Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group

Abstract

Purpose: Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker.

Methods: Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2).

Results: Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (MYCN) or 12-18 months (MYCN, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively.

Conclusion: A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.

FIG 1.

Risk classifier v2 algorithm for patients with (A) locoregional and (B) metastatic tumors. (A) Patients with locoregional tumors with neuroblastoma and ganglioneuroblastoma (nodular) are classified based on INRG stage (L1 and L2), age, resection, biomarkers (MYCN, ploidy, and SCAs), and INPC. Select patients with all favorable features are eligible for surveillance on the current non–high-risk COG ANBL1232 protocol. L1 or L2 tumors with histopathology diagnostic category of ganglioneuroma or ganglioneuroblastoma-intermixed will be classified as low-risk regardless of biomarkers (and thus are not included in the figure). Ages are broken down by < 18 months, 18 months to < 5 years, and ≥ 5 years based on age categories used by INPC. ^aIf tumor progresses during observation, biopsy or resect and reclassify with biomarkers (as in COG ANBL1232). ^bConsider complete resection if feasible. ^cIf no tumor burden symptoms, consider observation (as in COG ANBL1232). (B) Patients with metastatic tumors are classified by stage (M and MS), age, INPC, and biomarkers. For MS patients, presence or absence of symptoms may influence therapy independent of biomarker status. In previous risk classifiers, missing data were considered as unfavorable. In COG v2, missing data for SCA will not be considered as unfavorable based on the low incidence of SCA in otherwise favorable subsets. ^dBiopsy contraindicated, defer biopsy until stable (note: biomarker results may modify Risk Class). ^eHepatomegaly alone is an MS symptom in patients age < 3 months of age (see COG ANBL1232). ^fResponse-based therapy (as in COG ANBL1232). ^gMS score–based therapy (as in COG ANBL1232). COG, Children's Oncology Group; DI, DNA index; dia., diameter; FH, favorable histology; GTR, gross-total resection; INPC, International Neuroblastoma Pathology Classifier; INRG, International Neuroblastoma Risk Group; MYCN+, MYCN amplified; MYCN−, MYCN not amplified; SCA, segmental chromosomal aberration; UH, unfavorable histology; v1, version 1; v2, version 2.

FIG 2.

Outcome analyses for risk groups on COGv1 and v2 risk classifiers. (A and B) 5-year EFS and OS for LR, IR, and HR groups according to COG v1. (C and D) 5-year EFS and OS for LR, IR, and HR groups according to COG v2. Log-rank tests were used to compare survival distributions and are shown on the relevant figures and in the Data Supplement. The patient cohorts, eligibility details, and missing data are described in the CONSORT Diagram (Data Supplement). COG, Children's Oncology Group; EFS, event-free survival; HR, high-risk; IR, intermediate-risk; LR, low-risk; OS, overall survival; v1, version 1; v2, version 2.