title: Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.
abstract: OBJECTIVE
  To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS).
  
  
  METHODS
  Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS.
  
  
  RESULTS
  Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%.
  
  
  CONCLUSIONS
  The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. meyersp@mskcc.org
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Schwartz
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
authors.forename: Donna
authors.initials: D
authors.lastname: Betcher
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bernstein
authors.forename: Ernest
authors.initials: E
authors.lastname: Conrad
authors.forename: William
authors.initials: W
authors.lastname: Ferguson
authors.forename: Mark
authors.initials: M
authors.lastname: Gebhardt
authors.forename: Allen M
authors.initials: AM
authors.lastname: Goorin
authors.forename: Michael B
authors.initials: MB
authors.lastname: Harris
authors.forename: John
authors.initials: J
authors.lastname: Healey
authors.forename: Andrew
authors.initials: A
authors.lastname: Huvos
authors.forename: Michael
authors.initials: M
authors.lastname: Link
authors.forename: Joseph
authors.initials: J
authors.lastname: Montebello
authors.forename: Helen
authors.initials: H
authors.lastname: Nadel
authors.forename: Michael
authors.initials: M
authors.lastname: Nieder
authors.forename: Judith
authors.initials: J
authors.lastname: Sato
authors.forename: Gene
authors.initials: G
authors.lastname: Siegal
authors.forename: Michael
authors.initials: M
authors.lastname: Weiner
authors.forename: Robert
authors.initials: R
authors.lastname: Wells
authors.forename: Lester
authors.initials: L
authors.lastname: Wold
authors.forename: Richard
authors.initials: R
authors.lastname: Womer
authors.forename: Holcombe
authors.initials: H
authors.lastname: Grier
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D012516:Osteosarcoma / Q000188:drug therapy* / Q000601:surgery; D011446:Prospective Studies
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; C035104:muramylNAc-Ala-isoGln-Lys-tripeptide; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate