Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.
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.
Meyers
Paul A
PA
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. meyersp@mskcc.org
Schwartz
Cindy L
CL
Krailo
Mark
M
Kleinerman
Eugenie S
ES
Betcher
Donna
D
Bernstein
Mark L
ML
Conrad
Ernest
E
Ferguson
William
W
Gebhardt
Mark
M
Goorin
Allen M
AM
Harris
Michael B
MB
Healey
John
J
Huvos
Andrew
A
Link
Michael
M
Montebello
Joseph
J
Nadel
Helen
H
Nieder
Michael
M
Sato
Judith
J
Siegal
Gene
G
Weiner
Michael
M
Wells
Robert
R
Wold
Lester
L
Womer
Richard
R
Grier
Holcombe
H
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
D000119:Acetylmuramyl-Alanyl-Isoglutamine; C035104:muramylNAc-Ala-isoGln-Lys-tripeptide; D004317:Doxorubicin; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate