Cardiotoxicity from Chemotherapy : From Early Predictors to Therapeutics Richard Sheppard MD FRCPC Director of Heart Failure Research Heart Function Clinic Jewish General hospital
Objectives 1. Discuss the epidemiology of chemotherapyinduced cardiotoxicity (focus on changes in left ventricular function) in the context of the some specific agents. 2. Discuss the current approach to treatment of established cardiomyopathy from chemotherapeutic agents in the treatment.
Role of the Clinical Cardiologist Interaction of the oncologist with: General Cardiologist Often first line Heart Failure Specialist Severe LV Dysfunction Echocardiographer Questions related to reports or imaging quality/interpretation
Chemotherapy and cardiotoxicity Roles of the Cardiologist Clinical assessment Identifying risk factors Symptomatic Asymptomatic Can my patient get chemotherapy? Organizing Follow-up Medical therapy Echocardiography 2D 3D MUGA DEFINING CARDIOTOXICITY
Chemotherapy and cardiotoxicity: Anthracyclines Trastuzumab Kinase Inhibitors The Agents Others Other chemotherapeutic agents Radiation
Cumulative probability of developing doxorubicin-induced congestive heart failure (CHF) plotted against total cumulative dose of doxorubicin in all patients receiving the drug (3941 patients; 88 cases of congestive heart failure). Anthracyclines Shan K et al. Ann Intern Med 1996;125:47-58
Anthracyclines Oxidative stress with myocardial fibrosis and necrosis Possible direct toxic effect on local adrenergic neurotransmission that impacts myocardial contraction Apoptosis and dysregulation of calcium homeostasis in sarcoplasmic reticulum
Epidemiology AC Toxicity Anthracyclines Some studies suggest 60% 2-year mortality (older data, less SOC therapy) Over 50% of all patients exposed show some cardiac dysfunction up to 20 years later and 5% will have overt HF symptoms Acute, early and late toxicity Dose dependent
Epidemiology AC Toxicity Smith et al. 2010 BMC Cancer AC Increases risk of cardiotoxicity by 5.43 fold Increases risk of sub-clinical cardiotoxicity by 6.25 fold Any cardiotoxicity is increased by 2.27 fold Risk of cardiac death increases by 4.94 fold Higher risk with bolus compared to infusions Lower risk with epirubicin and liposomal doxorubicin and with cardioprotective agents (dexrazoxane)
AC Toxicity
Trastuzumab HER2-receptor blockade HER2 Receptors are there for embryonic cardiac development Protection against cardiotoxins HER2 levels elevated in HF and LV Dysfunction (inverse correlation) Knockout Mice with no HER@ gene show signs of Dilated CMP and susceptibility to anthracycline induced cardiotoxicity
Trastuzumab (Herceptin) First signs were in Slamon et al. NEJM 2001 Phase III, 469 patients AC+ HER (also a group with paclitaxel) vs. AC alone in metastatic breast cancer 28% symptomatic/asymptomatic cardiotoxicity in patients receiving herceptin vs. 8% who did not. Among the patients with toxicity, most with NYHA III-IV were in the AC group with herceptin After CREC formed (Cardiac Review and Evaluation Committee) examined reviewed Range of 3-7% using single agent rx Incidence of severe HF and cardiac death ranges from 0.6% to 4%
Trastuzumab (Herceptin)
Kinase Inhibitors
Kinase Inhibitors Nat Rev Drug Disc 2011
Kinase Inhibitors Unintended inhibition of specific kinases Kinases in the cardiomyocyte that are essential for cell survival In study of GI stromal tumors, 18% of patients getting Sutent had CHF or > 15 point decline in EF (Chu et al. Lancet 2007) One other safety study of Tykerb (lapatinib) suggesting cardiotoxicity
Kinase Inhibitors No good predictors, to date Ongoing studies Human studies focus on imaging and biomarkers Animal studies focus on models of cardiotoxicity, as in zebra fish and rodent models to better understand CV development There are also potential CV benefits of these meds: Pulmonary HTN Autoimmune diabetes Restenosis post PCI Post MI remodeling Genetic forms of HCM
Therapies in Chemotherapy Associated Cardiotoxicity Defining cardiotoxicity remains a challenge Who do you treat? What therapy do you use? What is end point for therapy? Can you ever stop therapy?
Therapies in Chemotherapy Associated Cardiotoxicity Cardinale et al. Circ 2006. Treatment with ACEi based on troponin I elevation after HDC Started 1 month after last cycle HDC for 1 year Normal EF at baseline Primary Endpoint : Drop of > 10 units, less than 50%
Therapies in Chemotherapy Associated Cardiotoxicity Nakamae et al. Cancer 2005 40 patients CHOP with or without 80 mg Valsartan
Therapies in Chemotherapy Associated Cardiotoxicity Kalay et al. JACC 2006 50 patients getting anthracycline (ANT) Coreg 12.5 mg po qd started before ANT and up to 6 months after End Point was LVEF
Therapies in Chemotherapy Associated Cardiotoxicity Acar et al. JACC 2011 40 patients undergoing ANT therapy 40 mg of atorvastatin vs. no statin (anti-oxidative, anti-inflammatory) 1 cycle per month End point was LVEF
From Bench to Bedside Early Detection and Prediction of Cardiotoxicity in Chemotherapy-Treated Patients Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M Am J Cardiol 2011;107:1375-1380
Univariate analysis of predictors of cardiotoxicity The change of LVEF at 3 months was not predictive of later cardiotoxicity The change in L-S, R-S and troponins at 3 months was predictive of later cardiotoxicity
Results By multiple regression analysis, (1) a longitudinal strain; and, (2) hs-tn-i were independent predictors of later cardiotoxicity Whereas patients with both findings have a 9-fold increase in the risk of CIC, The absence of either confers significant protection where only 3% develop CIC
Summary Established therapies and novel therapies Definition of cardiotoxicity Management aimed specifically at cardiotoxicity Imaging of patients with (potential) cardiotoxicity Predicting Cardiotoxicity
Future Directions Cardiology-Oncology Link Clinical Care Cardiology consultation when, where? Follow-up Cardio-Oncology Program initiative