Μυοκαρδιοπάθεια από τη θεραπεία του καρκίνου. Δημήτρης Φαρμάκης Ιατρική Σχολή ΕΚΠΑ Αθήνα

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1 Μυοκαρδιοπάθεια από τη θεραπεία του καρκίνου Δημήτρης Φαρμάκης Ιατρική Σχολή ΕΚΠΑ Αθήνα

2 Estimated and projected cancer survivors in USA de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013

3 Causes of death in cancer survivors Causes of death in 1807 cancer survivors followed for 7 years Other 16% Heart disease 33% Cancer 51% Ning et al. Cancer Res 2012

4 Determinants of cardiovascular injury in cancer patients Cancer Pre-existing RF and CVD Cancer therapy

5 Pre-existing RF and CVD Cancer Cancer therapy 1. Effects of cancer therapy Chemotherapy and targeted agents

6 1. Effects of cancer therapy: Radiation-induced cardiac injury Groarke et al, Eur Heart J 2014

7 Cancer Pre-existing RF and CVD Cancer therapy 2. Effects of cancer Farmakis et al, J Am Coll Cardiol 2014

8 Cancer Pre-existing RF and CVD Cancer therapy 3. Effects of RF and CVD

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10 Cardiovascular complications of cancer therapy 1. Myocardial dysfunction and heart failure 2. Coronary artery disease 3. Arrhythmias 4. Arterial hypertension 5. Valvular heart disease 6. Thromboembolic disease 7. Peripheral vascular disease and stroke 8. Pulmonary hypertension 9. Other: pericardial disease, ANS dysfunction

11 Cardiovascular complications of cancer therapy 1. Myocardial dysfunction and heart failure 2. Coronary artery disease 3. Arrhythmias 4. Arterial hypertension 5. Valvular heart disease 6. Thromboembolic disease 7. Peripheral vascular disease and stroke 8. Pulmonary hypertension 9. Other: pericardial disease, ANS dysfunction Indirect causes or precipitating factors for heart failure

12 Myocardial dysfunction Class Drug Incidence Anthacyclines Doxorubicin 3-48% Alkylating agents Cyclophosphamide 7-28% Antimicrotubule agents Docetaxel 2-13% Monoclonal Ab Trastuzumab 1-20% Tyrosine kinase inhibitors Sunitinib 3-19% Proteasome inhibitors Carfilzomib 11-15% Adapted from ESC 2016

13 Anthracycline-trastuzumab interaction Ewer and Ewer, Nat Rev Cardiol 2015

14 Strategies for prevention and management of cardiotoxicity

15 Strategies for prevention and management of cardiotoxicity Before cancer therapy: Identification and evaluation of high-risk patients Optimal control of CV disease and risk factors ESC 2016

16 Strategies for prevention and management of cardiotoxicity Before cancer therapy: Identification and evaluation of high-risk patients Optimal control of CV disease and risk factors During cancer therapy: Cardiac monitoring for early signs of cardiotoxicity Timely implementation of preventive or therapeutic measures ESC 2016

17 Strategies for prevention and management of cardiotoxicity Before cancer therapy: Identification and evaluation of high-risk patients Optimal control of CV disease and risk factors During cancer therapy: Cardiac monitoring for early signs of cardiotoxicity Timely implementation of preventive or therapeutic measures After cancer therapy: Long-term surveillance programs ESC 2016

18 Identification of high-risk patients Demographics Risk factors Heart disease Cancer therapy Age <18 y >65 y Female gender (anthracyclines) Diabetes Hypercholesterolemia Smoking Obesity Heart failure or LV dysfunction CAD Hypertensive HD (LVH) Valvular HD (mod./severe) Prior antracyclines Prior chest radiotherapy Combined chemo/targeted agents Combined chemo and chest radiation Sedentary life Cardiomyopathies Cumulative dose (antrhacyclines) Sign. arrhythmias (AF, VT) Modified from ESC 2016

19 Strategies for primary prevention of cardiotoxicity ESC 2016

20 Strategies for primary prevention of cardiotoxicity ESC 2016

21 Strategies for primary prevention of cardiotoxicity? ESC 2016

22 RCTs on primary prevention Trial Agent N Design/Fup Results Cardinale (2006) Enalapril 114 RCT/12mo No LVEF MACE incidence Pituskin (2015) Bisoprolol Perindopril 99 RCT/12mo No LVEF Gulati (2015) Candesartan 120 RCT/2-16mo No LVEF Akpek (2015) Spironolactone 83 RCT/6mo No LVEF No TNI and BNP Acar (2011) Atorvastatin 40 RCT/6mo No LVEF Modified form Cardinale et al, Curr Cardiol Rep 2016

