When osteosarcoma progresses during standard MAP chemotherapy (cisplatin, doxorubicin, high-dose methotrexate), the disease is classified as refractory and requires immediate reassessment by a pediatric sarcoma team at a high-volume center [1][2][3]. The treatment strategy shifts away from curative intent toward disease control and local palliation, especially if metastases are present [4][5][6].

Second-line chemotherapy is typically offered, with ifosfamide plus etoposide being the most common combination, though gemcitabine/docetaxel, cyclophosphamide/topotecan, and high-dose ifosfamide are alternatives depending on prior exposure and clinical trial availability [7][3][8][9]. Targeted agents such as sorafenib and regorafenib have shown activity in refractory cases [10]. Aggressive surgical resection of the primary tumor and any resectable metastases should be explored if feasible, as local control remains important [1][2]. Radiation therapy may be considered for symptom control, though osteosarcoma is generally less radiosensitive than many cancers [11]. Clinical trials offering immunotherapy or novel molecularly targeted agents should be actively pursued. The specific treatment plan depends critically on whether disease is localized or metastatic and whether surgical resection is possible.