Cancer and the heart: New evidence and open issues

Dimitrios Farmakis, MD, PhD, FESC

Assist. Professor, European University Cyprus

Cardio-Oncology Clinic, Heart Failure Unit, “Attikon” Hospital

Cardiac Clinic for Haemoglobinopathies, “Laiko” Hospital

Disclosures

• Related to this presentation: Consultation fees from Daiichi-Sankyo

The need for Cardio-Oncology

Estimated and projected cancer survivors in USA

de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013

Causes of death in cancer survivors

Ning et al. Cancer Res 2012

Causes of death in 1807 cancer survivors followed for 7 years

Cancer51%

Heart disease33%

Other16%

Causes of death in breast cancer survivors

Patnaik et al, Breast Cancer Res 2011

Leading causes of death by time since breast cancer diagnosis

63,566 breast cancer women

Childhood cancer survivors in UK

Skinner et al. Lancet Oncol 2006Kroll et al. Cancer Stats Monograph 2004

• In 2000, 26000 childhood cancer survivors in UK• Childhood cancer survival rates, 25% in 1960s vs. 75% in 1990s

Mortality in childhood cancer survivors

• The Childhood Cancer Survivor Study

• 20,227 childhood cancer 5-year survivors, diagnosed 1970-1986, up to 25 years follow-up

• Standardized mortality ratio (SMR):

– Overall mortality: 10.8 (10,3-11.3)

– Cardiac mortality: 8.2 (6.4-10.4)

Mertens et al, J Clin Oncol 2001

The determinants of cardiovascular complications in cancer

Direct effects• Invasion of cardiac structures• Primary cardiac tumors• Metastatic cardiac tumorsIndirect effects• Metabolic disorders, SNS

activation etc

Direct effects • Cardiomyocytes• Endothelial cells

Indirect effects • Metabolic disorders etc

Cardio-toxicity

Cancer

CV disease and risk factors

Cancer therapy

• Chemotherapy • Targeted agents • Radiotherapy• Supportive therapies

Farmakis et al. Eur J Heart Fail 2018

Determinants of cardiotoxicity in cancer

Effects of cancer therapy

Cancer

Cancer therapy

Pre-existing RF and CVD

Lenneman and Sawyer, Circ Res 2016

Effects of cancer

Farmakis et al, J Am Coll Cardiol 2014

Cancer

Cancer therapy

Pre-existing RF and CVD

Effects of RF and CV disease

Cancer

Cancer therapy

Pre-existing RF and CVD

The spectrum of cardiovascular complications in cancer

Specturm of cardiovascular complications in cancer

1. Myocardial dysfunction and heart failure

2. Coronary artery disease

3. Arrhythmias

4. Arterial hypertension

5. Valvular heart disease

6. Thromboembolic disease

7. Peripheral vascular disease and stroke

8. Pulmonary hypertension

9. Other: pericardial disease, ANS dysfunction

Myocardial dysfunction and heart failure: Not just anthracyclines!

Modified from ESC 2016

Class Drug Incidence

Anthacyclines Doxorubicin 3-48%

Alkylating agents Cyclophosphamide 7-28%

Antimicrotubule agents Docetaxel 2-13%

Monoclonal Ab Trastuzumab 1-20%

Tyrosine kinase inhibitors Sunitinib 3-19%

Proteasome inhibitors Carfilzomib 11-15%

Chemotherapy-induced cardiotoxicity:Not just LV dysfunction!

Suter & Ewer, Eur Heart J 2012

Class Drug

Arterial hypertension VEGF inh.

Myocardial ischemia Fluopyrimidines, cisplatin

Thromboembolism Cisplatin, VEGF inh.

