Inclusion Criteria:  1) histologically confirmed high-grade osteosarcoma; 2) initial treatment in the Orthopedic/Oncology Departments of Peking University People's Hospital or Peking University Shougang Hospital; 3) progression less than 6 months after first-line chemotherapy with a combination of high-dose methotrexate, doxorubicin, cisplatin and ifosfamide (first-line chemotherapy); 4) measurable lesions according to the Response Evaluation Criteria for Solid Tumors (RECIST 1.1) ; 5) Eastern Cooperative Oncology Group performance status ≤ 2 ; 6) acceptable haematologic, hepatic, and renal function.  Exclusion Criteria:  those who had been previously treated with antiangiogenic TKIs and single IE chemotherapy; those who had severe or uncontrolled medical disorders that could jeopardize the outcomes of the study. These confounding conditions included, cardiac clinical symptoms or disease with left ventricular ejection fraction<50%, and hypertension that could not be well controlled with antihypertensive drugs.; All patients were assessed by the sarcoma board including a thoracic surgeon with at least 10 years surgical experience. Patients with lung metastases only were carefully assessed for eligibility for metastasectomy, of whom those who were suitable for surgery were excluded from this study; weight loss of 20% or more before illness; brain or leptomeningeal metastasis; surgical procedure or radiotherapy within 4 weeks of enrollment; activegastroduodenal ulcer, previous condition associated with risk of bleeding or requiring anticoagulation; proteinuria or hematuria, denutrition with albuminemia <25 g/L; women who were pregnant or breast feeding, other malignancy; positive HBV/HCV/HIV serology, and known allergy to the experimental agents.