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Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group. Pediatr Blood Cancer 2016 Jan;63(1):54-61

Date

09/24/2015

Pubmed ID

26398490

Pubmed Central ID

PMC4779061

DOI

10.1002/pbc.25753

Scopus ID

2-s2.0-84983208745   33 Citations

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/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.

Author List

Schwartz CL, Wexler LH, Krailo MD, Teot LA, Devidas M, Steinherz LJ, Goorin AM, Gebhardt MC, Healey JH, Sato JK, Meyers PA, Grier HE, Bernstein ML, Lipshultz SE

Author

Cindy L. Schwartz MD, MPH Chief, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Antineoplastic Combined Chemotherapy Protocols
Bone Neoplasms
Cardiotonic Agents
Child
Child, Preschool
Cisplatin
Dexrazoxane
Doxorubicin
Etoposide
Female
Humans
Ifosfamide
Infant
Infant, Newborn
Male
Methotrexate
Osteosarcoma
Treatment Outcome
Ventricular Dysfunction
jenkins-FCD Prod-461 7d7c6113fc1a2757d2947d29fae5861c878125ab