Management of hot flushes in ER+ breast cancer: Can we do this effectively & safely? Dr. Mei-Lin Ah-See Consultant Oncologist

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1 Management of hot flushes in ER+ breast cancer: Can we do this effectively & safely? Dr. Mei-Lin Ah-See Consultant Oncologist Mount Vernon Cancer Centre

2 Overview Why am I here? Why do our patients get hot flushes? Why can t we use HRT? Treatment options: Practical tips Prescription medication Complimentary therapies NICE & a Clinician Quick Guide

3 NCRI Breast Clinical Studies Group Subgroup on Symptom Management

4 185 Clinician Survey I believe the treatment of hot flushes is an unmet need Strongly agree Agree Disagree Strongly disagree 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0%

5 666 patient survey: Have any of these health care professionals ever asked you about hot flushes/night sweats? no answer no yes GP Surgeon Oncologist Breast Care Nurse

6 Patient Perspective N=666, median age=50 (25-69) Do you experience hot flushes? Do you experience night sweats? yes no yes no not aswered How much of a problem are your hot flushes? (scale of 1 to 10: 1 not a problem - 10 a major problem) 1 to 5 6 to 10 no answer

7 666 patient survey: Are your hot flushes/night sweats bad enough for you to consider stopping your endocrine therapy

8 Endocrine Therapy Adherence Dundee Study Low adherence (<80%) associated with poorer survival (HR1.20, p=0.019) % median adherence 20 Multifactorial Years after start Mukubate et al BJC 20013

9 Endocrine therapy induced menopausal symtoms ER/PR positive tumours Premenopausal Tamoxifen GnRH agonists + aromatase inhibitor Postmenopausal Tamoxifen Aromatase inhibitor

10 Chemotherapy induced early menopause Mechanism: Interferes with follicular maturation Primordial follicle depletion Risk factors: Increasing age Chemotherapy duration Alkylating agents

11 Mathematical Model of Risk of Menopause: First Year after Diagnosis Goodwin et al, JCO 1999

12 HRT in Breast Cancer Patients HABITS Holmberg et al, Lancet women with previous breast cancer (21% on tamoxifen) HRT vs. non-hrt Stopped early at 2.1 yr FU New breast cancer event: 26 HRT vs 7 non-hrt Resulted in early cessation Stockholm study & UK HRT trial

13 Management Options Practical advise & Lifestyle changes Prescription Medication Complementary Therapies

14 Practical Advise & Lifestyle Changes

15 Practical Advise & Lifestyle Changes Cooling techniques e.g. layers, natural fibres Avoid triggers e.g. alcohol, spicy foods Weight Loss (Exercise)

16 Prescription Medication

17 Prescription Medication Clonidine Antidepressant drugs Selective Serotonin-norepinephrine reuptake inhibitor Selective Serotonin Reuptake Inhibitors Gabapentin (Low dose progesterone) (HRT)

18 Clonidine Centrally acting alpha-agonist (Antihypertensive) 2 RCT transdermal patch ( 0.1mg/day oral dose vs. placebo) HF 44% clonidine vs. 27% placebo (p=0.04) Oral clonidine 100mcg nocte vs. placebo HF 38% clonidine vs. 24% placebo (p=0.006) severity HF 45% clonidine vs. 26% placebo Commonly used doses= 25-75mcg twice a day Side-effects sleep disturbance, hypertensive crisis Goldberg JCO 1994; Pandya Ann Intern Med 2000

19 Selective Serotonin Reuptake Inhibitors (SSRIs) Paroxetine RCT 10mg or 20mg better than placebo ( HF by 45.6%, 56.1% & 13.7% respectively) But potent CYP2D6 inhibitor reduces endoxifen levels NOT RECOMMENDED if on tamoxifen Fluoxetine RCT 20mg better than placebo ( HF by 50% vs. 36% ) Also potent CYP2D6 inhibitor - NOT RECOMMEMDED if on tamoxifen Sertraline 50mg daily vs. placebo 1 EP = no hot flushes not reached but some benefit seen with sertraline Citalopram Pilot studies single agent 10-20mg/day reduction 53-64% Stearns JCO 2005; Loprinzi JCO 2002; Kimmick The Breast Journal 2006; Barton 2003; Loprinzi 2005

20 Selective Serotonin-norepinephrine reuptake inhibitor (SNRI) Venlafaxine - Weak inhibitor of CYP2D6 3RCTs: Venlafaxine 3 dose levels Decrease in HF frequency from baseline at 4 weeks Decrease in severity score Placebo 19% 27% 37.5mg daily 30% p< % 75mg daily 46% p< % 150mg daily 57% p< % Skin conductance monitoring: 37.5mg & 75mg better than placebo Commonly used doses= mg daily Side-effects sexual dysfunction, nausea Loprinzi Lancet 2000; Carpenter The Oncologist 2007

21 Venlafaxine vs. Clonidine 3 RCTs: - Clonidine 75mcg bd vs. Venlafaxine 37.5mg bd Venlafaxine superior to clonidine but 1 EP HF at 4 weeks - Clonidine 50mcg bd vs. venlafaxine 75mg od (doubleblind cross over, 8 weeks treatment) Equivalent 55% vs. 49% HF reduction Higher drug discontinuation with venlafaxine (nausea, appetite loss, taste alteration, reduced libido) Loibl, Ann Oncol 2007; Buijs, Breast Cancer Res Treat 2009; Boekhout, JCO 2011

