CARDIOTOXICITY IN ONCOLOGY PRACTICEEvandro de Azambuja, MD, PhD

Jules Bordet Institute, Brussels, Belgium

Advances in cancer treatments have improved patients outcomes

New molecules targeting different pathways are being tested in cancer

However, there is an increase in cardiac toxicities, which may dramatically impact in

patient’s quality of life

CARDIOTOXICITY: THE

MAGNITUDE OF THE PROBLEM

Myocardial dysfunction and heart failure

Coronary artery disease

QT prolongation

Systemic hypertension

Thrombotic disease

Arrhythmias

Myocardial infarction

Valvular disease

CARDIOVASCULAR ADVERSE

EVENTS OF ANTICANCER AGENTS

SELECTED POTENTIAL CARDIAC

DRUGS IN ONCOLOGY

Focus on heart failure and myocardial dysfunction

Agent Incidence (%) Agent Incidence (%)

Doxorubicin 2-48 Pertuzumab <1.5

Epirubicin 1-3.3 Lapatinib <1

Liposomal A 2 Sunitinib 2.7-19

Cyclophosphamide 7-28 Sorafenib 4-8

Ifosfamide 17 Pazopanib 7-11

Docetaxel 2-13 Imatinib <3

Paclitaxel <1 Everolimus <1

Bevacizumab 1.6-4 Temsirolimus <1

Trastuzumab 1.7-20

Adapted from ESC Guidelines; European Heart Journal 2016

ANTHRACYCLINE EQUIVALENT

DOSES

Drug Relative cardiotoxicity Maximum dose (mg/m²)

Doxorubicin 1 400

Epirubicin 0.7 900

Daunorubicin 0.75 800

Idarubicin 0.53 150

BASELINE RISKS FOR

CARDIOTOXICITY

Life styles risk factors

Previous cardiotoxictreatments

Demographic and other CV risk

factors

Previous cardiovascular diseases

HF, MIAge, HAS, DM

Smoking, alcohol, obesity

Prior A

Prior RT

The most common used definition in clinical practice and clinical trials is*:

A LVEF value <50% and a decrease >10% from its baseline value

CARDIOTOXICITY DEFINITION

*Definition used by the European Society of Cardiology (ESC)

CARDIAC REMODELLING

From N Eng J Med, Hill JA, et al., Cardiac Plasticity, 358:1370–1380. Copyright © 2008 Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society.

MECHANISMS OF CARDIOTOXICITY

de Azambuja E, et al., Cardiac toxicity with anti-HER-2 therapies-what have we learned so far? Target Oncol 2009;4(2):77–88.

© Springer-Verlag 2009, with permission of Springer

CANCER DRUG-ASSOCIATED

CARDIOTOXICITY

Type I Type II

Agent Epirubicin Trastuzumab

Cellular effects Myocardium death Dysfunction

Biopsy findings Typical anthracycline changes No typical changes

Dose response Cumulative Not cumulative

Reversibility No Generally reversible

SEER DATABASE: INCIDENCE OF

HEART FAILURE IN OLDER PATIENTS

10-YEAR CHF (66-70 years)

29%

32.5%

38.4%

Pinder M, et al., J Clin Oncol. 2007;25(25):3808-3815. Reprinted with permission. © (2007) American Society of Clinical Oncology. All rights reserved

Time (months)

Pro

port

ion

free

of C

HF

Shortness of breath

Swelling of feet and legs

Chronic fatigue

Dyspnoea

Swollen or tender of abdomen

Cough

Increased urination at night

Confusion

SYMPTOMS OF HEART FAILURE

Increase in mortality

DIAGNOSTIC TOOLS FOR

CARDIAC TOXICITY

Technique Advantages Limitations

Echocardiography Widely used, no irradiation,

assess dynamics and other

cardiac structures

Operator dependent and limited

in case of thoracic

abnormalities

MUGA reproducibility Irradiation, limited structure and

functional information

Cardiac MRI Accurate and reproducible,

detects diffuse myocardial

fibrosis

Not widely available, costs,

claustrophobia

Cardiac biomarkers

(e.g. HS troponin, NT-

proBNP)

