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  • FIGO Santiago, Chile 11/03
  • Many peptides are too large to have bioavailability if taken orally. Ganirelix (Organon/Schering), Abarilex (Serano/Merck KGAA Germany). Elagolix (Neurocrine Biosciences NBIX) has molecule small enough to be taken orally. Currently only endometriosis studies underway (PETAL study vs. Lupron).
  • Testosterone and andostrenedione to estrone and estradiol
  • Meditrina Thomas Collet entering Phase II

Fibroid update lecture_2013 Fibroid update lecture_2013 Presentation Transcript

  • Update &New Rx Optionsfor FibroidsJay Goldberg, MD, MSCP
  • Learning Objectives• Describe the efficacy and safetyof Uterine Fibroid Embolization• Describe medications beingstudied for fibroid therapy• Describe technologies beingdeveloped for fibroid therapy
  • Uterine Fibroids• Benign, monoclonal,smooth muscle tumors• Most common tumor ofthe female reproductivetract• 20-77% ofpremenopausal women• Symptoms: Bleeding,Bulk, and Fertility
  • Conventional Treatments forSymptomatic Fibroids• Expectant management• Medical management– (NSAIDs, OCPs, GnRH agonist)• Endometrial Ablation• Myomectomy (50,000 / year in US)• Hysterectomy (250,000 / year in US)• **Uterine Fibroid Embolization(40,000 / year)
  • Fibroid Treatment AlgorithmGoldberg Expert Opin Obstet Gynecol 2007
  • Perceptions of Hysterectomyin Symptomatic Fibroid PatientsNOT Desiring Fertility• 21% favorable• 61% unfavorable– 67% of black women– 55% of whitewomenGoldberg Obstet Gynecol 2008
  • New & Future Treatmentsfor Symptomatic Fibroids• **Uterine Fibroid Embolization(40,000 / year)• Medical therapies:GnRH Antagonists, Aromatase Inhibitors,SPRMs• Mirena®IUD• HIFUS
  • Uterine Fibroid Embolization• First described as a primary treatment for fibroidsin 1995 by Jacque Ravina, MD, of France• Increasingly popular minimally invasiveprocedure performed by interventional radiologists• >400,000 women have undergone UFE
  • Ravina & GoldbergFIGO World CongressSantiago, Chile
  • Uterine Fibroid Embolization• Interventional Radiologists (IRs)• Polyvinyl alcohol (PVA) particles orspherical acrylic co-polymer beads• Infused into the uterine arteries underfluoroscopy• 15-120 minutes
  • How effective isUterine ArteryEmbolizationin relieving fibroidsymptoms?
  • Ontario UFE TrialPron Fertil Steril 2003;79:120-7Reduction involumeUterus 35%Dominant fibroid 42%•8 Ontario hospitals•N = 538•3 months
  • Spies Obstet Gynecol 2001;98:29-34Improvement insymptoms1 yearMenorrhagia 90%Bulk 91%•N = 200
  • REST TrialNEJM 2007;356:360-70• Randomized trial of Embolization versusSurgical Treatment for fibroids• 106 UFE; 43 hysterectomy + 8 myomectomy• SF-36 scores same at 1 year• Back to work: UFE (20 days) v Surgery (62)• 9% of UFEs had repeat UFE or hysterectomy• Conclusions: Faster recovery after UFE must beweighed against 9% risk for retreatment.
