Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: Results of the SIOPEN study

Department of Paediatric Oncology, Southampton General Hospital, Southampton, UK.
European journal of cancer (Oxford, England: 1990) (Impact Factor: 5.42). 07/2013; 49(17). DOI: 10.1016/j.ejca.2013.07.002
Source: PubMed


In children older than 1year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery.
In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin-Etoposide and Vincristin-Cyclophosphamide-Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%.
Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18months or with favourable histology.
This strategy provides encouraging results in children older than 1year or 12months with localised unresectable NB without MYCN amplification. However, in children older than 18months and with unfavourable histology, additional treatment is recommended.

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    ABSTRACT: Background International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.ProcedureOf 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS).ResultsAge at diagnosis (P < 0.0001), tumor MYCN status (P < 0.0001), and poorly differentiating/undifferentiated histology (P = 0.03) were independent predictors of EFS. Compared to other Stage 3 subgroups, outcome was inferior for patients ≥547 days with MYCN-NA neuroblastoma (P < 0.0001), and within this cohort, serum ferritin ≥96 ng/ml was associated with inferior EFS (P = 0.02). For patients <547 days of age with MYCN-NA tumors, serum ferritin levels were prognostic of overall survival (OS) (P = 0.04) and chromosome 11q aberration was prognostic of EFS (P = 0.03).Conclusions Among patients with INSS Stage 3 neuroblastoma patients, age at diagnosis, MYCN status and histology predict outcome. Patients <547 days of age with MYCN-NA tumors that lack chromosome 11q aberrations or those with serum ferritin <96 ng/ml have excellent prognosis and should be considered for therapy reduction. Prospective clinical trials are needed to identify optimal therapy for those patients ≥547 days of age with undifferentiated histology or elevated serum ferritin. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
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    ABSTRACT: BACKGROUND:The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.
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    ABSTRACT: Neuroblastoma prognosis varies tremendously based on the stage and biologic features of the tumor. Treatment varies depending on the risk group and can range from surgery alone for stage 1 tumors to aggressive multimodality treatment for MYCN-amplified tumors. Although surgery plays a role in the diagnosis and management of all stages of neuroblastoma, the importance of that role, especially the extent of resection, in high-risk neuroblastoma continues to evolve. In the past five years, there have been several advances in neuroblastoma surgery. Studies have demonstrated that patients with low-risk disease can be treated with surgery alone, and in a subset of patients who are neonatally diagnosed with adrenal tumors, surgery can be avoided in 80%. Recent abstracts have supported a role for >90% resection of the primary tumor in high-risk patients. This article also reviews the surgical approaches to difficult thoracic and abdominal tumors, as well as the role for minimally invasive surgery in the management of localized neuroblastoma. Georg Thieme Verlag KG Stuttgart · New York.
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