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Chemotherapy Induced Cardiotoxicity. Prof. Drs. Hanan Amin. Chemotherapy :- radiotherapy or combined use of both have the potential to cause cardiotoxicity. Chemotherapy Induced Cardiotoxicity. • The number of long-term survivors of cancer is increasing

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Chemotherapy induced cardiotoxicity

Chemotherapy InducedCardiotoxicity

Prof. Drs. Hanan Amin

Chemotherapy induced cardiotoxicity

Chemotherapy :-

radiotherapy or combined use of both have the potential to cause cardiotoxicity.

Chemotherapy induced cardiotoxicity1
Chemotherapy InducedCardiotoxicity

• The number of long-term survivors of

cancer is increasing

• By 2010 1 of every 450 child may be a

survivor of malignant disease

• Many will have been exposed to


– Effective in treating broad spectrum of malignancies

Definition :

  • Cardiotoxicity is defined as one or more of the following :

  • Cardiomyopathy in terms of reduction of left ventricular ejection fraction (LVEF) either global or more severe in the septum.

  • Symptoms associated with heart failure Hf e.g. pulmonary roles, peripheral oedema, hepatomegally,…..

  • Signs associated with Hf such as S3 , gallop, tachycardia or both.

  • Reduction in LVEF from baseline that is the range of less than or equal to 5% to less than 55% with accompanying signs or symptoms of Hf, or a reduction in LVEF in the range of equal to or greater than 10% to less than 55% without accompanying signs or symptoms.

Chemotheraphy causing cardiotoxicity
Chemotheraphy causing cardiotoxicity




- Idarubicin





-5 –flouracil


-Vinca Alkaloid





Radiation causing cardiotoxicity
Radiation causing cardiotoxicity

Cardiac doses of radiation up to 25 Gy. Are generally safe.

,However, it may involve all cardiac structures :-

1-Acute true medical and or / surgery emergencies Eg. Tamponade,Ami,Arrest.

2-Cronic due to collagen deposition.

Anthracycline cardiotoxicity
Anthracycline Cardiotoxicity

• Cytotoxic antibiotics

• Daunorubicin, doxorubicin, epirubicin

and idarubicin

• Highly effective against hematologic

and solid malignancies

• First line defense in the management of

many tumors

Anthracycline cardiotoxicity1
Anthracycline Cardiotoxicity


Anthrocycline induced cardiomyopathy is related to cumulative dose. It occurs in 11% of cancer patients after a cumulative dose of less than 400 mg/m2, 23%

after 400-599 mg/m2, 47% after 500-799 mg/m2 and 100% after 800 mg/m2.

Anthracycline cardiotoxicity2
Anthracycline Cardiotoxicity

Leads to free radical formation

– Molecules containing an odd number of


• H2O2, hydroxyl radicals, ect.

– Are highly reactive and damaging to tissues

• Peroxidation

– Are countered by antioxidants and by

intracellular enzymes

Anthracycline cardiotoxicity3
Anthracycline Cardiotoxicity

– Cardiac degradation of anthrcyclines leads to

free radical formation (enzymatic)

– Anthracyline-ferric iron complex are formed in

the heart

– Cardiac tissue has very limited capacity to

deal with free radicals

– Mitochondria are particularly susceptible to

free radical damage

Anthracycline cardiotoxicity4
Anthracycline Cardiotoxicity

• Other anthracycline induced mechanisms

of cell injury

– Apoptosis

– Elevated calcium accumulation in


– Modulation of cardiac gene expression

Anthracycline cardiotoxicity5
Anthracycline Cardiotoxicity

Adverse effects on the heart

– Electrophysiological changes

– Heart failure

– Reduced exercise tolerance

– Cardiomyopathy

– Pericarditis

– Myocarditis

Anthracycline cardiotoxicity6
Anthracycline Cardiotoxicity

Risk Factors

– Dosing schedule

• Single large dose > risk than smaller, frequent


• Bolus injection > risk than continuous infusion

– Age of patient

• > 65 YOA

• < 4 YOA

Anthracycline cardiotoxicity7
Anthracycline Cardiotoxicity

Risk Factors

– History of mediastinal irradiation

• Amplifies preexisting CAD

• Exacerbation of vascular injury

• Pericardial effusion

• Pericardial fibrosis (restrictive disease)

• Myocardial fibrosis (valvular disease)

