Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial

Fecha de publicación: 01/04/2017

Autores de IIS La Fe

Victoria Castel Sánchez

Autor
Adela Cañete Nieto

Autor

Participantes ajenos a IIS La Fe

Ladenstein, R
Pötschger U
Pearson ADJ
Brock, P
Luksch, R
Yaniv, I
Papadakis, V
Laureys, G
Malis, J
Balwierz, W
Ruud, E
Kogner, P
Schroeder, H
de Lacerda, AF
Beck-Popovic, M
Bician, P
Garami, M
Trahair, T
Ambros, PF
Holmes, K
Gaze, M
Schreier, G
Garaventa, A
Vassal, G
Michon, J
Valteau-Couanet, D
SIOP Europe Neuroblastoma Group (SIOPEN)

Grupos

Investigación Clínica y Traslacional en Cáncer

Leader

José Gómez Codina

Abstract

Background High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. Methods We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1: 1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m(2) given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0.8-1.2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m(2)) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4.1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m(2) per day for 4 days, and melphalan 70 mg/m(2) per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials. gov, number NCT01704716, and EudraCT, number 2006-001489-17. Findings Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7.2 years (IQR 5.3-9.2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p= 0.0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. Interpretation Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma.

Datos de la publicación

ISSN/ISSNe:: 1470-2045, 1474-5488
Tipo:: Article
Páginas:: 500-514
DOI:: 10.1016/S1470-2045(17)30070-0
Factor de Impacto:: 16,085 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

No hay documentos

Métricas

- Citations
  Citation Indexes: 266
  Policy Citations: 1
- Captures
  Readers: 269
- Mentions
  News Mentions: 6
  References: 1
see details

Filiaciones

Ladenstein, R:: Children's Cancer Research Institute (CCRI)-S(2)IRP: Studies and Statistics for Integrated Research and Projects, Medical University, Vienna, Austria

St Anna Children's Hospital and Department of Paediatrics of the Medical University, Vienna, Austria

Med Univ, CCRI, S2IRP, Vienna, Austria

Med Univ, St Anna Childrens Hosp, Vienna, Austria

Med Univ, Dept Paediat, Vienna, Austria
Pötschger U:: Children's Cancer Research Institute (CCRI)-S(2)IRP: Studies and Statistics for Integrated Research and Projects, Medical University, Vienna, Austria
Pearson ADJ:: Paediatric and Adolescent Drug Development Team, Oak Centre for Children and Young People, Institute of Cancer Research, Royal Marsden Hospital, Sutton, UK
Brock, P:: Department Paediatric Oncology, Great Ormond Street Hospital, London, UK

Great Ormond St Hosp Sick Children, Dept Paediat Oncol, London, England
Luksch, R:: Dipartimento di Ematologia e Onco-ematologia Pediatrica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Fdn IRCCS Ist Nazl Tumori, Dipartimento Ematol & Oncoematol Pediat, Milan, Italy
Castel, V:: Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain

Hosp Univ la Fe, Pediat Oncol Unit, Valencia, Spain

Politecn La Fe, Pediat Oncol Unit, Valencia, Spain
Yaniv, I:: Sackler Faculty of Medicine, Tel Aviv University, Schneider Children's Medical Center of Israel, Petach, Tikvah, Israel

Tel Aviv Univ, Schneider Childrens Med Ctr Israel, Sackler Fac Med, Petach, Tikvah, Israel
Papadakis, V:: Department of Paediatric Haematology-Oncology, Agia Sofia Children's Hospital Athens, Athens, Greece

Agia Sofia Childrens Hosp Athens, Dept Paediat Haematol Oncol, Athens, Greece
Laureys, G:: Department of Pediatric Hematology/Oncology and Stem Cell Transplantation University Hospital Ghent, Ghent, Belgium

Univ Hosp Ghent, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Ghent, Belgium
Malis, J:: Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic

Univ Hosp Motol, Dept Pediat Hematol & Oncol, Prague, Czech Republic
Balwierz, W:: Department of Pediatric Oncology and Hematology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland

Jagiellonian Univ, Coll Med, Inst Pediat, Dept Pediat Oncol & Hematol, Krakow, Poland
Ruud, E:: Department of Paediatric Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway

Oslo Univ Hosp, Rikshosp, Dept Paediat Med, Oslo, Norway
Kogner, P:: Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden

Karolinska Inst, Astrid Lindgren Childrens Hosp, Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Stockholm, Sweden
Schroeder, H:: Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark

Aarhus Univ Hosp Skejby, Dept Pediat, Aarhus, Denmark
de Lacerda, AF:: Department of Paediatric and Adolescent Oncology, Portuguese Institute of Oncology, Lisbon, Portugal

Portuguese Inst Oncol, Dept Paediat & Adolescent Oncol, Lisbon, Portugal
Beck-Popovic, M:: Department of Pediatrics and Pediatric Surgery, Pediatric Haematology Oncology Unit, University Hospital Lausanne, Lausanne, Switzerland

Univ Lausanne Hosp, Dept Pediat & Pediat Surg, Pediat Haematol Oncol Unit, Lausanne, Switzerland
Garami, M:: Second Department of Pediatrics, Semmelweis University, Budapest, Hungary

Semmelweis Univ, Dept Pediat 2, Budapest, Hungary
Trahair, T:: Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia

Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia
Canete, A:: Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain

Hosp Univ la Fe, Pediat Oncol Unit, Valencia, Spain

Politecn La Fe, Pediat Oncol Unit, Valencia, Spain
Ambros, PF:: Children's Cancer Research Institute Department of Tumour Biology, Medical University, Vienna, Austria

Med Univ, Childrens Canc Res Inst, Dept Tumour Biol, Vienna, Austria
Holmes, K:: Department Paediatric Surgery, St Georges Hospital, London, UK

St George Hosp, Dept Paediat Surg, London, England
Gaze, M:: Department of Oncology, University College Hospital, London, UK

Univ Coll Hosp, Dept Oncol, London, England
Schreier, G:: Center for Health and Bioresources, AIT Austrian Institute of Technology, Graz, Austria

Austrian Inst Technol, Ctr Hlth & Bioresources, Graz, Austria
Garaventa, A:: Oncology Unit, Istituto Giannina Gaslini, Genoa, Italy

Ist Giannina Gaslini, Oncol Unit, Genoa, Italy
Vassal, G:: Children and Adolescent Oncology Department, Gustave Roussy, Paris-Sud University, Paris, France

Univ Paris Sud, Gustave Roussy, Children & Adolescent Oncol Dept, Paris, France
Michon, J:: Children, Adolescent and Young Adults Department, Institut Curie, Paris, France

Inst Curie, Children Adolescent & Young Adults Dept, Paris, France
Valteau-Couanet, D:: Children and Adolescent Oncology Department, Gustave Roussy, Paris-Sud University, Paris, France

Univ Paris Sud, Gustave Roussy, Children & Adolescent Oncol Dept, Paris, France