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/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data.
  
  
  METHODS
  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.
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Schwartz
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Wexler
authors.affiliation: University of Southern California, Los Angeles, California.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Teot
authors.affiliation: University of Florida College of Medicine and Children's Oncology Group, Gainesville, Florida.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laurel J
authors.initials: LJ
authors.lastname: Steinherz
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Goorin
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gebhardt
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.affiliation: City of Hope National Medical Center, Pasadena, California.
authors.forename: Judith K
authors.initials: JK
authors.lastname: Sato
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Holcombe E
authors.initials: HE
authors.lastname: Grier
authors.affiliation: IWK Health Centre, Nova Scotia, Canada.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bernstein
authors.affiliation: Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, Michigan.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D064730:Dexrazoxane / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D012516:Osteosarcoma / Q000188:drug therapy*; D016896:Treatment Outcome; D018754:Ventricular Dysfunction / Q000517:prevention & control
chemical_list: D002316:Cardiotonic Agents; D064730:Dexrazoxane; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate
keywords: dexrazoxane cardioprotection; intensified chemotherapy; newly diagnosed; nonmetastatic osteosarcoma