Ο ογκολογικός ασθενής και η καρδιά του
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1 Ο ογκολογικός ασθενής και η καρδιά του Δημήτρης Φαρμάκης Αν. Καθηγητής, Πανεπιστήμιο Κύπρου Καρδιακή Ανεπάρκεια & Καρδιο-Ογκολογία, ΠΓΝ «Αττικόν»
2 Disclosures Consultation fees, speaker honoraria or travel grants from Boehringer-Ingelheim, Daiichi-Sankyo, Menarini, Novartis, Pfizer, Servier.
3 Outline The burden The pathophysiology The spectrum The role of Cardiologist The open issues
4 The burden
5 Estimated and projected cancer survivors in USA de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013
6 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
7 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
8 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
9 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
10
11 The pathophysiology
12 Determinants of cardiotoxicity in cancer Farmakis et al. Eur J Heart Fail 2018
13 1. Effects of cancer therapy Lenneman and Sawyer, Circ Res 2016
14 Main cardiotoxic agents Ameri, Farmakis et al, Eur J Heart Fail 2018
15 Molecular pathways of anthracycline cardiotoxicity Lenneman and Sawyer, Circ Res 2016
16 Pathophysiology of anthracycline cardiotoxicity Henriksen, Heart 2017
17 Increased Top2β in peripheral blood in anthracycline-sensitive patients Anthracycline-sensitive (n=21): low doxodose (<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)
18 Molecular pathways of ErbB2-targeted therapies cardiotoxicity Lenneman and Sawyer, Circ Res 2016
19 ErbB2 is essential in the prevention of dilated cardiomyopathy ErbB2-knock-out mice developed spontaneous dilated cardiomyopathy Cardiomyocytesisolated from these mice were more susceptible to anthracycline toxicity Crone et al, Nat Med 2002
20 Anthracycline-trastuzumab synergy Ewer and Ewer, Nat Rev Cardiol 2015
21 2. Effects of cancer Farmakis et al, J Am Coll Cardiol 2014
22 Cancer and heart failure interaction Ameri, Farmakis et al, Eur J Heart Fail 2018
23 Common risk factors in cancer and heart failure Farmakis et al, Int J Cardiol 2016
24 3. Effects of RF and CV disease
25 Risk factors for cardiotoxicity 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) ValvularHD (mod./severe) Prior antracyclines Priorchest radiotherapy Combined chemo/targeted agents Combined chemo and chest radiation Sedentary life Cardiomyopathies Cumulative dose (antrhacyclines) Sign.arrhythmias (AF, VT) Farmakis et al, in press
26 The spectrum
27 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% Farmakis et al, Eur J Heart Fail 2018
28 Cancer therapy cardiotoxicity: Not just LV dysfunction! Class Drug Arterial hypertension VEGF inh. Myocardial ischemia Fluopyrimidines, cisplatin Thromboembolism QT prolongation Arrhythmias Myocarditis Cisplatin, VEGF inh. Arsenic trioxide, lapatinib, vandetanib Alkylating agents, taxanes, anthracyclines Check-point inhibitors Farmakis et al. (in press)
