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LV dysfunction
Vasospasm and ischemia
Hypertension
VTE
Conduction disease
Arrhythmias
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Anthracyclines
 Doxorubicin
(Adriamycin)
 Epirubicin (Ellence)
 Idarubicin (Idamycin
PFS)
Alkylating agents
 Cyclophosphamide
(Cytoxan)
 Ifosfamide (Ifex)
Antimetabolites
 Clofarabine (Clolar)
•Monoclonal antibody-based
tyrosine kinase inhibitors
•Bevacizumab (Avastin)
•Trastuzumab (Herceptin)
•Proteasome inhibitor
•Bortezomib (Velcade)
•Small molecule tyrosine
kinase inhibitors
•Dasatinib (Sprycel)
•Imatinib mesylate
(Gleevec)
•Lapatinib (Tykerb)
•Sunitinib (Sutent)
Antimicrotubule agents
 Docetaxel (Taxotere)
Yeh et al, Circulation 2004
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Antimetabolites
◦ Capecitabine (Xeloda)
◦ Flurouracil (Adrucil)
Mab based-TKI
◦ Bevacizumab (Avastin)
Small molecule TKI
◦ Erlotinib (Tarceva)
◦ Sorafenib (Nexavar)
Antimicrotubule agents
◦ Paclitaxel (Taxol)
◦ Docetaxel (Taxotere)
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Mab based-TKI
◦ Bevacizumab (Avastin)
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Small molecule TKI
◦ Sorafenib (Nexavar)
◦ Sunitinib (Sutent)
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Alkylating agents
◦ Cisplatin
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Angiogenesis inhibitors
◦ Lenalidomide (Revlimid)
◦ Thalidomide (Thalomid)
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Small molecule TKI
◦ Erlotinib (Tarceva)
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Histone deacetylase inhibitor
◦ Vorinostat (Zolinza)
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Angiogenesis inhibitors
◦ Thalidomide (Thalomid)
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Antimicrotubule agents
◦ Paclitaxel (Taxol)
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Histone deacetylase inhibitor
◦ Vorinostat (Zolinza)
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Misc
◦ Arsenic trioxide
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Small molecule tyrosine kinase inhibitors
• Dasatinib (Sprycel)
• Lapatinib (Tykerb)
• Nilotinib (Tasigna)
Type 1
Type II
Doxorubicin
Trastuzumab
Cellular destruction
Cellular dysfunction
Cumulative /Dose dependent
Non-cumulative /Non dose
dependent
Usually irreversible
Usually reversible.
Ewer 2008
Incidence of Doxorubicin-induced HF is
 3% to 5% with 400 mg/m2,
 7% to 26% at 550 mg/m2,
 18% to 48% at 700 mg/m2
 Maximum lifetime cumulative dose for
doxorubicin is 400 to 550 mg/m2 .
 Epirubicin or Idarubicin appear to have less
incidence of HF
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Cumulative dose;
intravenous bolus administration;
higher single doses;
history of prior irradiation;
the use of other concomitant cardiotoxic agents
female gender;
Underlying cardiovascular disease; age (young and
old age
increased length of time since anthracycline
completion
Anthracycline Cardiotoxicity
Lemmens, K., K. Doggen, and G.W. De Keulenaer, Role of neuregulin-1/ErbB
signaling in cardiovascular physiology and disease: implications for therapy
of heart failure. Circulation, 2007. 116(8): p. 954-60.
Pleomorphic
mitochondrion
Z band widening and
splitting
Enlarged and edematous
vacuole
Guarneri, V., et al., Long-term cardiac tolerability of trastuzumab in
metastatic breast cancer: the M.D. Anderson Cancer Center experience.
J Clin Oncol, 2006. 24(25): p. 4107-15.
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Wide variation in definition of cardiotoxicity.
Wide range of incidence of asymptomatic LV
dysfunction (3.2% - 33%)
Percentage of Responders According to the Time Elapsed From AC Administration and
Start of HF Therapy
Cardinale, D. et al. J Am Coll Cardiol 2010;55:213-220
Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply.
