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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study will establish which is the \u201cstandard regimen\u201d 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.isrctn.com\/ISRCTN92192408\">92192408<\/jats:ext-link>\n                      on 4 November 2013.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13063-019-4026-8","type":"journal-article","created":{"date-parts":[[2020,1,17]],"date-time":"2020-01-17T08:02:23Z","timestamp":1579248143000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":111,"title":["International randomised controlled trial for the treatment of newly diagnosed EWING sarcoma family of tumours \u2013 EURO EWING 2012 Protocol"],"prefix":"10.1186","volume":"21","author":[{"given":"Jennifer","family":"Anderton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Moroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perrine","family":"Marec-B\u00e9rard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Gaspar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Laurence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Mart\u00edn-Broto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Gelderblom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cormac","family":"Owens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Fern\u00e1ndez-Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Fenwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Whelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Wheatley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette","family":"Brennan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,17]]},"reference":[{"issue":"7","key":"4026_CR1","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.1002\/1097-0142(19910401)67:7<1886::AID-CNCR2820670712>3.0.CO;2-U","volume":"67","author":"IM Ambros","year":"1991","unstructured":"Ambros IM, Ambros PF, Strehl S, Kovar H, Gadner H, Salzer-Kuntschik M. 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Since then, there have been 11 approved substantial amendments and the latest version of the protocol (version 5.0) was approved by the ethics committee on 7 August 2017. This latest amendment to protocol version 5.0 was to change the consolidation treatment for patients with poor risk localised disease to VAI plus BuMel, following the results of the earlier trial EURO-E.W.I.N.G. 99 becoming available demonstrating this treatment to be superior. Please note that the dates of ethical approvals are for the submissions made by the coordinating sponsor in the UK; each NCC has to submit to and gain approvals from the relevant regulatory bodies in their country (or countries). Central ethical approval for the whole UK was confirmed by the NRES Committee North West - Greater Manchester Central (reference approval number 12\/NW\/0827), and we will not begin recruiting at other centres and in other countries until the relevant country-specific and local ethical approval has been obtained.Written informed consent is obtained from each patient or parent\/legal guardian (or both) for each randomisation prior to performing any trial-related procedure. At trial entry, the patient or parent\/legal guardian or both are also given the option of consenting to the collection, storage and analysis of additional tumour, blood and bone marrow samples for use in biological studies associated with the trial but this does not affect whether they can enter the trial. Patients have the right to withdraw from the study at any time and for any reason without prejudice to their future medical care.With the patient\u2019s consent (and where national legislation\/guidance permits), their full name, date of birth, hospital number, medical practitioner details and national registry numbers (e.g., National Health Service Number in the UK) are collected at trial entry to allow long-term follow-up via other health-care professionals (e.g., patient\u2019s medical practitioner) and national cancer registries. Personal data recorded on all documents are regarded as strictly confidential and are handled and stored in accordance with the relevant data protection legislation in the member state. Patients are identified using only their unique trial number and, if national legislation permits, their initials and date of birth on the header section of the eRDC screens and in correspondence between the applicable NCC and participating sites.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"96"}}