 LV dysfunction  Vasospasm and ischemia  Hypertension  VTE  Conduction disease  Arrhythmias

 Anthracyclines  Doxorubicin (Adriamycin)  Epirubicin (Ellence)  Idarubicin (Idamycin PFS)  Alkylating agents  Cyclophosphamide (Cytoxan)  Ifosfamide (Ifex)  Antimetabolites  Clofarabine (Clolar)  Antimicrotubule agents  Docetaxel (Taxotere) 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) Yeh et al, Circulation 2004

 Antimetabolites ◦ Capecitabine (Xeloda) ◦ Flurouracil (Adrucil)  Mab based-TKI ◦ Bevacizumab (Avastin)  Small molecule TKI ◦ Erlotinib (Tarceva) ◦ Sorafenib (Nexavar)  Antimicrotubule agents ◦ Paclitaxel (Taxol) ◦ Docetaxel (Taxotere)

 Mab based-TKI ◦ Bevacizumab (Avastin)  Small molecule TKI ◦ Sorafenib (Nexavar) ◦ Sunitinib (Sutent)

 Alkylating agents ◦ Cisplatin  Angiogenesis inhibitors ◦ Lenalidomide (Revlimid) ◦ Thalidomide (Thalomid)  Small molecule TKI ◦ Erlotinib (Tarceva)  Histone deacetylase inhibitor ◦ Vorinostat (Zolinza)

 Angiogenesis inhibitors ◦ Thalidomide (Thalomid)  Antimicrotubule agents ◦ Paclitaxel (Taxol)

 Histone deacetylase inhibitor ◦ Vorinostat (Zolinza)  Misc ◦ Arsenic trioxide Small molecule tyrosine kinase inhibitors Dasatinib (Sprycel) Lapatinib (Tykerb) Nilotinib (Tasigna)

Type 1Type II DoxorubicinTrastuzumab Cellular destructionCellular dysfunction Cumulative /Dose dependentNon-cumulative /Non dose dependent Usually irreversibleUsually 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

 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, (8): p

Guarneri, V., et al., Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol, (25): p Enlarged and edematous vacuole Pleomorphic mitochondrion Z band widening and splitting

 Wide variation in definition of cardiotoxicity.  Wide range of incidence of asymptomatic LV dysfunction (3.2% - 33%)

Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply. Cardinale, D. et al. J Am Coll Cardiol 2010;55: Percentage of Responders According to the Time Elapsed From AC Administration and Start of HF Therapy

(depends on who you ask)

Stages in the evolution of HF and recommended therapy by stage. et al. Circulation 2001;104: Copyright © American Heart Association

Circulation 2003, 108:

 Normal LVEF >50% at baseline ◦ Baseline MUGA within first 100 mg/m2 in all patients. ◦ Next MUGA 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; , 1987

 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%

 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.

 LVEF = (ED counts – Background counts)- (ES counts – Background Counts) (ED counts – Background counts)

 Digoxin  Heparin  Hydralazine  Penicillin  Quinidine  Prazosin  Methyldopa  Quinidine

 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.

 Exclusion of LV apex in ES ROI  Background counts too high.  Inferoposterior wall motion abnormality.

ProsCons EasyInaccurate 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): Early detection of anthracycline-induced cardiotoxicity by radionuclide angiocardiography. Suzuki J, et al

Salerno M. Multi-modality imaging of diastolic function. J Nucl Cardiol. 2010;17:316–27 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

Ho C Y, Solomon S D Circulation 2006;113:e396-e398 Copyright © American Heart Association

 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

 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.

  >28 open studies looking at monitoring of cardiotoxicity.  11 looking at CMRI with 4 actively recruiting.