ECHO 2013 / Cancer Treatment Related Cardiotoxicity
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Higher Cumulative Incidence of CHF and/or Cardiomyopathy in Older Breast Cancer Patients After Anthracycline and Trastuzumab Treatment
35.6% over 5 years AC + T
Bowles EJA et al. Natl Cancer Inst 2012
Cancer Treatment-Related Cardiotoxicity
•The burden of disease due to cancer treatment related cardiotoxicity is significant.
•Chemotherapeutic related cardiotoxicity
•Monitoring and detection of cardiotoxicity
•Gaps in Knowledge
Cardiotoxicity Profiles of Chemotherapeutic Agents
35+ FDA approved molecular targeted anti-cancer therapies since 1997
Curr Probl Cardiol 2008;33:163-196
Cardiotoxicity of Chemotherapy:
Anthracyclines
•Discovery in early 1960s, a major advance in treatment of:
–Leukemia
–Lymphoma (HL, NHL)
–Breast CA
–Sarcoma
•Most used: doxorubicin, daunomycin, epirubicin
•Cardiotoxicity:
–Acute (within 24 hrs)
•Rare
•ECG changes, myocardial dysfunction, pericarditis, arrhythmias
–Early onset (within the 1st year of treatment)
•Most common and clinically recognized form of cardiotoxicity
–Late onset chronic progressive (at least 1 year after exposure up to 20 years)
•Seen in survivors of childhood malignancy and other adult cancers
–Risk Factors
•Prior mediastinal radiation, advanced age, younger age, female gender, pre-exisitng heart disease, hypertension, genetic predisposition
Cardiotoxicity of Anthracycline
Dose Dependent: CHF vs. Cumulative Dose
Van Hoff DD, Ann Intern Med 1979;91:710
Swain SM, Cancer 2003; 27:2869
Cardiotoxicity of Anthracycline
Cardiac Apoptosis in Murine Model
Baseline |
24 hr post 20 mg/kg DOX |
Apoptosis in myocardial sections
Scherrer-Crosbie M, EHJ 2006
Mechanism of Action:
Anthracyclines and LV Dysfunction
Anthracyclines
Iron |
Mitochondrial respiration |
Antioxidants |
ROS |
ROS scavengers |
|
Lipid, protein, DNA damage |
|
Myocyte death/ myocardial dysfunction
Figure 1. Modified from: Mol Genet Metab. 2000 Sep-Oct;71(1-2):436-44.
Normal EM myocardial biopsy
Early Stage |
Advanced Stage |
End Stage |
250mg/m2 |
500mg/m2 |
>550mg/m2 |
Dilation of SR, |
Marked |
Myofibrillar disarry and |
swollen mitochondria |
vacuolization |
interstial fibrosis |
Anthracycline Induced
Cardiomyopathy
Survival following diagnosis of CHF according to underlying diagnosis
|
0.100 |
|
|
|
Surviving |
|
|
Peripartum cardiomyopathy |
|
0.75 |
|
|
|
|
|
|
|
|
|
Patients |
|
|
Idiopathic cardiomyopathy |
|
0.50 |
Cardiomyopathy due to |
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|
|
of |
|
Cardiomyopathy due to |
|
|
|
doxorubicin therapy |
|
||
Proportion |
|
|
ischemic heart disease |
|
|
Cardiomyopathy due to infiltrative myocardial disease |
|
||
0.25 |
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|
|
|
|
|
|
|
|
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0.00 |
|
|
|
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0 |
10 |
25 |
30 |
|
|
Years |
|
|
Modified, Felker G et al. N Engl J Med 2000;342:1077-1084