BACKGROUND: Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication. PROCEDURE: Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios. RESULTS: The cohort included 1053 patients with median follow-up 5.5 years and EFS 27 ± 1%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi-variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250 U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 ± 9% for score = 0 versus 6 ± 3% for score = 5 (P < 0.0001). CONCLUSIONS: A simple score can identify an "ultra-high risk" (UHR) cohort (score = 5) comprising 8% of patients with 5-year EFS <10%. These patients appear not to benefit from induction therapy and could potentially be directed earlier to alternative experimental therapies in future trials.

Department of Paediatric and Adolescent Oncology Institut Gustav Roussy Viellejuif France

Department of Paediatric Medicine Rikshospitalet Oslo University Hospital Oslo Norway

Department of Paediatrics Institut Curie Paris France

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 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

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

Paediatric Haematology Oncology Agia Sofia Children's Hospital Athens Greece

Paediatric Haematology Oncology Great Ormond Street Hospital and UCL Institute of Child Health London UK

Paediatric Haematology Oncology Hospital for Sick Children and University of Toronto Toronto Canada

Paediatric Haematology Oncology Hospital Nino Jesús Madrid Spain

Paediatric Haematology Oncology Our Lady's Children's Hospital Crumlin Dublin Ireland

Paediatric Haematology Oncology Schneider Children's Medical Center of Israel Petah Tikva Israel

Paediatric Haematology Oncology St Anna Kinderspital and St Anna Kinderkrebforschung Vienna Austria

Paediatric Oncology Istituto Giannia Gaslini Genova Italy

Paediatric Oncology Leeds Teaching Hospital NHS Trust Leeds UK

Pediatric Oncology Unit Hospital Universitario y Politecnico La Fe Valencia Spain

Studies and Statistics on Integrated Research and Projects St Anna Kinderkrebsforschung Vienna Austria

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