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Originally published as JCO Early Release 10.1200/JCO.2008.19.2153 on December 1 2008 © 2009 American Society of Clinical Oncology.
The Drama of the Gifted Disease
Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta/Emory University, Atlanta, GA
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Neuroblastoma is indeed a gifted disease. There is as much or more knowledge about neuroblastoma, both clinically and biologically, than almost any other childhood cancer and most adult cancers. It has been known for years that neuroblastoma has a schizophrenic personality and is at least two distinct clinical-biologic entities.1 Strong prognostic factors can accurately predict whether children have good or bad disease at diagnosis. As an example, tumor overexpression of the MYCN oncogene, the first human oncogene correlated with outcome in any cancer, portends an extremely poor prognosis.2 Patients with the good disease have an extremely favorable prognosis; those with the bad disease have had little, if any, improvement in overall survival during the last 25 years, despite increasingly intensive chemotherapy that includes myeolablative therapy with blood or bone marrow transplant rescue.2 Even attempts at secondary prevention through mass screening have been ineffective, because, in general, the bad diseases are not detected preclinically.3,4 In two papers in this issue of Journal of Clinical Oncology, Monclair et al5 and Cohn et al6 describe a new proposed neuroblastoma staging system that is based on image-defined risk factors (IDRFs) and that does not depend on the extent of surgery, as the widely accepted International Neuroblastoma Staging System (INSS) does.7 In the article by Monclair et al,5 a new International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) is proposed, which shows good correlation between the old INSS disease stage 1 and the new INRGSS stage L1 (in which L stands for localized) and between the old INSS combined stages 2 and 3 with the new INRGSS stage L2. For patients who have metastatic disease, the old stage 4 is almost identical to the new stage M, and the old 4S is similar to the new stage MS; differences in the latter are based in part on age and extent of localized tumor. These results are based on analysis of 611 patients enrolled on a former Societe Internationale Oncologie Pediatrique European Neuroblastoma trial that examined surgical risk factors for localized neuroblastoma,8 only 474 of whom had available outcome data. In the article by Cohn et al,6 the data from 8,800 patients were utilized to develop overall INRGs, which correlated INSS as a surrogate for INRGSS with other clinical and biologic variables, including stage, age, histology, tumor differentiation, MYCN, 11q aberrations, and DNA ploidy. Sixteen pretreatment letter designations, or groups, into which all neuroblastoma patients can be categorized, are described. The investigators subsequently bunched several of these groups into four larger strata that represent very low–, low-, intermediate-, and high-risk disease on the basis of event-free survival (EFS). These broader strata represent a suggested approach for cooperative groups worldwide that may want to treat children in uniform ways for certain risk groups, although the authors also make it clear that any cooperative group can bunch the 16 risk groups any way they wish from a therapeutic point of view. This overall project involved major worldwide neuroblastoma experts and an analysis of a massive amount of data by an EFS regression tree approach. The 16 groups are well characterized in the incorporation of the most important prognostic factors. There are some clear advantages to this new approach, if it is found valid. First, the major histologic classification system that has been adopted throughout much of the world9 depends on age as well as histology for determining prognosis, which makes the system less robust. The new histologic staging approach utilizes two histologic criteria devoid of age—cellular histology and tumor differentiation—both of which appear to lend important prognostic information. Next, getting international consensus for the 16 risk groups will definitely make treatment comparisons across cooperative groups, including comparing the 16 risk groups individually as opposed to broader strata, as noted above, much easier when moving forward. Third, utilizing a presurgical staging system will allow one to more accurately determine any surgery planned, its extent, and the ability to ask important surgical questions in future trials. Finally, the new staging system eliminates the difficult decisions of determining whether a tumor crosses the midline or has positive nodes, either radiologically or surgically. Clearly, the more refined one can get with a classification system, the easier the task of improving the outcomes or reducing therapy. However, enthusiasm for the new proposed INRG must be tempered by major concerns regarding the limitations of this project. First, there has been limited validation to date of the new INRGSS compared with the older, well-established INSS. Besides the article by Monclair et al,5 the only other attempt to compare IDRFs with INSS was a study of 520 patients on the German Society for Pediatric Hematology/Oncology NB 97 Trial.10 Although, again, there was good correlation between INSS and INRG and demonstration of significant EFS differences between patients with and without IDRFs, results of a multivariate Cox regression analysis led to the conclusion that "IDRF failed as an independent risk predictor in localized neuroblastoma. INSS more precisely identified patients with poor prognosis."10 Although the article by Monclair et al5 states that "it was not the goal of this analysis to compare outcomes for INRGSS versus INSS," the investigators used INSS in the article by Cohn et al6 to determine the new INRGs. Additional validation must be done with larger groups of patients, including those from North America. In addition, it is unknown whether specific IDRFs can be reliably determined by institutional radiologists compared with a review panel. Although we certainly support the goal of determining stage independent of the extent of surgery, substitution of imaging studies also presents certain difficulties. This is related to inter- and intrareader concordance. In studies from other disciplines in which a new prognostic evaluation scheme