22 Venlafaxine vs. Clonidine 3 RCTs: - Clonidine 75mcg bd vs. Venlafaxine 37.5mg bd Venlafaxine superior to clonidine but 1 EP HF at 4 weeks -Venlafaxine 75mg od vs. Clonidine 100mcg od - Clonidine 50mcg bd vs. venlafaxine 75mg od (doubleblind cross over, 8 weeks treatment) Equivalent 55% vs. 49% HF reduction Higher drug discontinuation with venlafaxine (nausea, appetite loss, taste alteration, reduced libido) Loibl, Ann Oncol 2007; Buijs, Breast Cancer Res Treat 2009; Boekhout, JCO 2011

23 Gabapentin Antiepileptic, neuropathic pain 1 RCT (n=371) Placebo vs. Gabapentin 100mg tds vs. 300mg tds HF 15% vs. 31% vs. 46% Only Gabapentin 300mg tds significant decrease Commonly used doses= mg tds Side-effects: somnolence, fatigue Pandya, Lancet 2005

24 Low dose Progesterone Megestrol Acetate (Megace) n=97 breast cancer, n=66 prostate cancer Placebo vs. Megace 20mg twice daily Reduction HF 21% vs. 85% (p<0.001) Commonly used doses= 20mg twice daily Side-effects: increased appetite, fluid retention Is it safe in Breast Cancer patients?? Loprinzi, NEJM 1994

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26 Normalised Tumour Volume Effect of combination Tamoxifen & Progesterone on Xenograft t (days) Estrogen induced tumours Control Progesterone Tamoxifen Tamoxifen + progesterone Mohammed et al, Nature 2015, courtesy of Jason Carroll

27 Complementary Therapies

28 Complementary Therapies Acupuncture Mind-body Interventions Yoga Relaxation Paced breathing Hypnosis Cognitive Behavioural Therapy Herbal Remedies

29 Hot flush thresholds with and without symptoms No symptoms Thermoneutral zone Core body temperature Courtesy Myra Hunter

30 Hot flush thresholds with and without symptoms No symptoms Thermoneutral zone Core body temperature Hot flushes Symptoms Narrowed thermoneutral zone Shivering Courtesy Myra Hunter

31 Hot flush thresholds with and without symptoms No symptoms Thermoneutral zone Core body temperature Symptoms Hot flushes Lower oestrogen Narrowed thermoneutral zone Shivering stress Courtesy Myra Hunter

32 Acupuncture Superior to control No better than sham acupuncture? Acupuncture vs. Venlafaxine: - 50% both - returned after stopping especially in venlafaxine - 18 adverse effects with venlafaxine vs. none with acupuncture 2015 by American Society of Clinical Oncology Venzke, Complement Ther Med 2010, Vincent, Menopause 2007, Walker, JCO 2010

33 Acupuncture vs. Gabapentin: Randomized Placebo-controlled trial 2015 by American Society of Clinical Oncology SA=Sham Acupuncture, EA=Electroacupuncture GP=Gabapentin, PP=Placebo pills Mao, JCO 2015 Mean reduction in HFCS greatest for EA followed by SA, GP then PP (-7.4 vs vs vs. -3.4; p<0.001) Equivalent to HF EA 47.8% SA 45% GP 39.4% PP 22.3% Fewer AEs with acupuncture (3.1% vs 39.3% GP, 20% PP)

34 Cognitive Behavioural Therapy Behaviour Avoid situations, hide face, Open windows, stop what I m doing until it passes Physical Symptoms Heat, sweaty, palpitations, red face, Breathless, nausea, tingling Feelings Embarrassed, ashamed, anxious, angry, trapped, frustrated, out of control Thoughts People will think something is wrong My body is letting me down Not another one! I can t cope! Courtesy Myra Hunter

35 MENOS 1: Clinically significant reduction in Hot Flush problem rating group CBT vs Usual Care (n=96) % weeks 26 weeks CBT UC Mann, Lancet Oncology 2013

36 EVA study RCT (n=422) CBT vs. Exercise vs. CBT + Exercise vs. Waiting list control Significant reduction HF problem rating with CBT groups only Duijts, JCO 2012

37 MENOS 4 A multicentre Randomised Controlled Trial (RCT) of a breast care nurse delivered CBT intervention to reduce the impact of hot flushes in women with breast cancer Funding approval

38 1 RCT (n=105) Vitamin E Vitamin E 800IU vs. placebo No significant benefit (25% vs 22% reduction) Evening primrose oil Gamma Linolenic acid Mixed results Non-Breast Cancer RCT significant reduction severity HF (42% vs. 32%) but not for frequency or duration Other RCT - no better than placebo Barton, J Clin Oncol 1998; Farzaneh, Arch Gynecol Obstet 2013; Chenoy BMJ 1994

39 Avoid Phytoestrogens Black Cohosh Red Clover Dong Quay Soy (isoflavanes)

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41 Clinician Quick Guide Simple & Practical advise for all patients Patient still bothered with symptoms Non-drug options: Cognitive Behavioral Therapy (CBT) Acupuncture Hypnotherapy Relaxation Therapy Menopause Clinic referral Drug options: (Evening Primrose Oil) Clonidine 25-75mcg twice daily Venlafaxine mg daily Gabapentin mg thrice daily Weak SSRIs e.g. citalopram 10-20mg daily?hormonal therapy (discuss risks vs. benefits): Megace 20mg twice daily, HRT

42 Acknowledgements Jo Armes Anne Armstrong Claire Balmer Charlotte Coles Janet Dunn Deborah Fenlon Jacqueline Filshie Myra Hunter Mary Ann Lumsden Adrienne Morgan Delyth Morgan Carolyn Morris Mary O Brien Emma Pennery Katrina Randle Karen Roberts Felicity Swift Lesley Turner Annie Young Adele Richmond Andreia Fernandes Jennifer Sassarini Jenney Goodare Jillian Noble Susannah Stanway Marcus Galea Isabel White