(depends on who you ask)
Stages in the evolution of HF and recommended therapy by stage.
et al. Circulation 2001;104:2996-3007
Copyright © American Heart Association
Circulation 2003, 108:1404-1418
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Normal LVEF >50% at baseline
◦ Baseline MUGA within first 100 mg/m2 in all
patients.
◦ Next MUGA 200-300 mg/m2.
◦ Next MUGA 450 mg /m2
◦ (400 mg/m2 if high risk- Cyclophosphamide, CAD,
abnormal ECG, mediastinal radiation)
◦ MUGA prior to every dose >450 mg/m2
◦ DISCONTINUE IF
 EF reduces ≥ 10% from baseline AND reaches ≤ 50%
Schwartz RD et al, Amer J. Med. 82;1109 -1118, 1987
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Abnormal LVEF <50% at baseline
◦ Baseline MUGA within first 100 mg/m2 in all
patients.
◦ Serial MUGAs prior to each subsequent dose.
◦ DISCONTINUE if LVEF ≥10% from baseline or
absolute LVEF ≤ 30%
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Assessment of EF at 0, 3, 6, 9, 12 months
MUGA or Echo with Tissue Doppler assessment
Use the same modality in follow up
If >10% absolute LVEF reduction but >50% EF, please follow
up with yearly echos .
If >10% reduction to <50%, please institute heart failure
therapy and refer to a Cardiologist.
If hypertension or DM coexist, please consider ACEI as first
line.
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LVEF =
(ED counts – Background counts)- (ES counts – Background Counts)
(ED counts – Background counts)
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Digoxin
Heparin
Hydralazine
Penicillin
Quinidine
Prazosin
Methyldopa
Quinidine
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Inclusion of LA in ES ROI
Inclusion of ascending aorta in ROI
Background too dark (falsely low counts)
Anterior wall motion abnormality.
Temporal smoothing of LV volume curve.
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Exclusion of LV apex in ES ROI
Background counts too high.
Inferoposterior wall motion abnormality.
Pros
Cons
Easy
Inaccurate in many situations
(Arrhythmias, drugs, inaccurate
ROIs)
“Highly reproducible”
Radiation exposure.
“Low interobserver and
intraobserver variability. “
Costly –
Medicare $291.3
SPECT MUGA $759
Standardized against contrast
ventriculography EF.
Low temporal and spatial
resolution.
No change in EF , but indices
of early diastolic function,
showed a significant
decrease.
•1/3 peak filling rate/ the
end-diastolic count (EDC)
(1/3 PFR/EDC)
•1/3 filling fraction (1/3
FF).
•Delayed time to peak
filling – (Normal is less
than 180 ms)
Angiology 1999, Jan;50(1):37-45.
Early detection of anthracycline-induced cardiotoxicity by radionuclide angiocardiography.
Suzuki J, et al
Count time curves from a patient prior to (A) and after (B) anthracycline
treatment, with marked reduction in the slope of the curve (TPFR)
representing abnormal diastolic filling
Salerno M. Multi-modality imaging of diastolic function. J Nucl Cardiol. 2010;17:316–27
Ho C Y , Solomon S D Circulation 2006;113:e396-e398
Copyright © American Heart Association
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42 Women , mean age 47± 9 years
25 % women developed Trastuzumab mediated
cardiac toxicity at 3 months.
TDI parameters: (S′), early diastolic (e′), and late
diastolic (a′) velocities.
Doppler-independent strain
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Significant difference in the lateral S′
between normals and pts with LV dysfn.
Both peak global longitudinal and radial
strain decreased as early as 3 months in the
CM group
Biomarkers did not predict injury
MUGA EF was decreased in all 10 at 6
month follow up.
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www.clinicaltrials.gov
>28 open studies looking at monitoring of
cardiotoxicity.
11 looking at CMRI with 4 actively recruiting.