BACKGROUND/OBJECTIVES: There is an unmet need to improve outcomes in patients with metastatic Ewing sarcoma (ES). This retrospective, multicenter study aimed to evaluate the efficacy and safety of the topotecan-cyclophosphamide (TC) regimen in adult patients with metastatic ES who had previously been treated with chemotherapy. METHODS: This study enrolled 75 patients who were treated at five oncology centers in Turkey between 2011 and 2020. Patients were treated with the TC regimen, consisting of topotecan at 0.75 mg/m RESULTS: The median progression-free survival was 3.06 months (95% CI, 2.91-3.22), and the median overall survival was 6.16 months (95% CI, 5.14-7.18). Patients who received the TC regimen in the second line demonstrated longer OS (7.55 months 95% CI, 5.37-14.17) compared to those who received it in the third line or later (5.70 months 95% CI, 4.07-6.60) ( CONCLUSIONS: This study showed that the use of the TC regimen in the second line resulted in better efficacy and overall survival outcomes compared to its use in the third line or later. However, in the entire population, the TC regimen demonstrated only a modest effect on metastatic ES. TC can be considered one of the palliative treatment options for metastatic ES.