Cancer and the heart: New evidence and open issues

Transcription

1 Cancer and the heart: New evidence and open issues Dimitrios Farmakis, MD, PhD, FESC Assist. Professor, European University Cyprus Cardio-Oncology Clinic, Heart Failure Unit, Attikon Hospital Cardiac Clinic for Haemoglobinopathies, Laiko Hospital

2 Disclosures Related to this presentation: Consultation fees from Daiichi- Sankyo

3 The need for Cardio-Oncology

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

5 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

6 Causes of death in breast cancer survivors Leading causes of death by time since breast cancer diagnosis 63,566 breast cancer women Patnaik et al, Breast Cancer Res 2011

7 Childhood cancer survivors in UK In 2000, childhood cancer survivors in UK Childhood cancer survival rates, 25% in 1960s vs. 75% in 1990s Skinner et al. Lancet Oncol 2006 Kroll et al. Cancer Stats Monograph 2004

8 Mortality in childhood cancer survivors The Childhood Cancer Survivor Study 20,227 childhood cancer 5-year survivors, diagnosed , up to 25 years follow-up Standardized mortality ratio (SMR): Overall mortality: 10.8 (10,3-11.3) Cardiac mortality: 8.2 ( ) Mertens et al, J Clin Oncol 2001

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10 The determinants of cardiovascular complications in cancer

11 Determinants of cardiotoxicity in cancer CV disease and risk factors Chemotherapy Targeted agents Radiotherapy Supportive therapies Cancer Cancer therapy Direct effects Invasion of cardiac structures Primary cardiac tumors Metastatic cardiac tumors Indirect effects Metabolic disorders, SNS activation etc Cardiotoxicity Direct effects Cardiomyocytes Endothelial cells Indirect effects Metabolic disorders etc Farmakis et al. Eur J Heart Fail 2018

12 Pre-existing RF and CVD Cancer Cancer therapy Effects of cancer therapy Lenneman and Sawyer, Circ Res 2016

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

14 Cancer Pre-existing RF and CVD Cancer therapy Effects of RF and CV disease

15 The spectrum of cardiovascular complications in cancer

16 Specturm of cardiovascular complications in cancer 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

17 Myocardial dysfunction and heart failure: Not just anthracyclines! 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% Modified from ESC 2016

18 Chemotherapy-induced cardiotoxicity: Not just LV dysfunction! Class Arterial hypertension Myocardial ischemia Thromboembolism QT prolongation Arrhythmias Drug VEGF inh. Fluopyrimidines, cisplatin Cisplatin, VEGF inh. Arsenic trioxide, lapatinib, vandetanib Alkylating agents, taxanes, anthracyclines Suter & Ewer, Eur Heart J 2012

19 Challenging the classical knowledge

20 Molecular pathways of anthracycline cardiotoxicity Lenneman and Sawyer, Circ Res 2016

21 Τopoisomerase-2β (Top2β) Vejpongsa & Yeh, J Am Coll Cardiol 2014

22 Increased Top2β in peripheral blood in anthracycline-sensitive patients Anthracycline-sensitive (n=21): low doxo dose (<250 mg/m 2 ) and LVEF drop (>10% to <55%) Anthracycline-resistant (n=15): high doxorubicin (>450 mg/m 2 and preserved LVEF) Top2β >0.5 ng/μg 0,4 24% Anthra-resistant Anthra-sensitive Top2β levels >0.5 ng/μg a risk factor Vejpongsa et al, Circulation 2013 (abstr)

23 Dose-dependent incidence of anthracyclineinduced LV dysfunction ESC 2016

24 Doxorubicin-induced heart failure Swain et al, Cancer 2003

25 Doxorubicin-induced heart failure by age group Swain et al, Cancer 2003

26 Doxorubicin-induced heart failure or LVEF decline Swain et al, Cancer 2003

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

28 Time course of LVEF decline post-anthracycline under close monitoring 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

