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Learning Objectives Contemporary Management of Symptomatic Leiomyomata
By the end of this talk, you will be able to:
understand the burden of fibroid disease Yoav Brill MD FRCSC Obstetrician and Gynecologist Toronto East General Hospital
recognize the associated signs and symptoms outline current medical and surgical options for treating uterine fibroids
Faculty/Presenter Disclosure
Disclosure of Commercial Support
• Current Management of Symptomatic Uterine Leiomyomas ….Yoav Brill, MD, FRCSC Obstetrician & Gynecologist Toronto East General Hospital
• Grants/Research Support: None • Speakers Bureau/Honoraria: Toronto East General Hospital, Warner Chillcot, Bayer Healthcare • Consulting Fees: None • Other: National Advisory Boards for ACTAVIS and AstraZeneca
• The Drugs & Therapeutics Day program has received financial support from Abbott Laboratories, Bayer Healthcare, Bristol Myers Squibb, Novartis Pharmaceuticals Canada Inc., Pfizer Canada in the form of an educational grant • The speaker has received an honorarium from the Department of Family Practice, Toronto East General Hospital
• Potential for conflict(s) of interest: None to declare
Mitigating Potential Bias Introduction • The Speaker and the Organizing Committee of the Drugs & Therapeutics Update have complete control over the content of this program. There has been NO Influence from the funders on the content.
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07/04/2014
Impact of Uterine Fibroids on Hysterectomy Rates
Uterine Fibroids Are Common
National hysterectomy rate in Canada: 338 per 100,000 women
Estimated prevalence of clinically relevant fibroids
Estimated cumulative incidence of fibroids
1.0
Black 0.8
White
0.6 0.4 0.2 0.0 36
38
40
42
44
46
Prevalence of clinically relevant fibroids
Cumulative incidence of fibroids
1.0
48
140 120
Rural Urban
135
130 108
0.8
100 0.6
Black
80
66
White
0.4
64
60 44
0.2
49
45
48
40 38
40
42
44
46
48
Age (years)
39 28
0.0 36
Age (years)
160
27
20 0 Uterine fibroids
Baird DD, et al. Am J Obstet Gynecol 2003;188:100-7
Burden of Uterine Fibroids
Menstrual disorders
Genital prolapse
Gynecologic Endometriosis Other cancers conditions
Source: CIHI 2010 Report. https://secure.cihi.ca/free_products/Healthindicators2010_en.pdf
Types of Fibroids
Most common indication for hysterectomy in the world1 Substantial impact on US health care system (est. $2.2 billion annually)2
$135 million in direct surgical costs in Canada3 Other costs include increased doctor visits, increased absenteeism and decreased productivity
Many of the costs are borne directly by the patient themselves
1. CIHI 2010 Report. https://secure.cihi.ca/free_products/Healthindicators2010_en.pdf 2. Islam S, et al. J Clin Endocrinol Metab 2013;98:921-34 3. Data on file
Indman P. http://efibroids.com/category/uterine-fibroids-basic-information/types-of-fibroids
Range of Symptoms Associated with Uterine Fibroids* Nearly half of women with fibroids have significant and often disabling symptoms.1
Symptoms can include:
When symptomatic, fibroids can be linked 3 to at least three major problems:
Bleeding complaints
Pregnancy complications
Mass effects related to the size and location of fibroids
Abnormal
or heavy menstrual bleeding1,2
Pain,1,2
pressure,1,2 and urinary symptoms2
Impairment of
These symptoms and consequences 3 have been shown to diminish quality of life
quality of
life (QOL)2
*Not all fibroids are symptomatic
1. Tropeano G, et al. Hum Reprod Update 2008;14:259-74 2. Downes E, et al. Eur J Obstet Gynecol Reprod Biol 2010;152:96-102 3. Viswanathan M, et al. Evid Rep Technol Assess (Full Rep) 2007;154:1-122
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Medical Management of Uterine Fibroids
Medical Management of Uterine Fibroids
Therapies are intended to reduce or eliminate uterine fibroid symptoms through one of the following options: Reduction
of the size of tumours
Reduction
of the amount of bleeding
Choiceoftherapyisinfluencedbythepatient’s: Symptom Tumour
severity
characteristics (e.g., volume, localization)
Age Uterine
preservation wishes
Fertility
