Dexrazoxane safely supported cumulative doxorubicin dose escalation (450-600 mg/m2) without compromising tumor response or increasing secondary malignancy risk in osteosarcoma.
Cohort
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Does dexrazoxane prevent cardiotoxicity without impairing chemotherapy efficacy in children and adolescents with nonmetastatic osteosarcoma receiving doxorubicin?
Dexrazoxane safely provides cardioprotection without impairing tumor response in children and adolescents receiving intensified doxorubicin for osteosarcoma.
BACKGROUND: Although chemotherapy has improved outcome of osteosarcoma, 30-40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data. PROCEDURE: Children and adolescents with nonmetastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for "standard responders" (SR, <98% tumor necrosis at definitive surgery). RESULTS: Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m(2)) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in five patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ± 0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible. CONCLUSIONS: Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.
Schwartz et al. (Wed,) conducted a cohort in Nonmetastatic osteosarcoma. Dexrazoxane vs. Historical control data was evaluated on Cardioprotection (left ventricular fractional shortening) and interference with chemotherapy-induced cytotoxicity (tumor necrosis). Dexrazoxane safely supported cumulative doxorubicin dose escalation (450-600 mg/m2) without compromising tumor response or increasing secondary malignancy risk in osteosarcoma.