Multidisciplinary treatment has improved the prognosis of Ewing sarcoma (ES) over the last decades, with the introduction of multi-agent chemotherapy and multidisciplinary patient management. This improvement was due from both the use of intensified systemic treatments and optimization of local treatments, using surgery and radiotherapy in different combinations and sequences.
Nowadays the treatment generally consists of induction chemotherapy, followed by surgery and/or local radiotherapy, and then maintenance chemotherapy.
Extended international collaboration has enabled prognostic groups to be better defined and risk-adapted treatment strategies to be tailored to patients.
The most remarkable steps along the way in which chemotherapy has improved the prognosis for ES are different: 1-The benefit of adding ifosfamide and etoposide (IE) to the vincristine, doxorubicin, and cyclophosphamide (VDC) combination for localized ES was demonstrated; this benefit was not demonstrated in patients with metastatic disease (Grier 2003). 2-The randomized EuroEwing99 R1 trial addressed the equivalence of ifosfamide and cyclophosphamide in localized disease: the conclusion was that cyclophosphamide might be able to replace ifosfamide in consolidation treatment of standard-risk ES (Le Deley 2016) 3-A randomized Childrens Oncology Group trial demonstrated that dose-intensifying chemotherapy by shortening the interval between treatments with the regimen VDC/IE (Vincristine+Doxorubicin+Cyclophosphamide, and Ifosfamide+Etoposide) led to a longer 5-year event-free survival in cases of localized disease. Compared with those assigned to the 3-week standard treatment interval, patients assigned to the 2-week treatment interval had a longer 5-year event-free survival (Womer 2012) . This result was corroborated by the EuroEWING Consortium Study 2012, where the compressed VDC/IE regimen was randomly compared with VIDE (vincristine, ifosfamide, doxorubicin, and etoposide), which was the backbone induction regimen of the EEC-99 trial (Brennan 2020). 4-The efficacy of a consolidation treatment with high-dose melphalan/busulfan (BuMel) + stem cell rescue was examined in prospective phase II non-randomized studies (Ferrari 2011), and in a large randomized study by the EuroEWING Consortium. For localized ES with a poor histological response to induction chemotherapy, there were signs of BuMel proving more effective than standard maintenance chemotherapy (Whelan 2018). Evidence of efficacy of BuMel in metastatic disease is limited to patients with pulmonary metastases, in which case its value is debatable, and has to be set against a significantly higher risk of severe acute and late side effects when compared with standard maintenance chemotherapy (Dirksen 2019).
There is an unmet medical need to improve prognosis of patients with synchronous metastatic disease or relapse. In the last decades, efficacy of new drugs was disappointing and no new drugs have been successfully introduced up to now in front line treatment. Early clinical data suggest that strategies using multi-tyrosine kinase inhibitors (TKI) carrying anti-angiogenic activities are among the most active new drugs tested. Several TKI are currently being tested as single-agent in patients with relapse/refractory Ewing sarcoma with encouraging results in phase II trials, and may show efficacy (Attia 2017, Italiano 2020).
Given the complexity and rarity of Ewing sarcoma, it is essential for patients to be treated at selected reference institutions with specific expertise and multidisciplinary skills.
