New Treatments for Uterine fibroids

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New Treatments for Uterine fibroids

• Prof Mary Ann Lumsden
• Prof of Gynaecology and Medical Education
• February 2013

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Background

• Commonest benign tumour
• Incidence 25-40
• 50 asymptomatic
• Malignant potential lt 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

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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)

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Mean SF36 scores for women with symptomatic and
age-matched women in the normal population

N 47
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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
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Diagnosis
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MRI vs Ultrasound

• Symptoms
• Examination
• MRI
• USS

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Fibroid Imaging
Ultrasound
MRI
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Uterine Fibroids - Coronal image
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Currently available therapies

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

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Surgery

• Hysterectomy
• Myomectomy

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Hysterectomy

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

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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

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Developing Therapies
MR Guided Thermal Ablation vaporisation Laser
ablation Focused Ultrasound (FUS)

• Medical Interferon-?
• SPRModulators Asoprosnil
• Anti-progesterones (RU486)

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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

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Clinical Effect
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Ulipristal Acetate vs placebo- PEARL 1
Donnez et al 2012
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Ulipristal Acetate vs GnRH agonist PEARL 2
Donnez et al 2012
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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

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Minimally Invasive Techniques

• Uterine artery embolisation
• High Intensity Focused Ultrasound (HIFU)
• MRI-guided laser ablation
• Myolysis
• Laparoscopic occlusion of uterine vessels

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High Intensity Focused Ultrasound
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• Accurate target just the tumour
• Non-invasive
• Avoid general anesthesia
• Low complication rate
• Low side-effect profile
• Preserve fertility
• Cost-effective

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Ultrasound pathway into fibroid

• Ensures safety and accuracy of targeting
• Bowel, bone or scar in pathway is an absolute
  contraindication

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Treatment Plan
FUS planned using axial MR images. Each green
circle represents an individual treatment pulse
or sonication, to build up a confluent lesion
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Post treatment
Gadolinium enhanced MRI showing Non-Perfused
Volume
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Post treatment Sagittal View
Non - perfused area ringed in yellow
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Outcome after MRgFUS No serosal damage or
adhesions
Myomectomy 6 weeks post MR-guided ablation
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MRgFUS - Pain Experienced
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Symptom Reduction - Timescale
MRgFUS uterine fibroids
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Adverse Events

• Mild and self limiting
• Leg or Buttock pain
• UTI (1)
• Skin burn (lt 1)
• NO serious infective complications
• NO Emergency hysterectomy
• One overnight admission in 6 years

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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
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Comparison of Mode of Delivery after MRgFUS
Complication General Population Fibroid Patients UAE Laparoscopic Myomectomy MRgFUS
Caesarean Delivery 22 48.5 66 77.8 36
Preterm Delivery 5-10 16 14 7.4 5
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)

• References Cardozo E, Segars J et al. Estimated
  annual cost of uterine leiomyomata in US. AJOG,
  March 2012.
• J. GoldbergL Pereira. Pregnancy outcomes
  following treatment for fibroids UAE versus
  laparoscopic myomectomy, ObstetGynecol2006,
  184024
• 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. 200916
  11-21.

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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

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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

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Uterine Artery Embolisation
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Procedure
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Uterine artery embolisation
Pre
Post
Image courtesy of Dr J Moss, Dept Of Radiology,
GGH.
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Impact of UAE on size
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Median reduction in Menstrual Blood Loss
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NEJM 2007356360-70
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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

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Quality of Life Scores Mean 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
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Minor complications
UAE
Surgery
27
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Total complications
p ns
48
Major adverse events
UAE
Surgery
1 year women
10 (20)
13 (12)
5 year women
7 (7)
3 (6)
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
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Re-interventions
hysterectomy, UAE, myomectomy, endometrial
ablation
Treatment failure(????)
Complications(???)
Total re-interventions(?????)
51
Intervention for treatment failure
Surgery
UAE
1 (2)
Total
28 (26)
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REST Trial 5 year Follow Up
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Cost utility analysis
Surgery
Mean difference (95CI)
UAE
1751
1 year
2702
948 (398-1432)
2467
2961
5 years
554 (-43-1173)
Initial cost benefit at 1 year lost
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Summary

• UAE offers more rapid recovery and shorter stay
• Complication profile similar to surgery
• QoL gain equal to surgery
• Re-intervention rate significantly higher
• Cost neutral with surgery at 5 years
• High satisfaction score both procedures

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Uterine Artery EmbolisationFertility

• Particles reaching ovary
• Global reduction in ovarian blood flow
• Temporary amenorrhoea relatively common
• Permanent amenorrhoea 1-2
• Fertility outcome?
• Endometrial atrophy (normal FSH)

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Pregnancy Complications
Normal Population UAE
IUGR 5 3
Preterm Delivery 5- 10 18, 13
PPH 5 18, 15, 20
LSCS Walker et al 2006, Dutton et al 2007 22 67, 72, 80
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REST TrialOvarian Failure post Treatment
UAE Surgical
gt40 years 0 0
gt 40 years 13 (14 gt 45 years) 3
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Conclusions

• UAE is successful in treating fibroid related
  symptoms such as HMB
• Complications appear no more likely than after
  surgery.
• Ovarian failure is very rare in younger women
• The effect on fertility and pregnancy is still
  unknown
• Should be considered in parous women with heavy
  menstrual bleeding particularly if they have
  completed their families.
• Possibly most appropriate treatment where there
  are multiple fibroids

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Acknowledgements

• Dr Jon Moss
• Dr Mona Khaund
• Dr Lillian Murray
• Dr Richard Edwards
• Prof Gordon Murray
• Miss Salma Rashid
• Sister Dorothy Lyons
• Scottish gynaecologists and interventional
  radiologists.
• Prof Lesley Regan
• Prof Hilary Critchley