Accurate, reproducible, widely

available, high sensitivity

Lack of evidence of use and its

role in routine surveillance not

well established

Adapted from ESC Guidelines; European Heart Journal 2016

ROLE OF CARDIAC BIOMARKERS

Cardiac dysfunctionCardiomyopathy

cell death

Brain Natriuretic Peptide

(BNP)Normal – elevated elevated

Troponin (TnT, TNI) Normal elevated

CARDIOTOXICITY OF

ANTHRACYCLINES

Focus on late toxicity in breast cancer

Zambetti et al. 2001 Bonneterre et al. 2004 Ganz et al. 2008 de Azambuja et al. 2015

No. of patients in the

original cohort /No. of disease free

1,000 / approximately 50% 565 / 278 1,176 potential 777 / 269

No. of patients assessed for cardiac safety

355 150 180 82

Type of anthracycline Doxorubicin Epirubicin Doxorubicin Epirubicin

Cumulative dose of anthracyclines (mg/m²)

294600 (N= 85) and 300

(N=65)360

800 (N= 29) and 480 (N=26)

Year of cardiac evaluation 11 8 5-8 and 10-13 18

Method of evaluation Echocardiogram Echocardiogram MUGA scan Echocardiogram and MRI

Main results 8% systolic dysfunction with A and 2% with CMF

2.3% CHF with FEC100;

Asymptomatic LVEF drop in

18 patients in FEC100 and 1 in FEC50

5-8 years (N=156): mean

LVEF (61.4% for A and

64.8% for CMF; p= 0.01)

10-13 years (N=110): mean

LVEF (63.4% for A and 62.8% for CMF; p= 0.64)

CHF: 5.5% in HDE* group,

1.9% in SDE* and 0.4% in

CMF (p=0.02 and <0.001,

respectively).

LVEF <50% by either MRI

or echocardiogram: 4% in

CMF and 16% for

anthracyclines (SDE+HDE) (p=0.15)

*SDE: standard dose epirubicin: HDE: high dose epirubicinAdapted from Azim HA Jr, et al., Ann Oncol. 2011(9): 1939-47

HER2-POSITIVE BREAST CANCER

Adapted from Capelan M, et al., Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol 2013(2):273-82, with permission from

the European Society for Medical Oncology

Trial Treatment regimen # pts Any LVEF drop CHF

Piccart M et al.; de

Azambuja et al. (HERA)

Chemotherapy 1744 15 (0.9) 0

Chemotherapy + 1 y Trastuzumab 1682 69 (4.7) 14 (0.8)

Romond et al.

(NSABP-B31)

AC + Paclitaxel 743 Not reported 9 (1.2)

AC + Paclitaxel + Trastuzumab 947 114 (12) 36 (3.8)

Advani et al.

(N9831)

AC + Paclitaxel 664 64 (9.6) 6 (0.9)

AC + Paclitaxel + Trastuzumab 710 119 (16.7) 19 (2.6)

AC + Paclitaxel/Trastuzumab 570 136 (23.8) 20 (3.5)

Slamon et al.

(BCIRG 006)

AC + Docetaxel 1073 114 (11.2) 8 (0.8)

AC + Docetaxel + Trastuzumab 1074 206 (19.1) 21(2.0)

Docetaxel + Carboplatin +

Trastuzumab1075 97 (9.4) 4 (0.4)

Spielman et al.

(PACS 04)

FEC/ED 268 7 (2.6) 1 (0.4)

EC/ED + Trastuzumab 260 29 (11.1) 4 (1.5)

TRIALS

TRASTUZUMAB-ASSOCIATED

CONGESTIVE HEART FAILURE

WITH 1 YEAR OF THERAPY

0

1.30.9

0.4 0.4

0.8

4

2.6

2

1.5

3.5

0.4

0

1

2

3

4

5

HERA NSABP B31 N9831 BCIRG 006 PACS 04

CH

F (

%)

Obs 1 y Trast Trast Comb

HERA TRIAL (N=5,102 PATIENTS)

OBSERVATIONn=1698

Women with locally determined HER2-positive invasive early breast cancer

Surgery + (neo)adjuvant CT ± RT

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

Randomisation

1 year Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1703

2 years Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule

n=1701

After ASCO 2005, option of switch to Trastuzumab

CT, chemotherapy; RT, radiotherapy.

Piccart-Gebhart MJ, et al., N Eng J Med 2005; 353:1659-1672

de Azambuja E, et al., Trastuzumab-Associated Cardiac Events at 8 Years of Median Follow-Up in the Herceptin Adjuvant Trial (BIG 1-01) J Clin Oncol

2014;32(20):2159–65. Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved.

