Ifosfamide is likely to be the go-to therapy in recurrent Ewing sarcoma 

Ifosfamide was more efficacious than topotecan plus cyclophosphamide in patients with primary recurrent or refractory Ewing sarcoma, despite a higher discontinuation rate due to toxicity in the ifosfamide arm. The phase 3 rEECur trial is the first randomised study to deliver efficacy, safety, and quality-of-life data to inform physicians on chemotherapy treatment decisions for patients with recurrent Ewing sarcoma. 

No established standard-of-care exists for patients with recurrent/refractory Ewing sarcoma, because there have not been any randomised trials comparing different chemotherapy regimens in this population. Therefore, the phase 3 rEECur trial, presented by Dr Martin McCabe (University of Manchester, UK), randomised patients with previously treated Ewing sarcoma to ifosfamide (n=78) or topotecan plus cyclophosphamide (n=162). The primary outcome was event-free survival (EFS) [1].

The median EFS was numerically higher in the ifosfamide arm (5.7 months) than in the topotecan plus cyclophosphamide arm (3.5 months) and trended towards significance (HR 0.73; 95% CI 0.51‒1.05). In addition, the 6-month EFS rates were 47% and 37% in the ifosfamide and topotecan plus cyclophosphamide arm, respectively. Interestingly, exploratory subgroup analysis revealed that the effect appeared to be more pronounced in younger patients (<14 years; HR 0.37) than in older patients (HR 0.93). The overall survival (OS) analysis displayed similar results, with a median OS of 15.4 months in the ifosfamide arm and a median OS of 10.5 months in the topotecan plus cyclophosphamide arm, with a trend towards a significant difference (HR 0.73; 95% CI 0.50‒1.08).

The rate of grade ≥3 adverse events (AEs) was higher in the ifosfamide arm (57%) than in the topotecan plus cyclophosphamide arm (44%), mainly due to a higher rate of nervous system (8% vs 3%) and renal/urinary disorders (8% vs 0%) in the ifosfamide arm. In the topotecan plus cyclophosphamide arm, 53% of the patients discontinued due to progression compared with 22% in the ifosfamide arm. However, 26% of the patients in the ifosfamide group discontinued due to AEs but no patients in the topotecan plus cyclophosphamide group did so. Dr McCabe commented that this was a high-dose trial and that dose reductions were not allowed in the ifosfamide arm. In the topotecan plus cyclophosphamide arm, dose reductions were allowed. Finally, quality-of-life data suggested that improvements were made in the ifosfamide arm but not in the topotecan plus cyclophosphamide arm.

1. McCabe MG, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). LBA2, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.

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Posted on 5 August, 2022