International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours - EURO EWING 2012 Protocol

Trials. 2020 Jan 17;21(1):96. doi: 10.1186/s13063-019-4026-8.


Background: Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative 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: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) 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, or 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 randomly assigned 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 or metastases (or both), 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 consider that international cooperation is needed to provide answers in a timely manner.

Trial registration: Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 54540667 on 4 November 2013.

Keywords: Ewing sarcoma family of tumours; Randomised controlled trial.

Publication types

  • Clinical Trial Protocol
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bone Density Conservation Agents / therapeutic use*
  • Bone Neoplasms / drug therapy*
  • Busulfan / administration & dosage
  • Child
  • Child, Preschool
  • Consolidation Chemotherapy
  • Cyclophosphamide / administration & dosage
  • Dactinomycin / administration & dosage
  • Doxorubicin / administration & dosage
  • Etoposide / administration & dosage
  • Female
  • Humans
  • Ifosfamide / administration & dosage
  • Induction Chemotherapy
  • Male
  • Middle Aged
  • Sarcoma, Ewing / drug therapy*
  • Vincristine / administration & dosage
  • Young Adult
  • Zoledronic Acid / therapeutic use*


  • Bone Density Conservation Agents
  • Dactinomycin
  • Vincristine
  • Etoposide
  • Zoledronic Acid
  • Doxorubicin
  • Cyclophosphamide
  • Busulfan
  • Ifosfamide