CARDIOTOXICITY IN ONCOLOGY PRACTICE

Transcription

1 CARDIOTOXICITY IN ONCOLOGY PRACTICE Evandro de Azambuja, MD, PhD Jules Bordet Institute, Brussels, Belgium

2 CARDIOTOXICITY: THE MAGNITUDE OF THE PROBLEM Advances in cancer treatments have improved patients outcomes New molecules targeting different pathways are being tested in cancer However, there is an increase in cardiac toxicities, which may dramatically impact in patient s quality of life

3 CARDIOVASCULAR ADVERSE EVENTS OF ANTICANCER AGENTS Myocardial dysfunction and heart failure Coronary artery disease QT prolongation Systemic hypertension Thrombotic disease Arrhythmias Myocardial infarction Valvular disease

4 SELECTED POTENTIAL CARDIAC DRUGS IN ONCOLOGY Focus on heart failure and myocardial dysfunction Agent Incidence (%) Agent Incidence (%) Doxorubicin 2-48 Pertuzumab <1.5 Epirubicin Lapatinib <1 Liposomal A 2 Sunitinib Cyclophosphamide 7-28 Sorafenib 4-8 Ifosfamide 17 Pazopanib 7-11 Docetaxel 2-13 Imatinib <3 Paclitaxel <1 Everolimus <1 Bevacizumab Temsirolimus <1 Trastuzumab Adapted from ESC Guidelines; European Heart Journal 2016

5 ANTHRACYCLINE EQUIVALENT DOSES Drug Relative cardiotoxicity Maximum dose (mg/m²) Doxorubicin Epirubicin Daunorubicin Idarubicin

6 BASELINE RISKS FOR CARDIOTOXICITY Previous cardiovascular diseases Demographic and other CV risk factors HF, MI Age, HAS, DM Prior A Prior RT Smoking, alcohol, obesity Previous cardiotoxic treatments Life styles risk factors

7 CARDIOTOXICITY DEFINITION The most common used definition in clinical practice and clinical trials is*: A LVEF value <50% and a decrease >10% from its baseline value *Definition used by the European Society of Cardiology (ESC)

8 CARDIAC REMODELLING From N Eng J Med, Hill JA, et al., Cardiac Plasticity, 358: Copyright 2008 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

9 MECHANISMS OF CARDIOTOXICITY de Azambuja E, et al., Cardiac toxicity with anti-her-2 therapies-what have we learned so far? Target Oncol 2009;4(2): Springer-Verlag 2009, with permission of Springer

10 CANCER DRUG-ASSOCIATED CARDIOTOXICITY Type I Type II Agent Epirubicin Trastuzumab Cellular effects Myocardium death Dysfunction Biopsy findings Typical anthracycline changes No typical changes Dose response Cumulative Not cumulative Reversibility No Generally reversible

11 Proportion free of CHF SEER DATABASE: INCIDENCE OF HEART FAILURE IN OLDER PATIENTS 10-YEAR CHF (66-70 years) 29% 32.5% 38.4% Time (months) Pinder M, et al., J Clin Oncol. 2007;25(25): Reprinted with permission. (2007) American Society of Clinical Oncology. All rights reserved

12 SYMPTOMS OF HEART FAILURE Shortness of breath Swelling of feet and legs Chronic fatigue Dyspnoea Swollen or tender of abdomen Cough Increased urination at night Confusion Increase in mortality

13 DIAGNOSTIC TOOLS FOR CARDIAC TOXICITY Technique Advantages Limitations Echocardiography Widely used, no irradiation, assess dynamics and other cardiac structures Operator dependent and limited in case of thoracic abnormalities MUGA reproducibility Irradiation, limited structure and functional information Cardiac MRI Cardiac biomarkers (e.g. HS troponin, NTproBNP) Accurate and reproducible, detects diffuse myocardial fibrosis Accurate, reproducible, widely available, high sensitivity Not widely available, costs, claustrophobia Lack of evidence of use and its role in routine surveillance not well established Adapted from ESC Guidelines; European Heart Journal 2016

