Disclosure Principal Investigator, The ULTRA Study Nationwide - - PowerPoint PPT Presentation

New Treatments For Uterine Fibroids

Vanessa Jacoby, MD, MAS Associate Professor Obstetrics, Gynecology, & Reproductive Sciences University of California, San Francisco

Disclosure

Principal Investigator, The ULTRA Study Nationwide registry of laparoscopic radiofrequency ablation Funded by Acessa Health under contract with UCSF *Investigator Initiated Research (IIR) *Study design, implementation, analysis, and publication are independent of Acessa Health

Impact of Fibroids

• 30% of premenopausal women
• Up to 80% of African-American

women

• #1 reason for hysterectomy

(250,000/year)

• $34 billion/year to care for

women with fibroids.

• $17 billion for lost work and

disability after surgery

Cardozo et al, AJOG, 2012 March

Outline

• Medical Management
• Antifibrinolytics
• Hormonal modulation
• Complementary treatments
• Devices
• Focused Ultrasound
• Radiofrequency ablation

Antifibrinolytic: Tranexamic Acid

• Nonhormonal medication for heavy menses
• Binds to plasmin to inhibit fibrinolysis

Tranexamic Acid: Pivotal RCT

Freeman et al, AJOG, 2011, pg 319. e1-7

2% decrease 26% decrease 39% decrease

N=297

Tranexamic Acid RCTs: Subgroup with Fibroids in Two Pivotal Trials

Eder et al, Women’s Health, 2013

With fibroids, N=147 Without fibroids, N=224 44% decrease 36% decrease

Tranexamic Acid: Limitations

Freeman et al, AJOG, 2011, pg 319. e1-7

• Unknown fibroid size, number, location in subgroup
• Excluded if MD thought fibroids better for surgery
• Potential thrombotic risk (VTE)
• Not observed in meta-analysis (n=1,400)
• Women on OCP and others with VTE risk

have been excluded

Medical Management: Hormonal Manipulation

New Drug Targets: Selective hormone modulation

Estrogen Progesterone

Selective Progesterone Receptor Modulators (SPRM)

• Agonist and Antiagonist effect at PR binding site
• Decrease fibroid volume
• Induce apoptosis, suppress vascularization, reduce

collagen deposition

• Reduce bleeding
• Endometrial changes, suppress ovulation (but not

estrogen levels), amenorrhea

Selective Progesterone Receptor Modulators (SPRM)

Ulipristal Acetate:

decreased bleeding, improved QOL

Ulipristal (PEARL I and II)

• European trials (85-90% white participants)
• Placebo vs. Ulipristal (n=242)
• Lupron vs. Ulipristal (n=307)
• Participants with heavy bleeding, anemia, uterus

<16 weeks (largest fibroid <10cm)

• Received13 weeks of medication prior to surgery

Donnez et al, NEJM, 2012: 366:421-32.

Ulipristal Trials: PEARL I and II

Ulipristal vs. Placebo Ulipristal vs. Lupron

U 5mg N=95 Placebo N=48 U 5mg N=93 Lupron N=93

PBAC<75 (normal)

91% 19%* 75% 80%

Amenorrhea

73% 6%* 90% 89%

Change in fibroid volume

• 21%

+3%*

• 36%
• 53%

Moderate to severe hot flashes

*p<.05 compared

with 5mg

11% 40%* Donnez et al, NEJM, 2012

Ulipristal (VENUS I)

• US Trial, 25 sites

(68% African-American/black participants)

• Placebo vs. 5mg vs. 10mg (n=157)
• Participants with heavy bleeding,

uterus <20 weeks (largest fibroid <10cm)

• Received12 weeks of medication

Simon et al, Obstet Gynecol, March 2018

Ulipristal Trials: VENUS I

Placebo Ulipristal 5mg Ulipristal 10mg

N=56 N=53 N=48

Amenorrhea

1.8% 47.2%* 58.3%

Amenorrhea by day 11

43.4%* 58.3%*

Change in fibroid volume

+7.2%

• 9.6%*
• 16.3%

Hot flashes

5.7% 4.2%

Hypertension

p<.05 compared with 5mg

6.3% 3.0% Simon et al, Obstet Gynecol, March 2018

PRM Endometrial Changes

• PRM-associated endometrial

changes (PAEC)

• PAEC occurs in 8-20% of women
• Concern for possible long-term

transformation to endometrial hyperplasia/ca

• PAEC regresses spontaneously

after stopping drug

Long-Term Ulipristal Endometrial Changes: PEARL IV

• Trial of 4 treatment periods, 12 weeks each with

menses in between (spontaneous or northindrone)

• N=230 on 5mg daily, N=221 on 10mg
• EMB prior to treatment, all normal
• During study, EMB after each 12 week cycle
• Simple hyperplasia, n=3
• Complex atypical hyperplasia,

n=1 during study, N=1 at 3 month f/u

• Endometrial adenocarcinoma, n=1

Donnez et al, Fert Ster, Jan 2016

Ulipristal and Liver Toxicity

December 2017.. May 2018.. August 2018…

Ulipristal and Liver Toxicity

• 52 cases liver toxicity reported worldwide

(voluntary reporting!)

