1. Managing Menopausal Symptoms after Breast Cancer Rod Baber

2. What are menopausal symptoms ?  Vasomotor symptoms:  hot flushes  night sweats  Vulvo-vaginal dryness  Sleep disturbance  Mood disturbance  Sexual dysfunction NIH State-of-the-Science Panel. Ann Intern Med 2005

3. Why do breast cancer patients get menopausal symptoms?  Around 60% affected  Young women with chemotherapy-induced ovarian failure  Young women undergoing oophorectomy  Peri and postmenopausal women who stop HRT on diagnosis of breast cancer  Pre and postmenopausal women taking endocrine therapy (for up to 10 years)  Hot flushes are more frequent and severe than in spontaneous menopause  Anti-estrogen therapies may exacerbate symptoms:  Vaginal dryness particularly severe with aromatase inhibitors Hickey et al 2008, Kemp et al 2014, Marino et al 2014, Howell et al 2005, ACOG 2014

4. Why are menopausal symptoms after breast cancer problematic?  They may impair quality of life:  Worse than the cancer treatment for some women  May impact on tolerance of endocrine therapy  Up to 40% discontinue because of hot flushes  May add to common post-cancer problems such as sleep disturbance and fatigue  May have implications for prognosis  Risks of early menopause may contribute to morbidity and mortality  Osteoporosis and cardiovascular disease Howard-Anderson et al 2012, Chen et al 2013

5.  Most severe symptoms around the LMP  Mean duration of vasomotor symptoms at natural menopause is 8-10 years  Duration after surgical or chemo-induced menopause unknown Politi et al 2008, Col et al 2008, Freeman et al 2014 How long do hot flushes last ?

6. How can symptoms be managed?  Most women have several symptoms  Vasomotor symptom are the most common reason to seek treatment, but additive effect of symptoms is unknown  Estrogen is the most effective treatment for VMS (85% reduction) and also improves  Vulvo-vaginal dryness  Potentially mood and sleep  Bone health MacLennan et al 2006, Suckling et al 2006, Soares and Frey 2010, Formoso et al 2012

7. Menopausal symptoms after breast cancer: what can be done?  No single non-hormonal treatment for VMS, vaginal symptoms, mood and bone health  Need to prioritise and consider multiple interventions  Effective non-pharmacological and non-hormonal therapies are available  Tailor interventions to individual symptom burden

8. 3. Establish what is wanted from Intervention Reduction in (what) symptomsInformation / Other outcomes 2. Assess menopausal symptoms Hot flushes, night sweats, insomniaJoint aches and pains, vaginal dryness…. 1. Assess Cause of menopausal symptoms Discontinued Endocrine HRT Therapy Treatment induced menopause Managing Menopausal Symptoms after Breast Cancer

9. Managing atrophic vaginitis after breast cancer  Prevalence after breast cancer unknown  Affects ~ 40% at menopause  Vaginal dryness, discomfort, pruritis, dyspareunia, UTI, urgency  Worse with AI than tamoxifen  Vaginal Lubricants: Sylk, Astroglide, Passion, Wet, Olive oil  Vaginal Moisturisers: Replens  Vulval Lignocaine gel 4%  Vaginal Estrogens -Ovestin (Oestriol), Vagifem (E2) tablets  Ospemifene Suckling et al 2006, Dorr et al 2010, Maarmari 2013, Barentsen et al 1997, Burich et al 2012

10. Managing atrophic vaginitis after breast cancer  Vaginal estrogens are the most effective treatment, but are systemically absorbed  Vaginal estradiol significantly increases systemic E2 in users of aromatase inhibitors  Many oncologists now caution against their use  Clinical implications unknown  Tamoxifen is probably estrogenic in vagina Kendall et al 2006, Ferrazzi et al 1977, Freidrich et al 1998

11. Managing atrophic vaginitis after breast cancer Clinical message  Avoid vaginal estrogens in AI users  If considering then discuss with oncologist  Consider vaginal estrogens in TAM users  Still discuss with oncologist  Relative efficacy of vaginal lubricants unknown  Vulval lignocaine (4%) reduces dyspareunia and sexual distress in breast cancer survivors Goetsch et al 2014

