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Chemotherapy Induced Professor Usama Roshdy El Safy

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Chemotherapy Induced Professor Usama Roshdy El Safy Powered By Docstoc
					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
• 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 :

 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
1-Anthracyclines:-
-Doxorubicin
-Daunorubicin
- Idarubicin

2-Alkylators:-
-Cyclophosphamide
-Cisplatin

3-Antimetabolite:-
-5 –flouracil

4-Antimicrotubule:-
-Vinca Alkaloid

5-Cytokaines:-
-Interlukin
-Interferon
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

• Cytotoxic antibiotics
• Daunorubicin, doxorubicin, epirubicin
and idarubicin
• Highly effective against hematologic
and solid malignancies
• First line defense in the management of
many tumors
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 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 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 Cardiotoxicity

• Other anthracycline induced
  mechanisms
of cell injury
– Apoptosis
– Elevated calcium accumulation in
mitochondria
– Modulation of cardiac gene
  expression
Anthracycline Cardiotoxicity

Adverse effects on the heart
– Electrophysiological changes
– Heart failure
– Reduced exercise tolerance
– Cardiomyopathy
– Pericarditis
– Myocarditis
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 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 Cardiotoxicity
• Risk Factors
– Simultaneous administration of other
antineoplastic agents (cyclophosphomides,
actinomycin D, bleomycin, cisplatin,
methotraxate)
– Poor nutrition
– Diabetes
– Gender
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: 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: Stages

Acute Toxicity:
– Cardiac monitoring during dosing?
• Not typically
• History
• Presence of CV risk factors
• Previous dosage history
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: 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: Stages

• Late onset-Cardiotoxicity
– Takes years to decades to develop
– Mortality estimated at 30-60%
Anthracycline Cardiotoxicity: Stages

 Late onset-Cardiotoxicity
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: 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
Anthracycline Cardiotoxicity: Heart
Failure
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
Failed heart
Anthracycline Cardiotoxicity: Heart
Failure
• Gross Changes
– Increased ventricular volume
– Increased then decreased ventricular
  wall
thickness
– These geometric changes increases
wall tension and decreases pumping
efficiency
Anthracycline Cardiotoxicity: Heart
Failure
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
• JVD
• Ascities
– Orthopnia
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
   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
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
deterioration
Monitoring cardiovascular toxicity
– Monitor for arrhythmias, ischemic
  cardiac
events, cardinal CHF symptoms and
pericardial disease
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

– Prolonged infusion
– 2nd generation anthracyclines
• Synthethic
• Idarubicin, epirubicin, zorubicin
• CV events comparable at similar
   cytotoxic
levels
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
– 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 cardiotoxicity

Physical therapy implications
– Patient education
– PT awareness
• History
• CHF does not preclude therapeutic
  exercise
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
• 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
• 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

 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
effects
 Agents associated with hypertension
 Bevacizumab (Avastin)
 Cisplatinin (Platinol)
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)

				
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