• 4 liver transplants
• 700,000 women who have taken the drug

GnRH Antagonist: Elagolix

• Suppresses pituitary-ovarian axis
• NOT Lupron: oral dosing, no hormone “flare”
• Phase 2 randomized trial (N=271, 74% African-

American/black):

• Premenopausal women, bleeding >80cc/cycle,

12 week treatment, 200-600mg, QD or BID

• 2 groups with add back (daily vs. cyclic

progestin)

GnRH Antagonist: Elagolix

Reduction in blood loss from baseline to last month of treatment Improvement in fibroid symptoms and QOL in some, not all groups Hot flashes: Elagolix alone 46-63% Elagolix/add back 19-27% Placebo12%

Archer et al, Fert Steril, July 2017

Aromatase Inhibitors: letrozole and anastrozole

Fibroid

Aromatase Enzyme

Androgens Estrogen

• Blocks action of aromatase enzyme in ovaries

and peripheral tissue, including fibroids

Letrozole: Decreases Fibroid Volume

Fibroid volume in cc

Parsanezhad et al, Fert Ster: Jan 2010: 93:1

46% decrease

Aromatase Inhibitors

• Benefits
• Estrogen levels in serum remain normal
• No hot flashes
• Limitations
• Small, mostly uncontrolled trials, none in U.S.
• No assessment of fibroid symptoms
• Long Term Risks
• Unknown for premenopausal women
• Concern for osteoporosis because postmenopasual women

with breast cancer on AIs have increased risk of fracture compared tamoxifen.

Complementary Treatments

Epigallocatechin (EGCG)

• Anti-inflammatory
• Anti-proliferative
• Antioxidant
• Animal and in vitro

– Inhibit proliferation and induce apoptosis in fibroid cells

Zhang et al, Fertil Steril 2010 and AJOG 2010

Green Tea Randomized Trial

• Placebo-controlled trial

N=39

• EGCG 800mg vs. Placebo
• Improved fibroid symptoms
• Increased Hb

(11.7 to 12.4 (g/dL)

• Decreased volume 33%
• No information on baseline

fibroid volume

• No U.S. data

Roshdy et al, Jo Women’s Health, 2013

Complementary Treatments

• Reduces cell proliferation
• Increases apoptosis
• Regulates extracellular matrix (ECM)
• Regulates gene transcription of ER/PR

Vitamin D: Epidemiologic Evidence

• Women with sufficient levels of vitamin D (>20ng/mL)

less likely to have uterine fibroids (OR 0.68, CI 0.48-0.96), N=1,036

Baird et al. Epidemiology 2013;24:447-53

• Women with vitamin D deficiency more likely to have

fibroids ( OR 2.5, CI 1.2-4.9), N=384

Paffoni et al. J Clin Endocrinol Metab 2013;98:E1374-8

• Inverse relationship between vitamin D and fibroid size

Sabry et al. Int J Womens Health 2013;5:93-100

Fibroid Devices

• Unlike new drugs, FDA does not require

comparative trials for new devices

• Low quality evidence for devices when enter market
• Treatments aim to destroy fibroid tissue, decrease

volume, improve symptoms

MR Guided Focused Ultrasound (MRgFUS)

• Focused ultrasound beam heats tissue to 150-1850 F
• Coagulative necrosis occurs

FDA approved 2003, very limited availability across U.S.