12. Treating VMS without hormones  Target day or night VMS  Getting a good nights sleep may make the day manageable  Review the likely “cause” of the VMS  Early menopause  Stopping HRT  Endocrine therapy  Interventions may differ depending on cause  Some VMS improve by swapping endocrine therapies Thomas et al 2008. Hickey et al 2008, Baum et al 2008

13. Alternative Therapies Alternative Therapies  Phytoestrogens :  Pure isoflavones may be effective, but mixed evidence to suggest that supplements are effective.  Genistein reduces hot flush frequency (20%) and severity (26%) compared to placebo  Black Cohosh: Data mixed but insufficient to recommend  Dong Quai: Thought to enhance endogenous estrogens. 1RCT, no better than placebo  TCM: Unconvincing data in Western trials, more success in trials of Asian women  Acupuncture: Evidence inconclusive Hickey M, Baber R Drug Safety 2005;28: 1085-1100Baber R. Maturitas 2010; 66: 344-49

14. Boekhout A H et al. JCO 2011 Clonidine  25-50ug bd  Alpha adrenoreceptor agonist, reduces vasoconstriction  Clinical effect modest side effects: constipation, dry mouth, drowsiness  Long term data lacking Prescription treatments for vasomotor symptoms

15. Butt et al 2008 Reddy et al 2006, Aguirre et al 2010, Pinkerton et al 2014 Can be used in women already taking SSRI/SNRI Gabapentin for hot flushes  Gamma amino butyric acid analogue used as anticonvulsant  Probably acts as hypothalamic thermoregulatory  4 RCTs show significant reduction in vasomotor symptoms at 900mg per day with a clear dose response relationship  Initial side effects include drowsiness, confusion and ataxia  Start with 300mg and build up slowly as required Hickey M, Baber R Drug Safety 2005;28: 1085-1100

16. Loprinzi et al JCO 2010 Pregabalin for hot flashes

17. Loprinzi et al 2000 and 2002,Stearns et al 2005, Evans et al 2006, Speroff et al 2008, Pinkerton et Al 2013. Simon et al 2013, Freeman et al 2012, Carpenter et al 2012, Ensrud et al 2012, Joffe et al, in prep, Carpenter et al, 2012, La Croix et al 2012, Reed et al 2012, Suvanto-Luukkonen et al 2005, Pinkerton et al NAMS NameReduction in hot flushesDuration of studiesAdditional benefits Desvenlafaxine 100mg 64% (vs 51% placebo) One year Improved sleep Nausea, constipation, sexual dysfunction Venlafaxine 75mg SR 60% (vs 27% placebo) 8 weeks Improved sleep Nausea, constipation, sexual dysfunction Escitalopram (10- 20mg) 55 % (vs 36% placebo) 8 weeks Improved sleep, mood, quality of life and hot flash interference Does not impair sexual function. No discontinuation syndr at 10mg Citalopram 10mg49% (vs 23% placebo) 6 weeks 9 months Does not impair sexual function. No discontinuation syndrome Ineffective Fluoxetine 20mg50% (vs 36% placebo) 6 weeks 9 months Nausea, constipation, sexual dysfunction Ineffective/ AND PAROXETINE? Paroxetine 12.5mg Paroxetine 7.5mg 56% (vs 28% placebo) 43% (vs 37% placebo) 40% (vs 32% placebo) 6 weeks 12 weeks 24 weeks Nausea, fatigue, dizzyness, insomnia. No discontinuation syndrome at lower doses No change in sexual function Improved sleep and reduced burden of hot flashes Antidepressants for hot flushes

18. Venlafaxine 75mg equivalent to 0.25mg estradiol for VMS Joffe H et al JAMA Internal Medicine July 2014 Volume 174, Number 7

