Originally published as JCO Early Release 10.1200/JCO.2008.16.6785 on December 1 2008

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The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report

Susan L. Cohn, Andrew D.J. Pearson, Wendy B. London, Tom Monclair, Peter F. Ambros, Garrett M. Brodeur, Andreas Faldum, Barbara Hero, Tomoko Iehara, David Machin, Veronique Mosseri, Thorsten Simon, Alberto Garaventa, Victoria Castel, Katherine K. Matthay

From the Department of Pediatrics, The University of Chicago, Chicago, IL; Section of Paediatrics, Institute of Cancer Research and Royal Marsden Hospital, Surrey; Children's Cancer and Leukaemia Group Data Centre, University of Leicester, Leicester, United Kingdom; Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL; Section for Paediatric Surgery, Division of Surgery, Rikshospitalet University Hospital, Oslo, Norway; Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria; Division of Oncology, The Children's Hospital of Philadelphia, Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA; Institute of Medical Biostatistics, Epidemiology and Informatics, University of Mainz, Mainz; Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany; Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan; Service de Biostatistiques, Institut Curie, Paris, France; Department of Hematology–Oncology, Gaslini Institute, Largo Gaslini, Genoa, Italy; Unidad de Oncologia Pediatrica, Hospital Infantil La Fe, Valencia, Spain; and the Department of Pediatrics, University of California School of Medicine, San Francisco, CA

Corresponding author: Susan L. Cohn, MD, Section of Pediatric Hematology/Oncology, University of Chicago, 5841 Maryland Ave, MC 4060, Rm N114, Chicago, IL 60637; e-mail: scohn{at}peds.bsd.uchicago.edu

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 85%, 50% to 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.

published online ahead of print at www.jco.org on December 1, 2008.

Supported in part by the William Guy Forbeck Research Foundation and the Little Heroes Pediatric Cancer Research Foundation; and Cancer Research UK and NHS funding to the NIHR Biomedical Research Centre (to A.D.J.P.).

S.L.C. and A.D.J.P. are co-chairs of the INRG Task Force, contributed equally to this article, and share first authorship.

Presented in part at the Advances in Neuroblastoma Research 12th Conference, May 17-20, 2006, Los Angeles, CA; the International Society of Paediatric Oncology 38th Congress, September 18-21, 2006, Geneva, Switzerland; the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and Advances in Neuroblastoma Research 13th Conference, May 21-24, 2008, Chiba, Japan.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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