title: 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.
abstract: 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.
  
  
  
  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/m2given 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/m2) 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/m2per day for 4 days, and melphalan 70 mg/m2per 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.
authors.affiliation: 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. Electronic address: ruth.ladenstein@ccri.at.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ladenstein
authors.affiliation: Children's Cancer Research Institute (CCRI)-S(2)IRP: Studies and Statistics for Integrated Research and Projects, Medical University, Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pötschger
authors.affiliation: Paediatric and Adolescent Drug Development Team, Oak Centre for Children and Young People, Institute of Cancer Research, Royal Marsden Hospital, Sutton, UK.
authors.forename: Andrew D J
authors.initials: ADJ
authors.lastname: Pearson
authors.affiliation: Department Paediatric Oncology, Great Ormond Street Hospital, London, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Brock
authors.affiliation: Dipartimento di Ematologia e Onco-ematologia Pediatrica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Luksch
authors.affiliation: Pediatric Oncology Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Castel
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Schneider Children's Medical Center of Israel, Petach, Tikvah, Israel.
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.affiliation: Department of Paediatric Haematology-Oncology, Agia Sofia Children's Hospital Athens, Athens, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadakis
authors.affiliation: Department of Pediatric Hematology/Oncology and Stem Cell Transplantation University Hospital Ghent, Ghent, Belgium.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Laureys
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Malis
authors.affiliation: Department of Pediatric Oncology and Hematology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Walentyna
authors.initials: W
authors.lastname: Balwierz
authors.affiliation: Department of Paediatric Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ruud
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Schroeder
authors.affiliation: Department of Paediatric and Adolescent Oncology, Portuguese Institute of Oncology, Lisbon, Portugal.
authors.forename: Ana Forjaz
authors.initials: AF
authors.lastname: de Lacerda
authors.affiliation: Department of Pediatrics and Pediatric Surgery, Pediatric Haematology Oncology Unit, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Beck-Popovic
authors.affiliation: Clinic of Pediatric Oncology and Hematology, University Children's Hospital, Banska Bystrica, Slovakia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Bician
authors.affiliation: Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Garami
authors.affiliation: Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
authors.forename: Toby
authors.initials: T
authors.lastname: Trahair
authors.affiliation: Pediatric Oncology Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Canete
authors.affiliation: Children's Cancer Research Institute Department of Tumour Biology, Medical University, Vienna, Austria.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ambros
authors.affiliation: Department Paediatric Surgery, St Georges Hospital, London, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Holmes
authors.affiliation: Department of Oncology, University College Hospital, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Gaze
authors.affiliation: Center for Health and Bioresources, AIT Austrian Institute of Technology, Graz, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Schreier
authors.affiliation: Oncology Unit, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Garaventa
authors.affiliation: Children and Adolescent Oncology Department, Gustave Roussy, Paris-Sud University, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.affiliation: Children, Adolescent and Young Adults Department, Institut Curie, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Michon
authors.affiliation: Children and Adolescent Oncology Department, Gustave Roussy, Paris-Sud University, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002066:Busulfan / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007390:International Agencies; D008207:Lymphatic Metastasis; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D005047:Etoposide; D016190:Carboplatin; D002066:Busulfan; D008558:Melphalan