14 ROLE OF CARDIAC BIOMARKERS Brain Natriuretic Peptide (BNP) Cardiac dysfunction Normal elevated Cardiomyopathy cell death elevated Troponin (TnT, TNI) Normal elevated

15 CARDIOTOXICITY OF ANTHRACYCLINES Focus on late toxicity in breast cancer Zambetti et al Bonneterre et al Ganz et al de Azambuja et al No. of patients in the original cohort / No. of disease free No. of patients assessed for cardiac safety 1,000 / approximately 50% 565 / 278 1,176 potential 777 / Type of anthracycline Doxorubicin Epirubicin Doxorubicin Epirubicin Cumulative dose of anthracyclines (mg/m²) (N= 85) and 300 (N=65) (N= 29) and 480 (N=26) Year of cardiac evaluation and Method of evaluation Echocardiogram Echocardiogram MUGA scan Echocardiogram and MRI Main results 8% systolic dysfunction with A and 2% with CMF 2.3% CHF with FEC100; Asymptomatic LVEF drop in 18 patients in FEC100 and 1 in FEC years (N=156): mean LVEF (61.4% for A and 64.8% for CMF; p= 0.01) years (N=110): mean LVEF (63.4% for A and 62.8% for CMF; p= 0.64) CHF: 5.5% in HDE* group, 1.9% in SDE* and 0.4% in CMF (p=0.02 and <0.001, respectively). LVEF <50% by either MRI or echocardiogram: 4% in CMF and 16% for anthracyclines (SDE+HDE) (p=0.15) *SDE: standard dose epirubicin: HDE: high dose epirubicin Adapted from Azim HA Jr, et al., Ann Oncol. 2011(9):

16 HER2-POSITIVE BREAST CANCER Adapted from Capelan M, et al., Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol 2013(2):273-82, with permission from the European Society for Medical Oncology

17 TRIALS Trial Treatment regimen # pts Any LVEF drop CHF Piccart M et al.; de Azambuja et al. (HERA) Romond et al. (NSABP-B31) Advani et al. (N9831) Slamon et al. (BCIRG 006) Spielman et al. (PACS 04) Chemotherapy (0.9) 0 Chemotherapy + 1 y Trastuzumab (4.7) 14 (0.8) AC + Paclitaxel 743 Not reported 9 (1.2) AC + Paclitaxel + Trastuzumab (12) 36 (3.8) AC + Paclitaxel (9.6) 6 (0.9) AC + Paclitaxel + Trastuzumab (16.7) 19 (2.6) AC + Paclitaxel/Trastuzumab (23.8) 20 (3.5) AC + Docetaxel (11.2) 8 (0.8) AC + Docetaxel + Trastuzumab (19.1) 21(2.0) Docetaxel + Carboplatin + Trastuzumab (9.4) 4 (0.4) FEC/ED (2.6) 1 (0.4) EC/ED + Trastuzumab (11.1) 4 (1.5)

18 CHF (%) TRASTUZUMAB-ASSOCIATED CONGESTIVE HEART FAILURE WITH 1 YEAR OF THERAPY 5 Obs 1 y Trast Trast Comb HERA NSABP B31 N9831 BCIRG 006 PACS 04

19 HERA TRIAL (N=5,102 PATIENTS) Women with locally determined HER2-positive invasive early breast cancer Surgery + (neo)adjuvant CT ± RT Centrally confirmed IHC 3+ or FISH+ and LVEF 55% Randomisation OBSERVATION n=1698 After ASCO 2005, option of switch to Trastuzumab 1 year Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n= years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly schedule n=1701 CT, chemotherapy; RT, radiotherapy. Piccart-Gebhart MJ, et al., N Eng J Med 2005; 353:

20 CUMULATIVE INCIDENCE OF CARDIAC ENDPOINTS IN THE THREE ARMS de Azambuja E, et al., Trastuzumab-Associated Cardiac Events at 8 Years of Median Follow-Up in the Herceptin Adjuvant Trial (BIG 1-01) J Clin Oncol 2014;32(20): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