QT prolongation Arsenic trioxide, lapatinib, vandetanib

Arrhythmias Alkylating agents, taxanes, anthracyclines

Challenging the classical knowledge

Molecular pathways of anthracycline cardiotoxicity

Lenneman and Sawyer, Circ Res 2016

Τopoisomerase-2β (Top2β)

Vejpongsa & Yeh, J Am Coll Cardiol 2014

Increased Top2β in peripheral blood in anthracycline-sensitive patients

• Anthracycline-sensitive (n=21): low doxo dose (<250 mg/m2) and LVEF drop (>10% to <55%)

• Anthracycline-resistant (n=15): high doxorubicin (>450 mg/m2 and preserved LVEF)

Vejpongsa et al, Circulation 2013 (abstr)

0,4

24%

Anthra-resistant Anthra-sensitive

Top2β >0.5 ng/μg

• Top2β levels >0.5 ng/μg a risk factor

Dose-dependent incidence of anthracycline-induced LV dysfunction

ESC 2016

Doxorubicin-induced heart failure

Swain et al, Cancer 2003

Doxorubicin-induced heart failure by age group

Swain et al, Cancer 2003

Doxorubicin-induced heart failure or LVEF decline

Swain et al, Cancer 2003

Suter & Ewer, Eur Heart J 2012

Temporal effects of cardiotoxic therapies

Time course of LVEF decline post-anthracycline under close monitoring

Cardinale et al, Circulation 2015

• Mean time to LVEF decline: 3.5 months• 98% of cases within 1st year

• 5 pts with LVEF decline at 5.5 years: 4 had CAD, 1 had additional Rth 1 year before

Reversibility of cardiotoxicity: Type I and II agents

Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

Molecular pathways of ErbB2-targeted therapies cardiotoxicity

Lenneman and Sawyer, Circ Res 2016

ErbB2 is essential in the prevention of dilated cardiomyopathy

• ErbB2-knock-out mice developed spontaneous dilated cardiomyopathy

• Cardiomyocytes isolated from these mice were more susceptible to anthracycline toxicity

Crone et al, Nat Med 2002

Ewer and Ewer, Nat Rev Cardiol 2015

Anthracycline-trastuzumab interaction

Seidman et al, J Clin Oncol 2002

CREC: Cardiac Review and Evaluation Committee

LV dysfunction:Trastuzumab: 3-7%Trastuzumab+doxorubicin: 27% (16% HF ΝΥΗΑ ΙΙΙ/ΙV)Trastuzumab+paclitaxel: 13% (vs 1% paclitaxel)

Reversibility of cardiotoxicity: Type I and II agents

Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

Cardinale et al, Circulation 2015

Effects of ACEi and BB on anthracycline-induced cardiotoxicity

• 2625 pts receiving anthracycline chemo (breast Ca or NHL)

• Enalapril and carvedilol or bisoprolol:

• 82% LVEF recovery:– 11% full recovery (pre-chemo value)

– 71% partial recovery (increase >5% and >50%)

• Mean time to LVEF recovery: 8 months

Cardinale et al, JACC 2010

• 201 pts, LVEF <45% due to anthracycline chemotherapy• Enalapril +/- carvedilol• Response rates:

42% LVEF incr. >50% - 13% LVEF incr. >10% but <50% - 45% LVEF incr. <10% but <50%• Time of therapy onset a crucial determinant of response

Effects of ACEi and BB on anthracycline-induced cardiotoxicity

Reversibility of cardiotoxicity: Type I and II agents

Εwer et al, J Clin Oncol 2005; Suter & Ewer, Eur Heart J 2012

Open issues

Primary prevention of cardiotoxicity

ESC 2016

ESC 2016

Primary prevention of cardiotoxicity

ESC 2016

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Primary prevention of cardiotoxicity

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Modified form Cardinale et al, Curr Cardiol Rep 2016

RCT on primary prevention

Trial Agent N Design/Fup Results

Cardinale (2006) Enalapril 114 RCT/12mo No LVEF ↓ MACE incidence ↓

Pituskin (2015) BisoprololPerindopril

99 RCT/12mo No LVEF ↓

Gulati (2015) Candesartan 120 RCT/2-16mo No LVEF ↓

Akpek (2015) Spironolactone 83 RCT/6mo No LVEF↓No TNI and BNP↑

Acar (2011) Atorvastatin 40 RCT/6mo No LVEF ↓

Early detection of cardiotoxicity

Ewer and Ewer, Nat Rev Cardiol 2015

Tools for detecting cardiotoxicity

ESC 2016

Tools for detecting cardiotoxicity

ESC 2016

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Troponin predicts cardiac events and LVEF decline

Cardinale et al, Circulation 2004

TnI measured soon after chemotherapy (early TnI) and 1 month later (late TnI).

