Journal ArticleDOI
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
Ruth Ladenstein,Ruth Ladenstein,Ulrike Pötschger,Andrew D.J. Pearson,Penelope Brock,Roberto Luksch,Victoria Castel,Isaac Yaniv,Vassilios Papadakis,Genevieve Laureys,Josef Malis,Walentyna Balwierz,Ellen Ruud,Per Kogner,Henrik Schroeder,Ana Forjaz de Lacerda,Maja Beck-Popovic,Pavel Bician,Miklós Garami,Toby Trahair,Adela Cañete,Peter F. Ambros,Keith Holmes,Mark N. Gaze,Günter Schreier,Alberto Garaventa,Gilles Vassal,Jean Michon,Dominique Valteau-Couanet +28 more
TLDR
This international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, andMelphalan.Abstract:
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/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. Funding European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.read more
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Journal ArticleDOI
Neuroblastoma
TL;DR: Neuroblastoma is a type of cancer that most often affects children and can spread to other parts of the body such as the bones, liver, or skin.
Journal ArticleDOI
Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial
Ruth Ladenstein,Ulrike Pötschger,Dominique Valteau-Couanet,Roberto Luksch,Victoria Castel,Isaac Yaniv,Genevieve Laureys,Penelope Brock,Jean Michon,Cormac Owens,Toby Trahair,Godfrey Chi-Fung Chan,Ellen Ruud,Henrik Schroeder,Maja Beck Popovic,Guenter Schreier,Hans Loibner,Peter F. Ambros,Keith Holmes,Maria Rita Castellani,Mark N. Gaze,Alberto Garaventa,Andrew D.J. Pearson,Holger N. Lode +23 more
TL;DR: An international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma, aiming to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2.
Journal ArticleDOI
Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial.
Julie R. Park,Julie R. Park,Susan G. Kreissman,Wendy B. London,Arlene Naranjo,Susan L. Cohn,Michael D. Hogarty,Sheena C. Tenney,Daphne A. Haas-Kogan,Peter J. Shaw,Jacqueline M. Kraveka,Stephen S. Roberts,James Duncan Geiger,John J. Doski,Stephan D. Voss,John M. Maris,Stephan A. Grupp,Lisa Diller +17 more
TL;DR: T tandem autologous transplant resulted in a significantly better EFS than single transplant among patients aged 30 years or younger with high-risk neuroblastoma, however, because of the low randomization rate, the findings may not be representative of all patients withhigh-risk Neuroblastoma.
Journal ArticleDOI
Neuroblastoma: Clinical and Biological Approach to Risk Stratification and Treatment
TL;DR: The goal has been to decrease therapy for low-risk patients to avoid long-term complications while augmenting and targeting therapies for high- risk patients to improve overall survival.
Journal ArticleDOI
Neuroblastoma-A Neural Crest Derived Embryonal Malignancy.
TL;DR: Factors and processes within the neural crest that when dysregulated have the potential to be initiators or drivers of neuroblastoma development are discussed and will give valuable information for the development of medicines that specifically target molecules within Neuroblastoma cells.
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Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma
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Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children's Oncology Group Study
Katherine K. Matthay,C. Patrick Reynolds,Robert C. Seeger,Hiroyuki Shimada,E. Stanton Adkins,Daphne A. Haas-Kogan,Robert B. Gerbing,Wendy B. London,Judith G. Villablanca +8 more
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