Management of Menopausal Symptoms in Patients with Breast Cancer. Mike Dixon Edinburgh Breast Unit

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1 Management of Menopausal Symptoms in Patients with Breast Cancer Mike Dixon Edinburgh Breast Unit

2 Menopausal symptoms have a major impact on Quality of Life

4 Variety of Symptoms associated with the Menopause

6 Common Menopausal Symptoms in Breast Cancer Patients Vasomotor Symptoms Hot Flashes, Night Sweats and Sleep Disturbances Impaired Sexual Functioning Vaginal Dryness, Painful Intercourse and Loss of Sexual Interest

8 Hot Flashes: Pathophysiology Possible Causes Exaggerated response of the thermoregulatory center in the hypothalamus to decreased estrogen and progesterone levels Sympathetic activation of central 2-adrenergic receptors, which modulate core temperature threshold for widespread cutaneous vasodilatation and profuse sweating in the upper body

10 Hot Flashes in Breast Cancer Survivors Prevalence and severity of hot flashes higher in survivors than in healthy women Occur at younger age

11 Hot Flashes Treatment 1 Lifestyle adaptation Avoid spicy food, alcohol, hairdryers and anxiety Dress in layers Stop smoking as may be more severe in smokers Control weight Gaining >10% of pre diagnosis weight more hot flashes c/w women remaining within 10% weight loss reduces hot flushes

13 Hot Flashes Alternative Therapies Acupuncture as effective as venlafaxine in 1 study fewer side-effects with effective for longer Group cognitive behaviour therapy (e.g., relaxation, paced respiration, and sleep advice) benefit mood, sleep, and quality of life Magnesium 400mg up to 800mg: 25 pts - 56% effective Efficacy of black cohosh and phytoestrogens (including soy and red clover) unproven safety unknown

14 You really have to see a doctor about your hot flashes

15 Hot Flashes: Antidepressant Treatments Paroxetine (SSRI) 12.5 mg daily fluoxetine not as effective 62% reduction in hot flash score Sexual dysfuction, headache, agitation Venlafaxine (SNRI) mg daily + Citalopram 46-66% reduction in hot flash score Sexual dysfunction, nausea, sleep disturbances, dry mouth Mirtazepine - (NaSSA) 15-30mg 56-62% reduction in hot flash score Somnolescence SSRI: selective serotonin reuptake inhibitor. SNRI: serotonin noradrenaline reuptake inhibitor NaSSA: noradrenergic (norepinephrine) and specific serotoninergic antagonist

16 Citalopram for Hot Flashes 254 women randomised Placebo vs 10, 20 and 30mg of Citalopram Percent Mean Daily Reduction Equally effective if taking Tamoxifen or an AI 10mg few side effects 20mg broader and more helpful effects Depression dose 20-60mg Barton et al JCO 2010 ;28 (20):

17 Hot Flashes: Drug Treatments Gabapentin - serotonin noradrenaline reuptake inhibitor (SNRI) 35 66% reduction in hot flash score dizziness, fatigue, weight gain + drowsiness Clonidine 0.1mg centrally acting adrenergic agonist up to 56% reduction in hot flash score Light headedness, dry mouth + drowsiness Patients prefer venlafaxine 2:1 to gabapentin Venlafaxine more effective than Clonidine Bordeleau et al JCO 2010;28: Loprinzi et al JCO 2011; 29:

18 Global warming? No Another Menopause Cruise

19 Hot Flashes: Hormonal Drug Treatments Megestrol Acetate mg/day oral Medroxyprogesterone Acetate mg im one-time dose - half life 6 weeks More effective than non-hormonal agents Reduces hot flashes by about 80%,

20 Megestrol vs Gabapentin 120 Breast Cancer Patients with Hot Flashes Megestrol 40mg BD vs Gabapentin 300mg daily After 8 weeks: Hot flash assessment Megestrol Acetate more effective than Gabapentin Flashes less frequent 64.3% vs 44.8% p=0.005 Flashes less severe 37.1% vs 24.6% p=0.04 No flashes 40% vs 13.3% p= Ahimahalle et al IJHOSCR 2012: 6; 6-10

21 Menopause Clinic Yes the drug has been very successful and I can see it has put a stop to your hot flashes. But maybe we should reduce the dose??

22 Dose of Megestrol Acetate 286 women with Breast Cancer, 85% on tamoxifen Placebo vs Megace 20mg daily vs 40 mg daily Success >75% reduction in flashes 14% vs 65% vs 48% success p< mg dose more side effects Equally effective +/- tamoxifen Trend to being more effective in women >50 y 20mg dose best Wendall Goodwin et al JCO 2008: 26 ;

23 Safety of Megestrol Acetate Used for breast cancer treatment at 160mg dose Response rates similar to tamoxifen 45% of patients in one study continued for >3years Efficacy does not wear off Studies of use of Progestogens as HRT conflicting RR 0.9 in one study: JAMA 2000: 283; RR 2.24 in Nurses Health Study NEJM 1995:332; Appear safer with Tam / AI than when given alone Few reports of Recurrence on treatment