preservation wishes
Miller CE. J Minim Invasive Gynecol 2009;16:11-21
Summary of Currently Used Medical Therapies for the Treatment of Uterine Fibroids (1)
Approach
Treatment Goal
Advantages
Disadvantages
Potential Issues for Fertility/Future Pregnancy
Oral Regulate and decrease contraceptives1,2 cyclic bleeding *
• Non-surgical • Symptomatic relief of bleeding
•No effect on fibroid size •Breakthrough bleeding and other side effects •Increased risk VTE3
None
Progestin1,2*
Regulate and decrease bleeding
• Non-surgical • Symptomatic relief of bleeding
•No effect on fibroid size •Inconsistent bleeding pattern •Side effects
None
Levonorgestrelreleasing IUD1*
Regulate and decrease • Non-surgical bleeding, may eliminate • Symptomatic periods relief of bleeding
•No effect fibroid size •Spontaneous expulsion of device4 •Efficacy not evaluated on women with submucosal fibroids 5
None
1.ACOG. Obstet Gynecol 2010;115:206-18 2.Miller CE. J Minim Invasive Gynecol 2009;16:11-21 3.Allan GM, et al. Can Fam Physician 2012;58:1097 4.Zapata LB, et al. Contraception 2010;82:41-55 5.Mirena® Product Monograph. July 2013
*Not indicated for uterine fibroids IUD = Intrauterine device
Summary of Currently Used Medical Therapies for the Treatment of Uterine Fibroids (2) Approach
Treatment goal
Advantages
Disadvantages
GnRH agonist +/- add-back1
Pre-operative therapy in premenopausal women to shrink fibroids and/or relieve anemia
Danazol1
Relief of menorrhagia • Non-surgical • Temporary relief and no immediate • Symptomatic relief • Side effects (waterwishes for pregnancy. • May have some retention, weight gain, reduction in fibroid hirsutism) size
Antifibrinolytic With periods, to (tranexamic decrease flow acid)2
GnRH = Gonadotropin-releasing hormone
Potential issues for fertility/future pregnancy
• Non-surgical •Fibroid regrowth on None • Symptomatic relief cessation of bleeding and •Adverse events pressure (menopausal symptoms, symptoms bone loss) • Reduction in fibroid size
• Non-surgical • No reduction in fibroid • Symptomatic relief size of acute bleeding • Limited data in symptomatic uterine fibroids
None
None
1.De Leo, et al. Drug Safety 2002;25:759-79 2.Naoulou B, Tsai MC. ACTA Obstet Gynecol Scand 2012;91:529-37
GnRH Agonists to Treat Uterine Fibroids
GnRH Agonists
Are typically used in younger women as a pre-operative therapy to reduce uterine fibroid size Continuous administration of GnRH agonist
Initial flare in gonadotropin release
Flare is followed by GnRH receptor down-regulation and desensitization
Down-regulation causes a hypogonadotropic state
Used in perimenopausal women to reduce uterine fibroid bulk before the onset of menopause, when uterine fibroids normally decline Effects are not immediate and can be associated with symptom worsening due to the flare effect, which may be blocked with an aromatase inhibitor Reduction in estrogen and progesterone secretion by ovaries within one month
Miller CE. J Minim Invasive Gynecol 2009;16:11-21
Not indicated for the treatment of uterine fibroids (off label) Use limited to 6 months in young women, due to hypoestrogenic effects, unless used in conjunction with HRT
Miller CE. J Minim Invasive Gynecol 2009;16:11-21
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GnRH Agonists Randomized trial: GnRH agonists vs. placebo
Repeated administration of GnRH agonists suppresses pituitary stimulation of ovarian estrogen production. This leads to a reduction in: – Bleeding2 – Fibroid volume2 – Uterine volume1,2
Change in uterine volume (n = 128)1 38 16
19
5 0 -19
(p < 0.01)
-36
-56
Fibroids return to pretreatment size 24 weeks after cessation of therapy1,2
(p < 0.001)
-38
-45 12 weeks
24 weeks
12
24
GnRHa
Placebo 1.Friedman AJ, et al. Obstet Gynecol 1991;77:720-5 2.Lethaby A, et al. BJOG 2002;109:1097-108
Ulipristal Acetate to Treat Uterine Fibroids Selective Progesterone Receptor Modulator (SPRMs) Rapidly reduces heavy bleeding while directly reducing fibroid size1,2
Ulipristal Acetate Clinical Review Rapidly stopped excessive bleeding (within a week), normalizes menstrualbleedingin90−98%ofpatients(PBAC 90% of patients have normalized bleeding (PP population)
