F. A. TARAN*, C. M. C. TEMPANY†, L. REGAN‡, Y. INBAR§, A. REVEL¶ and E. A. STEWART**

1. Magnetic Resonance-guided Focused Ultrasound (MRgFUS)compared with Abdominal Hysterectomy for treatmentof Uterine leiomyomasJournal of Ultrasound Obstetrics and Gynecology 2009; Volume34: 572–578 F. A. TARAN*, C. M. C. TEMPANY†, L. REGAN‡, Y. INBAR§, A. REVEL¶ and E. A. STEWART** *OB-GYN Dept, Mayo Clinic, Rochester, MN and †Dept of Radiology and **Depts of OB-GYN and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA, ‡Dept of OB-GYN, St. Mary’s Hospital, London, UKand §Dept of Radiology, Sheba Medical Center, Tel-Hashomer and ¶Dept of OB-GYN, Hadassah Medical Center, Jerusalem, Israel

2. Definition of Terms • Magnetic Resonance-guided Focused Ultrasound (MRgFUS)- A noninvasive, outpatient, surgical procedure that uses high intensity focused ultrasound waves to destroy tissue in combination with Magnetic Resonance Imaging (MRI), which guides and monitors the treatment - Approved by the US FDA in 2004 http://www.focusedultrasound/for_clinicians/mrgfus.php

3. Definition of Terms • Uterine leiomyomas - Benign myometrial neoplams, very common - Frequently found in women between the ages 30-45 - Represent the primary indication for hysterectomy in the United States http://en.wikipedia.org/wiki/Leiomyoma

4. Objective of the Study • To compare women undergoing magnetic resonance-guided focused ultrasound (MRgFUS) to a group of women undergoing total abdominal hysterectomy based on patient demographics, safety parameters, quality of life outcomes, and disability measure.

5. Methodology • Study was conducted in 14 medical centers in the United States, Israel, the UK, and Germany • Pre-menopausal women with symptomatic fibroids were recruited for MRgFUS or hysterectomy

6. Methodology • 109 women underwent MRgFUS at 7 sites • Brigham and Women’s Hospital, Boston, MA (n = 24) • Sheba Medical Center, Tel-Hashomer, Israel (n = 20) • St. Mary’s Hospital, London (n = 19) • Johns Hopkins Hospital, Baltimore, MD (n = 16) • Mayo Clinic, Rochester, MN (n = 12) • Charit´e Hospital, Berlin (n = 9) • Hadassah Medical Center, Jerusalem, Israel (n = 9)

7. Methodology • 83 women underwent hysterectomy at 7 sites • University of Texas Southwestern, Dallas, TX (n = 35) • Ha’Emek Medical Center, Afula, Israel (n = 20) • William Beaumont Hospital, Royal Oak, MI (n = 16) • John Radcliffe Hospital, Oxford, UK (n = 6) • Texas Institute of Clinical Research,Ft Worth,TX (n = 3) • Wayne State University, Detroit, MI (n = 2) • Frauenklinik Universitatsklinikum Benjamin Franklin, Berlin (n = 1)

8. Methodology Inclusion criteria • Pre-menopausal women • Symptomatic uterine fibroids • At least 18 years old • Do not want children in the future

9. Methodology Exclusion criteria • Uterus larger than 24 weeks gestational size • Hematocrit <25% • Positive pregnancy test • Contraindication to surgery • Contraindication to MRI (aneurysm clip, deep brain stimulator, cardiac pacemaker, implantable defibrillator)

10. Methodology • Symptom assessment used the Uterine Fibroid Symptom and Quality of Life Questionnaire (UFS-QOL) - validated disease-specific instrument - 8 item Symptom Severity Scale (SSS) and 6 dimensions of health-related quality of life (HRQL) - raw SSS of at least 21/40 required

11. Methodology • In addition, the Short Form-36 health survey questionnaire was administered to provide an additional method of assessment of HRQL at baseline, and at months 1, 3, and 6 of follow-up

12. Study Procedures • MRgFUS treatment was based on leiomyoma size, symptomatology, and accessibility of the fibroid to the FUS beam • Abdominal hysterectomy was performed based on the physician’s standard of care

13. Outcome Measures • Significant clinical complications: • Fever >38°C on any 2 post treatment days • Blood transfusion • Unintended major surgical procedure • Discharge to a rehabilitation facility • Discharge with an appliance (drain, catheter) • Outpatient interventional treatment • Rehospitalization • Life-threatening event • Death within 42 days of treatment

14. Statistical Analysis • All data were entered into an internet-based database designed by ClickFind • Data entry application has a robust audit trail and data were verified before analysis • Data were then exported on a spreadsheet for transfer to SAS statistical software for analysis

15. Statistical Analysis • Comparison between groups were conducted using chi-square tests for categorical variables, and t-tests for continuous variables • For the significant clinical complications analysis, Fisher’s exact test was used • All tests were two-tailed • P < 0.05 considered statistically significant

16. Objective of the Study • To compare women undergoing magnetic resonance-guided focused ultrasound (MRgFUS) to a group of women undergoing total abdominal hysterectomy based on patient demographics, safety parameters, quality of life outcomes, and disability measure.

