CARDIOVASCULAR TOXICITY INDUCED BY ANTITUMOUR THERAPY

Florian SCOTTE, MDPhD

Suresnes, France

DISCLOSURESDISCLOSURESDISCLOSURESDISCLOSURES

• Consultant / Advisory Boards / Speaker: Tesaro, Sanofi, Roche, MSD, TEVA, Norgine, Prostrakan, Leo pharma, Janssen, Hospira, Boehringer, AMGEN, Pierre Fabre Oncologie, Vifor Pharma

• Associations: ESMO, ASCO, MASCC, AFSOS, AESCO

SURVIVOR CARE …SURVIVOR CARE …SURVIVOR CARE …SURVIVOR CARE …

Cumulative incidence curves

of cardiovascular disease

events

Chun Chao et al. J Clin Oncol 2016; 34:1626-1633

PediatricPediatricPediatricPediatric experienceexperienceexperienceexperienceC

um

ula

tiv

e M

ort

ali

ty (

%)

0 25 30 352015105

Years since diagnosis

0

10

15

5

1970s

3.1% (2.7 – 3.5)

1980s

2.4% (2.2 – 2.7)

1990s

1.9% (1.6 – 2.2)

15-Year Cumulative

Mortality

Armstrong GT et al, N Engl J Med., 2016

CARDIAC SURVIVOR FLOWSHARTCARDIAC SURVIVOR FLOWSHARTCARDIAC SURVIVOR FLOWSHARTCARDIAC SURVIVOR FLOWSHART

Overarching clinical questions addressed in the clinical practice guideline

SH. Armenian et al. JCO 2017, 35, 893-911.

THE CARDIOLOGIST !!!!!THE CARDIOLOGIST !!!!!THE CARDIOLOGIST !!!!!THE CARDIOLOGIST !!!!!

Ischemic eventsBaseline ECG

BNP Troponin 1 monitoring

Anamnesis

Hypertension

Anamnesis

Comorbiditiesangiotensin-converting

enzyme inhibitors

Calcium channel blockers

QT prolongation�Arrhythmias

�Torsade de pointes

Cardiac Heart FailureCongestive Heart Failure

Left Ventricular Dysfunction

Pericardial effusions

Myopericarditis

AssessAssessAssessAssess PrevalencePrevalencePrevalencePrevalence of of of of CardiovascularCardiovascularCardiovascularCardiovascular DiseasesDiseasesDiseasesDiseases by by by by type of type of type of type of malignancymalignancymalignancymalignancy

SG. Al-Kindi et al. Mayo Clin Proc. 2016;91(1):81-83

AssessAssessAssessAssess CardiacCardiacCardiacCardiac RiskRiskRiskRisk FactorsFactorsFactorsFactors

Individual risk factors

• Tobacco use

• Hypertension

• Diabetes

• Dyslipidemia

• Obesity

• Age (> 60 years)

• Cardiac history

Treatment related risk factors

• Anthracyclines

• Radiotherapy (heart area)

• Monoclonal antibody

• Other cardiotoxic drugs

AssessAssessAssessAssess PrevalencePrevalencePrevalencePrevalence by by by by AnticancerAnticancerAnticancerAnticancer TreatmentTreatmentTreatmentTreatment ((((HeartHeartHeartHeart FailureFailureFailureFailure) ) ) )

Drug Type of CV failure Frequency

Anthracyclines Anthracycline induced

cardiomyopathy

3-26% (≤ 550 mg/m2)

Acute 1%

1 year after Tt completion

Alkylating agents

(cyclophosphamide)

Left Ventricular Dysfunction

Pericardial effusions

Myopericarditis

7 – 28%

Dose related (≥ 1,5 g/m2/day)

inhibitors of microtubule

polymerization

Congestive Heart Failure 0,7% - 1,6%

Depends co-drugs

Monoclonal antibodies and

targeted agents

Cardiac Heart Failure 3 – 34%

Tyrosine Kinase Inhibitors (HER2-

EGFR)

1,4% symptomatic cardiac failure

≥10% asymptomatic drop LVEF

Curigliano et al. Annals Oncol 2012; 23 (7)

• Doxorubicin >500 mg/m2

• Liposomal doxorubicin >900 mg/m2

• Epirubicin >720 mg/m2

• Mitoxantrone >120 mg/m2

• Idarubicin >90 mg/m2

CardiacCardiacCardiacCardiac ToxicityToxicityToxicityToxicity InducedInducedInducedInduced by by by by TrastuzumabTrastuzumabTrastuzumabTrastuzumab