– Preexisting heart disease and arterial


Anthracycline cardiotoxicity8
Anthracycline Cardiotoxicity

• Risk Factors

– Simultaneous administration of other

antineoplastic agents (cyclophosphomides,

actinomycin D, bleomycin, cisplatin,


– Poor nutrition

– Diabetes

– Gender

Anthracycline cardiotoxicity stages
Anthracycline Cardiotoxicity: Stages

  • Acute Toxicity:-

  • Occur anytime from initiation of theraphy up to 2 weeks after termination of ttt

  • – Rare

  • – Directly connected with the administration of a

  • single dose or after a course of the antibiotic

Anthracycline cardiotoxicity stages1
Anthracycline Cardiotoxicity: Stages

Acute Toxicity:

– ECG changes

• Often asymptomatic and rarely fatal

• Synergistic action between drug and


• Discontinue drug if occurs

• Tends to be reversible

• Result of an autonomic defect

Anthracycline cardiotoxicity stages2
Anthracycline Cardiotoxicity: Stages

Acute Toxicity:

– Cardiac monitoring during dosing?

• Not typically

• History

• Presence of CV risk factors

• Previous dosage history

Anthracycline cardiotoxicity stages3
Anthracycline Cardiotoxicity: Stages

Subacute Toxicity

– Occurs days to weeks post treatment

– Rare and often asymptomatic

– Toxic pericarditis and/or myocarditis

– Appearance of CHF at this point is a

harbinger of poor outcomes for the patient

Anthracycline cardiotoxicity stages4
Anthracycline Cardiotoxicity: Stages

• Chronic Cardiotoxicity

Early onset

– < 1 yr. post treatment

– Dose dependent

– Manifests itself as CHF secondary to


– Exact incidence unclear

• 1%-18%

• May miss subtle declines in LV function

Anthracycline cardiotoxicity stages5
Anthracycline Cardiotoxicity: Stages

• Late onset-Cardiotoxicity

– Takes years to decades to develop

– Mortality estimated at 30-60%

Anthracycline cardiotoxicity stages6
Anthracycline Cardiotoxicity: Stages

  • Late onset-Cardiotoxicity

Anthracycline cardiotoxicity stages7
Anthracycline Cardiotoxicity: Stages

• Late Cardiotoxicity

– Characterized by

• LV systolic failure (CHF)

• Diastolic failure

• Reduced cardiac contractility

• Reduced cardiac compliance

– Anatomic changes

• Thinned ventricular walls, reduced heart


• Cardiac fibrosis

Anthracycline cardiotoxicity stages8
Anthracycline Cardiotoxicity: Stages

Late Cardiotoxicity

– Monitoring/detection

• Needed but problematic

– Long term follow ups absent

– Very subtle

– Diastolic failure

• Stress Angiography

• Left ventricular end-systolic wall stress

Definition of heart failure hf

– “A complex clinical syndrome that can result

from any structural or functional cardiac

disorder that impairs the ability of the ventricle

to fill with or to eject blood”


– “The situation where the heart is incapable of

maintaining a cardiac output adequate to

accommodate metabolic needs and

venous return”


Anthracycline cardiotoxicity heart failure1
Anthracycline Cardiotoxicity: HeartFailure

• Gross Changes

– Increased ventricular volume

– Increased then decreased ventricular wall


– These geometric changes increases

wall tension and decreases pumping


Anthracycline cardiotoxicity heart failure2
Anthracycline Cardiotoxicity: HeartFailure

Microscope Changes

– Mitochondrial defects

– Diminished cardiac myocyte calcium

handling properties

– Decreased vascularization

– Apoptosis

– Fibrosis causing increased cardiac stiffness

Heart failure

• Cardinal symptoms

– Dizziness, fainting, fatigue or weakness

– Weight gain (due to fluid buildup)

– Exercise intolerance

– Dyspnea

– Possible fluid retention/edema


• Ascities

– Orthopnia




• At high risk for developing HF, no

structural damage to the heart


• Structural damage, asymptomatic


• Structural damage, symptomatic


• End stage

Criteria for cardiac function deterioration
Criteria for cardiac function deterioration

  • ECG findings :

  • Prolonged QT interval.

  • complete heart block.

  • Ventricular ectopy.

  • ST elevation or depression.

  • T wave changes.

