Chemotherapy- Associated Heart Failure M. Birhan Yılmaz M.D, FESC Professor of Medicine Department of Cardiology Cumhuriyet University Sivas, TURKEY
In last 20 years life-expectancy for patients with cancer is steadily improving There is a large group at risk of treatment-related complications CARDIOTOXICITY
CARDIOTOXICITY Strong impact on quality of life and patient survival, regardless of the basic problem of cancer Negative impact on the patient's cardiac prognosis Significant limitation of therapeutic options
CARDIOTOXICITY Incidence ranging from 5% to 65% of treated cases, in relation to the total dose of drugs administered and over the duration of follow-up considered Drugs most frequently associated with cardiotoxicity are anthracyclines (doxorubicin, epirubicin), taxanes, alkylating agents and trastuzumab
CARDIOTOXICITY Systemic Therapy Anthracyclines Alkylanting Agents Antimicrotubule Agents Antimetabolities Monoclonal Antibodies Hormonal Agents
CARDIOTOXICITY Acute or subacute Alteration of ventricular repolarization phase, duration of QT, arrhythmias, ischemia, acute heart failure, myocarditis-pericarditis-like syndrome Chronic (early / late) Asymptomatic left ventricular dysfunction, systolic and/or diastolic dysfunction, severe form of dilated cardiomyopathy, cardiac death
Type I chemotherapy-related cardiac dysfunction (CRCD), typically anthracycline-induced, is due, at least in part, to oxidative stress on cardiac muscle resulting in free radical formation and cell death; it is irreversible and typically associated with significant ultrastructural changes at biopsy. Type II CRCD (trastuzumab-induced) is associated with reversible myocardial dysfunction rather than structural damage, is highly reversible (up to 79%) and generally is not dose-related Todaro MC et al. Int J Cardiol 2013;168: 680 687
CARDIOTOXICITY Peroxidation of membranes and influx of calcium Pathogenesis Decrease of Glutathione-peroxidase OXYGEN-FREE-RADICALS (iron-based stress oxidative) Mitochondrial dysfunction (persistence of 8-H Guanosine) Depletion of GATA-4
Chemotherapy agents Commonly treat breast cancer and lymphomas Can cause cardiomyopathy Myocyte damage Production of toxic radicals Increase in oxidative stress Lipid peroxidation Vacuolation Myocyte replacement by fibrous tissue Anthracyclines
Anthracycline Cardiotoxicity Anthracycline induced cardiomyopathy is related to cumulative dose. It occurs in 11% of cancer patients after a cumulative dose of less than 400 mg/m2, 23% after 400-599 mg/m2, 47% after 500-799 mg/m2 and 100% after 800 mg/m2.
Risk Factors Cumulative dose Age Other cardiotoxic chemotherapy agents Radiation History of CVD
Symptoms Chemotherapy-Induced palpitations, shortness of breath, chest pain, fatigue Acute Cardiovascular Complications Short-term Arrythmias Chronic Cardiotoxicity Clinical heart failure Cardiomyopathy May be a link between acute and chronic cardiotoxicity
STAGE A ACC/AHA Classification Heart Failure HIGH-RISK PATIENTS in the absence of heart disease Hypertension, coronary artery disease, diabetes mellitus, previous treatment with cardiotoxic drugs, alcohol abuse, history of rheumatic fever, family history of cardiomyopathy. B C PATIENTS WITH CARDIAC DISEASE BUT WITHOUT SIGNS OR SYMPTOMS PATIENTS WITH A HISTORY OF HEART FAILURE Left ventricular hypertrophy or fibrosis, dilatation of the left ventricle or reduced contractility, asymptomatic valvular heart disease, myocardial infarction Dyspnea or fatigue due mainly to left ventricular dysfunction. Asymptomatic patients treated for heart failure
SCREENING FOR CARDIOTOXICITY 1. Identify patients at high risk for developing cardiotoxicity 2. Diagnosis and treatment of left ventricular dysfunction to prevent progression to overt heart failure
Screening for cardiotoxicity Risk factors of chronic anthracycline cardiotoxicity -Total dose ( doxorubicin 450 mg/mq) -Pediatric o geriatric -Prior cardiotoxic treatments (chemotherapy and or radiotherapy) -Previous cardiac events -Presence of genetic cardiovascular risk -Body mass index 30 -Females
CARDIOTOXICITY EARLY IDENTIFICATION Monitoring of cardiac function during and after chemotherapy EF > 10 percentage points, or if < 50% Discontinuation of treatment Before beginning the therapy a value of LVEF 50% is a criterion of exclusion from the treatment; during the therapy, the cardiac functionality must be monitored every 9-12 weeks
Changes in LVEF and timing of detection with several screening strategies during and after cancer treatment
NEW ECHO-TECHNOLOGIES PW-DMI Strain/S-Rate Strain-2D Quantitative evaluation of global and regional, radial and longitudinal, systolic and diastolic myocardial function
Figure 1 Study Protocol Participants were studied before chemotherapy and at standardized intervals every 3 months during anthracycline, paclitaxel, and trastuzumab therapy using serial questionnaires and echocardiograms for a total of 6 study visits per... Bonnie Ky, Mary Putt, Heloisa Sawaya, Benjamin French, James L. Januzzi Jr., Igal A. Sebag, Juan Carlos Pla... Early Increases in Multiple Biomarkers Predict Subsequent Cardiotoxicity in Patients With Breast Cancer Treated With Doxorubicin, Taxanes, and Trastuzumab Journal of the American College of Cardiology, Volume 63, Issue 8, 2014, 809-816 http://dx.doi.org/10.1016/j.jacc.2013.10.061
Figure 3 Model-Based Probability of Cardiotoxicity According to Changes in MPO and TnI Levels (A) Bars represent the probability of cardiotoxicity according to changes in biomarkers in both TnI and MPO at standardized time intervals. Both Low refers t... For each increase in SD in TnI (a change of 106.8 mg/l), there was a nearly 40% increased risk of subsequent cardiotoxicity (HR: 1.38; 95% CI: 1.05 to 1.81; p ¼ 0.020). MPO had a similar effect size (HR: 1.34; 95% CI: 1.00 to 1.80; p = 0.048; per each increase in SD [a change of 355.6 pmol/l]).
Carvedilol appears protective during adriamycin based chemotherapy Data expressed as mean values. Kalay et al. JACC. Dec 2006. 48:2258-62
ACE Inhibition appears quite important for prevention of toxicity Cardinale D et al. Circulation. 2006;114:2474-2481
Dexrazoxane Iron chelator Has been shown to prevent or reduce the severity of heart damage caused by doxorubicin. Thought to protect the heart muscle by blocking the formation of oxygen free radicals. 24