Improvements in Children’s Oncology Group neuroblastoma risk stratification through a change in age cut-off and use of INRGSS

We thank the authors for their supportive comments on our manuscript about the revision to the Children's Oncology Group (COG) neuroblastoma risk stratification based on a change in age cut-off from 12 to 18 months (1,2).The authors have provided a well-described and helpful overview of the application of biomarkers to risk stratify patients, as well as describing treatment and late effects.They have nicely summarized the comparative evidence of our successful reduction of therapy due to the described COG risk stratification changes.In addition to the change in age cut-off, COG risk stratification is anticipated to improve by using the INRGSS (International Neuroblastoma Risk Group Staging System) (3) instead of INSS (International Neuroblastoma Staging System) (4,5).INSS was utilized in 2006 when the change in age cut-off was made, but has since been replaced by the INRGSS in the COG neuroblastoma risk classifier version 2.INRGSS is a pre-surgical staging system which quantifies the disease extent at diagnosis, compared to INSS, which is post-surgical and dependent on surgical discretion.The authors describe the use of the International Neuroblastoma Pathology Classification (INPC) as a biomarker in COG risk stratification.Age is one of the factors used to classify tumors as INPC favorable or unfavorable.In the context of risk stratification, using both age and INPC leads to a duplication of the prognostic contribution of age, i.e., confounding.Further improvements in risk stratification should utilize the underlying components of INPC [histologic category, mitosis-karyorrhexis index (MKI), and grade of differentiation] as separate risk factors, to eliminate this problematic confounding (6).We thank the authors for describing the LEAHRN (Late Effects After High-Risk Neuroblastoma) study, the first comprehensive study specifically focused on late effects in survivors of high-risk neuroblastoma (7).These survivors were diagnosed on/after January 1, 2000, with a minimum of 5 years follow-up after diagnosis.The authors state that survivors were treated between 2000-2006; however, many LEAHRN patients were treated after 2006 with more contemporary therapy.The authors state that "While this re-classification saved children to be exposed to unnecessary treatments, their outcome should remain unaltered".Certainly, it was our hope that their outcome remains 'unaltered', but we should clarify our intent.We hypothesized that despite receiving less intensive therapy, these groups would maintain the same outstanding survival outcomes as they had when they received high-risk

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