Intensified chemotherapy with dexrazoxane cardioprotection in newly diagnosed nonmetastatic osteosarcoma: A report from the Children's Oncology Group Journal Article

Authors: Schwartz, C. L.; Wexler, L. H.; Krailo, M. D.; Teot, L. A.; Devidas, M.; Steinherz, L. J.; Goorin, A. M.; Gebhardt, M. C.; Healey, J. H.; Sato, J. K.; Meyers, P. A.; Grier, H. E.; Bernstein, M. L.; Lipshultz, S. E.
Article Title: Intensified chemotherapy with dexrazoxane cardioprotection in newly diagnosed nonmetastatic osteosarcoma: A report from the Children's Oncology Group
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% tumor necrosis at definitive surgery). 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%) 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. © 2015 Wiley Periodicals, Inc.
Keywords: osteosarcoma; adolescent; cancer chemotherapy; child; treatment outcome; treatment response; leukemia; unclassified drug; major clinical study; constipation; cisplatin; doxorubicin; diarrhea; drug safety; hypophosphatemia; side effect; methotrexate; drug megadose; anorexia; etoposide; esophagitis; nausea; stomatitis; vomiting; creatinine; hemoglobin; ifosfamide; febrile neutropenia; hyperglycemia; hypomagnesemia; alanine aminotransferase; aspartate aminotransferase; bilirubin; dysphagia; hyperkalemia; hypermagnesemia; hypokalemia; hyponatremia; hypotension; folinic acid; mesna; drug dose increase; wound infection; catheter infection; epistaxis; heart protection; heart ventricle arrhythmia; hearing disorder; hypocalcemia; tumor necrosis; pharyngitis; heart left ventricle function; nonmetastatic osteosarcoma; razoxane; human; male; female; priority journal; article; dexrazoxane cardioprotection; intensified chemotherapy; newly diagnosed
Journal Title: Pediatric Blood and Cancer
Volume: 63
Issue: 1
ISSN: 1545-5009
Publisher: Wiley Periodicals, Inc  
Date Published: 2016-01-01
Start Page: 54
End Page: 61
Language: English
DOI: 10.1002/pbc.25753
PROVIDER: scopus
PUBMED: 26398490
PMCID: PMC4779061
Notes: Article -- Export Date: 3 February 2016 -- Source: Scopus
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MSK Authors
  1. Leonard H Wexler
    145 Wexler
  2. Paul Meyers
    260 Meyers
  3. John H Healey
    412 Healey