ΝT-proBNP predicts LVEF decline

Cardinale & Sandri, Prog Cardiovasc Dis 2010

2D strain predicts LV dysfunction early

Stoodley et al, Eur J Echocard 2011

Florescu et al, J Am Soc Echocardiogr 2014

• Α decrease in longitudinal strain after the 3rd cycle of epirubicin was the best predictor of cardiotoxicityafter treatment

• >15% reduction in global longitudinal strain

• Mid-wall or subepicardial LGE• Prevalence 0-100%

CMR-LGE in anthracycline-induced cardiomyopathy

Thavendiranathanet al, Circ Cardiovasc Imaging 2013

Thavendiranathanet al, Circ Cardiovasc Imaging 2013

• Myocardial fibrosis is diffuse and may be missed by LGE • Extracellular volume fraction (ECV) with pre- and post-contrast

T1 mapping may illustrate diffuse myocardial injury

Assessment of myocardial fibrosis in anthracycline-induced cardiomyopathy

ECV values (mean/SD) were increased in the basal, mid, and apical short-axis images.

Antithrombotic therapy for AFib in cancer

• Anticoagulation if CHA2DS2VASc >=2 and PTL >50,000/mm3

ESC 2016

Antithrombotic therapy for AFib in cancer

Farmakis et al, J Am Coll Cardiol 2014

• Anticoagulation if CHA2DS2VASc >=2 and PTL >50,000/mm3

ESC 2016

Cardiac journey of cancer patients

Cardinale et al, Curr Cardiol Rep 2016

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Thank you!

Cardiovascular consultation in cancer: To whom? When? How?

To whom? The importance of risk stratification

Modified from ESC 2016

Demographics Risk factors Heart disease Cancer therapy

Age <18 y>65 y

Diabetes Heart failure or LV dysfunction

Prior antracyclines

Female gender (anthracyclines)

Hypercho-lesterolemia

CAD Prior chest radiotherapy

Smoking Hypertensive HD(LVH)

Combined chemo/targetedagents

Obesity Valvular HD (mod./severe)

Combined chemo and chest radiation

Sedentary life Cardiomyopathies Cumulative dose (antrhacyclines)

Sign. arrhythmias (AF, VT)

Cardiovascular evaluation of cancer patients: In whom?

• Patients with coexistent CV disease

• Patients with a constellation of CV risk factors

• Patients with prior known cardiotoxic therapies

• Patients scheduled for known cardiotoxic cancer therapies

When?

• Before cancer therapy

• During cancer therapy

• After cancer therapy

Cardiovascular evaluation of cancer patients: When?

• Before cancer therapy:

– Initial evaluation of high-risk patients

– Optimal treatment/control of CV disease and risk factors

• During cancer therapy:

– Cardiac monitoring for early signs of cardiotoxicity

– Timely implementation of therapeutic measures

– Modification of cancer therapy if needed

• After cancer therapy:

– Long-term surveillance

During cancer therapySpecific management strategies

• Myocardial dysfunction/heart failure:

– LVEF decrease >10% and <50% or symptomatic HF: start ACEi and BB, stop of cancer therapy

– LVEF decrease >10% but >50%: repeated LVEF in 3 w

• Coronary artery disease/events:

– Patients on pyrimidine analogues: close ECG monitoring for ischemia

– Discontinuation of chemotherapy if ischemia occurs; re-challenge only when no alternatives, pretreatment with nitrates and/or CCB

• Arterial hypertension:

– Start antihypertensive agents (avoid non-dihydropyridine CCB)

– Reduce dose or stop VEGF inhibitors if BP not controlled; re-challenge once BP controlled

• OT prolongation:

– Stop treatment if QTc >500 ms or QTc prolonged >60 ms or dysrhythmias

ESC 2016

ESC 2016

After cancer therapy Long-term surveillance for cancer survivors

• Myocardial dysfunction: periodic screening (echo, biomarkers) in patients treated with anthracyclines or with reversible LV dysfunction during cancer therapy

• CAD: periodic screening in patients with mediastinal radiation, starting 5 years post-treatment and at least every 5 years thereafter

• Carotid artery disease: ultrasound scanning in patients with previous neck irradiation

• Radiation-induced valvular heart disease: periodic screening (echo) at 10 years post-radiation and every 5 years thereafter