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Chemotherapy Induced Cardiac Toxicity

Russell Huntsinger, MDCardiologist

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What is Cardiac Toxicity?

• Damage to the heart muscle by a toxin is called cardiac toxicity.

• They may cause arrhythmias• May lead to heart failure

– Does not mean that that the heart has stopped or is about to stop

– The heart muscle cannot pump with enough force to supply the body with blood containing essential oxygen and nutrients.

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Chemotherapy Agents that Cause Cardiac Toxicity

• Doxorubicin (Adriamycin)

• Epirubicin

• Idarubicin

• Cyclophosphamide

• Fluorouracil

• Mitoxantrone

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Anthracyclines

• Are the most common cause of cardiac toxicity in cancer patients.

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Anthracyclines

• Used to treat a wide range of hematological and solid malignancies.

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Chemotherapy drugs that have been reported to cause abnormalities in heart rhythm

• Gemtuzumab ozogamicin

• Paclitaxel

• Idarubicin

• Tyrosine kinase inhibitors

• Monoclonal antibodies

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Occurrence

• Clinical heart failure generally occurs within a month to a year after anthracycline treatment.

• May occur up to 6 -10 years or later.

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How is it diagnosed

• Heart sound – stethoscope

• Chest X-ray

• ECG

• Echo

• MUGA scan

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What are the symptoms?

• Fatigue

• Shortness of breath on exertion

• Discomfort lying in supine

• Swelling of the ankles

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• Long cardiac toxicity can manifest as ventricular dysfunction and clinical heart failure.

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Why?

• It is thought that direct myocardial injury is from free radicals.

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How Can Cardiac Toxicity be Prevented

• Altering the amount of dose– Limit anthracyclines

For example:• if doxorubicin is less than 550mg/m2, there is

a less than 1% chance of cardiac toxicity.• If doxorubicin is between 560-1155 mg/m2,

the risk increases to 30%Cur Med Chem. 2001;13:1649-1660.

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• Reported incidence of heart failure in adjuvant anthracycline therapy trials is 2% or less.

• Recent studies have reported 10-50% occurrence of subclinical decline in left ventricular function > 10% points after anthracycline treatment.

J Am Coll Cardiol 2007; 50:1435

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Reducing Drug Cardiotoxicity

• Structural modifications to the doxorubicin molecule (epirubicin).

• Incorporation into liposomes (doxorubicin)

• Development of structurally related drugs (mitoxantrone).

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Method of Administration

• Evidence that the method of drug administration may affect the risk of cardiac toxicity.

• Rapid administration of drugs results in high blood levels, which may cause more heart damage than the same amount of drug given over a longer period of time.

• Small doses of drug, more frequently can decrease the toxicity compared to large doses of drugs at longer intervals.

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Advancements in chemotherapy administration

• Liposomal anthracyclines are anthracycline encapsulated in a liposome.

• By enclosing in lipose, it stays in body longer due to the immune system doesn’t target it for elimination and the liver doesn’t break it down as quickly.

• Current studies indicate that the risk for heart problems is considerable lower with liposomal doxorubicin formulations than with conventional doxorubicin.

Oncologist. 2003;8 Suppl 2:17-24.

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Types of liposomal anthracyclines

• Liposomal daunorubicin (DaunoXome)

• Pegylated liposomal doxorubicin (Doxil)– Has been studied most extensively and has

demonstrated the most significant reductions in heart problems

– Has shown a similar anticancer effect to doxorubicin, but with less cardiac toxicity

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Dexrazoxane (Zinecard)

• Has been shown to prevent or reduce the severity of heart damage caused by doxorubicin.

• Thought to protect the heart muscle by blocking the formation of oxygen free radicals.

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Diagnostics

• Performed through echocardiogram.

• Abnormalities in diastolic dysfunction through Doppler.

• Cardiac biomarkers such as troponin or B-type natriuretic peptide (BNP) in monitoring chemotherapy induced cardiotoxicity is still be studied.

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How is it treated

• Stopping or reducing the dose.

• Diuretics

• Digitalis drugs

• ACE inhibitors

• Beta-Blockers

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• Endomyocardial biopsy may be useful to help diagnosis anthracycline induced cardiotoxicity.

• Histological scaling has correlated with left ventricular function on radionuclide ventriculogram.

• Has limitations with availability of technique and high likelihood of missing the involved areas via biopsy.

Dis Manage 2008; 11: 1-6

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Survivorship and Cardiac Function

• As effectiveness of cancer treatment continues to improve, the population of long term survivors of childhood cancer will grow – an increase of late onset of cardiomyopathy will occur.

• Prognosis after heart failure is generally poor compared to that associated with idiopathic or ischemic cardiomyopathy.