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
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%)
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.
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
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.