Curigliano et al. Annals Oncol 2012; 23 (7)

AssessAssessAssessAssess PrevalencePrevalencePrevalencePrevalence by by by by AnticancerAnticancerAnticancerAnticancer TreatmentTreatmentTreatmentTreatment ((((CardiacCardiacCardiacCardiac IschemiaIschemiaIschemiaIschemia))))

Drug Type of CV failure Frequency Delay

Antimetabolites: 5FU Cardiac Ischemia

Coronary artery thrombosis

Arteritis, Vasospasm

1 – 68%

Within 2-5 days of starting therapy

inhibitors of microtubule

polymerization: paclitaxel

Myocardial ischemia 5%

Endocrine Agents: Aromatase

Inhibitors

Myocardial infarction

Cardiac failure

0.5%

Targeted Agents (VEGF): sunitinib Modest increase in cardiac

troponins

18%

Curigliano et al. Annals Oncol 2012; 23 (7)

AlgorithmAlgorithmAlgorithmAlgorithm for the management of for the management of for the management of for the management of cardiotoxicitycardiotoxicitycardiotoxicitycardiotoxicity in in in in patients patients patients patients receivingreceivingreceivingreceiving anthracyclinesanthracyclinesanthracyclinesanthracyclines

Curigliano et al. Annals Oncol 2012; 23 (7)

ACE = angiotensin-converting enzyme

inhibitors

BB = betablocking agents

AlgorithmAlgorithmAlgorithmAlgorithm for continuation and discontinuation of for continuation and discontinuation of for continuation and discontinuation of for continuation and discontinuation of trastuzumabtrastuzumabtrastuzumabtrastuzumab basedbasedbasedbased on LVEF on LVEF on LVEF on LVEF assessmentsassessmentsassessmentsassessments

Curigliano et al. Annals Oncol 2012; 23 (7)

Elevated baseline troponin I (> 40 ng/L) (13.6% - 56 of 412 pts)

Elevated baseline troponin T (> 14 ng/L), (24.8% - 101 of 407 pts)

increased significant LVEF drop risk

HR = 4.52; (P = 0.001) HR = 3.57; (P = 0.001)

CHECPOINT INHIBITORS AND CARDIAC SAFETYCHECPOINT INHIBITORS AND CARDIAC SAFETYCHECPOINT INHIBITORS AND CARDIAC SAFETYCHECPOINT INHIBITORS AND CARDIAC SAFETY

• Cardiac AEs Incidence <1%, (higher with IT combination)

• Wide range of toxicities:

• Myocarditis,

• Pericarditis,

• Arrhythmias,

• Cardiomyopathy

• Impaired ventricular function

• Early consultation with a cardiologist is recommended [V, B].

• High-dose corticosteroids and Immunosuppressive drugs successful

Y.Tomita et al. Annals Oncology 2017; 28; 11: Letter to the editors. 2893-95

Acute Acute Acute Acute coronarycoronarycoronarycoronary syndrome as a possible immunesyndrome as a possible immunesyndrome as a possible immunesyndrome as a possible immune----relatedrelatedrelatedrelatedadverse adverse adverse adverse eventeventeventevent in a in a in a in a lunglunglunglung cancer patient cancer patient cancer patient cancer patient achievingachievingachievingachieving a a a a completecompletecompletecompleteresponseresponseresponseresponse to antito antito antito anti----PDPDPDPD----1 immune checkpoint 1 immune checkpoint 1 immune checkpoint 1 immune checkpoint antibodyantibodyantibodyantibody

Activated T cells produce pro-atherogenic cytokines such as IFN-c and TNF-a that

contribute to both growth and destabilization of lesions resulting in rupture [1]. This

leads to a hypothesis that PD-1 blockade therapy might be involved in provoking the

growth and destabilization of atherosclerotic lesions and causing ACS by immune

activation in the coronary atherosclerotic lesions.

FIRST CASE REPORT: Acute Coronary Syndrome

Checkpoint Checkpoint Checkpoint Checkpoint inhibitorsinhibitorsinhibitorsinhibitors SAE SAE SAE SAE inducedinducedinducedinduced

Champiat S. et al Annals of Oncology 27: 559–574, 2016

“Supportive care makes excellent cancer care possible”

“Dorothy M.K. Keefe,

past-President of MASCC