In recent years, the need to develop an international consensus for pretreatment risk stratification for children with NB has become increasingly apparent. To achieve this goal, an international task force established the INRG classification system. The prognostic effect of 13 variables in an 8,800-patient cohort was analyzed, with EFS, not OS, as the primary end point for the reasons identified earlier in this article. The INRG classification system includes the seven factors that were highly statistically significant and also considered clinically relevant. Similar to other series, patients with widely disseminated stage 4 disease had significantly worse outcome than those with locoregional disease or stage 4S NB.9,23
As described in the article by Monclair et al,14
a new pretreatment staging system was designed for the INRG classification system. In the INRGSS, extent of locoregional disease is determined by the absence or presence of image-defined risk factors (L1 and L2, respectively). Stage M will be used for disseminated disease, analogous to INSS stage 4. Similar to INSS stage 4S tumors, metastases are limited to skin, liver, and bone marrow without cortical bone involvement in INRGSS MS disease. However, the definition of MS has been expanded to include toddlers age 12 to younger than 18 months and large “unresectable” primary tumors (L1 or L2). As discussed in the companion article by Monclair et al,14
the inclusion of L2 tumors is based on the excellent outcome of all 30 children enrolled on the SIOPEN 99.2 trial who met the criteria for INSS stage 4S disease and, in addition, had midline infiltration of the primary tumor, after treatment with a few cycles of chemotherapy or observation alone (B. De Bernardi, personal communication, February 2008). Although there is some concordance of patients between the INRGSS and the INSS staging systems, the two systems differ in the sense that the INSS staging system contains inherent confounding of surgical treatment versus extent of tumor, whereas INRGSS removes that confounding because it is assigned before surgery. The important similarity of the two systems is that INRGSS retains the prognostic value of staging that has been well documented for INSS staging, with statistically significantly higher EFS for L1 compared with L2. There is statistical justification for use of INRG staging for assigning patients to pretreatment groups, although prospective evaluation of the risk grouping based on the INRGSS staging system will be mandatory.
The analysis of the INRG data confirmed that the predictive ability of age is continuous in nature for NB. By convention, virtually all cooperative groups have used the 12-month cutoff to determine risk.1
Similar to a previous study of COG patients,20
our analysis of the INRG cohort indicated that the optimal age cutoff is between 15 and 19 months. Children age 12 to younger than 18 months with hyperdiploid stage 4 disease who lack MYCN
amplification have excellent outcome when treated with intensive therapy on high-risk clinical trials.24,25
These results suggest that therapy may be reduced safely in a subset of young children with stage 4 disease, and clinical trials testing this question have recently been developed. An age cutoff of 18 months (547 days) was, therefore, selected for the INRG classification system for all children except those with diploid, stage M tumors without amplification of MYCN
for whom the more conservative, 12-month cutoff will be maintained.
Tumor histology is another well established prognostic variable in NB.12,13
To avoid confounding of age and INPC, we tested histologic category, MKI, grade of tumor differentiation, and age in the EFS tree regression analyses in lieu of INPC. We found that histologic category and tumor differentiation were statistically significantly associated with EFS. Consistent with the inferior prognosis that has been reported in patients with Shimada unfavorable histology INSS stage 3 tumors that lack MYCN
we found that outcome was worse for patients age 18 months and older with MYCN
-nonamplified stage 2, 3 poorly differentiated or undifferentiated tumors compared with those with differentiating tumors.
To accurately stratify patients with locoregional tumors using the INRG classification system, sufficient samples of tumor tissue will be required for genetic/expression studies and for histologic category determination. In addition, there is a need for wide-scale education of pediatric pathologists to ensure that different histopathologic grades are uniformly and reproducibly recognized. The challenges of distinguishing GNB-intermixed from GNB-nodular are significant when the entire tumor is not resected. Surgical biopsy needs to be guided by the radiological appearances of the tumor, with any heterogeneous areas targeted. Adequate tissue samples are mandatory to evaluate histologic grade of differentiation in locoregional NBs that lack MYCN amplification in children 18 months of age or older. In most cases, multiple “true-cut” cores will yield sufficient tissue to determine tumor grade of differentiation, but fine-needle aspirates are not likely to provide adequate quantities of tissue for histologic analysis and are not appropriate. In metastatic tumors, fine-needle aspirates may provide adequate information for genetic analysis.
A number of genetic aberrations have been identified in NB tumors that are strongly associated with outcome. Our analysis confirmed the unfavorable prognostic significance of MYCN
amplification, and in the INRG classification system, MYCN
status is used to stratify patients into different pretreatment risk groups. We also found that 11q aberration was associated with worse outcome in patients with L2 or MS tumors that lack MYCN
amplification. Similar to previous studies,25,27-29
the prognostic value of DNA ploidy was demonstrated in children younger than 18 months of age with stage 4 disease and normal MYCN
copy number. Recommendations regarding standardized methods for evaluating MYCN
copy number, tumor cell ploidy, and other genetic aberrations in NB tumors will be reported in a future article.
Recent studies suggest that low-risk tumors may be best defined by the absence of MYCN
gene amplification and any structural genetic abnormalities, (including either 11q and/or 1p aberrations and/or 17q gain).30,31
The Task Force agreed that it would be optimal to evaluate genetic aberrations in NB tumors using genome-wide methods. However, because this type of analysis is not routinely performed by the large cooperative groups, incorporation of more global genetic data in the current INRG was not considered feasible at the present time. The immediate challenges are (1) to ensure that adequate tumor material is available for prospective “comprehensive” genetic investigations on every patient and (2) to identify technologies that are not cost prohibitive and will yield rapid and reproducible results. It is anticipated that the future INRG classification system will rely on the genetic profile of NB tumors, rather than the presence or absence of individual genetic abnormalities.
A limitation of this analysis is that there was no statistical adjustment for treatment, and therefore, patients in any of the 16 lettered rows may have received very different therapy. It is intended to extend the INRG database prospectively, and it will be critical to collect data on details of therapy.
In conclusion, the INRG classification system will ensure that children diagnosed with NB in any country are stratified into homogenous pretreatment groups. We strongly recommend that cooperative groups begin using this risk schema now. The very low-, low-, intermediate-, and high-risk categories were defined according to EFS cutoffs. These four categories were included in the classification schema to assist treating physicians in evaluating the prognostic impact of the combination of factors in each of the 16 lettered rows in the INRG classification system. Although these risk categories could have been defined differently, we selected EFS cutoff values that are commonly used for treatment stratification at the present time. For example, at most centers around the world, patients with features that are associated with estimated EFS rates of less than 50% are treated with intensive, multimodality strategies, whereas those predicted to have more than 85% EFS receive minimal therapy. We anticipate that risk group stratification will be further refined as treatment for high-risk disease improves and genome-wide DNA and expression analysis of tumors becomes more routine. It must be emphasized that we are not recommending that treatment be assigned according to these four broad risk-group categories. Rather, the key to reaping the benefits of this system will be the assignment of patients in one of the 16 pretreatment lettered designations in the INRG classification system to a single treatment group without splitting that row in different treatment subgroups. We anticipate that eligibility criteria for treatment protocols will likely include several of the 16 INRG pretreatment designations, and that the combinations of the 16 pretreatment groups that will be included in clinical trials studies conducted by each of the cooperative groups may be different. Therefore, it will be critical to individually report the outcome of patients assigned to each of the 16 pretreatment designations. This approach will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world, provide a platform to ask randomized surgical questions, and lead to the development of international collaborative studies.