The Drama of the Gifted Disease
Authors: William G. Woods, Michael P. LaQuaglia
Journal: Journal of Clinical Oncology (2008)

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. 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. 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. Even attempts at secondary prevention through mass screening have been ineffective, because, in general, the bad diseases are not detected preclinically. In two papers in this issue of Journal of Clinical Oncology, Monclair et al and Cohn et al 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. In the article by Monclair et al, 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, only 474 of whom had available outcome data. In the article by Cohn et al, 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 world 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, 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. 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.” Although the article by Monclair et al 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 al to determine the new INRGs. Additional validation must be done with larger groups of patients, including those from North America. In addition, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 2 JANUARY 1