Complete dexrazoxane cardioprotection for cardiac function but incomplete female cardioprotection for cardiac structure in doxorubicin-treated osteosarcoma survivors: Hearts too small for the body.

Abstract

10519 Background: Dexrazoxane is protective for lower-dose doxorubicin ( < 300 mg/m2) cardiotoxicity in childhood cancer, but the effect of dexrazoxane (DXRZ) administered with higher-dose (HD) doxorubicin (DOXO) is unknown. Methods: We evaluated patients from Children’s Oncology Group trials for localized (P9754) and metastatic (AOST0121) osteosarcoma (OS) who received HD DOXO (375-600 mg/m2) preceded by DXRZ (10:1 ratio), methotrexate, and cisplatin; some also received ifosfamide alone or ifosfamide/etoposide ± trastuzumab. Cardiotoxicity was identified by echocardiography and by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. Results: 81 DXRZ -treated OS patients ( age at enrollment = 13.7 years; range 3.8 - 23.7 years) had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. Female sex and longer follow-up since DOXO were associated with a significantly smaller LV dimension z-score normalized to BSA (μ = -1.20, 95%CI [-1.70, -0.70]). Similarly, in the one-third of patients treated > 81 days after minimal expected treatment (groups equally partitioned by time), significantly thinner LV posterior wall thickness for BSA (μ = -0.57, [-1.05, -0.09]) was found. Interventricular septal wall thickness (μ = -0.84, [-1.2, -0.48]) and LV mass (μ = -0.73, [-1.06, -0.40]) were significantly smaller for BSA than normal for both sexes. For females, these became significantly more abnormal with increasing length of follow-up. Females also showed progressive increases in NT-proBNP. Conclusions: DXRZ is cardioprotective for HD DOXO in terms of LV function and heart failure. Females had progressive abnormalities of LV structure, leading to smaller hearts for body size. This was associated with increasing cardiac stress, as measured by NT-proBNP. DXRZ protection was incomplete for HD DOXO effects on LV structure, resulting in higher LV stress and risk for late LV dysfunction. DXRZ should continue to be used in this population, including for females who exhibit more cardiotoxicity than males at specific cumulative DOXO doses.