CUMULATIVE INCIDENCE OF

CARDIAC ENDPOINTS IN THE THREE ARMS

ACUTE RECOVERY OF ANY

CARDIAC EVENT IN THE 1 YEAR

TRASTUZUMAB ARM

Acute recovery %

(n= 83)

79.5

20.5

Yes No

Median time to recovery: 6.6 months

de Azambuja E, et al., J Clin Oncol 2014; 32(20): 2159-2165

ESMO ALGORITHM FOR

CONTINUATION/DISCONTINUATION

OF TRASTUZUMAB BASED ON LVEF

Curigliano G, et al., Ann Oncol 2012; 23(7)

LVEF assessment

LVEF <50% LVEF ≥50%

LVEF <40%

Hold treatmentRepeat LVEF in 3 weeks

LVEF 40%-50% Start treatment

LVEF 10% point below baseline

LVEF higher than 10% below baseline

Continue treatmentHold treatment

Repeat LVEF in 3 weeks

LVEF <40% LVEF >45% OR LVEF 40%-50%

STOP TREATMENT RESUME TREATMENT

CARDIAC FUNCTION ASSESSMENT

Anthracycline CT

Taxane

CT

Trastuzumab

HER2 +

EBC

Before CT After A-based CT

LVEF assessment every 3 months

during treatment of whenever required

MEDICAL TREATMENT

Treatment of a cardiac event

Angiotensin converting enzymes inhibitors (ACE-Is or ARBs) and beta-blockers are

recommended in patients with symptomatic HF or asymptomatic cardiac dysfunction

unless contraindication

In case of anti-HER2 agents, therapy can be reinitiated if LVEF value returns to

baseline or normal values

MEDICAL TREATMENT

Strategies for prevention of cardiotoxicity

Identifying patients with high cardiac risk

Modifying life style to decrease cardiac risk

Using less cardiotoxic regimens if possible

The use of dexrazoxane in metastatic patients requiring anthracycline chemotherapy

(doses > 300 or >540 mg/m2 for doxorubicin and epirubicin, respectively)

Prophylactic ACE-I (or ARB) and beta-blockers in selected cases treated with

anthracyclines or trastuzumab (small trials)

MEDICAL TREATMENT

Strategies for prevention of cardiotoxicity

Enalapril and carvedilol vs. normal care before high-dose anthracyclines

Prevention in 6 months LVEF decrease with both drugs

Their use in low risk patients remains controversial

Candesartan (ARB) attenuates decrease in LVEF compared to beta blocker or placebo

in patients with early breast cancer treated with A-based chemotherapy

ACEi or beta blockers have no effect on cardiac remodelling in patients treated with

trastuzumab

Therapies Possible mechanisms Incidence

Fluoropyrimidines

(5-FU, capecitabine)

Endothelial injury and vasospasm Myocardial ischemia: 18%

Silent myocardial ischemia: 50%

Platinum salts Procoagulant status; arterial

thrombosis

Thrombosis: 2%

In long-term survivors (8% 20 y

testicular cancer)

VEGF inhibitors Procoagulant status; arterial

thrombosis; endothelial injury

AT with bevacizumab: 3.8%

Radiotherapy Thrombosis; endothelial injury,

plaque rupture 30 y

In long-term survivors

(13% 30 y Hodgkin lymphoma)

CARDIOTOXICITY

Coronary artery disease

Adapted from ESC Guidelines; European Heart Journal 2016

CARDIOTOXICITY

Coronary artery disease

Early recognition of patients at risk

Limited options for medical and interventional treatments

Contraindication to antiplatelet and anticoagulants generally present

Patients treated with concomitant neurotoxic agents and RT: silent events!