21 ACUTE RECOVERY OF ANY CARDIAC EVENT IN THE 1 YEAR TRASTUZUMAB ARM Acute recovery % (n= 83) Yes No Median time to recovery: 6.6 months de Azambuja E, et al., J Clin Oncol 2014; 32(20):

22 ESMO ALGORITHM FOR CONTINUATION/DISCONTINUATION OF TRASTUZUMAB BASED ON LVEF LVEF assessment LVEF <50% LVEF 50% LVEF <40% LVEF 40%-50% Start treatment Hold treatment Repeat LVEF in 3 weeks LVEF 10% point below baseline Hold treatment Repeat LVEF in 3 weeks LVEF higher than 10% below baseline Continue treatment LVEF <40% STOP TREATMENT LVEF >45% OR LVEF 40%-50% RESUME TREATMENT Curigliano G, et al., Ann Oncol 2012; 23(7)

23 CARDIAC FUNCTION ASSESSMENT Taxane CT Anthracycline CT Trastuzumab HER2 + EBC LVEF assessment every 3 months during treatment of whenever required Before CT After A-based CT

24 MEDICAL TREATMENT Treatment of a cardiac event Angiotensin converting enzymes inhibitors (ACE-Is or ARBs) and beta-blockers are recommended in patients with symptomatic HF or asymptomatic cardiac dysfunction unless contraindication In case of anti-her2 agents, therapy can be reinitiated if LVEF value returns to baseline or normal values

25 MEDICAL TREATMENT Strategies for prevention of cardiotoxicity Identifying patients with high cardiac risk Modifying life style to decrease cardiac risk Using less cardiotoxic regimens if possible The use of dexrazoxane in metastatic patients requiring anthracycline chemotherapy (doses > 300 or >540 mg/m 2 for doxorubicin and epirubicin, respectively) Prophylactic ACE-I (or ARB) and beta-blockers in selected cases treated with anthracyclines or trastuzumab (small trials)

26 MEDICAL TREATMENT Strategies for prevention of cardiotoxicity Enalapril and carvedilol vs. normal care before high-dose anthracyclines Prevention in 6 months LVEF decrease with both drugs Their use in low risk patients remains controversial Candesartan (ARB) attenuates decrease in LVEF compared to beta blocker or placebo in patients with early breast cancer treated with A-based chemotherapy ACEi or beta blockers have no effect on cardiac remodelling in patients treated with trastuzumab

27 CARDIOTOXICITY Coronary artery disease Therapies Possible mechanisms Incidence Fluoropyrimidines (5-FU, capecitabine) Platinum salts VEGF inhibitors Radiotherapy Endothelial injury and vasospasm Myocardial ischemia: 18% Silent myocardial ischemia: 50% Procoagulant status; arterial thrombosis Procoagulant status; arterial thrombosis; endothelial injury Thrombosis; endothelial injury, plaque rupture 30 y Thrombosis: 2% In long-term survivors (8% 20 y testicular cancer) AT with bevacizumab: 3.8% In long-term survivors (13% 30 y Hodgkin lymphoma) Adapted from ESC Guidelines; European Heart Journal 2016

28 CARDIOTOXICITY Coronary artery disease Early recognition of patients at risk Limited options for medical and interventional treatments Contraindication to antiplatelet and anticoagulants generally present Patients treated with concomitant neurotoxic agents and RT: silent events! Drug rechallenge is generally not recommended

29 CARDIOTOXICITY QT prolongation Can be caused by several anticancer drugs High incidence with some drugs such as arsenic trioxide (26-93%) Can also be caused by electrolyte disturbances, predisposing factors and concomitant medications Can lead to life-threatening arrhythmias such as torsade de pointes Arrhythmias can occur before, during and shortly after treatment