  • REST TrialCIRSE Annual Meeting, Valencia, Spain 2010• 5 year outcomes• Symptom and QOL outcomes similar• Satisfaction scores similar (UFE 90% v.surgery 87%)• Re-intervention higher with UFE (26% UFEv. 0% surgery)• Initial cost benefit for UFE, equal after 5years due to re-intervention
  • REST TrialMoss BJOG 2011• 5 year outcomes• Symptom and QOL outcomes similar• Satisfaction scores similar (UFE 90% v.surgery 87%)• Re-intervention higher with UFE (26% UFEv. 0% surgery)• Initial cost benefit for UFE, equal after 5years due to re-intervention
  • UFE Long-Term DataLength offollow-upPatientscompletingfollow-up%AsymptomaticAdditionalproceduresSpiesObstet Gynecol 20055 years 182 / 200 73 %25 hysterectomies8 myomectomies3 repeat UFEWalkerBJOG 20065-7 years 172 / 258 75 %9 hysterectomies6 myomectomies9 hysteroscopic resections1 endometrial ablation3 hysteroscopiesKatsumoriAJR 20065 years 80 / 96 90 % 10 %Total5 – 7years434/554 77 % 17 %
  • Is UAE a good procedurewith desired future fertility?Pregnancy afterUterine Artery EmbolizationJay Goldberg, MD, Leonardo Pereira, MD,Vincenzo Berghella, MDObstetrics & Gynecology 2002
  • Pregnancy afterUterine Artery Embolization(Goldberg Obstet Gynecol 2002)PregnancycomplicationPTD SAB Malpre-sentationPPH CS SGAAfter UAE forfibroids (%)22 32 22 9 65 9Generalpopulation(%)5-10 10-15 5 4-6 22 10Similar results:Walker AJOG 2006 & Pron Obstet Gynecol 2003
  • Pregnancy outcomes followingtreatment for fibroids:UAE vs Laparoscopic MyomectomyAJOG 2004Jay Goldberg, MD1, Leonardo Pereira, MD1, Vincenzo Berghella,MD1, James Diamond, PhD1, Emile Daraï, MD2, Piero Seinera,MD3, Renato Seracchioli, MD4Jefferson Medical College, Philadelphia, USA1, Tenon Hospital, Paris, France2,S. Anna Hospital, Turin, Italy3, S. Orsola Hospital, Bologna, Italy4
  • Pregnancy complications following UFE &Laparoscopic Myomectomy (LM) for fibroidsComplication UFE LM GeneralpopulationOddsratioP-valuePreterm delivery 5/32(16%)3/104(3%)5-10% 6.2 0.008Malpresentation 4/35(11%)3/104(3%)5% 4.3 0.046Spontaneousabortion12/51(24%)20/133(15%)10-15% 1.7 0.175Postpartumhemorrhage2/35(6%)1/104(1%)4-6% 6.3 0.093Small forgestational age1/22(5%)8/95(8%)10% 0.5 0.541Goldberg AJOG 2004
  • The Gyn as the gatekeeper for UFE• Wall Street Journal article (October 24, 2004)• Economic disincentive to refer(Goldberg OBG Management 2003)• Should UFE be offered to appropriate candidatesas part of an informed consent?(Goldberg Obstet Gynecol Surv 2005 & Contemp OB/GYN 2005)
  • Medications for Fibroids• Tranexamic Acid• GnRH Antagonists• Aromatase Inhibitors• SERMs• SPRMs
  • Tranexamic Acid• Oral anti-fibrinolytic• Lowers endometrial tissue plasminogen activator(tPA)• FDA approved for Rx of menorrhagia 11/09– Used in Europe for > 10 years• Contra-indicated in women at risk for thrombosis– Do not use in combo with estrogen containing meds• 1,300 mg po TID x up to 5 days during menses• $174 for thirty 650-mg tablets
  • Tranexamic AcidLukes et al. ACOG 2010 abstract• Double blind trial vs. placebo• N = 294 women with menorrhagia• Menstrual blood loss decreased by:– 39% with 3900 mg daily– 25% with 1950 mg daily– 5% with placebo
  • Tranexamic AcidMuse et al. ACOG 2010 abstract• N = 187 women with menorrhagia• Menstrual blood loss decreased by:–38% with 3900 mg daily–12% with placebo
