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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

anthracyclines

– Effective in treating broad spectrum of malignancies


Definition
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

1-Anthracyclines:-

-Doxorubicin

-Daunorubicin

- Idarubicin

2-Alkylators:-

-Cyclophosphamide

-Cisplatin

3-Antimetabolite:-

-5 –flouracil

4-Antimicrotubule:-

-Vinca Alkaloid

5-Cytokaines:-

-Interlukin

-Interferon

6-Atra


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

Incidence:-

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

electrons

• 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

mitochondria

– 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

dosing

• 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

hypertension


Anthracycline cardiotoxicity8
Anthracycline Cardiotoxicity

• Risk Factors

– Simultaneous administration of other

antineoplastic agents (cyclophosphomides,

actinomycin D, bleomycin, cisplatin,

methotraxate)

– 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

hypokalemia

• 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

cardiomyopathy

– 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

weight

• 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
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”

Braunwald

– “The situation where the heart is incapable of

maintaining a cardiac output adequate to

accommodate metabolic needs and

venous return”

Katz



Anthracycline cardiotoxicity heart failure1
Anthracycline Cardiotoxicity: HeartFailure

• Gross Changes

– Increased ventricular volume

– Increased then decreased ventricular wall

thickness

– These geometric changes increases

wall tension and decreases pumping

efficiency


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
HEART FAILURE

• Cardinal symptoms

– Dizziness, fainting, fatigue or weakness

– Weight gain (due to fluid buildup)

– Exercise intolerance

– Dyspnea

– Possible fluid retention/edema

• JVD

• Ascities

– Orthopnia


Stages
stages

ACC/AHA CLASSIFICATION

– STAGE A

• At high risk for developing HF, no

structural damage to the heart

– STAGE B

• Structural damage, asymptomatic

– STAGE C

• Structural damage, symptomatic

– STAGE D

• 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

levels


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

levels

• 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

blood


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.


Cyclophosphomides
Cyclophosphomides

• Associated with acute and subacute

cardiac events

• High dose regimens carry greater risk

• Total dose per course best predictor of

cardiotoxicity

• Prior treatment with anthracycline or

mediastinal irradiation increases risk

• Long term affects are usually not seen in

those who survive acute effects


5 fluorouracil
5-Fluorouracil

• Acute creates ischemic insult

• Clinically ranges from angina pectoris to

myocardial infarction

• Rechallenge generally produces same

effect

• Withdraw 5-FU and initiate anti-ischemic

therapy

• 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)