New Treatments for Uterine fibroids

1. New Treatments for Uterine fibroids Prof Mary Ann Lumsden Prof of Gynaecology and Medical Education February 2013

2. Background Commonest benign tumour Incidence 25-40% 50% asymptomatic Malignant potential < 1% Main aim of treatment– symptom relief and improve quality of life Clinical symptom - menorrhagia +/- dysmenorrhea - reproductive dysfunction - bulk-related Treatment options - surgical - medical - minimally invasive surgical & non-surgical techniques

3. Uterine fibroids and fertility Systematic Reviews to assess effect of myomectomy on fertility. Systematic review and metanalysis of controlled studies Sub-mucosal fibroids decreased clinical pregnancy and implantation rates compared with infertile controls without fibroids. Intra-mural fibroids decreased fertility and increased pregnancy loss compared with women with no fibroids. Sub-serosal fibroids had no effect on fertility and myomectomy had no beneficial effect in this group (Pritts et al Fertil Steril 2009; Klatsky et al Am J Obstet Gynecol 2008; Somigliana et al 2007)

4. Mean SF36 scores for women with symptomatic and age-matched women in the normal population[N =47]

5. Uterine Fibroids are costly Estimated annual US spend $6-$34 billion * Source: Cardozo E, Segars J et al. Estimated annual cost of uterine leiomyomata in US. American Journal of Obstetrics and Gynecology, March 2012. published online Dec 2011

6. Diagnosis

7. MRI vs Ultrasound • Symptoms • Examination • MRI • USS

8. Fibroid Imaging Ultrasound MRI

9. Uterine Fibroids - Coronal image

10. Currently available therapies • Surgical • Hysterectomy (Abdominal/Vaginal/LAVH) • Myomectomy (Abdominal/Endoscopic) • Medical • Symptom control • Gonadotrophin releasing hormone agonists • Uterine artery embolisation

11. Surgery • Hysterectomy • Myomectomy

12. Hysterectomy • Very successful option • Amenorrhoea guaranteed • Appropriate where pathology present • Allows oophorectomy where appropriate • but • small but significant mortality • significant morbidity

13. Hysterectomy • Mortality of 1/1000-2000 • VALUE audit 14/37,000 • Major complications in 3% • Minor complications in 15 - 30% • but • Level of satisfaction high • A new treatment needs to be very effective to be better

14. Fig. 1

17. Developing Therapies • Medical: Interferon- • SPRModulator’s – Asoprosnil • Anti-progesterones (RU486) • MR Guided Thermal Ablation –vaporisation • Laser ablation • Focused Ultrasound (FUS)

18. Progesterone Receptor Modulators • Agonist and antagonistic effects of progesterone • Bind principally to progesterone receptor • Little effect on ovarian function • Act directly on endometrium (mainly on blood vessels) • Induce amenorrhoea • Shrink fibroids by 20-40% • Well tolerated

19. Clinical Effect

20. Ulipristal Acetate vs placebo- PEARL 1 Donnez et al 2012

21. Ulipristal Acetate vs GnRH agonist – PEARL 2 Donnez et al 2012

22. Progesterone Receptor Modulators • Conclusion • Significant decrease in menstrual blood loss • Minimal spotting and breakthrough bleeding • Modest decrease in uterine size • Well tolerated • Cause unusual effects on the endometrium

23. Minimally Invasive Techniques Uterine artery embolisation High Intensity Focused Ultrasound (HIFU) MRI-guided laser ablation Myolysis Laparoscopic occlusion of uterine vessels

24. High Intensity Focused Ultrasound

25. Accurate – target just the tumour • “Non-invasive” • Avoid general anesthesia • Low complication rate • Low side-effect profile • Preserve fertility • Cost-effective

26. Ultrasound pathway into fibroid • Ensures safety and accuracy of targeting • Bowel, bone or scar in pathway is an absolute contraindication

27. Treatment Plan FUS planned using axial MR images. Each green circle represents an individual treatment pulse or ‘sonication’, to build up a confluent lesion

