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EURAMOS I : Objectives

Primary objectives

  • In a randomized trial, to examine whether the addition of ifosfamide and etoposide (IE) to post-operative chemotherapy with cisplatin, doxorubicin and methotrexate improves event-free survival for patients with resectable osteosarcoma and a poor histological response to 10 weeks of pre-operative chemotherapy.
  • In a randomized trial, to examine whether the addition of interferon-a (ifn) as maintenance therapy after post-operative chemotherapy with cisplatin, doxorubicin and methotrexate improves event-free survival for patients with resectable osteosarcoma and a good histological response to 10 weeks of pre-operative chemotherapy.
Secondary objectives

  • To investigate whether the addition of IE to post-operative therapy for poor responders, and the addition of ifn as maintenance therapy for good responders, leads to an improvement in the following outcomes:

    Overall survival
    Short-term toxicity
    Long-term toxicity
    Quality of life

  • To investigate whether the addition of IE to post-operative therapy for poor responders, and the addition of ifn as maintenance therapy for good responders, leads to an improvement in event-free and overall survival in patients with localized osteosarcoma at entry.
  • To investigate whether biological or clinical correlates to histological response and outcome can be identified.
  • To establish whether this international cooperation in clinical trials for osteosarcoma is feasible.
  • To examine the outcome of the entire cohort of patients.
ELIGIBILITY CRITERIA

Registration eligibility criteria

  • Histological evidence of high grade osteosarcoma of the extremity or axial skeleton including those arising as second malignancies
  • Resectable disease (defined as disease that is amenable or may become amenable to complete and potentially curative resection. Referral to a recognized specialist center may be appropriate)
  • Age < 40 years at date of diagnostic biopsy
  • Registration within 30 days of diagnostic biopsy
  • Start chemotherapy within 30 days of diagnostic biopsy
  • Neutrophils > 1.5 x 109/L (or WBC > 3 x 109/L if neutrophils are not available) and platelet count > 100 x 109/L
  • Glomerular Filtration Rate > 70 mL/min/1.73 m2
  • Serum bilirubin < 1.5 x ULN
  • Sufficient cardiac function to receive anthracyclines: SF > 28% or EF > 50%
  • Adequate performance status (Karnofsky score > 60 or WHO < 2 for patients (age > 16), Lansky score > 60 (age < 16). Patients whose performance status is adversely affected by a pathologic fracture but who are able to undergo treatment are eligible (see Appendix A.2 for details)
  • Patient fit to undergo protocol treatment and follow-up
  • Written informed consent
Exclusion criteria are as follows:

  • Unresectable disease, primary or metastatic or both
  • Low grade osteosarcoma
  • Juxtacortical (periosteal, parosteal) osteosarcoma
  • Craniofacial osteosarcoma
  • Any previous treatment for osteosarcoma
  • Any previous chemotherapy for any disease
  • Any other medical condition precluding treatment with protocol chemotherapy
  • Pregnant or lactating women
Randomization eligibility criteria

  • Assessment of histological response in primary tumor within 35 days of definitive surgery
  • Two courses of cisplatin and doxorubicin administered before surgery
  • Between two and six courses of methotrexate administered before surgery
  • No severe toxicity precluding post-operative treatment
  • No progression of metastatic disease or new metastatic disease
  • Macroscopically complete surgical resection of the primary tumor
  • In patients with metastatic disease, complete removal of all metastases or complete removal planned and deemed feasible
  • Essential data collection will be provided
  • Written consent to undergo randomization