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 Cancer therapy related disturbance in myocardial and/or vascular function

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myocyte injury

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impaired myocardial energetics/metabolism

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endothelial injury/thrombosis

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altered vascular smooth muscle cell function

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pericardial/valvular injury

National Cancer Institute

Cause of Death 10 year probability Cardiac 6% Breast Cancer 4% Breast Cancer, Other 2% Cerebrovascular 2% Lung CA 1% Other 1% Hanrahan ¡EO, ¡J ¡Clin ¡Oncol ¡2007 ¡

Frequency and Cause of Death in Early Stage Breast Cancer

Haykowsky ¡M, ¡Mackey ¡J ¡J ¡Am ¡Coll ¡Cardiol ¡2007 ¡

“Cardiotoxicity” The Multiple Hit Hypothesis

CVD only diagnosed in 25.5% cases at time of breast cancer diagnosis Patnaik ¡JL ¡Breast ¡Cancer ¡Res ¡2011 ¡

Heart ¡Failure ¡

Anthracyclines ¡ Trastuzumab ¡ Suni4nib ¡ High ¡dose ¡ ¡cyclophosphamide ¡

Thrombosis ¡

Tamoxifen ¡ CisplaJn ¡

Hypertension ¡

Bevaci-­‑ ¡ zumab ¡

Ischemia ¡

5-­‑FU/Capecitabine ¡ Sorafenib ¡ Taxanes ¡ Anastrazole ¡ Bortezomib ¡

Cardiovascular Effects of Common Cancer Treatments

Chest ¡ ¡ Irradia4on ¡

McLean BA J Card Fail 2013

‰ Clinical trials ‰ Asymptomatic LV dysfunction 10-25% ‰ HF incidence 1-5% ‰ 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 Yeh ETH Am Coll Cardiol 2009

* ‰Age > 65 or < 4 years * ‰Cumulative dose > 240mg/m2 * ‰Hypertension * ‰CAD * ‰Cardiac irradiation * ‰? Dyslipidemia * ‰Age > 60 * ‰EF < 55% * ‰Antihypertensive Rx * ‰Concurrent or prior exposure to

anthracyclines (>240mg/m2) Rastogi ¡ ¡Proc ¡Am ¡Soc ¡Clin ¡Oncol ¡2007 ¡ Curigliano ¡G ¡Ann ¡Oncol ¡2012 ¡ Lotrionte ¡M ¡Am ¡J ¡Cardiol ¡2013 ¡ Chotenimitkhun ¡Can ¡J ¡Cardiol ¡2015 ¡ ¡ “More precise results can only be attained through collaborative, patient-level pooled analyses stemming from large contemporary cohort studies.”

Altena ¡R. ¡Lancet ¡Oncol ¡2009. ¡

I ¡= ¡RadiaJon, ¡Anthracyclines ¡ II ¡= ¡Trastuzumab ¡ III ¡= ¡Anthracyclines ¡

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

§ ‰Global longitudinal strain

§ ‰ 10% decrease in GLS predicts cardiotoxicity but variability also 10% § ‰ 50% diagnostic accuracy

Cardinale D. J Clin Oncol 2010 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

Bosch et al JACC 2013 Intervention Group Enalapril + Carvedilol Control Group

* ‰High dose/continuous infusion * ‰Prior CAD * ‰Prior chest irradiation * ‰Concurrent chemotx * ‰Diltiazem effective in small

case series

Cardinale D. Can J Cardiol 2006. Ambrosy AP. Am J Cardiol 2012. Yeh ETH. J Am Coll Cardiol 2009.

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HTN 22%

* ‰High Grade in 7%

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Renal dysfunction RR 1.36

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Responsive to Medical Rx without need to discontinue adjuvant Rx

Zhu X. Acta Oncol 2009.

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Radiation dose

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Cardiac exposure

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Younger age at exposure

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Time since exposure

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Cardiotoxic chemotx

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Clinical risk factors

Jaworski ¡C ¡J ¡Am ¡Coll ¡Cardiol ¡2013 ¡ Darby ¡SC ¡New ¡Engl ¡J ¡Med ¡2013 ¡

* ‰Lower dose + Targeted * ‰CT planning * ‰No human studies of

pharmacotherapy

* ‰One recent abstract

showing protective effects

• f captopril in chest

irradiated small animals

* ‰CAD * ‰Small vessel lumens * ‰Restenosis rates higher * ‰LIMA often atretic * ‰Higher post CABG mortality * ‰Heart Failure

* ‰ACC/AHA guidelines

Jaworski ¡C ¡et ¡al ¡J ¡Am ¡Coll ¡Cardiol ¡2013 ¡ Van ¡der ¡Veen ¡C ¡ ¡ ESTRO ¡annual ¡meeJng ¡April ¡2013 ¡

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Lack of evidence based guidelines

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Poorly co-ordinated effort between cardiologists and

• ncologists

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No risk models assessments

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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 each year

Population: 4 Million

Edmonton Cardio-Oncology Program

Cardiology Team Oncology 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 ¡ Arrhythmia management ¡ Pericardial disease - restrictive or constrictive cardiomyopathy ¡

2015 CJC Position statement in preparation

• ‰ 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

• ‰ Edith Pituskin
• ‰ John Mackey
• ‰ Anil Joy
• ‰ Keith Tankel
• ‰ Peter Venner
• ‰ Michael Sawyer

MAHI

• ‰ Justin Ezekowitz
• ‰ Sheri Koshman
• ‰ Gavin Oudit

Basic Science

• ‰ Mark Haykowsky
• ‰ Lee Jones
• ‰ Richard Thompson
• ‰ Jason Dyck

Thank you