30 CARDIOTOXICITY QT prolongation: risk factors Correctable Electrolyte imbalance Nausea / vomiting Diarrhea Use of loop diuretics Hypokalemia ( 3.5 meq/l) Hypomagnesaemia ( 1.6 mg/dl) Hypocalcemia ( 8.5 mg/dl) Hypothyroidism Concurrent use of QT-prolonging drugs Antiarrhythmic Antibiotics or antifungals Psychotropic or antipsychotic Antidepressant Antiemetic antihistamine Non-correctable Family history of sudden death Personal history of syncope Baseline QTc interval prolongation Female gender Advanced age Heart disease Myocardial infarction Impaired renal function Impaired hepatic function Adapted from ESC Guidelines; European Heart Journal 2016

31 CARDIOTOXICITY QT prolongation: diagnostic 12-lead ECG at baseline and during treatment (only in selected cases) QTc interval >450 ms in men and >460 ms in women QTc prolongation >500 ms and a QT (i.e. change form baseline) of >60 ms are of particular concern

32 CARDIOTOXICITY QT prolongation management Consider stop or alternative treatments if: QTc prolongation >500 ms and a QT of >60 ms are particular concern Correct electrolyte disturbances, thyroid function, etc. Avoid combining drugs that may increase the risk of QT prolongation

33 CARDIOTOXICITY Systemic arterial hypertension Frequently observed with anti-vegf inhibitors (nearly 50%) Proposed mechanisms: nitric oxide pathway inhibition, vascular rarefaction, oxidative stress, and glomerular injury Early (few days) or late onset (1 year later)

34 CARDIOTOXICITY Systemic arterial hypertension Identify patients at high risk Blood pressure goal <140/90 Close monitoring is required to avoid severe HAS ACE or ARB inhibitors and beta-blockers are preferred especially if HF or LVEF drops Non-dihydropyridine calcium channel blockers are considered first-line as well Anti-VEFG: stop or drug reduction!

35 CARDIOTOXICITY Thrombotic disease Frequently observed in cancer patients Tumoural cells can trigger coagulation through different pathways May occurs as: Arterial thrombosis: about 1% Venous thrombosis: up to 20% of hospitalised cancer patients

36 CARDIOTOXICITY Thrombotic disease Cancer-related Patient-related Treatment-related Primary cancer Histology Advanced stage Demographics Comorbidities Prior history of VTE Low performance status Major surgery Hospitalisation Chemo or antiangiogenic Endocrine Transfusions Central venous catheter Adapted from ESC Guidelines; European Heart Journal 2016

37 CARDIOTOXICITY Thrombotic disease No screening methods available Diagnosis mainly based on clinical symptoms Prompt suspicion and management are required Cancer remains a risk factor for thrombosis (first episode and recurrence) Thromboprophylaxis based on individual patient s benefit/risk assessment

38 CARDIOTOXICITY Radiotherapy Most events occur at long-term (several years after treatment) To reduce the risk of cardiotoxicity: Heart-sparing techniques The use of 3D treatment planning The use of CT scan or MRI to plan RT treatment American Society of Echocardiogram recommends an echocardiography 10 year post-rt and serial exams every 5 year thereafter

39 CONCLUSIONS Cardiotoxicity has emerged as a frequent problem in oncology Cardiac events can be at early or late onset Anthracyclines cause irreversible damage and should be avoided in patients at high cardiac risk Trastuzumab cardiac events generally happen during treatment and are mostly reversible

40 CONCLUSIONS Thorough cardiac risk assessment should take place prior to any cancer treatment Prompt diagnosis and treatment are required to avoid bad prognosis of HF Hypertension should be treated to avoid treatment interruptions and life threating conditions Late valvular diseases should be considered in patients previously exposed to radiotherapy Close collaboration with cardiologists is fundamental

41 Because of the importance of cardiac toxicity of anticancer therapies, a new discipline was created: cardio-oncology

42 ESC Position Paper In 2016, The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) developed a position paper on cancer treatments and cardiovascular toxicity under the auspices of the ESC Committee for Practice Guidelines Zamorano JL, et al., Eur Heart J 2016;37:

43 THANK YOU!