Inclusion Criteria:

* 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, clavicle, or scapula
* 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
* Performance status - Lansky 50-100% (for patients under 16 years of age)
* Performance status - Karnofsky 50-100%\*
* Performance status - WHO or ECOG 0-2\*
* Platelet count ≥ 100,000/mm³
* Neutrophil count ≥ 1,500/mm³
* WBC ≥ 3,000/mm³
* Bilirubin ≤ 1.5 times upper limit of normal
* Creatinine clearance ≥ 70 mL/min
* 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)
* Ejection fraction ≥ 50% by radionuclide angiogram
* Shortening fraction ≥ 28% by echocardiogram
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No known HIV positivity
* No prior chemotherapy for any disease
* Prior radiotherapy for another malignancy allowed
* No prior treatment for osteosarcoma
* No patients with any of the following:

* Craniofacial osteosarcoma