Intensified chemotherapy with dexrazoxane cardioprotection in newly diagnosed nonmetastatic osteosarcoma: A report from the Children's Oncology Group.
Schwartz CL1,
Wexler LH2,
Krailo MD3,
Teot LA4,
Devidas M5,
Steinherz LJ2,
Goorin AM4,
Gebhardt MC4,
Healey JH2,
Sato JK6,
Meyers PA2,
Grier HE4,
Bernstein ML7,
Lipshultz SE8.
Abstract
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/m2 ) 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 abstracttext="" at="" definitive="" necrosis="" surgery="" tumor="">
RESULTS:
Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m2 ) 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 a="" abstracttext="" also="" as="" been="" etoposide="" event="" feasible.="" first="" had="" has="" high-dose="" ifosfamide="" in="" intensification="" leukemia="" observed="" one="" prior="" rate="" secondary="" similar="" to="" trials.="" was="" what="" with="">
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. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
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