29 Reversibility of cardiotoxicity: Type I and II agents Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

30 Molecular pathways of ErbB2-targeted therapies cardiotoxicity Lenneman and Sawyer, Circ Res 2016

31 ErbB2 is essential in the prevention of dilated cardiomyopathy ErbB2-knock-out mice developed spontaneous dilated cardiomyopathy Cardiomyocytes isolated from these mice were more susceptible to anthracycline toxicity Crone et al, Nat Med 2002

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

33 CREC: Cardiac Review and Evaluation Committee LV dysfunction: Trastuzumab: 3-7% Trastuzumab+doxorubicin: 27% (16% HF ΝΥΗΑ ΙΙΙ/ΙV) Trastuzumab+paclitaxel: 13% (vs 1% paclitaxel) Seidman et al, J Clin Oncol 2002

34 Reversibility of cardiotoxicity: Type I and II agents Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

35 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

36 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

37 Reversibility of cardiotoxicity: Type I and II agents Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

38 Open issues

39 Primary prevention of cardiotoxicity ESC 2016

40 Primary prevention of cardiotoxicity ESC 2016

41 Primary prevention of cardiotoxicity??? ESC 2016

42 RCT 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

43 Early detection of cardiotoxicity Ewer and Ewer, Nat Rev Cardiol 2015

44 Tools for detecting cardiotoxicity ESC 2016

45 Tools for detecting cardiotoxicity??? ESC 2016

46 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

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

48 2D strain predicts LV dysfunction early >15% reduction in global longitudinal strain Stoodley et al, Eur J Echocard 2011 Α decrease in longitudinal strain after the 3 rd cycle of epirubicin was the best predictor of cardiotoxicity after treatment Florescu et al, J Am Soc Echocardiogr 2014

49 CMR-LGE in anthracycline-induced cardiomyopathy Mid-wall or subepicardial LGE Prevalence 0-100% Thavendiranathanet al, Circ Cardiovasc Imaging 2013

50 Assessment of myocardial fibrosis in anthracycline-induced cardiomyopathy ECV values (mean/sd) were increased in the basal, mid, and apical short-axis images. Myocardial fibrosis is diffuse and may be missed by LGE Extracellular volume fraction (ECV) with pre- and post-contrast T1 mapping may illustrate diffuse myocardial injury Thavendiranathanet al, Circ Cardiovasc Imaging 2013

51 Antithrombotic therapy for AFib in cancer Anticoagulation if CHA 2 DS 2 VASc >=2 and PTL >50,000/mm 3 ESC 2016

52 Antithrombotic therapy for AFib in cancer Anticoagulation if CHA 2 DS 2 VASc >=2 and PTL >50,000/mm 3 ESC 2016 Farmakis et al, J Am Coll Cardiol 2014

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

54 Thank you!

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56 Cardiovascular consultation in cancer: To whom? When? How?

57 To whom? The importance of risk stratification 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

58 Cardiovascular evaluation of cancer patients: In whom? Patients with coexistent CV disease Patients with a constellation of CV risk factors Patients with prior known cardiotoxic therapies Patients scheduled for known cardiotoxic cancer therapies

59 When? Before cancer therapy During cancer therapy After cancer therapy

60 Cardiovascular evaluation of cancer patients: When? Before cancer therapy: Initial evaluation of high-risk patients Optimal treatment/control of CV disease and risk factors During cancer therapy: Cardiac monitoring for early signs of cardiotoxicity Timely implementation of therapeutic measures Modification of cancer therapy if needed After cancer therapy: Long-term surveillance

61 During cancer therapy Specific management strategies Myocardial dysfunction/heart failure: LVEF decrease >10% and <50% or symptomatic HF: start ACEi and BB, stop of cancer therapy LVEF decrease >10% but >50%: repeated LVEF in 3 w Coronary artery disease/events: Patients on pyrimidine analogues: close ECG monitoring for ischemia Discontinuation of chemotherapy if ischemia occurs; re-challenge only when no alternatives, pretreatment with nitrates and/or CCB Arterial hypertension: Start antihypertensive agents (avoid non-dihydropyridine CCB) Reduce dose or stop VEGF inhibitors if BP not controlled; re-challenge once BP controlled OT prolongation: Stop treatment if QTc >500 ms or QTc prolonged >60 ms or dysrhythmias ESC 2016

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