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. Biological therapies, such as PEG-interferon alfa-2b, may stimulate the immune system in different ways and stop tumor cells from growing. Giving combination chemotherapy before surgery may shrink the tumor so it can be removed by surgery. Giving PEG-interferon alfa-2b together with combination chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving PEG-interferon alfa-2b together with combination therapy after surgery is more effective than combination chemotherapy alone after surgery in treating osteosarcoma.

PURPOSE: This randomized phase III trial is comparing two different combination chemotherapy regimens with or without PEG-interferon alfa-2b given after a different combination chemotherapy and surgery in patients with osteosarcoma.

OBJECTIVES:

Primary

• Compare whether adjuvant maintenance therapy comprising doxorubicin, cisplatin, and high-dose methotrexate (MAP) alone vs MAP combined with ifosfamide and etoposide improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a poor histological response (HR) to neoadjuvant induction therapy comprising MAP.
• Compare whether adjuvant maintenance therapy comprising MAP alone vs MAP and PEG-interferon alfa-2b improves event-free survival of patients with resectable high-grade osteosarcoma who achieve a good HR to neoadjuvant induction therapy comprising MAP.

Secondary

• Compare overall survival of patients treated with these regimens.
• Compare short- and long-term toxicity of these regimens in these patients.
• Compare quality of life of patients treated with these regimens.
• Compare event-free survival and overall survival of patients with localized osteosarcoma treated with these regimens.
• Correlate biological or clinical changes with histological response and outcomes in patients treated with these regimens.
• Determine outcomes of patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study.

• Patients receive doxorubicin IV continuously over 48 hours on days 1-2 and cisplatin IV over 4 hours on days 1 and 2 in weeks 1 and 6. Patients also receive high-dose methotrexate (MTX)* IV over 4 hours on day 1 in weeks 4, 5, 9, and 10. Patients then proceed to surgery.

NOTE: *Patients must receive ≥ 2 but ≤ 6 doses of high-dose MTX.

• Surgery: Patients undergo amputation or limb salvage surgery in week 11. Tumor tissue is evaluated for histological response to induction therapy. Patients whose tumor is not amenable to macroscopically complete surgical resection undergo radiotherapy and/or other investigational therapy off study. Patients who undergo macroscopically complete surgical resection of the primary tumor or metastases AND who have no disease progression or unacceptable toxicity proceed to maintenance therapy.
• Patients are assigned to 1 of 2 groups according to histological response (good [< 10% viable tumor] vs poor [≥ 10% viable tumor]). Patients in each group are stratified according to site of primary tumor and presence of metastases.
• Patient are randomized to 1 of 2 treatment arms within 35 days after surgery.
• Arm I (MAP; weeks 12-29): Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 17, 22, and 26 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 17. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 16, 20, 21, 24, 25, 28, and 29.
• Arm II (MAPifn; weeks 12-104): Patients receive doxorubicin, cisplatin, and high-dose MTX as in arm I . Patients than receive PEG-interferon alfa-2b subcutaneously once daily on day 1 in weeks 30-104.
• Patients are randomized to 1 of 2 treatment arms within 35 days after surgery.
• Arm I (MAP; weeks 12-29): Patients receive doxorubicin, cisplatin, and high-dose MTX as in group 1 arm I.
• Arm II (MAPIE; weeks 12-40): Patients receive doxorubicin IV continuously over 48 hours on days 1-2 in weeks 12, 20, 28, and 36 and cisplatin IV over 4 hours on days 1 and 2 in weeks 12 and 28. Patients also receive high-dose MTX IV over 4 hours on day 1 in weeks 15, 19, 23, 27, 31, 35, 39, and 40. Patients receive ifosfamide IV over 4 hours on days 1-5 in weeks 16, 24, and 32 and on days 1-3 in weeks 20 and 36 and etoposide IV over 1 hour on days 1-5 in weeks 16, 24, and 32.

In both groups, treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 1½-3 months for 2 years, every 2-4 months for 2 years, every 6 months for 6 years, and then every 6-12 months thereafter.

PROJECTED ACCRUAL: A total of 1,400 patients (630 good responders and 770 poor responders) will be accrued for this study within 4 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed high-grade osteosarcoma, including second malignancies
• Localized or metastatic disease
• The primary tumor must be located in the limbs or axial skeleton, including any of the following sites:
• Long bone of upper limb
• Short bone of upper limb
• Long bone of lower limb
• Short bone of lower limb
• Vertebral column
• Ribs, sternum, or clavicle
• Pelvic bones, sacrum, or coccyx
• Tumor (primary, metastatic, or both) resectable OR is expected to become resectable after neoadjuvant induction chemotherapy
• Suitable for neoadjuvant chemotherapy

PATIENT CHARACTERISTICS:

Age

• 5 to 40 at diagnostic biopsy

Performance status

• Lansky 50-100% (for patients under 16 years of age)
• Karnofsky 50-100%* OR
• WHO or ECOG 0-2* NOTE: *For patients 16 years of age and over

Life expectancy

• Not specified

Hematopoietic

• Platelet count ≥ 100,000/mm^3
• Neutrophil count ≥ 1,500/mm OR
• WBC ≥ 3,000/mm^3

Hepatic

• Not specified

Renal

• Glomerular filtration rate ≥ 70 mL/min OR
• Creatinine based on age as follows:
• No greater than 1.0 mg/dL (for patients 5 to 10 years of age)
• No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
• No greater than 1.5 mg/dL (for patients over 15 years of age)

Cardiovascular

• Ejection fraction ≥ 50% by radionuclide angiogram OR
• Shortening fraction ≥ 28% by echocardiogram

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known HIV positivity

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for any disease

Endocrine therapy

• Not specified

Radiotherapy

• Prior radiotherapy for another malignancy allowed

Surgery

• Not specified

Other

• No prior treatment for osteosarcoma