Focused Ultrasound A Non-Invasive Alternative Robert K. Zurawin, MD Baylor College of Medicine

Focused Ultrasound for Uterine Fibroids non-invasively ablate fibroid tissue without affecting intervening tissues MRI used in planning, guidance, & outcome prediction Incision-less (non-invasive) and re-treatable No ionizing radiation High safety profile No hospitalization Next day return to work/normal activity © 2013 by Focused Ultrasound Foundation

Principles of FUS Treatment High intensity focused ultrasound transducer in the table top of the MRI Treatment performed under conscious sedation Targeting done using MR image Treatment monitoring using MR thermometry Tissue is destroyed following multiple ultrasound sonications Patient goes home the same day Indication is for patients with symptomatic fibroids © 2013 by Focused Ultrasound Foundation

Real Time MRI Guidance and Monitoring 1 2 5 CLOSED LOOP THERAPY Imaging for precise tumor targeting Beam path visualization for controlled treatment 4 3 Post treatment contrast imaging for precise treatment validation Thermal dose accumulation MR thermometry temperature feedback © 2013 by Focused Ultrasound Foundation

Imaging of Uterine Fibroids Ultrasound MRI CT © 2013 by Focused Ultrasound Foundation

Focused Ultrasound for Uterine Fibroids © 2013 by Focused Ultrasound Foundation

The Procedure: Targeting Structures to be avoided Region to be treated © 2013 by Focused Ultrasound Foundation

The Procedure: Planning © 2013 by Focused Ultrasound Foundation

The Procedure: Treatment Temperature measurement Two sonication methods Point by point or volumetric © 2013 by Focused Ultrasound Foundation

The Procedure: Guidance Move to next target © 2013 by Focused Ultrasound Foundation

The Procedure: Confirmation Pre treatment Treatment plan Post treatment © 2013 by Focused Ultrasound Foundation

Evolution of Technology Initially in the 2004 Approval, FDA only allowed 30% of fibroid volume to be treated No treatment limits now Technology advancements allow Larger fibroids* Treatment envelope for deeper fibroids 300+% improvement in treatment time over 10 years Initial rate of 20+ mL/hr Current rate 80+ mL/hr *Y. S. Kim, J. H. Kim, H. Rhim, H. K. Lim, B. Keserci, D. S. Bae, B. G. Kim, J. W. Lee, T. J. Kim, and C. H. Choi, “Volumetric MR-guided high-intensity focused ultrasound ablation with a one-layer strategy to treat large uterine fibroids: initial clinical outcomes,” Radiology, vol. 263, no. 2, pp. 600–609, May 2012. © 2013 by Focused Ultrasound Foundation

Current State of Technology Two MR guided device manufacturers About 10,000 patients treated worldwide Widespread regulatory approval Very spotty reimbursement 155 publications on the use of Focused Ultrasound for uterine fibroid therapy Promising results for use in patients Seeking to improve fertility outcomes in patients with uterine fibroids Adenomyosis Sonalleve MR-HIFU* *For investigational use only © 2013 by Focused Ultrasound Foundation

General Screening Guidelines Symptomatic fibroids Pre- or peri-menopausal women Symptoms are bulk, pain or bleeding Pre-screening shows no pregnancy, malignancy or pelvic disease Screening US for diagnosis of fibroids and confirmed limited-to-no calcifications © 2013 by Focused Ultrasound Foundation

Pre-Treatment MRI Precise determination of size, location, number of fibroids Characterization of fibroid for treatment strategy Viability for Focused Ultrasound therapy Degree of vascularity (as assessed by perfusion with MRI) Identify calcifications Adenomyosis Malignancy screening Including suspicion of endometrial cancer and/or sarcoma © 2013 by Focused Ultrasound Foundation

Relative Contraindication Absolute Contraindication Patient Selection Indication Symptomatic Bleeding Pressure, pain Pre- or peri-menopausal Uterus size approx. 24 weeks gestation Relative Contraindication Morbidly obese or BMI ≥40 Degenerated fibroid Extensive scarring over beam path Desire for future pregnancy Bowels interfering with beam path Absolute Contraindication Currently pregnant MRI contraindication Calcified or dominantly degenerated © 2013 by Focused Ultrasound Foundation

Treating Multiple Fibroids © 2013 by Focused Ultrasound Foundation

Symptom Relief After FUS Treatment MR-Guided Focused Ultrasound of Uterine Leiomyomas: Review of a 12-month Outcome of 130 Clinical Patients Retrospective study of women treated at Mayo Clinic from 2005-2009 Mean tumor load per patient 350.3 cm3 (± 307.2) Mean non-perfused volume immediately after treatment 45.4% (±22.5) Gorny KR, Woodrum DA et al. Magnetic resonance–guided focused ultrasound of uterine leiomyomas: review of a 12-month outcome of 130 clinical patients. J Vasc Interv Radiol 2011 © 2013 by Focused Ultrasound Foundation

