      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 1 Doxorubicin Cellular destruction Cumulative /Dose dependent Usually irreversible Type II Trastuzumab Cellular dysfunction Non-cumulative /Non dose dependent 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

        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.

  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

 ◦ ◦ ◦ ◦ ◦ 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

 ◦ ◦ 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.

Pros Easy “Highly reproducible” “Low interobserver and intraobserver variability. “ Cons Inaccurate in many situations (Arrhythmias, drugs, inaccurate ROIs) Radiation exposure. 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

    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.

   www.clinicaltrials.gov

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