  • 2nd degree atrioventricular AV block.,

Criteria for cardiac function deterioration1
Criteria for cardiac function deterioration

  • ECHO findings :

  • Fractional shortening (SF)

  • Left ventricular ejection fraction LVEF less than 55%.

  • Radioinuclide cardiac cineangiocardiography (RNA, MUGA when good ECHO can not be obtained.

Criteria for cardiac function deterioration2
Criteria for cardiac function deterioration

Monitoring cardiovascular toxicity

– Monitor for arrhythmias, ischemic cardiac

events, cardinal CHF symptoms and

pericardial disease

Treatment of congestive heart failure
Treatment of congestive heart failure

  • Digoxin  improve vent. Contraclitiy.

  • Diuretics ↓NA, H2O retention

  • ACE inhibiting agents (captopril)  ↓ afterload.

  • Enalapril  ↑ contractility ↓ afterload.

  • Pts with cardio myopathy are at risk for vent. Arrhythmia. They should undergo a 24-hours ECG monitor on regular basis

Prevention of cardiotoxicity
Prevention of cardiotoxicity

– Prolonged infusion

– 2nd generation anthracyclines

• Synthethic

• Idarubicin, epirubicin, zorubicin

• CV events comparable at similar cytotoxic


Prevention of cardiotoxicity1
Prevention of cardiotoxicity

– Use of oxygen free radical scavengers

• Vitamin E, Q10-coenzyme, Vitamin C

– Dexrazoxane

• Chelates intracellular iron and reducing free radial


• Reduces cardiac damage and allows higher

anthracycline dosing

Preventing cardiotoxicity
Preventing cardiotoxicity

– Probucol

• Vitamin E derivative

• Lipid lowering

• Enhances antioxidants

– Liposomal formulations

• Pegylated liposomal doxorubicin (Caelyx)

• Drug is delivered in a liposome

• Better tumor delivery and longer half life in the


Preventing cardiotoxicity1
Preventing cardiotoxicity

Physical therapy implications

– Patient education

– PT awareness

• History

• CHF does not preclude therapeutic exercise

Guidelines for long term follow up
Guidelines for long-term follow up:

  • Frequency of testing is determined by the cumulative anthracycline doses:

    • Total cumulative dose (TCD)< 300 mg/m2  perform an ECHO before every other course.

    • TCD > 300 mg/m2 with or without mediastinal radiation  perform ECHO or MUGA every course.

  • After comptetion of therapy all patients should perform an ECHO at 12 months after discontinuation of therapy.

  • Patients with normal studies at the end of 1yr post therapy may have an ECHO, ECG every 2-3 ys.

  • Patients with abnormal studies should perform more follow up.


• Associated with acute and subacute

cardiac events

• High dose regimens carry greater risk

• Total dose per course best predictor of


• Prior treatment with anthracycline or

mediastinal irradiation increases risk

• Long term affects are usually not seen in

those who survive acute effects

5 fluorouracil

• Acute creates ischemic insult

• Clinically ranges from angina pectoris to

myocardial infarction

• Rechallenge generally produces same


• Withdraw 5-FU and initiate anti-ischemic


• Greater risk in patients with CAD

Chemotherapy causing other cv effects
Chemotherapy causing other CVeffects

  • Agents associated with hypotension

  • Etoposide (Vepesid)

  • Paclitaxel (Taxol)

  • Alemtuzumab (Campath)

  • Cetuximab (Erbitux)

  • Rituximab (Rituxan)

  • IL-2

  • Denileukin (Ontak)

  • Interferon-

  • All-trans retinoic acid (Tretinoin)

  • Homoharringtonine

Chemotherapy causing other cv effects1
Chemotherapy causing other CVeffects

  • Agents associated with hypertension

  • Bevacizumab (Avastin)

  • Cisplatinin (Platinol)

Chemotherapy causing other cv effects2
Chemotherapy causing other CV effects

  • Agents associated with other toxic effects

  • Cardiac tamponade or endomyocardial fibrosis: busulfan (Myleran)

  • Hemorrhagic myocarditis: cyclophosphamide (Cytoxan)

  • Bradyarrhythmias: paclitaxel (Taxol), thalidomide (Thalomid)

  • Raynaud phenomenon: vinblastine (Velban)

  • Autonomic neuropathy: vincristine (Oncovin)

  • QT prolongation or torsades de pointes: arsenic trioxide (Trisenox)

  • Pulmonary fibrosis: bleomycin (Blenoxane)