29 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
30 The role of cardiologist: In whom, when and how?
31 In whom? Patients with a history of cardiotoxicity Patients with coexistent CV disease Patients with a constellation of CV risk factors Patients previously exposed to cardiotoxictherapies
32 When? Before cancer therapy: Optimal treatment of CV disease and risk factors Primary prevention measures During cancer therapy: Close monitoring for early detection of cardiotoxicity Timely implementation of therapeutic measures After cancer therapy: Long-term surveillance
33 How? Cardiovascular monitoring Prevention Treatment Long-term follow-up
34 Cardiovascular monitoring ESC 2016
35 Echo monitoring for LVEF decline 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% to <50%) Mean time: 3.5 months 98% of cases within 1 st year 2% HF NYHA III-IV 0.3% hospitalized for AHF 0.2% died of AHF Cardinale et al, Circulation 2015
36 Early detection of cardiotoxicity Ewer and Ewer, Nat Rev Cardiol 2015
37 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
38 ΝT-proBNP predicts LVEF decline Cardinale & Sandri, Prog Cardiovasc Dis 2010
39 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
40 2D strain predicts LV dysfunction early Global longitudinal strain >10-15% predicts future LVEF decline Baseline 1 months 9 months Mougdil et al, Echocardiography 2018
41 Primary prevention ESC 2016
42 Dexrazoxane for primary prevention Meta-analysis, 10 RCTs, 1619 pts Reduction of heart failure by 70% No effect on tumor response rate, second malignancy or survival Inconclusive for adverse events van Dalen et al, Cochrane Database Syst Rev. 2011
43 Treatment Myocardial dysfunction/heart failure: LVEF decrease >10% and <50% or symptomatic HF: start ACEiand 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 QT prolongation: Stop treatment if QTc>500 msor QTcprolonged >60 msor dysrhythmias ESC 2016
44 Effects of ACEiand 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
45 Effects of ACEiand 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
46 Long-term follow-up in cancer survivors Myocardial dysfunction: periodic screening (echo, biomarkers) in patients treated with anthracyclinesor 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 valvularheart disease: periodic screening (echo) at 10 years post-radiation and every 5 years thereafter ESC 2016
47 Τhe open issues
48 Open issues Effectiveness of cardioactive agents in primary prevention Integration of biomarkers & sensitive echo techniques in clinical practice Biomarker/echo-guided primary prevention
49 Exercise for primary prevention Theoretical background Benefit proven in pre-clinical studies (rodent/murine models) Poor clinical evidence (observational studies, CRF as main outcome) Chen et al, Am J Physiol Heart Circ Physiol 2017 Scott et al, Circulation 2018
50 Main RCT on primary prevention: Carvedilol Trial Agent N Follow-up Endpoints Kalay(2006) Carvedilol mo LVEF decline diastolic dysfunction Bosch (2013) OVERCOME Tashakori Behoshiti (2016) Avila(2018) CECCY Guglinet al, Carvedilol & Enalapril Carvedilol 6,25 70 During chemo 90 6mo LVEF decline Heat failure, death Noeffect on LVEF LV strain decline Carvedilol mo No effect on LVEF TnI increase Carvedilol CR or lisinopril monts LVEFdecline only in anthra-pretreated Farmakis et al, in press
51 Main RCT on primary prevention: Other CV agents Trial Agent N Follow-up Results Cardinale(2006) Enalapril mo LVEF decline MACE Pituskin(2015) Bisoprolol Perindopril 99 12mo LVEF decline Gulati (2015) Candesartan mo LVEF decline Akpek (2015) Spironolactone 83 6mo LVEF decline TNI and BNP increase Acar (2011) Atorvastatin 40 RCT/6mo LVEF decline Farmakis et al, in press
52 Ongoing trials Trial Agent N Endpoints SAFE Biosoprolol, ramipril STOP Atorvastatin 90 CMR 480 Biomarkers, echo (GLS) McKennan Metformin 44 Echo (LVEF) COG-ALTE1621 Carvedilol 250 Biomarkers, echo TITAN Multidisciplinar ycare Biomarkers, echo, MACE Meattini et al, Med Oncol 2017 Farmakis et al, in press
53 Biomarker-guided prevention Enalapril in Tn elevation ICOS-ONE, open-label RCT 21 Italian hospitals, 273 pts 1 st line anthra Enalaprilin all or in Tn Mixed Tn assays (T/I, low/high sens.) Primary outcome, Tn elevation > ULN 23% vs. 26% (p=ns) LVEFdecline only in 1% Cardinale et al, Eur J Cancer 2018
54 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
55 Cardiac journey of cancer patients?? Cardinale et al, Curr Cardiol Rep 2016
56 Thank you!
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