Significance of clinical and biologic features in Stage 3 neuroblastoma: a report from the International Neuroblastoma Risk Group project.

Abstract

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. Of 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). Age 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). 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.