RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Zoledronic acid may stop the growth of tumor cells in bone. Giving chemotherapy with or without zoledronic acid before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving combination chemotherapy together with zoledronic acid is more effective than combination chemotherapy alone in treating osteosarcoma.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and zoledronic acid to see how well they work compared with combination chemotherapy alone in treating patients with osteosarcoma.

OBJECTIVES:

Primary

• Compare the progression-free survival of patients with osteosarcoma treated with combination chemotherapy with or without zoledronic acid.

Secondary

• Compare the overall survival of patients treated with these regimens.
• Compare the percentage of patients with a good histologic response.
• Compare the long and short term toxicity of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (< 18 years vs 18-25 years vs > 25 years), risk group (nonmetastatic or resectable vs metastatic or unresectable), and treatment center. Patients receive either methotrexate-based chemotherapy or doxorubicin hydrochloride-based chemotherapy according to age.

• Methotrexate-based chemotherapy (patients ≤ 25 years of age): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive methotrexate IV in weeks 1-3, 7, 8, 12, and 13 and etoposide IV and ifosfamide IV in weeks 4 and 9.
  • Arm II: Patients receive methotrexate, etoposide, and ifosfamide as in arm I. Patients also receive zoledronic acid IV in weeks 1, 5, 9, and 13.

All patients undergo surgery in week 14. After surgery, patients are assigned to 1 of 2 groups for further treatment, based on histological response.

• Good responders (< 10% viable cells): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive methotrexate IV in weeks 1-3, 7-9, 13-15, and 19-21 and etoposide IV in weeks 4 and 10. Patients also receive ifosfamide IV in weeks 4, 10, and 16.
  • Arm II: Patients receive methotrexate, etoposide, and ifosfamide as in arm I. Patients also receive zoledronic acid IV in weeks 3, 7, 11, 15, 19, and 23.

• Bad responders (> 10% viable cells): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive methotrexate IV in weeks 1, 5, 9, 13, and 17 and doxorubicin hydrochloride IV and cisplatin IV in weeks 2, 6, 10, 14, and 18.

  • Arm II: Patients receive methotrexate, doxorubicin hydrochloride, and cisplatin as in arm I. Patients also receive zoledronic acid IV as in arm II (good responders).

    • Doxorubicin hydrochloride-based chemotherapy (patients ≥ 18 years of age): Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive doxorubicin hydrochloride IV and ifosfamide hydrochloride IV in weeks 1, 4, 7, 10, and 13 and cisplatin IV in weeks 1, 7, and 13.

• Arm II: Patients receive doxorubicin hydrochloride, ifosfamide, and cisplatin as in arm I. Patients also receive zoledronic acid IV in weeks 1, 5, 9, and 13.

All patients undergo surgery in week 16. After surgery, patients are assigned to 1 of 2 groups for further treatment, based on histological response.

• Good responders (< 10% viable cells): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive doxorubicin hydrochloride IV in weeks 1 and 7 and ifosfamide IV in weeks 1, 4, 7, and 10.
  • Arm II: Patients receive doxorubicin hydrochloride and ifosfamide as in arm I. Patients also receive zoledronic acid IV in weeks 1, 5, 9, 13, 17, and 21.

• Bad responders (> 10% viable cells):

  • Arm I: Patients receive etoposide IV and ifosfamide IV in weeks 1, 4, 7, 10, and 13.
  • Arm II: Patients receive etoposide and ifosfamide as in arm I. Patients also receive zoledronic acid as in arm II (good responders).

PROJECTED ACCRUAL: A total of 440 patients will be accrued for this study.

Inclusion Criteria

• Histologically confirmed high-grade osteosarcoma
• Bilirubin ≤ 2 times upper limit of normal
• No medical condition that would preclude study treatment
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Shortening fraction ≥ 28%
• LVEF ≥ 50%
• Glomerular filtration rate ≥ 70mL/min
• No recent dental problem, including infection, traumatization, or surgery

Exclusion Criteria

• Low-grade osteosarcoma
• Small cell osteosarcoma
• Maxillary osteosarcoma
• Primary resected osteosarcoma
• Osteosarcoma with multiple metastases for which complete removal is not feasible even after shrinkage with chemotherapy
• Extra-osseous osteosarcoma
• Any prior osteonecrosis of the maxilla
• No prior chemotherapy or radiotherapy

IPD will not be shared at an individual level, they will be part of the study database including all enrolled patients.