Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: A report from the International Neuroblastoma Risk Group Project

Abstract Purpose Increasing age has been an adverse risk factor in children with neuroblastoma (NB) since the 1970’s, with a 12-month age-at-diagnosis cut-off for treatment stratification. Over the last 30 years, treatment intensity for children >12 months with advanced-stage disease has increased; to investigate if this strategy has improved outcome and/or reduced the prognostic influence of age, we analysed the International Neuroblastoma Risk Group (INRG) database. Patients and methods Data from 11,037 children with NB (1974–2002) from Australia, Europe, Japan, North America. Cox modelling of event-free survival (EFS) tested if the era and prognostic significance of age-of-diagnosis, adjusted for bone marrow (BM) metastases and MYCN status, effects on outcome had changed. Results Outcome improved over time: 3-year EFS 46% (1974–1989) and 71% (1997–2002). The risk for those >18 months against ⩽12 decreased: hazard ratio (HR); 4.61 and 3.94. For age 13–18 months, EFS increased from 42% to 77%. Outcome was worse if: >18 months (HR 4.47); BM metastases (HR 4.00); and MYCN amplified (HR 3.97). For 1997–2002, the EFS for >18 months with BM involvement and MYCN amplification was 18%, but 89% for 0–12 months with neither BM involvement nor MYCN amplification. Conclusions There is clear evidence for improving outcomes for children with NB over calendar time. The adverse influence of increasing age-at-diagnosis has declined but it remains a powerful indicator of unfavourable prognosis. These results support the age-of-diagnosis cut-off of greater than 18 months as a risk criterion in the INRG classification system.