19. Considerations for SSRI/SRNI  Many middle aged women will already be taking SSRI/SNRI for depression  Side effects are common  Some products may cause discontinuation syndromes  Primarily short-acting agents: Paroxetine, (des)venlafaxine  Fluoxetine and paroxetine may interact with tamoxifen Stearns et al 2004, 2006, Jin et al 2005,

20. HRT after Breast Cancer Three major Randomized trials HABITS  HABITS (Hrt After Breast cancer Is iT Safe) - 345 women, mean age 55, 2.1year follow up  Stockholm trial - 378 women, median age 56, 4.1 year follow up  LIBERATE - 3098 women, median age 53, 3 year follow up

21. HRT after Breast Cancer HABITS: Median follow up 2.1 years  RR of breast cancer 3.5 (1.5-8.1)  26% node positive  21% tamoxifen use  Most using continuous combined HT STOCKHOLM: Median follow up 4.1 years  RR of breast cancer 0.82 (0.35 – 1.9)  16% node positive  52% tamoxifen use  73% Estrogen only or long cycle (3/12) progestin Holmberg L Lancet 2004;363:453-4, von Schoultz E J Natl Canc Inst 2005;97:533-5

22. Breast Cancer recurrence (I.T.T) HR Livial v Placebo (95% CI) HR = 1.40 95% CI: 1.14-1.70 Kenemans P et al Lancet Oncology 2009;10:135-146

23. Hormone therapy in women at high risk of breast cancer  Family history has no additive impact on breast cancer risk with HRT use 1,2 although women with gene mutations are at vastly increased lifetime risk of breast cancer  HRT use and family history had independent and non interacting risk factors for breast cancer in WHI 3  Long term observational studies have reported no extra risk for those using HRT with a family history of breast cancer  HRT following risk reduction surgery appears not to increase risk 4,5  HRT in such women should use minimal progestrogen and ideally progesterone or dydrogesterone 1. Rippy L Marsden J Climacteric 2006;9:404-15 2. Sellars T et al Ann Intern Med 1997;127:973-80 3. Gramling R et al Epidemiology 2009;20:752-6 4. Rebeck T et al J Clin Oncol 2005;23:7804-10 5. Eisen J et al J Nat Cancer Inst. 2008;100:1361-67

24.  No change in digital thermography  Reduces troublesomeness of vasomotor symptoms by >50% in breast cancer patients  Side effects  Improved mood  Reduced anxiety Mann et al, 2012, Ayres et al 2012 Cognitive Behavior Therapy

25. USING THE EVIDENCE TO GUIDE PRACTICE Managing Menopause in high risk women

26.  Provide information about menopause and its management prior to chemotherapy  Try and work out what is causing the hot flushes – you may need to use several interventions  For troublesome VMS start with SNRI or Gabapentin  Consider increasing gabapentin at night if sleep disturbance  Most work within a week  Use non-pharmacological methods (CBT/mindfulness) to reduce impact Hickey et al 2008, 2012, Finch and Narod 2013, van Oostrom et al 2003, Scott et al, In press, Haines et al NAMS Clinical Guidance: Managing Menopause in high risk women

27. Managing menopausal symptoms after breast cancer  Attention to life style factors  Avoid alternative therapies and practitioners  Liason with Surgeon / Oncologist / GP  Reduce dose of adjuvant therapy  Vaginal lubricants, moisturisers or Oestriol ( Ospemifene C/I)  Clonidine, SSRI / SNRI, Gabapentin  Stellate Ganglion Block,  Cognitive Behavioural Therapy Hickey M, Baber R Drug Safety 2005;28: 1085-1100MacLennan A H Climacteric 2011;14:209-17

28. Patient referred to MSAC Clinic Patient seen by menopause specialist Patient seen by nurse specialist Management Issues resolved by Multidisciplinary team Information Evidence-based Clinical guidelines Data collection Assessment Treatment plan Hickey et al 2008, 2010, Marino et al 2013, Marino et al 2014 Model of multidisciplinary care: Menopause Symptoms After Cancer Clinic (MSAC)