Cardiotoxicity after doxorubicin and AZD2171, an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, in patients (pts) with breast cancer

Abstract

554 Background: AZD2171 selectively inhibits VEGFR 1,2,3. This trial examined the safety and efficacy of AZD2171 with anthracycline-containing therapy. Methods: Pts with previously untreated Stage IIB and III breast cancer received neoadjuvant AZD2171 (30mg) alone for one cycle (1 week) followed by daily AZD2171 and TAC chemotherapy with docetaxel (T), doxorubicin 50 mg/m2 (A) cyclophosphamide (C) for 6 cycles (Cy) every 3 weeks. Pts underwent breast surgery after completing neoadjuvant therapy. Eligible pts had left ventricular ejection fraction (EF) = 50%, and no uncontrolled HTN or cardiac history. Pts underwent electrocardiogram (EKG), and troponin first day (D) of every Cy and 24 hours after TAC as well as serial echocardiograms (echo). Cardiac stress MRI with dipyridamole was performed when pts had decreases in EF by echo. Results: Two pts received 2 Cy of AZD2171 alone, 9 Cy with TAC and AZD2171, and 1 Cy with TAC alone. Pt 1 and Pt 2 developed hypertension requiring medical therapy Cy4, D1 (148/97 mm Hg) and Cy2, D2 (169/93 mm Hg) respectively. Pt 1 had asymptomatic decrease in EF from 65% to 40% (grade 2) with global hypokinesis pre-Cy5 by echo. Troponin and EKG were negative for acute ischemia. Cardiac stress MRI was normal and EF returned to 60% within 48 hours. The pt continued therapy and pre-Cy7 EF was 51% by echo. Cumulative A dose received was 250mg/m2 pre-Cy7. AZD2171 was held while Cy7 TAC was continued. EF was 57% by echo 1 month after Cy7 TAC. Pt 2 had asymptomatic decrease in EF from 65% to 50% pre-Cy4 by echo with mild global hypokinesis. Troponin and EKG were negative for acute ischemia. Cardiac stress MRI showed EF of 56% with no ischemia. She continued AZD2171 and TAC. Pre-Cy5 EF was 35–40% (grade 3) with global hypokinesis. Troponin and EKG were negative. Cumulative dose of A received was 150mg/m2. AZD2171 and A were stopped; T and C were continued. EF normalized to 55% by cardiac stress MRI and echo within 21 days. Conclusion: Due to the systolic dysfunction that occurred with concurrent AZD2171 and doxorubicin administration, the study is closed. Future trials should administer AZD2171 and anthracyclines sequentially with stringent monitoring of blood pressure and ejection fraction. No significant financial relationships to disclose.