Ian Paterson, Mazankowski Alberta Heart Institute Division of - PowerPoint PPT Presentation

Ian Paterson, Mazankowski Alberta Heart Institute Division of Cardiology, University of Alberta

Peer Reviewed Funding: CIHR, ACF , AI-HS Industry: Servier Canada Inc, RocheCanada Inc.

What is your approach to the cardio-oncology patient? a) ‰ Not on my radar b) ‰ Allow GP and/or oncologist to manage c) ‰ Recommend referral to cardiologist d) ‰ Recommend referral to specialized clinic

56 year old woman Left breast invasive ductal carcinoma, HER2/neu + Scheduled to receive TCH (Taxotere, Carboplatin and Herceptin) Baseline Echo EF 40% NYHA class 1 Exam unremarkable

What would you recommend? a) ‰ Continue with cancer therapy plan b) ‰ Recommend alternative cancer therapy plan c) ‰ Start HF pharmacotherapy and continue with cancer therapy plan d) ‰ Start HF pharmacotherapy and recommend alternative cancer therapy

What would you recommend? a) ‰ Continue with cancer therapy plan b) ‰ Recommend alternative cancer therapy plan c) ‰ Start HF pharmacotherapy and continue with cancer therapy plan d) ‰ Start HF pharmacotherapy and recommend alternative cancer therapy

1. ‰ Learn about cancer therapies and their potential cardiovascular effects 2. ‰ Identify patients at risk for cardiotoxicity 3. ‰ Review current guidelines for treating cardiotoxicity and discuss strategies for preventing cardiovascular complications 4. ‰ Discuss a multidisciplinary approach to the care of cardio-oncology patients

Toxicity that affects the heart National Cancer Institute Cancer therapy related disturbance in myocardial and/or vascular function * ‰ myocyte injury * ‰ impaired myocardial energetics/metabolism * ‰ endothelial injury/thrombosis * ‰ altered vascular smooth muscle cell function * ‰ pericardial/valvular injury

Frequency and Cause of Death “Cardiotoxicity” in Early Stage Breast Cancer The Multiple Hit Hypothesis 10 year Cause of Death probability Cardiac 6% Breast Cancer 4% Breast Cancer, 2% Other Cerebrovascular 2% Haykowsky ¡M, ¡Mackey ¡J ¡J ¡Am ¡Coll ¡Cardiol ¡2007 ¡ Lung CA 1% Other 1% Hanrahan ¡EO, ¡J ¡Clin ¡Oncol ¡2007 ¡ CVD only diagnosed in 25.5% cases at time of breast cancer diagnosis Patnaik ¡JL ¡Breast ¡Cancer ¡Res ¡2011 ¡

Cardiovascular Effects of Common Cancer Treatments Heart ¡Failure ¡ Hypertension ¡ Anthracyclines ¡ Trastuzumab ¡ Suni4nib ¡ High ¡dose ¡ ¡cyclophosphamide ¡ Bevaci-­‑ ¡ Thrombosis ¡ Bortezomib ¡ zumab ¡ Chest ¡ ¡ Sorafenib ¡ Irradia4on ¡ Tamoxifen ¡ 5-­‑FU/Capecitabine ¡ CisplaJn ¡ Anastrazole ¡ Taxanes ¡ Ischemia ¡

McLean BA J Card Fail 2013

� ‰ Clinical trials � ‰ Asymptomatic LV dysfunction 10-25% � ‰ HF incidence 1-5% Yeh ETH Am Coll Cardiol 2009 � ‰ Medicare data N= 45,537, Age > 65 Time from Dx All Cancer Anthracyclines Trastuzumab A+T 1 year 7.5 / 100 9.8 / 100 16.7 / 100 22 / 100 2 years 13.3 / 100 15.3 / 100 23.2 / 100 33.2 / 100 3 years 18.7 / 100 20.2 / 100 32.1 / 100 41.9 / 100 Chen J Am Coll Cardiol 2012

* ‰ Age > 65 or < 4 years * ‰ Age > 60 * ‰ Cumulative dose > 240mg/m 2 * ‰ EF < 55% * ‰ Hypertension * ‰ Antihypertensive Rx * ‰ CAD * ‰ Concurrent or prior exposure to anthracyclines (>240mg/m 2 ) * ‰ Cardiac irradiation * ‰ ? Dyslipidemia “More precise results can only be attained through collaborative, patient-level pooled analyses stemming from large contemporary cohort studies.” Rastogi ¡ ¡Proc ¡Am ¡Soc ¡Clin ¡Oncol ¡2007 ¡ Curigliano ¡G ¡Ann ¡Oncol ¡2012 ¡ Lotrionte ¡M ¡Am ¡J ¡Cardiol ¡2013 ¡ Chotenimitkhun ¡Can ¡J ¡Cardiol ¡2015 ¡ ¡

I ¡= ¡RadiaJon, ¡Anthracyclines ¡ II ¡= ¡Trastuzumab ¡ III ¡= ¡Anthracyclines ¡ Altena ¡R. ¡Lancet ¡Oncol ¡2009. ¡

