The effects of dexrazoxane on cardiac status and second malignant neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS).

Abstract

9503 Background: Anthracyclines are highly efficacious in OS but associated with risk of cardiotoxicity. We conducted two studies using dexrazoxane as a cardioprotectant: i) AOST0121, a phase II study for metastatic OS and ii) P9754, a series of pilot studies including doxorubicin dose intensification in patients with localized OS. Methods: Patients on AOST0121 received methotrexate, doxorubicin (375 mg/m2), cisplatin, ifosfamide and etoposide (MAPIE). Those with HER2-positive tumors also received trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). On P9754, patients received MAP in Pilot 1, MAPI or MAPIE in Pilots 2 and 3. Total doxorubicin was 450 mg/m2 or 600 mg/m2 with each dose preceded by dexrazoxane (10:1 ratio). Etoposide was never given simultaneously with dexrazoxane. Measurements of left ventricular systolic function by echocardiography, serum troponin-T (cTnT, a myocardial injury marker) and N-terminal pro-brain natriuretic peptide (NT-proBNP, a cardiomyopathy marker) were obtained at baseline and repeated during therapy. Secondary malignancies were reported to the NCI. Results: None of the 47 patients (17 receiving trastuzumab) evaluated for cardiac toxicity on AOST0121 had significant changes in left ventricular fractional shortening, measurable cTnT, elevation of NT-proBNP or clinical evidence of cardiotoxicity (CTCv2.0). In P9754, 242 patients were evaluated for cardiotoxicity. Only 1 patient had CTCv2.0 grade 3 toxicity and 1 patient had a measurable cTnT. Three of 96 patients treated on AOST0121 and two of 272 patients on P9754 developed AML. Combining both studies: 5/398 or 1.4%. Conclusions: This large group of OS patients demonstrates that dexrazoxane is an effective cardioprotectant for doxorubicin alone (375-600 mg/m2), and in combination with trastuzumab. Dexrazoxane did not lead to an increase in secondary malignancies in OS patients treated with these regimens as compared to historical rates of 1-2%. Our results do not support the findings of a recent European Medicines Agency safety review that concluded dexrazoxane was unsafe for use in children and adolescents due to risk of SMN.