The Osteosarcoma Odyssey: Tracking the Evolution of Systemic Treatment Strategies

Osteosarcoma is an aggressive primary bone malignancy primarily affecting children and adolescents during peak growth periods. Historically, management was limited to surgical resection or amputation, which resulted in a dismal 20% long-term survival rate because of the presence of subclinical micrometastases. The introduction of systemic chemotherapy in the 1970s, particularly doxorubicin, cisplatin, and high-dose methotrexate, revolutionized outcomes by significantly increasing survival rates. The landmark “Multi-Institutional Osteosarcoma Study” definitively established combination chemotherapy as a necessity alongside surgery. Currently, the standard of care is a multimodal strategy comprising neoadjuvant chemotherapy, definitive surgery, and adjuvant chemotherapy. The MAP regimen remains the therapeutic backbone, achieving 60-70% survival for localised disease, though prognosis for metastatic or relapsed cases remains poor. While neoadjuvant chemotherapy does not offer a proven survival advantage over immediate surgery, it facilitates limb-salvage procedures and provides critical prognostic data through histological response assessment. Despite these historical successes, survival rates have plateaued over the last thirty years, and conventional agents cause severe permanent toxicities. Future directions focus on precision medicine to overcome chemoresistance and toxicity. Emerging strategies include targeted molecular therapies such as tyrosine kinase and IGF-1R inhibitors, alongside immunotherapy involving checkpoint inhibitors and CAR T-cells. Other innovations under investigation include antibody-drug conjugates, epigenetic modification therapy, and oncolytic viral therapy.