17. Baseline Patient Characteristics of Treatment groups

18. Results • Study population was typical of premenopausal women with symptomatic fibroids, with most women being in their forties and having an increased body mass index (BMI). • Women in the hysterectomy group were less likely to be Caucasian (54 vs. 80%; P < 0.001) and had higher BMI on average (29.9 ± 6.0 vs. 25.8 ± 5.2 kg/m2; P = 0.001)

19. Results • Both groups had significant levels of fibroid symptomatology and health-related impairment of quality of life at baseline, although the hysterectomy group had higher levels of symptoms • Women undergoing hysterectomy had significantly worse function on several subsections of the SF-36 questionnaire including physical functioning, bodily pain, vitality, emotional role and mental health

20. Summary of Significant Clinical Complication Events

21. Results • There were fewer SCCs occurring in the MRgFUS group (14 events vs. 33 events; P < 0.0001) • The rate fever was much lower in the MRgFUS group (3 events vs. 12 events; P = 0.005) • Unintended surgical procedures related to treatment (removal of foreign body from the bladder, surgical repair of hernia, revision of enterotomy and surgical repair of an iatrogenic colonic lesion) were performed in four (5%) women from the hysterectomy group • There were no deaths or life-threatening events in either group

22. Summary of Adverse and Serious Events

23. Results • At least one adverse event was reported by 88 (81%) women from the MRgFUS group and by 82 (99%) women from the hysterectomy group (P < 0.0001) • Adverse events related to pain or discomfort, the gastrointestinal tract, dermatological conditions and nervous system were reported significantly less frequently by women from the MRgFUS group

24. Health Survey and Disability Assessment scores at Months 1,3,6

25. Health Survey and Disability Assessment scores at Months 1,3,6

26. Health Survey and Disability Assessment scores at Months 1,3,6

27. Results • At 1 month, women from the MRgFUS group had significantly greater improvement scores for the physical-function, physical-role and social-function components • At 3 and 6 months these differences were not significant

28. Results • Disability was supported by data on return to normal activities • At 1 month, women undergoing MRgFUS reported 1.2 lost working days and 2.7 days kept from usual activities compared with 19.2 and 17.4, respectively, for women undergoing hysterectomy (P < 0.0001)

29. Conclusion • The results of this study show that MRgFUS treatment of uterine leiomyomas leads to clinical improvement with fewer significant clinical complications and adverse events compared to hysterectomy during the 6-month follow-up • Furthermore, MRgFUS treatment was associated with significantly faster recovery, including resumption of usual activities

30. Critical Appraisal Clinical Scenario • How does magnetic resonance-guided focused ultrasound (MRgFUS) compare as treatment for uterine leiomyomas with total abdominal hysterectomy based on patient demographics, safety parameters, quality of life outcomes, and disability measure?

31. Relevance Is the objective of the article similar to your clinical dilemma? • Yes, the objective is to compare a newer technique (MRgFUS) for Uterine leiomyoma treatment to the more classic Hysterectomy in terms of different outcomes. • Our clinical dilemma is to determine if non-invasive techniques (MRgFUS) could be as effective as invasive techniques like surgery (Hysterectomy)

32. Was there a representative sample of patients without the outcome at the start of the observation? Yes, this was described in the Inclusion and Exclusion criteria in selecting the population for the study. • Was follow up sufficiently long and complete? Yes, participants were followed up after 1 month, 3 months, and 6 months after treatment.

33. Was there adjustment for other prognostic factors? - YES. All models were adjusted for race and age, and models predicting infertility, pregnancy, and live birth were additionally adjusted for self reported infertility at baseline.

34. Were the criteria for determining the prognostic factor and outcome explicit and credible? • Yes, all outcomes were assessed with validated tools • Tools that were used were the following: • Uterine Fibroid Symptom and Quality-of-Life Questionnaire (UFS-QOL) which consists of an eight-item Symptom Severity Scale (SSS) and six dimensions of health-related quality of life (HRQL) • Short Form-36 health survey questionnaire

35. Overall, is the study valid? • Yes, all the validity questions were fulfilled. • The study was conducted in 14 medical centers in the United States, Israel, the UK and Germany. Can the results help me in caring for my patient? • Yes, being given data of a study that compares two different treatments for uterine leiomyomas based on various outcomes gives us the option of selecting non-invasive techniques without compromising the effectiveness of the treatment, and the safety and quality of life of our patients

36. THANK YOU!