Future Directions for the Treatment of Leiomyomas WILLIAM H. CATHERINO, MD, PHD PROFESSOR AND CHAIR-RESEARCH, DEPARTMENT OF OBSTETRICS AND GYNECOLOGY UNIFORMED SERVICES UNIVERSITY NATIONAL INSTITUTES OF HEALTH Objectives

At the completion of this lecture, you will:

u Understand the benefits and drawbacks of surgical intervention

u Understand the benefits and drawbacks of minimally invasive interventions

u Understand the benefits and drawbacks of medical interventions

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u Consultant: Abbvie, Allergan, Bayer u Research grant: Allergan u Wife, Scientific Director: EMD Serono

Please email [email protected] with any ?s Best Studied Therapies for Fibroids

Surgical Radiologic Medical ______>100 years of study Hysterectomy Open myomectomy GnRH agonists 25-34 years of study SERMs: Tamoxifen Endometrial Ablation GnRH agonists 20-24 years of study SERMs: Raloxifene Laparoscopic myomectomy Uterine artery embolization Retinoic acid 10-19 years of study SERMs: Letrozole, genestein Uterine artery obstruction SPRMs: Mifepristone, asoprisnil, ulipristal Robotic myomectomy GnRH antagonists 5-9 years of study Cryomyolysis MRI-guided high frequency u/s SPRMs: Telepristone Laparoscopic ablation

Please email [email protected] with any ?s Surgical Intervention Scientific Study Into Various Fibroid Treatments

Minimally Invasive Surgical Interventions Interventions Medical Interventions 180 80 20

135 60 15

90 40 10

45 20 5

0 2008 2010 2012 2014 2016 0 0 2008 2010 2012 2014 2016 20082009 2010201120122013 201420152016 hysterectomy Laparoscopic myomectomy UAE Ulipristal Leuprolide Hysteroscopic myomectomy Endometrial ablation Mifepristone Levonorgestrel Open myomectomy Radiofrequency ablation Letrozole Cetrorelix Robotic myomectomy MRI-Guided HiFU Triptorelin Vilaprisan Hysterectomy Decreasing Over Time

Please email [email protected] with any ?s Laparoscopic Myomectomy

• Shorter inpatient stay (52hrs vs. 98hrs)

• Less post-operative pain, but greater delayed pain

• Similar operative times, and recurrence rates

Sesti Surg Endosc 2008;22:917 Holzer Anesth Analg 2006;102:1480 • 1% risk of conversion to laparotomy Cagnacci Hum Reprod 2003;18:2590 Rossetti Hum Reprod 2001;16:770 Mais Am J Obstet Gynecol 1996;174:654 Seracchioli J Am Assoc Gynecol Laparosc 2002;9:333 Malzoni M, Eur J Gynaecol Oncol 2003;24:79 Please email [email protected] with any ?s Andrei Clin Exp Obstet Gynecol 1999;26:44 Robotic Myomectomy: Blood Loss & Op Time

u EBL versus Abdominal Myomectomy u Average Operative Time u Improved with RALM: Advincula 2007; Gobern 2013 u No difference: Griffin 2013 u Abdominal Myomectomy (N=770): 1 ⅔ hrs

u Change in Hct versus Abdominal Myomectomy u Robotic Myomectomy (N=708): 3 ⅙ hrs u Improved with RALM: Ascher-Walsh 2010 u Laparoscopic Myomectomy (N=422): 2 hrs u Change in Hgb versus Abdominal Myomectomy u Improved with RALM: Barakat 2011 u No difference: Nash 2011

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• 1:350 have unsuspected sarcoma

• Risk of upstaging and worsening prognosis

• “The FDA is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.” November 2014 Morcellation of Sarcoma Worsens Outcome

Please email [email protected] with any ?s Raspagliesi Gynecol Oncol 2017;144:90 Risks of ANY Fibroid Manipulation

Total Abdominal Hysterectomy

Myomectomy (Open, H/S, L/S), subtotal hyst, TAH with injury

Please email [email protected] with any ?s Perri Int J Gyn Cancer 2009;19:257 Impact of FDA Announcement on Practice

Please email [email protected] with any ?s Stentz Obstet Gynecol 2017;129:1007 Surgical => Nonsurgical Transition