Symptom Relief After FUS Treatment In normal commercial use, over 85% of patients experience sustained improvement in symptoms Months post-procedure Patients available for follow-up Symptom improvement Improved No relief Worse 3 105 90 (85.7%) 14 (13.3%) 1 (1%) 6 99 92 (92.9%) 7 (7.1%) 12 81 + 8 additional treatments counted as ‘no relief’ = 89 78 (87.6%) 11 (12.4%) Gorny KR, Woodrum DA et al. Magnetic resonance–guided focused ultrasound of uterine leiomyomas: review of a 12-month outcome of 130 clinical patients. J Vasc Interv Radiol 2011 © 2013 by Focused Ultrasound Foundation

Non Perfused Volume (NPV) Indicator of Treatment Durability* The higher the NPV the lower the likelihood of retreatment NPV increasing with learning curve and improved techniques At NPV of 60% need for retreatment is similar to UAE and myomectomy Add bar graph *Stewart et al. Obstet Gynecol 2007-Av. NPV ratio 21.9% (N=359). Okada et al. Ultrasound in Obstet Gynecol 2009-Av. NPV ratio 46.6% (N=287) Leblang et al. AJR 2010--Av. NPV ratio 55% (N=80).Matzko 2nd MRgFUS Symposium 2010-----Av. NPV ratio 59.1% (N=41),Matzko 1st European MRgFUS Symposium 2011 Av NPV- 67% © 2013 by Focused Ultrasound Foundation

Durability Versus Other Uterine Preserving Treatments References: Subramanian S, Clark MA, Isaacson K. Outcome and resource use associated with myomectomy. Obs & Gyn.2001; 98: 583-587 Nezhat FR, Roemisch M, et al. Recurrence rate after laparoscopic myomectomy. Am Assoc Gynecol Laparosc. 1998;5: 237-240 Rossseti et al. Long term results of laparoscopic myomectomy: recurrence rate in comparison with abdominal myomectomy. Hum Reprod. 2001:16:770-774 Doridot et al. Recurrence of leiomyomata after laparoscopic myomectomy. J Am Assoc Gynecol Laparosc. 2001;8: 495-500 Spies JB, Bruno J, et al. Long-term outcome of uterine artery embolization of leiomyomata. Obstet Gynecol. 2005; 106: 933-939 Goodwin SC, Spies JB, et al. Uterine artery embolization for treatment of leiomyomata: long-term outcomes from FIBROID registry. Obstet & Gynecol. 2008; 111: 22-32 Sharp HT. Assessment of new technology in the treatment of idiopathic menorrhagia and uterine leiomyomata. Obstet Gynecol. 2006;108: 990–1003 Stewart EA, Gostout B, Rabinovici J, et at. Sustained relief of leiomyoma symptoms by using focused ultrasound surgery. Obstet & Gynecol. 2007;110: 279-287 Morita Y, Ito N, Hikida H, Takeuchi S, Nakamura K, Ohashi H. Non-Invasive Magnetic Resonance Imaging Guided Focused Ultrasound Treatment for Uterine Fibroids – Early Experience, Eur J Obstet Gynecol Reprod. Biol., 2008, 139(2):199-203 © 2013 by Focused Ultrasound Foundation

Relationship Between Fibroid Shrinkage and Symptoms As fibroid volume shrinks, symptoms and quality of life improve Baseline 3 Months 6 Months QoL improvements and 50% fibroid shrinkage in 6 months Courtesy of UMC Utrecht, The Netherlands © 2013 by Focused Ultrasound Foundation

FUS Side Effects and Complications Expected side-effects of FUS-therapy Transitory 30% patients may experience nausea, vomiting, leg and buttock pain, abdominal tenderness Less frequent, transitory < 10% patients may experience swelling, abdominal cramping, vaginal bleeding, urinary difficulty < 3% patients may experience first degree skin burns (skin redness) and general pelvic pain Very rare complications (< 1% patients) Second and third degree skin burns Neuropathy < 0.1% (Taran 2009) Injury to abdominal/pelvic organs < 0.1% (Taran 2009) © 2013 by Focused Ultrasound Foundation

Ongoing Studies in the US SOnalleve FIbroid Ablation (SOFIA) Study Philips Sonalleve FDA pre-market approval RCT, comparison to sham 224 patients Conducted at St. Luke’s, Johns Hopkins, University of Chicago, University of Michigan, Vanderbilt, Sunnybrook Health Sciences Centre, Samsung Medical Center in Korea ExAblate UF V2 System for the Treatment of Symptomatic Uterine Fibroids Safety trial for the newer ExAblate for faster planning and treatment times, broader patient selection, and improved range of treatment 106 patients Conducted at Stanford, Brigham and Women’s, University of Virginia FIRSTT: Comparing MR-guided Focused Ultrasound to Uterine Artery Embolization for Uterine Fibroids Randomized study 180 patients Conducted at Mayo, Duke © 2013 by Focused Ultrasound Foundation

FUS and Pregnancy Patients who desire future pregnancy Semin Reprod Med 2010 © 2013 by Focused Ultrasound Foundation

