• Cardiac toxicity [ Designated as safety issue: Yes ]
  

OBJECTIVES:

• Determine the feasibility and safety of trastuzumab (Herceptin®) and chemotherapy in patients with HER2-overexpressing (2+ level of expression) metastatic osteosarcoma.
• Determine the response rate and 3-year event-free survival of patients treated with this regimen.
• Determine the cardiac toxicity and late effects of this regimen in these patients.
• Determine the response rate and 3-year event-free survival of poor-risk patients with HER2-negative tumors treated with chemotherapy without the addition of trastuzumab.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor HER2 status (positive vs negative).

Patients receive induction therapy comprising doxorubicin IV over 20 minutes followed by cisplatin IV over 4 hours on days 1 and 2 of weeks 1 and 6, and methotrexate IV over 4 hours on day 1 of weeks 4, 5, 9, and 10. Patients also receive leucovorin calcium IV or orally every 6 hours beginning 24 hours after each methotrexate dose and continuing for at least 10 doses until methotrexate levels sufficiently decrease. Within 24-36 hours after completion of induction therapy, patients receive filgrastim (G-CSF) daily until blood counts recover.

Patients undergo resection of any remaining primary tumor and/or metastatic lesions during week 11. Patient who are unable to undergo resection receive radiotherapy between weeks 11 and 17.

Patients receive post-induction therapy comprising doxorubicin IV over 20 minutes on days 1 and 2 of weeks 17, 25, and 29; cisplatin IV over 4 hours on days 1 and 2 of weeks 17 and 25; methotrexate IV over 4 hours on day 1 of weeks 16, 20, 24, 28, 32, and 33; etoposide IV over 1 hour on days 1-5 of weeks 13, 21, and 34; and ifosfamide IV over 4 hours on days 1-5 of weeks 13, 21, 29, and 34. Patients also receive leucovorin calcium and G-CSF as in induction therapy.

Patients whose tumors are found to overexpress HER2 (2+ level of expression) also receive trastuzumab IV over 30-90 minutes once a week for a total of 34 weeks in addition to the chemotherapy regimen.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 80 patients (40 patients per stratum) will be accrued for this study within 2.5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed high-grade osteosarcoma

  • Metastatic
  • Newly diagnosed
• No osteosarcoma arising in areas of Paget's disease or radiotherapy-induced sarcoma

• Presenting with at least 1 of the following:

  • Bone metastases with or without lung metastases
  • Bilateral lung metastases (any number of nodules)
  • Unilateral lung metastases with at least 4 nodules
• Planned resection of either the primary site or a metastatic site of disease after completion of induction therapy
• Must be currently enrolled on the tumor biology study COG-P9851

PATIENT CHARACTERISTICS:

Age:

• 30 and under at diagnosis

Performance status:

• ECOG 0-2 OR
• Karnofsky 50-100% (over age 10)
• Lansky 50-100% (age 10 and under)

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count > 1,000/mm^3
• Platelet count > 100,000/mm^3

Hepatic:

• Bilirubin ≤ 1.5 times normal
• SGPT ≤ 3 times normal

Renal:

• Creatinine ≤ 1.5 times normal OR
• Creatinine clearance or glomerular filtration rate ≥ 70 mL/min

Cardiovascular:

• Shortening fraction ≥ 28% by echocardiogram
• Ejection fraction ≥ 50% by echocardiogram or MUGA
• No history of pericarditis, myocarditis, symptomatic arrhythmia, or conduction disturbances

Other:

• Normal organ function
• HIV negative
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• See Disease Characteristics