Surgical Procedure Year Nonsurgical Procedure Year______

Lancing boils for infection Antiquity Penicillin 1928

Tubal ligation for contraceptive 1880 Oral contraceptives 1960

Lobotomy for seizure 1886 Phenobarbitol 1912

Cholecystectomy for gallstones 1882 Lithotripsy 1985

Mastectomy for breast cancer 1882 Tamoxifen 1980

TURP for prostatic hypertrophy 1909 GnRH analogues 1982

Please email [email protected] with any ?s Minimally Invasive Therapy Endometrial Ablation

Please email [email protected] with any ?s Yeasmin Arch Gynecol Obstet 2009;280:279 Uterine Artery Embolization vs. Hysterectomy

• Decreases leiomyoma size by 50%

• Return to work day 20 vs. day 62

• Quality of Life comparable for 2 years, but 25% underwent hysterectomy

• Higher minor complication rate and readmission rate

• Mara Cardiovasc Intervent Radiol 2008;31:73 Worse pregnancy outcomes Hehenkamp Radiology 2008;246:823 Volkers Am J Obstet Gynecol 2007;196:519.e1 Please email [email protected] with any ?s Hehenkamp Am J Obstet Gynecol 2005;193:1618 Pinto Radiology 2003;226:425 MRI Guided High Frequency Ultrasound

• Decreased symptoms • 60-70% for 6 months • 50% for 12 months

• By 12 months, 4-17% required surgery

• Better outcome with larger treatment area, but increased myometrial trauma Mikami Radiat Med 2008;26:198 Morita Eur J Obstet Gynecol Reprod Biol 2008;139:199 • In blinded trial, no better than placebo Rabinovici Ultrasound Obstet Gynecol 2007;30:771 Stewart Obstet Gynecol 2007;110:279 Please email [email protected] with any ?s Stewart Fertil Steril 2006;85:22 Tempany Radiology 2003; 226: 897 Ultrasound-Guided Laparoscopic / Percutaneous / Hysteroscopic Microwave Ablation

u Mean Reduction: 63.5% at 3 months, 86.7% at 12 months

u 10.6% adverse reactions (vaginal secretion, abdominal pain)

u Viable, full-term pregnancies are possible after treatment

u Trauma to surrounding tissue unmonitored Liu Int J Hyperthermia 2016;32:876 Berman J Reprod Med 2015;60:194-8 Chen Ultrason Sonochem 2015;27:671-6 Bongers Gynecol Surg 2015;12:61 Please email [email protected] with any ?s Galen JSLS 2014;18:182 Medical Therapy 2011 2012 2013 2014 2015 2016 2017 2018 Elagolix Vilaprisan Vilaprisan Vilaprisan Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Ulipristal Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Leuprolide Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Mifepristone Cetrorelix Cetrorelix Cetrorelix Cetrorelix Cetrorelix Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid Retinoic Acid ECGC ECGC ECGC Berberine Berberine Tranilast Halofuginone Halofuginone Halofuginone >100 pubs Levonorgestrel Levonorgestrel Levonorgestrel Levonorgestrel Levonorgestrel 70-99 pubs Triptorelin Triptorelin Triptorelin Triptorelin Triptorelin 10-69 pubs Letrozole Letrozole Letrozole Letrozole 1-9 pubs AG1478 AG1478 Last Pub Simvastatin Tamoxifen 2001 Goserelin Goserelin Goserelin Goserelin Targretin 2004 Raloxifene Raloxifene Raloxifene Raloxifene Pioglitazone 2005 Tibolone Tibolone Tibolone Tibolone Resveratrol 2005 Asoprisnil Asoprisnil Asoprisnil Asoprisnil E. alatus 2006 Liarozole Liarozole TKS050 2007

Celecoxib Celecoxib Ciglitazone 2007 Telapristone Telapristone Telepristone Isoliquiritigenin 2008 Lynesterol Lynesterol Curcumin 2011 Methoxyestradiol Methoxyestradiol Fulvestrant 2011 Buserelin Buserelin Perfenidone 2011 Leuprolide Acetate

Visual1-10,Scale: reported patient Analog Palomba Fertil Steril 1998;70:111 Oral GnRH Analogues

Please email [email protected] with any ?s Archer Fertil Steril 2017;108:152 Selective Progesterone Receptor Modulators

Please email [email protected] with any ?s Donnez NEJM 2012;366:421-32 Summary

u Options falling out of favor u Options with benefit in specific populations u Robotic myomectomy u Abdominal Laparoscopic surgery u Radiofrequency ablation u Endometrial ablation u MRI-guided high frequency ultrasound u Progestin-releasing IUD

u Uterine artery embolization u Options with increasing promise u Injectable GnRH analogues u SPRMs u Oral GnRH analogues Thank you!