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 INSS was utilized in 2006 when the change in age cut-off was made, but has since been replaced by the INRGSS in the COG neuroblastoma risk classifier version 2.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 therapy, albeit with fewer late effects. Fortunately, we were able to present evidence supporting that hypothesis.

We agree with the authors that it is a limitation of our study that only 20 of the 105 patients received treatment through enrollment on clinical trials, and actual treatment received is unknown for most. However, there is anecdotal evidence that most patients in North America who are not enrolled on a COG clinical trial are treated “as per” the clinical trial, receiving the standard-of-care intermediate-risk or high-risk treatment according to the COG risk stratification (8).

We agree with the authors that international data harmonization and novel molecular biomarkers will be critically important to further optimize risk stratification and outcomes (9). We only identified 105 patients enrolled over 30 years in our cohort of interest, highlighting the importance of international collaborations and shared data to better characterize and classify rare subgroups. Furthermore, until such time as predictive biomarkers and drugs for targeted therapy are available for neuroblastoma, research on improved prognostic stratification should continue, as one means to continue to improve outcome, minimize toxicity and improve quality of life.

Acknowledgments

Funding: The study was supported by COG NIH/NCI grant (U10 CA180886to W.B.L., M.S.I., M.D.H., and S.L.C.).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-319/coif). W.B.L., M.S.I., M.D.H., and S.L.C. report funding from Children’s Oncology Group (COG) NIH/NCI grant U10 CA180886. W.B.L. reports funding from COG (payments made to her institution), Alex’s Lemonade Stand, and Little Heroes Pediatric Cancer Research and she serves on the Data Safety Monitoring Board of Jubilant DraxImage. M.S.I. reports funding from the Canadian Inst of Health Research lab operating grant, COG meeting travel support, and serves as Chair of Neuroblastoma Biology (Children Oncology Group). H.B. has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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