40%
20%
80
Patients (%)
Primary efficacy end point (non-inferiority) Week 13
100%
ulipristal acetate 5 mg ulipristal acetate 10 mg Leuprolide 3.75 mg
60 40 20 0 0
10
20
30
40
50
60
70
80
90
100
Time (days) 0%
PP = Per protocol
ulipristal acetate 5 mg
ulipristal acetate 10 mg
Leuprolide 3.75 mg
Donnez J, et al. N Engl J Med 2012;366:421-32
7 days
30 days
Donnez J, et al. N Engl J Med 2012;366:421-32
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PEARL II: Effect on Fibroid Volume Reduction (Week 13) Median % volume reduction in the largest fibroids
0
ulipristal acetate 5 mg
ulipristal acetate 10 mg
PEARL II: Median % Volume Reduction in 3 Largest Fibroids After End of Treatment Follow-up
Leuprolide 0
Change from baseline at Week 13 (%) (PP population)
-10 -20
EOT 3-mo 6-mo
Follow-up EOT 3-mo 6-mo
Follow-up EOT
3-mo6-mo
-10 -17
-20 -30
-30 -40
-40
-36
-50
-42
-43
-45
-46 -50
-50
-57
-60 n = 45
-53
-60
Subpopulation of subjects in whom no surgery/UAE was performed
No significant difference between GnRH agonist and ulipristal acetate
Donnez J, et al. N Engl J Med 2012;366:421-32
-62
-55
n = 46
-56 n = 44
-70
ulipristal ulipristal Leuprolide acetate 5 mg acetate 10 mg Change from end of treatment (week 13) to 6-month follow-up for ulipristal acetate 5 mg and ulipristal acetate 10 mg vs. leuprolide: p < 0.05 EOT = End of treatment; mo = Months; UAE = Uterine artery embolization
Donnez J, et al. N Engl J Med 2012;366:421-32
Ulipristal Acetate PEARL III - open label study following 209 women for up to 4 cycles of Ulipristal 10mg daily for 3 months, separated by a full menstrual cycle
Amenorrhea rates were 79%, 89%, 88%, and 90% Median fibroids volume changes were 45%, —63%, -
Ulipristal
67%, and - 72%
Endometrial biopsies revealed benign histology, without hyperplasia
Conclusion: Repeated use of Ulipristal provides reliable control of effective, progressive shrinkage of fibroids, and appears safe for longer term use
Uterine Fibroid Embolization
Minimally Invasive Non-Surgical Options
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Uterine Fibroid Embolization Clinical Outcomes Cochrane review showed 30 to 46% reduction in volume of largest fibroid, 85% reduction in bleeding1
EMMY trial demonstrated 48.2% reduction in total myoma volume, 60.5% reduction in dominant myoma volume, no differences in bulk or pain related symptoms as compared to hyst.2 10-23% of women undergoing UFE will require some kind of further intervention1,2 1. Gupta et. al. 2006 2. Volkers et. al. 2007
Magnetic Resonance guided Focussed Ultrasound Surgery (MRgFUS)
Uterine Fibroid Embolization Advantages Minimally invasive, does not require GA, no need for prolonged hospitalization, works best for vascular lesions Disadvantages painful, requires sedation, requires at least overnight admission, need for additional intervention of up to 25%, premature ovarian failure, fertility implications, and increased risk of minor complications sepsis, hematoma at puncture site, postembolization syndrome fever, pain, nausea, and fatigue
MRgFUS Clinical Outcomes initial studies limited fibroid volume treated as per FDA as safety was main concern
volume shrinkage rates average 25% 1 Up to 28% of treated patients end up seeking alternative therapy within a year 2
Mayo Clinic 4 year study of 130 women 3 at 1 year 87.6% reported overall symptom improvement, 12.4% had no improvement 1. Stewart et. al. 2007 2. Fennessy et. al. 2007 3. Gorny et. al. 2011
MRgFUS Advantages Outpatient, non-surgical, real time 3D monitoring of thermal effects with MRI, works best with fibrous lesions
Surgical Intervention
Disadvantages expensive capital, long treatment times (3 hrs per session), fertility implications, limitations fibroid size, location, scars, presence of surgical clips, IUDs, etc. No RCTs so still considered experimental by many
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Surgical Options Endometrial Ablation Myomectomy Hysteroscopic Laparoscopic Abdominal Hysterectomy Vaginal Laparoscopic Assisted Vaginal Hysterectomy Total Laparoscopic Hysterectomy Laparoscopic Assisted Supracervical Hysterectomy Abdominal
Questions?
7
