Orlando, Florida – October 7-9, 2011

Breast Cancer and Cardiotoxic Chemotherapy and Radiotherapy

Laxmi S. Mehta, MD, FACCThe Ohio State University Medical Center

Assistant Professor of Clinical Internal MedicineClinical Director of the Women’s Cardiovascular Health ProgramAssociate Program Director of Education, Center for Women’s

Health

Albini, JNCI 2010

Outline

Cardiotoxic agentsBiomarkersPreventative strategiesFollow up

Classification

Type 1Cumulative-doses relatedIrreversible, cell deathTypical biopsy changesDoxorubicin is the model

Type 2Not cumulative-dose relatedPredominately reversible, cell dysfunctionAbsence of anthracycline-like biopsy changesTrastuzumab

Anthracyclines (doxorubicin)

Dose dependent risk of cardiotoxicityImmediate damage to myocardial cells by free radical generationCan be early, late or post-treatmentCardiomyopathy and heart failure most common concern of toxicityCan be treatedCell death cannot be reversedAgents that increase toxicity

PaclitaxelTrastuzumab

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Risk Factors Age > 70HTNHx CADFemale sexPrevious irradiationPrevious antracycline

Cumulative doxorubicin dosing240 mg/m2 asymptomatic decline in EF400 mg/m2 5.1% CHF incidence500 mg/m2 increased toxicity

Side EffectsAcute

PericarditisMyocarditisLV dysfunctionArrhythmias

DelayedCHF

Antracycline Cardiotoxicity

Taxanes: Paclitaxel

Interferes with metabolism and excretion of antracyclinesAcute asymptomatic bradycardia, 30%Serious arrhythmia, MIDecreased cardiotoxicity when combined with D

Slow infusion of both or increased time between themCumulative doxorubicin dose <360 mg/m2 , D T

Less of an issue with epirubicinNewer taxane agents

Trastuzumab

Humanized monoclonal antibodyApproved for treatment of HER2 overexpressing breast cancer

Approximately 25% to 30% of breast cancer cases Associated with poorer prognosis

Incidence of cardiac dysfunction and CHF 2-5%Adjuvant T cardiotoxic when given concomitantly with paclitaxel after ACThe long-term impact of trastuzumab-induced cardiotoxicity unclear, likely less severe than anthracycline-induced cardiotoxicity

1. Slamon D, et al. N Engl J Med. 2001;344:783-792. 2. Seidman A, et al. J Clin Oncol. 2002;20:1215-1221.

TrastuzumabMechanism for trastuzumab-induced cardiac dysfunction is different from doxorubicin

Typically reversibleWhen used following an anthracycline, the damage constitutes a sequential stressBest option to limit initial anthracycline damage

Animal testing suggests HER2 signaling in cardiac myocytes is important to prevent dilated cardiomyopathyOptimal duration of T unknownAsymptomatic declines in LV EF commonNot dose dependentRisk factors: age, HTN, BMI, previous LV dysfnx

1. Ewer MS, et al. Semin Oncol. 1999;26:96-101. 2. Crone SA, et al. Nat Med. 2002;8:459-465.

Radiation

Acute: pericarditis, pericardial effusion, arrhythmiasLeads to myocyte ischemia and fibrosis

Delayed: constrictive pericarditisCoronary endocyte damage leads to inflammation and then atherosclerosisCurrent radiotherapy focused, less radiation

Biomarkers

Natriuretic peptides to detect cardiotoxicity27 patients on antracyclines, serial BNP and echoBNP elevations after AC administration, cardiac tolerance to the agentPersistent elevation of BNP: poor prognosisA/E ratio correlated with increased BNP levels, may suggest diastolic dysfunction“Diagnosis of degree of cardiac tolerance by response to drug administration may be analogous to use of stress testing (exercise) to help define underlying left ventricular dysfunction.”

Suzuki et al. Am Heart J 1998

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LVEF percentage changes during the follow-up in TnI+ (squares) and TnI– (circles) patients.

Cardinale D et al. Ann Oncol 2002;13:710-715

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Cardinale et al. Circ. 2004;109:2749-2754

Troponin I is valuable in detecting Cardiotoxicity

How to Reduce Anthracycline Cardiotoxicity

Limit cumulative dose Expression of cardiotoxicity unusual at cumulative doses < 300 mg/m2

Modification of dose scheduleWeekly administration or every 2 weeks

Use continuous rather than rapid infusion Liposomal delivery systems

Prevention of Anthracyclin-induced Cardiotoxicity

Dexrazoxane—EDTA derivativeGiven during antracycline infusionDecreases oxidized iron levels in myocytesUse when cumulative anthracycline doses of at least 300 mg/m2

Can reduce anticancer effect of anthracyclinesIncrease thrombocytopenia and granulocytopeniaImproved survival seen in some studies

Unclear if improvement due to improved cardiac statusCan worsen thrombocytopenia and granulocytopenia

17Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Kalay, N. et al. J Am Coll Cardiol 2006;48:2258-2262

Comparison of left ventricular ejection fraction (EF) at baseline (black bars) and after adriamycin chemotherapy (white bars) in the 2 groups

18Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Kalay, N. et al. J Am Coll Cardiol 2006;48:2258-2262

Individual change in mitral early/late diastolic flow (E/A) ratio before and after chemotherapy (CT) in the 2 groups

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Figure 1. LVEF at baseline and during the 12-month follow-up in control subjects (left) and the ACEI group (right) in patients with (□) or without (▪) persistent TnI increase.

Cardinale D et al. Circulation 2006;114:2474-2481Copyright © American Heart Association

ACE-I: prevention of toxicity

Cardinale D et al. Circulation. 2006;114:2474-2481

Reversibility of LV dysfunction

Ewer, et al Journ of Clinical Oncology 2005,23;p 7820-6.

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Harbeck et al, 2011

Proposal for Imaging

Albini, JNCI 2010

Conclusions

Chemotherapeutic agents have cardiotoxicities.Close monitoring for symptoms and signs of CHF need to be performed in addition to echocardiographic monitoring.Preventative measures exist.Balance of cardiac and oncologic risks need to be taken into account.