International Randomised Controlled Trial for the Treatment of Newly Diagnosed Ewing Sarcoma Family of Tumours – EURO EWING 2012 Protocol

Background: Despite multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT), over many years, and involving many international co-operative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or Busulfan and Mephalan (VAI/VAC/BuMel) consolidation compared with vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or Busulfan and Mephalan (IE/VC/VAI/ BuMel) consolidation- randomisation 1 (R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome. Methods EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomised at two different time points, at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes and/or metastases, and achievement of local control at the end of treatment. Discussion This study will establish which is the "standard regimen" of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid, in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and that international co-operation is needed to provide answers in a timely manner. Trial registration Registered with EudraCT number 2012-002107-17 on 26th February 2012. Registered with ISRCTN number 54540667 on 4th November 2013.