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/m2 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/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/m2 per day for 4 days, and melphalan 70 mg/m2 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. FUNDING: European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.

2nd Department of Pediatrics Semmelweis University Budapest Hungary

Center for Health and Bioresources AIT Austrian Institute of Technology Graz Austria

Children Adolescent and Young Adults Department Institut Curie Paris France

Children and Adolescent Oncology Department Gustave Roussy Paris Sud University Paris France

Children's Cancer Research Institute Department of Tumour Biology Medical University Vienna Austria

Children's Cancer Research Institute IRP Studies and Statistics for Integrated Research and Projects Medical University Vienna Austria

Children's Cancer Research Institute 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

Clinic of Pediatric Oncology and Hematology University Children's Hospital Banska Bystrica Slovakia

Department of Oncology University College Hospital London UK

Department of Paediatric and Adolescent Oncology Portuguese Institute of Oncology Lisbon Portugal

Department of Paediatric Haematology Oncology Agia Sofia Children's Hospital Athens Athens Greece

Department of Paediatric Medicine Rikshospitalet Oslo University Hospital Oslo Norway

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology Oncology and Stem Cell Transplantation University Hospital Ghent Ghent Belgium

Department of Pediatric Oncology and Hematology Institute of Pediatrics Jagiellonian University Medical College Krakow Poland

Department of Pediatrics Aarhus University Hospital Skejby Aarhus Denmark

Department of Pediatrics and Pediatric Surgery Pediatric Haematology Oncology Unit University Hospital Lausanne Lausanne Switzerland

Department of Women's and Children's Health Karolinska Institutet Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden

Department Paediatric Oncology Great Ormond Street Hospital London UK

Department Paediatric Surgery St Georges Hospital London UK

Dipartimento di Ematologia e Onco ematologia Pediatrica Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Kids Cancer Centre Sydney Children's Hospital Randwick NSW Australia

Oncology Unit Istituto Giannina Gaslini Genoa Italy

Paediatric and Adolescent Drug Development Team Oak Centre for Children and Young People Institute of Cancer Research Royal Marsden Hospital Sutton UK

Pediatric Oncology Unit Hospital Universitario y Politecnico La Fe Valencia Spain

Sackler Faculty of Medicine Tel Aviv University Schneider Children's Medical Center of Israel Petach Tikvah Israel

Lancet Oncol. 2017 Apr;18(4):423-424. doi: 10.1016/S1470-2045(17)30069-4. PubMed

References provided by Crossref.org

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials

See more in PubMed

ClinicalTrials.gov
NCT01704716

EudraCT
2006-001489-17