Comparative outcomes of neoadjuvant chemotherapy versus upfront surgical resection in osteosarcoma: a systematic review and meta-analysis.

BACKGROUND: Osteosarcoma is an aggressive primary bone tumor commonly managed with multimodal therapy; however, the optimal sequencing of chemotherapy and surgery remains debated. Neoadjuvant chemotherapy (NACT) is widely used to facilitate limb-salvage surgery (LSS) and assess histologic response, yet its comparative benefit over upfront surgical resection remains unclear. This systematic review and meta-analysis aimed to compare oncologic and surgical outcomes between NACT followed by surgery versus upfront surgical resection in patients with osteosarcoma. METHODS: A systematic search of PubMed, CENTRAL, and Google Scholar was conducted up to June 2025. Eligible studies included patients with histologically confirmed osteosarcoma treated with NACT plus surgery or upfront surgical resection. The primary outcome was overall survival (OS); secondary outcomes included disease-free survival (DFS), local recurrence (LR), distant metastasis, surgical complications, and chemotherapy-related adverse effects. Random-effects meta-analyses reported risk ratios (RRs) with 95% CIs and prediction intervals; leave-one-out influence and Hartung-Knapp (HK) adjustments were performed. Certainty was appraised with GRADE. RESULTS: Twenty-five studies involving 4,867 patients were included; 14 studies qualified for meta-analysis. Pooled analysis showed no significant difference in OS (RR: 1.09; 95% CI: 0.95-1.24; p = 0.225) or DFS (RR: 1.18; 95% CI: 0.73-1.89) between groups. However, NACT significantly reduced LR risk (RR: 0.45; 95% CI: 0.25-0.79; p < 0.05) and was associated with higher LSS rates. GRADE certainty was low for OS/DFS and moderate for LR. CONCLUSION: Although NACT did not improve survival versus upfront surgery, it was associated with reduced local recurrence and greater feasibility of limb-salvage, supporting its role within multimodal care, particularly when local control and limb preservation are priorities, and in complex or high-risk presentations.