28. Post treatment Gadolinium enhanced MRI showing Non-Perfused Volume

29. Post treatment – Sagittal View Non - perfused area ringed in yellow

30. Outcome after MRgFUS – No serosal damage or adhesions Myomectomy 6 weeks post MR-guided ablation

31. MRgFUS - Pain Experienced

32. Symptom Reduction - Timescale MRgFUS uterine fibroids

33. Adverse Events • Mild and self limiting • Leg or Buttock pain • UTI (1%) • Skin burn (< 1%) • NO serious infective complications • NO Emergency hysterectomy • One overnight admission in 6 years

34. July 1st 2012 Post MR guided FUS Pregnancy data Total no. pregnancies 109 (105 patients) Mean age (range) 36.1 (27-49)years Months to conception 8.8 TOTAL deliveries 59 Term vaginal 38 Term C-Section 21 Elective TOP 10 Miscarriages 22 (20%) Ongoing pregnancies 18 Mean delivery weight 3.3kg Insightec central register

35. Comparison of Mode of Delivery after MRgFUS References: Cardozo E, Segars J et al. Estimated annual cost of uterine leiomyomata in US. AJOG, March 2012. J. Goldberg+L Pereira. Pregnancy outcomes following treatment for fibroids: UAE versus laparoscopic myomectomy, ObstetGynecol2006, 18:402–4 H. Homer, E. Saridogan, UAE for fibroids is associated with an increased risk of miscarriage, Fertility and Sterility 2009 J. Rabinovici et al. Pregnancy outcomes after 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. Potential savings to healthcare system: Fewer preterm deliveries and operative deliveries Lower cost care of premature babies (average lifetime cost preterm baby is $57,458) Lower cost to healthcare system, where (average cost of c-section is $13 - 20,298)

36. Of these 280 MRgFUS patients • 5 Hysterectomies: 1 within 1 year of MRgFUS, • 5 within 2 years • 6 Myomectomies: 1 within 6 months of MRgFUS, • 4 within 1 year • 2 within 2 years • 11 Uterine Artery Embolisations: • 1 within 6 months of MRgFUS, • 3 within 1 year • 11 within 2 years • TOTAL 28 (10%) re-intervention rate

37. MRgHIFU • Not suitable for large fibroids • Not suitable for large numbers of fibroids • Impact on recurrence rate unclear • Modest effect on size • Impact on menstrual blood less than UAE

38. Uterine Artery Embolisation

39. Procedure

40. Uterine artery embolisation Pre Post Image courtesy of Dr J Moss, Dept Of Radiology, GGH.

41. Impact of UAE on size

42. Median % reduction in Menstrual Blood Loss

43. NEJM 2007;356:360-70

44. REST Trialearly outcomes (12 months)（REST) Quality of life (QoL) equal to surgery reduced hospital stay more rapid recovery patient satisfaction very high both groups symptom scores better with surgery complication rates similar UAE more cost effective re-intervention rate 13% vs 4%

45. Quality of Life ScoresMean SF36 scores pre-treatment and age-matched women in the normal population

46. Mean SF scores at 5 years post treatment and age matched women in the normal population 100 90 80 70 60 50 40 30 Normative Embolisation Surgery 20 10 0 Physical functioning Role limitation physical Bodily pain General health Vitality Social functioning Role limitationemotional Mental health

47. Minor complications 1 year – women 36 (34%) 10 (20%) 5 years - women 12(13%) 4(8%) UAE Surgery 27% Total complications 44% p= ns

48. Major adverse events UAE Surgery 1 year women 10 (20%) 13 (12%) 5 year women 3 (6%) 7 (7%) Total adverse events 20 (19%) 13 (25%) p= ns

49. Major adverse events UAE Surgery bleed, anaesthetic, sepsis,retention, wound vasovagal Hospital stay 1 year wound sepsis, expulsion, pain,breast cancer, amenorrhoea 5 years MND death, anal sphincter repair, UTI expulsion, cancer death, hysterectomy, laparoscopy

50. Re-interventions hysterectomy, UAE, myomectomy, endometrial ablation Treatment failure（治疗失败） Complications（并发症） Total re-interventions（总重新干预）