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 *   myocyte injury

*   impaired myocardial energetics/metabolism

*   endothelial injury/thrombosis

*   altered vascular smooth muscle cell function

*   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.

*  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

*  CT planning

*  No human studies of pharmacotherapy

*  One recent abstract showing protective effects of 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  

*  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 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