Determinants of tumor necrosis and its impact on outcome in patients with Localized osteosarcoma uniformly treated with a response adapted regimen without high dose Methotrexate- A retrospective institutional analysis

Purpose: Response to neoadjuvant chemotherapy in form of tumor necrosis predicts outcome in osteosarcoma; although response-adapted treatment escalation failed to improve outcome among patients treated with high-dose methotrexate-based (HDMTx) chemotherapy. This study aimed to identify factors predicting tumor necrosis and its impact on survival among patients with non-metastatic osteosarcoma treated with a response-adapted non-HDMTx regimen.

Methods: A retrospective single-institutional study was conducted among non-metastatic osteosarcoma patients treated with neoadjuvant therapy between 2004-2019. Patients were treated uniformly with three cycles of neoadjuvant cisplatin/doxorubicin. Post-operatively, patients with favourable necrosis (≥90 %) received 3 cycles of cisplatin/doxorubicin, while patients with poor necrosis (<90 %) received escalated treatment with alternating six cycles of cisplatin/doxorubicin and ifosfamide/etoposide. Propensity score matching (PSM) analyses were conducted to ascertain independent impact of necrosis on event-free survival (EFS) and overall survival (OS).

Results: Of 594 registered osteosarcoma patients, 280 patients (median age 17 years; male 67.1 %) were included for analysis. 73 patients (26.1 %) achieved favourable necrosis. Patients with smaller tumor size (≤10 cm) (aOR = 2.28; p = 0.030), lower serum alkaline phosphatase (≤450 IU/L) (aOR = 2.10; p = 0.035), and who had surgery earlier (<115 days) (aOR = 2.28; p = 0.016) were more likely to have favourable necrosis. On 1:2 PSM analysis, patients not achieving favourable necrosis demonstrated inferior EFS (HR = 2.68; p = 0.003) and OS (HR = 3.42; p = 0.003).

Conclusions: Patients of osteosarcoma with smaller tumor, lower serum alkaline phosphatase and earlier surgery are more likely to achieve favourable necrosis. Tumor necrosis independently predicts outcome in osteosarcoma, and response-adapted treatment escalation fails to overcome the adverse impact of poor necrosis in non-HDMTx based regimen.