Stewart EA, Gostout B, et al, Obstet Gynecol, Aug 2007

MRgFUS Symptom Improvement

Largest trial to date (n=359) Low treatment volumes AE: abdominal pain (33%) skin burns (5%)

MRgFUS Outcomes

Study N NPV Shrinkage Reoperation

Stewart et al 2007 359

Variable

20% average Depends on NPV (24% at 2 years for 45% NPV) Gorny 2011 130 45% N/A 7.4% at 12 mo LeBlang 2010 80 55% 31% at 6 mo N/A Funaki 2009 91 40% at 24 mo 15% at 34 mo

Placebo-controlled Trial of MRgFUS

p=.90 p=.20

• 13
• 31

Jacoby V, et al, Fertil Steril, March 2016

Pilot, N=20 Symptom severity score

FIRSTT Study: UAE vs. MRgFUS

• RCT (n=57) and parallel cohort (n=34)
• Compared outcomes within 6 weeks of procedure
• No difference in quantity or quality of AEs

MRgFUS: less pain, lower use of opioids/NSAIDS, faster recovery (4 vs. 8 days, p<.001) UAE: Faster procedure (139 vs. 405 minutes, p<.001)

Barnard et al, AJOG, May 2017

Radiofrequency Ablation The Radiofrequency Ablation Device

Generator with Foot Pedal 3mm RF Handpiece Laparoscopic Ultrasound

• FDA approved for fibroids November 2012

(Acessa)

Radiofrequency Ablation

• Fibroids identified with

ultrasound (1cm incision)

• Radiofrequency (RF) probe

placed under ultrasound guidance (3mm incision)

• Monopolar RF energy

delivered to fibroids

• Tissue heats to 1000 C to

cause coagulative necrosis

• Fibroid cells reabsorbed

RF Ablation: Current Evidence

• Largest study, n=135
• FDA pivotal trial
• Uncontrolled, all women treated with RF ablation

Chudnoff et al, Green Jo, May 2013

Fibroid criteria

• <14 week uterus
• <6 fibroids
• <7cm fibroid

RF Ablation: Current Evidence

Chudnoff et al, Green Jo, May 2013

52% decrease in symptom score

RF Ablation: Current Evidence

Uterine Volume Fibroid Volume 3 months

• 15% (CI 11-20)*
• 40% (CI 36-44)*

12 months

• 24% (CI 19-30)*
• 45% (CI 39-52)*

*P<.001 Chudnoff et al, Green Jo, May 2013

Change in Fibroid and Uterine Volume from Baseline

RF Ablation: Current Evidence

• Adverse events: 4%
• Pregnancy (“not recommended” per FDA)
• Not studied in women who desire future fertility
• Insufficient data on pregnancy outcomes

Treatment Failure

• <1% at 1 year (1/135)
• 4.4% at 2 years (6/129)
• 4.5% at 3 years (4/88)
• TOTAL 11/135=8%

Chudnoff et al, Green Jo, May 2013 Guido et all, Health and Quality of Life Outcomes 2013, 11;139

RF Ablation: Randomized Trials

TRUST trial:

– Randomized trial of RF ablation vs. myomectomy vs. UAE – Open for enrollment in Canada and USA – Industry funded

LUSTER trial: n=51 in Germany, l/s RF ablation vs.myomectomy

– Primary outcome=less hospital time for RF ablation compared with l/s myomectomy (10 +5 hours vs. 29.9 +14.2 hours)

Brucker et al, Intern Jo Gyn Obstet, 2013

RF Ablation: Ongoing Studies

ULTRA: Uterine Leiomyoma Treatment with Radiofrequency Ablation)

• Nationwide post-market study of Acessa (N=150)
• 3 years of follow-up to assess change in symptoms, treatment failure,

pregnancy outcomes (NCT02100904)

Transcervical RF Ablation

FDA approved

August 2018 Sonata System

Handpiece: Ultrasound+RF Zone of ablation is fibroid only, not myometrium

Brolmann et al, Gynecol Surg, 2016

Transcervical RF Ablation FAST-EU Study

• 7 sites, Netherlands, Mexico, UK
• Heavy bleeding, FIGO 1-5 fibroids, <5cm
• N=50, no race/ethnicity data

Brolmann et al, Gynecol Surg, 2016

Hysteroscopic RF Ablation

3 months 12 months Fibroid volume

• 54.7±37.4%
• 66.6±32.1%

Symptom score

• 46.7 + 32.8%
• 55.1±41.0 %

Reoperation 8%

Brolmann et al, Gynecol Surg, 2016

Transcervical RF Ablation FAST-EU Study, ADVERSE EVENTS

• 34 events probably device related

7 dysmenorrhea 6 AUB 4 pelvic pain/cramping 2 UTI 1 Fibroid expulsion

Brolmann et al, Gynecol Surg, 2016

Conclusions

• New medications and complementary

treatments, limited data on safety and efficacy

• New procedures focus on shrinking

fibroids, uterine-preservation

• Long-term comparative studies are

needed!

Conclusions

• 3,000 women nationwide (9 sites)
• Compare effectiveness of all

treatments