Post FUS pregnancies Total number of pregnancies Mean age Average months to conception Total deliveries - Of them vaginal Elective pregnancy termination Spontaneous abortions Ongoing pregnancies Unknown Average baby weight at term delivery 117 36 9 64 (55%) 59% 10 (9%) 22 (19%) 9 (8%) 12 (10%) 7.21 lbs J Rabinovici, MD 3RD FUSF Symposium Washington, 2012 NOTE: There have been no prospective clinical trials to evaluate outcomes among women who have undergone ExAblate therapy and subsequently become pregnant. Patients of childbearing age should be cautioned of potential any potential complications if they were to become pregnant following ExAblate procedure. © 2013 by Focused Ultrasound Foundation

Laparoscopic Myomectomy Deliveries after FUS Vaginal delivery rates after MRgFUS (rather than C-section) are more similar to those of general population May result in fewer preterm deliveries and lower cost care for premature babies, than those of other treatments Complication General Population UF Patients UAE Laparoscopic Myomectomy MRgFUS Cesarean Delivery 22% 48.5% 66% 77.8% 36% Preterm Delivery 5-10% 16% 14% 7.4% 5% References: J. Goldberg and Leonardo Pereira. Pregnancy outcomes following treatment for fibroids: uterine fibroid embolization versus laparoscopic myomectomy, Obstetrics and Gynecology 2006, 18:402–4 H. Homer, E. Saridogan, Uterine artery embolization for fibroids is associated with an increased risk of miscarriage, Fertility and Sterility 2009 J. Rabinovici et al. Pregnancy outcome after magnetic resonance–guided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids, Fertility and Sterility 2008 Miller CE. Unmet Therapeutic Needs for Uterine Myomas. J Minimally Invasive Gynecol. 2009;16: 11-21. 27 Caution: Investigational Device. Limited by United States Law to Investigational Use. © 2013 by Focused Ultrasound Foundation 27

Pregnancy after FUS 41 yo. Nulligravida with 3 previous IVFs (the last one with oocytes from donor) Previous myomectomy Treated September 2010 Intramural fibroid Treatment volume of 130, NPV 80% Pregnancy: 7 months after treatment (frozen embryo transference) Courtesy of H. Millan, MD, Instituto Cartuja, Seville, Spain © 2013 by Focused Ultrasound Foundation

FUS In Spectrum of Treatment Options Myomectomy Patient population: intramural and subserosal uterine fibroids. Patients (Myomectomy) who want to become pregnant and who do not have contraindications for surgery Disadvantages/Risks: Surgical risks and perioperative morbidity, adhesion risk and complications Future Fertility: Yes, for Myomectomy only. Known risks shown in pregnancy post-procedure Uterine fibroid embolization Patient population: fibroids that are not subserous, submucosal or pedunculated. Wish to preserve uterus but are not interested in future fertility Disadvantages/Risks: Possible surgical risks of infection and bleeding. Future Fertility: Not recommended. 12% risk of placental abnormalities. Risk of ovarian failure, amenorrhea reported in <15% Focused Ultrasound Patient population: patients with symptomatic (<5 fibroids, range of sizes). Wish to preserve uterus and may/may not be family complete Disadvantages/Risks: Limits on types and location of fibroids that can be accessed. Risks of abdominal pain, transient lower leg or back pain, vaginal discharge or bleeding, fever skin burns. Future Fertility: Reports of 120+ deliveries. Risks are not yet fully defined, in several reports there is an indication MR-HIFU may improve fertility. © 2013 by Focused Ultrasound Foundation

Focused Ultrasound Meets Patient Needs Non-invasive low pain alternative to surgery Out-patient procedure Go home the same day Quick recovery: Return to normal activity in 2 days Uterus preserving therapy Option for future pregnancy *Source: AHRQ Publication No. 07-E011: Management of Uterine Fibroids: An Update of the Evidence. © 2013 by Focused Ultrasound Foundation

Meeting Patient Needs: The Potential Value for Patients % rating treatment their top choice BASE: ALL QUALIFIED RESPONDENTS (n*=968) *base varies slightly Q960 Please rank the following treatment options where “1” = your top choice and “6” = your bottom choice. © 2013 by Focused Ultrasound Foundation

Practice Building with Fibroid Center and Focused Ultrasound 53 27 4 16 10 15 20 2 6 11 42 22 18 12 7 8 40 60 80 100 120 140 2003 2004 2005 2006 LM LH AM AH MRgFUS 117 102 50 # of UF patients Case study: UF treatments at Shin-Suma Kobe, Japan Halo effect of cutting edge technology GYNs central to treatment team Offering of complete range of treatments for women, specifically a non-invasive, low morbidity option Drive increase in practice volume Before FUS 1 year after FUS 2 years after FUS 3 years after FUS Legend: LM Laparoscopic Myomectomy LH Laparoscopic Hysterectomy AM Abdominal Myomectomy AH Abdominal Hysterectomy MRgFUS MR guided Focused Ultrasound © 2013 by Focused Ultrasound Foundation