Preclinical models show that a daily antiangiogenic regimen at low-dose may be effective against chemotherapy-resistant tumors. The aim of this study is to evaluate the efficacy of maintenance therapy with continuous oral cyclophosphamide and methotrexate in patients with high grade, operable, metastatic osteosarcoma (OST) of the extremities. The primary end point is event-free survival (EFS) from randomization

The study design includes backbone of 10 weeks of preoperative therapy using MAP (high-dose methotrexate, cisplatin, doxorubicin and dexrazoxane). Metastatic patients were randomized to high-dose chemotherapy for 31 weeks (arm 1) or concomitant metronomic therapy (MTX plus cyclophosphamide) such as 31 weeks of high-dose chemotherapy, followed by 73 weeks of metronomic therapy after completion of high-dose chemotherapy, totaling 104 weeks of metronomic therapy (arm 2).

Inclusion Criteria:

• A newly diagnosed patient, previously untreated, with a high degree of malignancy, confirmed by biopsy. Participant with OST as a neoplasm are also eligible
• Participant with staging imaging studies performed less than four weeks. Otherwise, it should be re-staged
• If pre-chemotherapy amputation is necessary, the participant will enter the study being excluded from the evaluation of tumor necrosis grade according to Huvos, but eligible for survival analysis
• Participant aged ≥ 16 years should have a Karnofsky performance score> 50 or WHO / ECOG ≥ 2 and patients <16 years should have a Lansky performance score> 50. Participant with a performance score impaired by the presence of a pathological fracture are eligible
• Patients with normal organic function
• Sexually active participant should agree to use contraceptive methods throughout the treatment
• Female participant should have a negative pregnancy test

Exclusion Criteria:

• If the participant or their legal guardian refuses to sign the informed consent form / consent term it will not be included in the study.