Drug rechallenge is generally not recommended

CARDIOTOXICITY

QT prolongation

Can be caused by several anticancer drugs

High incidence with some drugs such as arsenic trioxide (26-93%)

Can also be caused by electrolyte disturbances, predisposing factors and concomitant

medications

Can lead to life-threatening arrhythmias such as torsade de pointes

Arrhythmias can occur before, during and shortly after treatment

CARDIOTOXICITY

QT prolongation: risk factors

Correctable Non-correctable

Electrolyte imbalance

• Nausea / vomiting

• Diarrhea

• Use of loop diuretics

• Hypokalemia (≤3.5 mEq/L)

• Hypomagnesaemia (≤1.6 mg/dL)

• Hypocalcemia (≤8.5 mg/dL)

• Family history of sudden death

• Personal history of syncope

• Baseline QTc interval prolongation

• Female gender

• Advanced age

• Heart disease

• Myocardial infarction

• Impaired renal function

• Impaired hepatic functionHypothyroidism

Concurrent use of QT-prolonging drugs

• Antiarrhythmic

• Antibiotics or antifungals

• Psychotropic or antipsychotic

• Antidepressant

• Antiemetic

• antihistamine

Adapted from ESC Guidelines; European Heart Journal 2016

CARDIOTOXICITY

QT prolongation: diagnostic

12-lead ECG at baseline and during treatment (only in selected cases)

QTc interval >450 ms in men and >460 ms in women

QTc prolongation >500 ms and a QT (i.e. change form baseline) of >60 ms are of

particular concern

CARDIOTOXICITY

QT prolongation management

Consider stop or alternative treatments if:

QTc prolongation >500 ms and a QT of >60 ms are particular concern

Correct electrolyte disturbances, thyroid function, etc.

Avoid combining drugs that may increase the risk of QT prolongation

CARDIOTOXICITY

Systemic arterial hypertension

Frequently observed with anti-VEGF inhibitors (nearly 50%)

Proposed mechanisms: nitric oxide pathway inhibition, vascular rarefaction, oxidative

stress, and glomerular injury

Early (few days) or late onset (1 year later)

CARDIOTOXICITY

Systemic arterial hypertension

Identify patients at high risk

Blood pressure goal <140/90

Close monitoring is required to avoid severe HAS

ACE or ARB inhibitors and beta-blockers are preferred especially if HF or LVEF drops

Non-dihydropyridine calcium channel blockers are considered first-line as well

Anti-VEFG: stop or drug reduction!

CARDIOTOXICITY

Thrombotic disease

Frequently observed in cancer patients

Tumoural cells can trigger coagulation through different pathways

May occurs as:

Arterial thrombosis: about 1%

Venous thrombosis: up to 20% of hospitalised cancer patients

CARDIOTOXICITY

Thrombotic disease

Cancer-related

• Primary cancer

• Histology

• Advanced stage

Patient-related

• Demographics

• Comorbidities

• Prior history of VTE

• Low performance status

Treatment-related

• Major surgery

• Hospitalisation

• Chemo or antiangiogenic

• Endocrine

• Transfusions

• Central venous catheter

Adapted from ESC Guidelines; European Heart Journal 2016

CARDIOTOXICITY

Thrombotic disease

No screening methods available

Diagnosis mainly based on clinical symptoms

Prompt suspicion and management are required

Cancer remains a risk factor for thrombosis (first episode and recurrence)

Thromboprophylaxis based on individual patient’s benefit/risk assessment

CARDIOTOXICITY

Radiotherapy

Most events occur at long-term (several years after treatment)

To reduce the risk of cardiotoxicity:

Heart-sparing techniques

The use of 3D treatment planning

The use of CT scan or MRI to plan RT treatment

American Society of Echocardiogram recommends an echocardiography 10 year

post-RT and serial exams every 5 year thereafter

CONCLUSIONS

Cardiotoxicity has emerged as a frequent problem in oncology

Cardiac events can be at early or late onset

Anthracyclines cause irreversible damage and should be avoided in patients at high

cardiac risk

Trastuzumab cardiac events generally happen during treatment and are mostly

reversible

CONCLUSIONS

Thorough cardiac risk assessment should take place prior to any cancer treatment

Prompt diagnosis and treatment are required to avoid bad prognosis of HF

Hypertension should be treated to avoid treatment interruptions and life threating

conditions

Late valvular diseases should be considered in patients previously exposed to

radiotherapy

Close collaboration with cardiologists is fundamental

Because of the importance of cardiac toxicity of

anticancer therapies, a new discipline was created:

cardio-oncology

ESC Position Paper

In 2016, The Task Force for cancer treatments and cardiovascular toxicity of the

European Society of Cardiology (ESC) developed a position paper on cancer

treatments and cardiovascular toxicity under the auspices of the ESC Committee

for Practice Guidelines

Zamorano JL, et al., Eur Heart J 2016;37:2768–2801

THANK YOU!