24 Other Hormonal Treatments E +/- P very effective in reducing hot flashes Increased recurrence HR 2.4 in HABITS Study Stockholm study 188 vs 190 pts HR 1.3 at 10.8yr More C/L cancers 15 vs 5 : LR 11 vs 15: Mets 12 vs 12 HRT appeared safe if >2yr after diagnosis and + Tam Tibolone - synthetic steroid - complex action Increased recurrence in LIBERATE HR 1.4 Fahlen et al Eur J Cancer 2013; 49; 52-9

25 What else can you do?

26 Studies of Different Doses of Tamoxifen Randomized double-blind trial: 1 vs 5 vs 20 mg/day Proliferation (Ki-67) fell at all doses No difference between doses 1 and 5mg less effect on Lipids and clotting factors 10mg or 20mg alternate days = 20mg biologically 10mg/day effective in breast pain and gynaecomastia Dose reduction probably safe with less hot flashes Increases compliance Decensi et al J Natl Cancer Inst 2003;95:779 90

27 Treatment of Hot Flashes

28 What do I use 1. General Advice 2. Megace 20mg day or MPA mg x1 3. Citalopram 10-20mg 4. Reduce tamoxifen dose 5. Gabapentin 300mg /day - nocte Increase dose by 300mg every 2-3days to dose of 300mg three times a day (900mg/day)

29 Vaginal Dryness and Dyspareunia More common with AIs than tamoxifen Lack of estrogen causes vaginal atrophy increases ph ( normal) change in vaginal flora Vaginal atrophy reduces quality of life and compliance

30 Lubricants: Results from Slug Model Iso-osmotic lubricant (Pre-Seed) Hypo-osmotic lubricant (Femglide) caused negative mucus production Moderately hyperosmotic lubricants (Replens, K-Y jelly) induced mild and moderate irritation Highly hyperosmotic lubricant (Astroglide) resulted in severe irritation and tissue damage Not all water-based products are the same

31 Most Studies are with Replens Restores vaginal ph to premenopausal levels - acidic Reduces vaginal dryness, itching, and irritation Two studies in breast cancer patients for the treatment of vaginal atrophy found as effective as estrogen vaginal cream initially Estrogen greater benefit long term

32 Topical Anaesthetics 5% lidocaine ointment overnight Helpful in overnight dyspareunia Topical gabapentin cream 6% applied TID useful in painful vulva Merit evaluation in Breast Cancer patients

33 Hormonal Therapies Topical Oestrogen : 90% Effective Vagifem 10 and 25µg vaginal tablets - estradiol Estring 7.5µg estradiol/ 24h NOT Femring Estrogen creams Estriol 0.01% Vagifem and Estring preferred by patients Can get Estriol pessaries 0.03mg - Topical Testosterone cream

34 Balancing Benefits vs Harms of Therapy

35 Oncologists Scared off Vaginal Estrogen Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors Kendall et al Ann Oncol. 2006;17: Estradiol levels measured in 6 women taking AIs Vagifem 25 µg daily for 2 weeks then twice weekly Baseline estradiol levels 3 pmol L At 14 days, estradiol levels increased to 72 pmol L 28 days estradiol levels 16 pmol L

36 Estrogen Absorbtion: Vagifem vs Estring Vagifem Estring Wills S et al SABCS 2009 Abstract 806

37 Comparison of Estring and Vagifem 3 patients used Estring, 4 used Vagifem Changes in Estradiol Levels: Mean and Standard Error Estring Vagifem Simmons et al JCO 2012:e128-9

38 Estring in Patients on AIs Only good data on 9 women 2 women had increase in circulating E2 1 woman marked increase Does not accumulate over time 38% decreased absorption with 2 nd ring Need mores studies Does appear safest of current options

39 I just can t read the fine print No wonder it s here Under side effects: Difficulty In reading fine print

40 Study of 20 women Vaginal Testosterone Witherby et al Topical Testosterone for Breast Cancer Patients with Vaginal Atrophy Related to Aromatase Inhibitors: A Phase I/II Study The Oncologist 2011;16: vs 300µg: 300µg more effective Estradiol levels remained suppressed Symptom scores improved from 2.0 to 0.7, p <.001 Improved dyspareunia - p =.0014 Improved vaginal dryness - p <.001 Median vaginal ph decreased 5.5 to p =.028 Median maturation index rose 20% to 40% - p <.001 Previous study of 500 µg showed increase in circulating E2

41 What do I use 1. Lubricants Pre seed and Replens 2. Estring if AI 3. Vagifem 10πg if on tamoxifen For the Future 1. Testosterone cream 300µg 2. Estriol cream or pessary +/- lyophilised lactobacilli

42 I am not talking about today the other problems patients get on hormone therapy

44 Or how menopausal symptoms significantly strain relationships..

46 There is also the problem of menopausal weight gain in women and men..

47 Very well It seems Your weight is perfect You just happen to be Eleven feet too short

48 Menopause and its symptoms a major issue..

50 Can we treat menopausal symptoms in women with breast cancer with drugs safely? Maybe

Managing menopause in Primary Care and recent advances in HRT

Managing menopause in Primary Care and recent advances in HRT Raj Saha, MD, DMRT, FRCOG PG Cert. Advanced Gynaecology Endoscopy Consultant Gynaecologist Heart of England NHS Foundation Trust Spire Parkway