  • Efficacy of Tranexamic Acid intreatment of idiopathic and non-functional heavy menstrual bleedingNaoulou Acta Obstet Gyn Scand 2012• Metanalysis of 10 studies• Effective and safe• 34-54% reduction in blood loss• 46-83% improvement in QOL parameters• “Limited evidence indicated potentialbenefit in fibroid patients withmenorrhagia”
  • GnRH Antagonist• High binding affinity for Pituitary receptors• Dose dependent rapid drop in gonadalsteroids• No initial flare as with Lupron®• Faster response• ↓ hypoestrogenic side effects than Lupron• No major side effects• Peptides too large for oral bioavailability(**2 new oral GnRH Antagonists testing **)
  • GnRH Antagonist Cetrorelix®for pre-op treatmentEngel Euro J Ob Gyn Repro Bio 2007• Prospective, randomized v Placebon=109• 22% ↓ in fibroid volume at 1 month*• 100% ↓ in menorrhagia*• 87% ↓ in pain*
  • GnRH Antagonist Elagolix®• Orally available• Ongoing clinical trials for fibroids andendometriosis• Estradiol suppressed by 24 hr. effectsrapidly reversed after discontinuation.Struthers J Clin Endo & Metab 2009
  • Aromatase InhibitorsAnastrazole (Arimidex)• Block Estrogen Synthetase  ovarian & peripheral estrogenproduction• Quick: Decrease Estradiol levels after 1 day• Significant  in fibroid volume at 1 month• No difference in FSH, LH levels• Side effects: hypoestrogenic, rash
  • Anastrazole (Arimidex)Varelas Obstet Gynecol 2007• Aromatase Inhibitor used to treat advancedbreast cancer in postmenopausal women• N = 35• 56% decrease in fibroid volume• 11% increase in Hgb• 63% improved menstrual pattern• Most effective if > 40 years• No serious adverse events
  • Selective Estrogen ReceptorModulators (SERMs)• Cochrane Review 2008• 3 studies totaling 215 patients• Raloxifene– lack of proliferative effect on endometrium• No significant fibroid reduction orclinical improvement• RR of DVT/PE 3.1 (95% CI 1.5-6.2)MORE study Ettinger 1999
  • Selective Progesterone ReceptorModulators (SPRMs or PRMs)• Fibroids responsive to Progesterone (P) as well asEstrogen (E)• P receptor ligands with uterine selectivity• RU486 (Mifepristone)– 47% reduction in fibroid volume, 41% amenorrhea(Fiscella Obstet Gynecol 2006)– 28% reduction in fibroid volume, increased Hgb(Engman Human Reprod 2009)– Antiglucocorticoid effects– Political backlash due to use as abortifacient
  • PRM AssociatedEndometrial Changes (PAEC)• Asoprisnil®(Schering & TAP)– Phase III trials of PRM discontinued due toEMB findings: ? endometrial hyperplasia• PAEC classified at NIH workshop• Novel, benign, multi-cystic effect on endometrium
  • Proellex®(CDB-4124)Repros Therapeutic, The Woodlands, TXWiehle & Goldberg US Obstet Gynecol 2008
  • Proellex®(CDB-4124)• Phase III trials ofPRM discontinueddue to hepatic sideeffects of elevatedtransaminases andbilirubin• Studies with vaginalProellex underway
  • Ulipristal (Ella®)• FDA approval foremergencycontraception 2010• Ongoing trials forfibroid treatment
  • Ulipristal v placebo forfibroids before surgeryDonnez NEJM 2012• Prospective randomized DBPC 13 weekstudy. n = 237• Bleeding controlled: 92% v 19%• Amenorrhea: 82% v 6%• Change in fibroid volume: -21% v +3%
  • GnRH Antagonists,Aromatase Inhibitors, SPRMs• Effective in treating bleeding and bulkfibroid symptoms• Oral medication• Uterine preservation• Avoid surgery• Short and Long term• GYN controlled• Safety concerns• Not coming to you any time soon
  • Mirena®IUDLevonorgestrel (LNG-IUS) releasing 20 µg/day