was tested, inter- and intrareader concordance was surprisingly variable.11,12 This necessitates central review of images and confirmation of IDRFs by a panel of experienced imagers as part of the prognostic evaluation of the INRG schema. Otherwise, many of the problems associated with surgical stage determination will be encountered again, albeit to a lesser degree. The biggest concern about the new staging system is that it takes no account of the critical importance of treatment effects on the risk classification. Again, the authors acknowledge this point, but no adjustment for this critical confounder was made. In previous large trials, the difference in prognosis between INSS stages 2 and 3 was significant. In fact, some patients who had stage 3 disease, even without unfavorable biologic factors, may have received much more intensive therapy than patients who had INSS stage 2 disease, in which tumors may have regressed or been treated in a minimal fashion; now, both of these could be lumped in the same lettered risk group. The INRG investigators do want to test this new approach in a prospective fashion that gives uniform therapy to specific risk groups. Even though the new INRG is relatively well thought out, one may find that this new approach falls flat on its face and potentially puts patients at risk. Furthermore, the INRG investigators missed a couple of great opportunities to add more clarity to their proposed risk groups. First, the children analyzed during the 12-year period of time had a 10% improvement in both EFS and overall survival between those treated in the first half (1990 to 1996) compared with the second half (1996 to 2002). A confirmatory analysis that utilized just the latter half of children who had more up-to-date therapy would have been helpful. Second, and most important, these manuscripts overwhelmingly analyzed and stratified patients who had localized disease; the vast majority of children who die as a result of this tumor present with metastatic, often bad, disease. Children who have neuroblastoma listed as high risk in the INRG, the vast majority of whom have M stage disease, account for greater than one third of the entire cohort in the study by Cohn et al (Table 4).6 By adding high serum ferritin as a risk factor for patients who have stage 4 disease and are older than 18 months of age, especially in MYCN-negative tumors, as shown in the study by Cohn et al (Fig 1D),6 investigators could have created a very high–risk stratum that represented almost one quarter of the total patients who collectively had less than 30% chance of EFS and overall survival. This still left approximately 10% of patients in the high-risk category, whose prognosis would be between 30% and 50%. More novel, innovative treatments, even at diagnosis, then could be targeted to the patients who had VHR disease. So what is the drama of the gifted disease (the name of which plays off Alice Miller's classic psychoanalytic exploration of narcissism, The Drama of the Gifted Child: The Search for the True Self13)? The proposed INRG may be an interesting and important tool to be studied, which may potentially help refine risk groups for whom less treatment is needed for cure. However, this is a side stage. The great drama remains: finding novel agents to hit targets, probably molecular, geared at bad neuroblastoma in children who have high-risk, and especially very high–risk, disease, which has heretofore proven resistant to current therapies. Despite the volume of information about neuroblastoma, including 16 INRG groups, we have yet to achieve cure rates that rival other common childhood cancers. These data suggest that none of the current treatments have heretofore successfully targeted the true villain, the neuroblastoma stem cell.2,14 Only then will the gifted disease successfully leave the stage. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: William G. Woods, Michael P. LaQuaglia Final approval of manuscript: William G. Woods, Michael P. LaQuaglia NOTES published online ahead of print at www.jco.org on December 1, 2008 REFERENCES
1. Woods WG, Lemieux B, Tuchman T: Neuroblastoma represents distinct clinical-biologic entities: A review and perspective from the Quebec Neuroblastoma Screening Project. Pediatrics 89:114-118, 1992 2. Maris JM, Hogarty MD, Bagatell R, Cohn SL: Neuroblastoma. Lancet 369:2106-2120, 2007[CrossRef][Medline] 3. Woods WG, Gao RN, Shuster JJ, et al: Screening of infants and mortality due to neuroblastoma. N Engl J Med 346:1041-1046, 2002 4. Schilling FH, Spix C, Berthold F, et al: Neuroblastoma screening at one year of age. N Engl J Med 346:1047-1053, 2002 5. Monclair T, Brodeur GM, Ambros PF, et al: The International Neuroblastoma Risk Group Staging System. J Clin Oncol [epub ahead of print on December 1, 2008] 6. Cohn SL, Pearson AD, London WB, et al: International Neuroblastoma Risk Group Classification System: The INRG Task Force. J Clin Oncol [epub ahead of print on December 1, 2008] 7. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the International Criteria for Neuroblastoma Diagnosis, Staging, and Response to Treatment. J Clin Oncol 11:1466-1477, 1993 8. Cecchetto G, Mosseri V, De Bernardi B, et al: Surgical risk factors in primary surgery for localized neuroblastoma: The LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23:8483-8489, 2005 9. Shimada H, Ambros IM, Dehner LP, et al: The international neuroblastoma pathology classification (Shimada) system. Cancer 86:364-372, 1999[CrossRef][Medline] 10. Simon T, Hero B, Benz-Bohm G, et al: Review of image defined risk factors in localized neuroblastoma patients: Results of the GPOH NB97 trial. Pediatr Blood Cancer 50:965-969, 2008[CrossRef][Medline] 11. Doria AS, de Castro CC, Kiss MH, et al: Inter- and intra-reader variability in the interpretation of two radiographic classification systems for juvenile rheumatoid arthritis. Pediatr Radiol 33:673-681, 2003[CrossRef][Medline] 12. Sharp J, Wolfe F, Lassere M, et al: Variability of precision in scoring radiographe abnormalities in rheumatoid arthritis by experienced readers. J Rheumatol 31:1062-1072, 2004 13. Miller A. The Drama of the Gifted Child: The Search for the True Self (Ward R, trans). New York, NY, Basic Books, 1981 14. Hansford LM, McKee AE, Zhang L, et al: Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res 67:11234-11243, 2007
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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