Cardinale ¡et ¡al ¡J ¡Am ¡Coll ¡Cardiol ¡2010 ¡

Plana. JASE 2014

Plana. JASE 2014

§ ‰ EF § ‰ Limited availability of 3-D echo and CMR § ‰ Troponin § ‰ ? time course: serial measurements § ‰ 67% sensitive for cardiotoxicity § ‰ Late marker: only 35% Tn I positive had LVEF recovery Cardinale D. J Clin Oncol 2010 § ‰ Global longitudinal strain § ‰ 10% decrease in GLS predicts cardiotoxicity but variability also 10% § ‰ 50% diagnostic accuracy Sawaya H. Am J Cardiol 2010 Sawaya H. Circ Cardiovasc Img 2012

1. ‰ Hold Chemotherapy if – ‰ baseline EF < 50% – ‰ follow-up EF < 50% AND dropped at least 5% AND heart failure – ‰ follow-up EF < 50% AND dropped at least 10% AND asymptomatic 2. ‰ Start HF Pharmacotherapy (ACEi and BB) – ‰ symptomatic HF and EF < 50% – ‰ asymptomatic HF and EF < 40% – ‰ ? duration 3. ‰ Resume/Discontinuation Chemotherapy follow-up EF > 45% – ‰ – ‰ discontinue if follow-up EF < 40% Adapted ¡from: ¡ Mackey ¡J ¡Current ¡Oncology ¡2008 ¡ Curigliano ¡G ¡Ann ¡Oncol ¡2012 ¡

RCT of 90 patients with hematological malignancies receiving anthracyclines Intervention Group Control Group Enalapril + Carvedilol Bosch et al JACC 2013

* ‰ High dose/continuous infusion * ‰ Prior CAD * ‰ Prior chest irradiation * ‰ Concurrent chemotx Yeh ETH. J Am Coll Cardiol 2009. * ‰ Diltiazem effective in small case series Ambrosy AP. Am J Cardiol 2012. Cardinale D. Can J Cardiol 2006.

* ‰ HTN 22% * ‰ High Grade in 7% * ‰ Renal dysfunction RR 1.36 * ‰ Responsive to Medical Rx without need to discontinue adjuvant Rx Zhu X. Acta Oncol 2009.

* ‰ Radiation dose * ‰ Cardiac exposure * ‰ Younger age at exposure * ‰ Time since exposure * ‰ Cardiotoxic chemotx * ‰ Clinical risk factors Jaworski ¡C ¡J ¡Am ¡Coll ¡Cardiol ¡2013 ¡ Darby ¡SC ¡New ¡Engl ¡J ¡Med ¡2013 ¡

* ‰ Lower dose + Targeted * ‰ CAD * ‰ CT planning * ‰ Small vessel lumens * ‰ No human studies of * ‰ Restenosis rates higher pharmacotherapy * ‰ LIMA often atretic * ‰ One recent abstract * ‰ Higher post CABG mortality showing protective effects of captopril in chest irradiated small animals * ‰ Heart Failure * ‰ ACC/AHA guidelines Van ¡der ¡Veen ¡C ¡ ¡ ESTRO ¡annual ¡meeJng ¡April ¡2013 ¡ Jaworski ¡C ¡et ¡al ¡J ¡Am ¡Coll ¡Cardiol ¡2013 ¡

* ‰ Lack of evidence based guidelines * ‰ Poorly co-ordinated effort between cardiologists and oncologists * ‰ No risk models assessments * ‰ Few RCTs for prevention/ treatment

140,000 Albertans with Hx of cancer * ‰ 30,000 with prior breast CA * ‰ 6,000 with prior lymphoma 2ndary prevention: 3500-7000 breast CA/lymphoma survivors with HF 18,500 new cancer diagnoses/year * ‰ 2,250 new breast CA/year * ‰ 650 new lymphoma/year 1ary prevention: 300-600 breast CA/ lymphoma patients at risk for HF Population: 4 Million each year

Edmonton Cardio-Oncology Program Oncology Team Cardiology Team Since Fall 2011 >350 unique patient clinic visits > 1200 echocardiograms

Primary Prevention High risk patient for cancer therapy related cardiomyopathy ¡ High risk patient for cancer therapy related ischemia ¡ High risk for arrhythmia ¡ Known cardiovascular disease requiring optimization prior to cancer therapy ¡ Secondary Prevention Suspected heart failure or cardiomyopathy/LV dysfunction on surveillance imaging ¡ Myocardial infarction or ischemia during adjuvant therapy ¡ Worsening and uncontrolled hypertension related to cancer therapy ¡ 2015 CJC Position statement Arrhythmia management ¡ in preparation Pericardial disease - restrictive or constrictive cardiomyopathy ¡

• ‰ MANTICORE – primary prevention RCT (perindopril vs. bisoprolol vs. placebo) • ‰ TITAN – primary prevention RCT – risk factor modulation + exercise vs. routine care • ‰ CAPRI – Provincial prospective registry of cancer patients at risk for cardiotoxicity

• ‰ Current treatments in breast cancer have improved survival but increased risk of HF • ‰ Both systemic and targeted therapies can cause myocyte cell damage and apoptosis • ‰ Cardiotoxicity associated with worse outcomes but may respond to early treatment • ‰ More study needed on mechanisms, screening and prevention

CCI MAHI • ‰ Edith Pituskin • ‰ Justin Ezekowitz • ‰ John Mackey • ‰ Sheri Koshman • ‰ Anil Joy • ‰ Gavin Oudit • ‰ Keith Tankel • ‰ Peter Venner Basic Science • ‰ Michael Sawyer • ‰ Mark Haykowsky • ‰ Lee Jones • ‰ Richard Thompson • ‰ Jason Dyck

Thank you