported on the decrease in menstrual bleeding associated with ablation of intramural fi- broids and the importance of intramural fibroids in the evalua- tion of heavy menstrual bleeding [16]. We previously reported that subjects who underwent the abla- tive therapy experienced significantly improved perioperative outcomes in terms of shorter hospital stays and less blood loss [11]. We found that these women also needed pain medication for fewer days than did the myomectomy patients, and the abla- tion subjects missed fewer days from work and returned earlier to normal activities. RFVTA of fibroids causes intracellular friction or heat, which re- sults in necrosis of the target fibroid tissue with resultant shrink- ing and absorption by the surrounding myometrium. In Chudnoff et al., contrast-enhanced magnetic resonance imaging revealed that the total mean fibroid volume decreased by 45.1 % at 12 months post ablation [8]. Because RFVTA does not require serosal and myometrial suturing, it can be used safely to treat fibroids smaller than 1 cm in diameter and has been used to ablate up to 29 fibroids in a single patient [8]. The ablation of small fibroids may preclude their growth with consequent symptoms. Day Baird et al. reported a prospective observational study of 36 women with fibroids, whose volumes were tracked every 3 months over one year [17]. They found that “much of the ob- served growth in fibroids < 5 cm in diameter appears to be asso- ciated with growth spurts. Treatments that could prevent spurts could limit the number of tumors that become large enough to cause symptoms.” This finding supports treatment or ablation of fibroids as small as 0.5 to 1.0 cm that might cause future symp- toms. All subjects in both groups saw their ultrasound scans at 3 and 6 months. The increased expression of satisfaction with treatment by the LM subjects compared to the RFVTA subjects may have 448 Hahn M et al. Radiofrequency Volumetric Thermal … Geburtsh Frauenheilk 2015; 75: 442 –449 GebFra Science been due to a lack of understanding of the clinical significance of fibroid ablation by the ablation group. These women may have expected a great decrease in size or disappearance of their fi- broids by 12 months as evidenced by ultrasound and may have correlated their perceptions at ultrasound with expected symp- tom improvement. The one elective surgical re-intervention in the RFVTA group was a myomectomy of a single intramural fi- broid that measured 6.3 cm at baseline, decreased to 2.5 cm by 6 months, and – on transvaginal ultrasound at 9 months – ap- peared to increase to 4 cm. The subject sought myomectomy pri- or to attempting pregnancy. Two hysterectomies were performed for reasons unrelated to fibroid symptoms. One was a preemptive treatment related to a STUMP fibroid, which was later confirmed to be nonmalignant [11]. The other was caused by the unknow- ingly aggressive treatment of hypermenorrhea via curettage (within a few weeks after the subject ʼs RFVTA procedure) with corresponding perforation of the uterus. All of the outcomes must be taken in the aggregate: most of the evaluations point toward similar benefits of improved efficacy and safety of RFVTA and LM. However, because of the local prac- tice of tissue sampling of large fibroids and the relative unfami- liarity with RFVTA by local gynecologists, two women under- went hysterectomy – perhaps both of them unnecessarily. The principal strength of the study was the computer-generated randomization of the subjects to either RFVTA or LM; random- ized controlled trials are, by definition, rigorous. Despite ran- domization, there were study limitations and weaknesses, which included an unexpected age discrepancy between the groups. This discrepancy might potentially have biased the results in terms of subjects ʼ perceptions of symptoms and their expecta- tions of symptom relief. Differences in reported symptomatology (l " Table 2 ) may also correlate with the age of the study partici- pants, but the small sizes of the study groups make it difficult to evaluate such a relationship; regardless, symptom differences were not statistically significant. Also, despite being randomized to one of the two laparoscopic treatments intraoperatively, pa- tients were told postoperatively their assigned treatment. This knowledge may have impacted their responses to questionnaires. Last, data were missing for 2 RFVTA subjects and 3 LM subjects at 12 months. Given the small size of the groups, inclusion of addi- tional responses from 2 and 3 more subjects could have made substantial differences in the reported outcomes.

! Twelve-month qualitative results from this study, in which sub- jects will be followed for 5 years, indicate similar efficacy, quality of life, and safety for both treatment groups.

! The authors wish to thank Wainwright Medical Communications (Los Gatos, California USA) for assistance with research and edito- rial support. The authors also thank Innovative Analytics (Kala- mazoo, Michigan USA) for statistical analysis of the study data. Conflict of Interest ! Halt Medical, Inc. (Brentwood, California USA) sponsored the study and provided materials and funding for the described pro- cedures and for independent third-party monitoring, statistical analyses, and writing support. None of the authors have other commercial disclosures.

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