Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate

TLDR

To determine whether adding ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high‑dose methotrexate could improve event‑free survival in newly diagnosed osteosarcoma patients. A randomized, prospective trial enrolled 677 osteosarcoma patients without metastatic disease, assigning them to one of four arms in a 2×2 factorial design, all receiving identical cisplatin, doxorubicin, and HDMTX doses and definitive surgical resection. The addition of MTP alone yielded a 3‑year EFS of 68 %, ifosfamide alone 61 %, both together 78 %, but the interaction between ifosfamide and MTP prevented factorial analysis, and ifosfamide alone did not improve EFS, suggesting MTP may improve EFS pending further study.

Abstract

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).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.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%.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.