23 Primary prevention recommendations by ΑHA AHA 2013

24 Detection of cardiotoxicity ESC 2016

25 Echo monitoring 2625 pts receiving anthracycline chemo (breast Ca or NHL) Close monitoring (3-monthy during chemo and 1 st year, 6- monthly for 4 years, yearly afterwards) 9% LVEF decline (decrease >10% and <50%) 2% HF NYHA III-IV 0.3% hospitalized for AHF (0.2% died of AHF) Cardinale et al, Circulation 2015

26 Time course of LVEF decline post-anthracycline Mean time to LVEF decline: 3.5 months 98% of cases within 1 st year 5 pts with LVEF decline at 5.5 years: 4 had CAD, 1 had additional Rth 1 year before Cardinale et al, Circulation 2015

27 Temporal effects of cardiotoxic therapies Suter & Ewer, Eur Heart J 2012

28 Troponin predicts cardiac events and LVEF decline TnI measured soon after chemotherapy (early TnI) and 1 month later (late TnI). Cardinale et al, Circulation 2004

29 ΝT-proBNP predicts LVEF decline Cardinale & Sandri, Prog Cardiovasc Dis 2010

30 2D strain predicts LV dysfunction early >15% reduction in global longitudinal strain

31 Myocardial dysfunction: Key recommendations LVEF decrease >10% to a value >50%: repeated LVEF assessment LVEF decrease >10% to a value <50%: ACEi (or ARB) and beta-blocker Symptomatic HF: ACEi (or ARB) and beta-blocker ESC 2016

32 Primary prevention recommendations by ΑHA AHA 2013

33 Effects of ACEi and BB on anthracycline-induced cardiotoxicity 2625 pts receiving anthracycline chemo (breast Ca or NHL) Enalapril and carvedilol or bisoprolol: 82% LVEF recovery: 11% full recovery (pre-chemo value) 71% partial recovery (increase >5% and >50%) Mean time to LVEF recovery: 8 months Cardinale et al, Circulation 2015

34 Effects of ACEi and BB on anthracycline-induced cardiotoxicity 201 pts, LVEF <45% due to anthracycline chemotherapy Enalapril +/- carvedilol Response rates: 42% LVEF incr. >50% - 13% LVEF incr. >10% but <50% - 45% LVEF incr. <10% but <50% Time of therapy onset a crucial determinant of response Cardinale et al, JACC 2010

35 Therapeutic algorithm for HFrEF ESC 2016

36 Therapeutic algorithm for HFrEF?? ESC 2016

37 Other management strategies Coronary artery disease: Patients on pyrimidine analogues: close ECG monitoring for ischemia Ιf ischemia occurs, discontinuation of chemotherapy; re-challenge only when no alternatives, pretreatment with nitrates and/or CCB Arterial hypertension: Start antihypertensive agents (avoid non-dihydropyridine CCB) If BP not controlled, reduce dose or stop VEGF inhibitors; re-challenge once BP controlled OT prolongation: If QTc >500 ms or QTc prolonged >60 ms or dysrhythmias, stop treatment Atrial fibrillation: Anticoagulation if CHA 2 DS 2 VASc >=2 and PTL count >50,000/mm 3 ESC 2016

38 Long-term surveillance programs for cancer survivors

39 Long-term surveillance for cancer survivors I Myocardial dysfunction: periodic screening (echo, biomarkers) in patients treated with anthracyclines or with reversible LV dysfunction during cancer therapy ESC 2016

40 Long-term surveillance for cancer survivors I Myocardial dysfunction: periodic screening (echo, biomarkers) in patients treated with anthracyclines or with reversible LV dysfunction during cancer therapy ESC 2016 Echo monitoring: 3-monthy during chemo and 1 st year, 6- monthly for 4 years, yearly afterwards Cardinale et al, Circulation 2015

41 Long-term surveillance for cancer survivors II CAD: periodic screening in patients with mediastinal radiation, starting 5 years post-treatment and at least every 5 years thereafter Carotid artery disease: ultrasound scanning in patients with previous neck irradiation Radiation-induced valvular heart disease: periodic screening (echo) at 10 years post-radiation and every 5 years thereafter ESC 2016

42 Future perspectives and research directions

43 Key unresolved issues Defining the optimal cardiac monitoring approach during cancer therapy Prospective validation of diagnostic criteria of early cardiotoxicity ESC 2016

44 Key unresolved issues Defining the optimal cardiac monitoring approach during cancer therapy Prospective validation of diagnostic criteria of early cardiotoxicity Guiding the choice between a primary vs. secondary prevention strategy Refining the predisposing factors for cardiotoxicity Efficacy and cost-effectiveness of primary prevention strategies Comparison of primary prevention vs. careful observation plus secondary prevention ESC 2016

45 Cardiac journey of cancer patients Cardinale et al, Curr Cardiol Rep 2016