Jennifer Anderton1, Veronica Moroz1, Perrine Marec-Bérard2,3,4, Nathalie Gaspar3,4,5, Valerie Laurence3,4,6, Javier Martín-Broto7,8, Ana Sastre9, Hans Gelderblom10, Cormac Owens11, Sophie Kaiser2, Melissa Fernández-Pinto12, Nicola Fenwick1, Abigail Evans13, Sandra Strauss13, Jeremy Whelan14, Keith Wheatley1, Bernadette Brennan15. 1. Cancer Research UK Clinical Trials Unit, University of Birmingham, Mindelsohn Way, Birmingham, B15 2TT, UK. 2. Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon cedex 08, France. 3. Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent (SFCE), 16 boulevard de Bulgarie, 35203 Rennes, France. 4. Groupe Sarcome Français - Groupe d'Etude des Sarcome Osseux (GSF-GETO), 28 rue Laënnec, 69373 Lyon cedex 08, France. 5. Gustave Roussy Cancer Campus, 114 rue Édouard-Vaillant, 94805 Villejuif, France. 6. Institut Curie, 26 Rue d'Ulm, 75005 Paris, France. 7. Institute of Biomedicine of Sevilla (IBIS, HUVR, CSIC, Universidad de Sevilla), Avda. Manuel Siurot, 41013 Sevilla, Spain. 8. University Hospital Virgen del Rocio, Av. Manuel Siurot, 41013, Seville, Spain. 9. Hospital Universitario La Paz, 261 Paseo de la Castellana, 28046 Madrid, Spain. 10. European Organisation for Research and Treatment of Cancer (EORTC), Avenue Mounier 83, B-1200 Brussels, Belgium. 11. Our Lady's Children's Hospital, Cooley Rd, Dublin D12 N512, Ireland. 12. Grupo Español de Investigación en Sarcomas (GEIS), Diego de León St, 47th 28006 Madrid, Spain. 13. University College London, Gower Street, London, WC1E 6BT, UK. 14. University College London Hospitals NHS Foundation Trust, 250 Euston Road, London, NW1 2PG, UK. 15. Royal Manchester Children's Hospital, Oxford road, Manchester, M13 9WL, UK. Bernadette.Brennan@mft.nhs.uk.
Abstract
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.
RCT Entities:
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.
Entities:
Keywords:
Ewing sarcoma family of tumours; Randomised controlled trial
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