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

Summary 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 wi...

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Published in:	The lancet oncology 2017-04, Vol.18 (4), p.500-514
Main Authors:	Ladenstein, Ruth, Prof, Pötschger, Ulrike, MSc, Pearson, Andrew D J, Prof, Brock, Penelope, MD, Luksch, Roberto, MD, Castel, Victoria, MD, Yaniv, Isaac, Prof, Papadakis, Vassilios, MD, Laureys, Geneviève, MD, Malis, Josef, MD, Balwierz, Walentyna, Prof, Ruud, Ellen, MD, Kogner, Per, Prof, Schroeder, Henrik, Prof, de Lacerda, Ana Forjaz, MD, Beck-Popovic, Maja, MD, Bician, Pavel, MD, Garami, Miklós, MD, Trahair, Toby, MD, Canete, Adela, MD, Ambros, Peter F, PhD, Holmes, Keith, MD, Gaze, Mark, MD, Schreier, Günter, PhD, Garaventa, Alberto, MD, Vassal, Gilles, Prof, Michon, Jean, MD, Valteau-Couanet, Dominique, MD
Format:	Article
Language:	eng
Subjects:	Adolescent Adult Antineoplastic Combined Chemotherapy Protocols - therapeutic use Bone marrow Bone Neoplasms - drug therapy Bone Neoplasms - secondary Busulfan Busulfan - administration & dosage Cancer therapies Carboplatin Carboplatin - administration & dosage Cell survival Chemotherapy Child Child, Preschool Children Children & youth Cisplatin Clinical trials Cyclophosphamide Doxorubicin Etoposide Etoposide - administration & dosage Failure analysis Female Follow-Up Studies Glomerular filtration rate Hematology, Oncology and Palliative Medicine Humans Infant International Agencies Intravenous administration Lymphatic Metastasis Male Medical prognosis Medicin och hälsovetenskap Melphalan Melphalan - administration & dosage Metastasis Motivation Neoplasm Staging Neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - pathology Oncology Physicians Prognosis Radiation therapy Stem cells Stomatitis Survival Survival analysis Survival Rate Topotecan Transplants & implants Tumors Veno-occlusive disease Vincristine Young Adult
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Summary:	Summary 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 Betwee
ISSN:	1470-2045 1474-5488 1474-5488