Effect of chemotherapy and surgery timing on mortality in upper and lower extremity osteosarcoma

Surgery with neoadjuvant and adjuvant chemotherapy represents the standard of care for extremity osteosarcoma despite a lack of high-quality evidence for its use, and trial evidence that suggests upfront surgery may result in better outcomes. This study estimated the difference in overall survival for the standard of care (neoadjuvant first) vs upfront surgery first followed by adjuvant chemotherapy (surgery first).

Using Surveillance, Epidemiology, and End Results data, we identified patients aged 5-29 years diagnosed with a primary cancer of upper or lower extremity osteosarcoma between 2007 and 2019 who received surgery and chemotherapy. Our primary endpoint was the 5-year survival difference between the surgery first and neoadjuvant first groups.

Adjusted 5-year survival was 74% for surgery first patients and 67% for neoadjuvant first patients, with a survival difference of 6.9% (95% confidence interval [CI] = -4.2% to 16.1%). In sensitivity analyses of 5-year survival, the results were consistent, showing a 6.8%-13.7% higher 5-year survival in surgery first patients. Statistically significant mortality risk factors included older age, larger tumor size, the type of resection (salvage vs amputation), and stage III-IV disease (vs stage I-II disease).

The evidence supporting neoadjuvant therapy in osteosarcoma care is weak. However, there is evidence that pausing chemotherapy in the perisurgical period might affect outcomes. Consequently, this study, and its consistency with the results from the only randomized trial to address this question, suggests that there is reason to revisit a prospective, randomized trial of osteosarcoma treatment regarding the timing of surgery and chemotherapy.