The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report

Abstract

Purpose: Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification.

Patients and methods: The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors.

Results: Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively.

Conclusion: By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

Fig 1.

EFS tree regression analysis of INRG analytic cohort. Unless otherwise noted, a split or branch occurs for the most highly statistically significant factor as identified using a Cox proportional hazards regression model. (A) Top levels of the overall tree. (B) Subtree for NB and GNB-nodular, non–stage 4 MYCN NON-AMP patients. The split of stage 2, 3 from stage 4S patients was a clinical decision and not the result of statistical significance. (C) Subtree for NB and GNB-nodular, non–stage 4 MYCN AMP patients. The split of stage 1 from stage 2, 3, 4S patients was a clinical decision and not the result of statistical significance. (D) Subtree for INSS stage 4 patients. EFS, event-free survival; OS, overall survival; DI, DNA index; AMP, amplified; NON-AMP, nonamplified; INRG, International Neuroblastoma Risk Group; NB, neuroblastoma; GNB, ganglioneuroblastoma; GN, ganglioneuroma; INSS, International Neuroblastoma Staging System; LDH, lactate dehydrogenase.

Fig 2.

International Neuroblastoma Risk Group (INRG) Consensus Pretreatment Classification schema. Pretreatment risk group H has two entries. 12 months = 365 days; 18 months = 547 days; blank field = “any”; diploid (DNA index ≤ 1.0); hyperdiploid (DNA index > 1.0 and includes near-triploid and near-tetraploid tumors); very low risk (5-year EFS > 85%); low risk (5-year EFS > 75% to ≤ 85%); intermediate risk (5-year EFS ≥ 50% to ≤ 75%); high risk (5-year EFS < 50%). GN, ganglioneuroma; GNB, ganglioneuroblastoma; Amp, amplified; NA, not amplified; L1, localized tumor confined to one body compartment and with absence of image-defined risk factors (IDRFs); L2, locoregional tumor with presence of one or more IDRFs; M, distant metastatic disease (except stage MS); MS, metastatic disease confined to skin, liver and/or bone marrow in children < 18 months of age (for staging details see text and Monclair et al14); EFS, event-free survival.