  • Mercorio Contraception 2003• Italian non-comparitive study of Mirena IUDfor women with fibroids/menorrhagia• Excluded “intracavitary abnormalities”• 13% expulsions• 22% withdrew for surgery• PBAC score ↓ 69% at 1 year (p< 0.01)– >100 (menorrhagia) in remaining 14/19 ♀• Hemoglobin ↓ despite LNG-IUS and Iron• Conclusion: Not for large fibroid uterus
  • Soysal Gynecol Obstet Invest 2005• Turkish study comparing LNG-IUS toThermal Balloon EMA for submucosalfibroids & menorrhagia• PBAC score ↓ (392→37) and ↑ in Hgb• No change in uterine size• No ↑ in expulsion rate• Conclusion: LNG-IUS safe and effective
  • MRI-Guided Focused HighIntensity UltraSound (HIFUS)• Thermal lesions arecreated within targetfibroids using MRI-guided focused highintensity ultrasound• FDA approved in 2004to treat uterine fibroids• ExAblate 2000 SystemInSightec & GE
  • Clinical outcomes of HIFUSStewart Fertil Steril 2006• Prospective study n = 82 at 1 year• 51% had 10-point improvement at 1year Symptom Severity Score (SSS)• 9% mean reduction in fibroid volume
  • MRI Guidance ofFocused Ultrasound• Questions about long termdurability, larger volumes, fertility• Performed by Radiologists, notGynecologists• Logistical issues• Not covered by insurers
  • Mini-laparotomysurgical technique• Modification of the Pelosimini-lap• Effective for SCH &Myomectomy• Alternative to laparoscopy& laparotomy• LOS: 1 day• Back to work within 2+weeks
  • Incision
  • Pocket
  • Protractor(recommended by Pelosi)
  • Tenaculum retrieval Morcellation
  • Case Studies
  • Case Study #1• 41-year-old gravida 0, desires fertility• Menorrhagia, anemia, bulk symptoms,infertility• Only hysterectomy recommended by GYN• US  20 cm uterus with multiple fibroids• 18 week uterus
  • Case Study #1Best treatment options?18 wk, bleeding, bulk, infertility1. Expectant management2. Endometrial ablation3. Mirena IUD4. UFE5. Myomectomy6. Hysterectomy
  • Case Study #1Best treatment options?18 wk, bleeding, bulk, infertility1.Expectant management2. Endometrial ablation3. Mirena IUD4. UFE5.Myomectomy6. Hysterectomy
  • Case Study #2• 45-year-old, no fertility desired• Menometrorrhagia, pelvic pressure• MRI  26 cm uterus with multiple,including submucosal andpedunculated, fibroids• 24 week uterus• EMB  benign endometrium
  • Case Study #2Best treatment options?24 wk submucosal & pedunclulatedfibroids, bleeding, bulk, no fertility desired1. Expectant management2. Endometrial ablation3. Mirena IUD4. UFE5. Myomectomy6. Hysterectomy
  • Case Study #2Best treatment options?24 wk submucosal & pedunclulatedfibroids, bleeding, bulk, no fertility desired1. Expectant management2. Endometrial ablation3. Mirena IUD4. UFE5. Myomectomy6. Hysterectomy
  • Case #3• 38-year-old, no fertility desired,smoker• Menorrhagia, anemia• Prior myomectomy and C-section• US  10 cm uterus with multiplesmall, including 2 cm submucosal,fibroids• 9 week size uterus, negative EMB
  • Case Study #3Best treatment options?9wk, bleeding, smoker, no fertility desired1. Expectant management2. COCs3. Endometrial ablation4. Mirena IUD5. UFE6. Hysteroscopic myomectomy7. Myomectomy8. Hysterectomy
  • Case Study #3Best treatment options?9wk, bleeding, smoker, no fertility desired1. Expectant management2. COCs3. Endometrial ablation4. Mirena IUD5. UFE6. Hysteroscopic myomectomy7. Myomectomy8. Hysterectomy
  • New Fibroid RxSummary• Majority of women unfavorable towardshysterectomy• UFE 17% failure rate at 5-7 years• ? Promising meds: GnRH Antagonists,Aromatase Inhibitors, & SPRMs• Mirena IUD contraception & ↓ bleeding• HIFU not quite there yet• Many new technologies in development