Progress in Defining and Treating High-Risk Neuroblastoma: Lessons From the Bench and Bedside

Neuroblastoma (NB) is remarkable for its biologic heterogeneity and broad range of clinical behavior. Although survival rates are greater than 90% for patients with biologically favorable disease, outcomes for children with a high-risk clinical phenotype remains poor, with long-term survival still less than 40%. This issue of Journal of Clinical Oncology includes four studies that are focused on defining and treating high-risk NB. Modern molecular techniques have provided the tools to better define high-risk NB, and a modest improvement in outcome has been seen with dose intensification. However, each of the studies emphasizes the need for more effective therapeutic approaches. Efforts to identify variables that accurately predict outcome for patients with NB have been ongoing for more than 35 years. In the 1970s, the dramatic influence of stage and age on prognosis were reported. During this era, aggressive multimodality therapy was recommended for patients with skeletal metastases, whereas infants were treated more gently. In the 1980s, MYCN amplification emerged as a powerful marker of adverse prognosis in NB. The clinical significance of tumor histology, ploidy and other genetic aberrations, including 1p loss, 11q loss, and 17q gain were also demonstrated. Combinations of clinical and biologic prognostic variables are now routinely used for risk-group assignment and treatment stratification, although the criteria used to define risk vary greatly throughout the world. Because definitions of risk are not uniform, direct comparison of risk-based clinical trials conducted in different regions of the world has not been possible. To address this problem, an international task force recently established the International Neuroblastoma Risk Group (INRG) classification system, on the basis of the analysis of 13 prognostic variables in an 8,800 patient cohort. By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the development of international collaborative studies. To date, the strategy to improve outcome in high-risk patients has largely been focused on delivering increasingly intensive multimodality therapy. Matthay et al report the long-term results of a randomized Children’s Oncology Group (COG) trial comparing a more intensive arm of consolidation therapy (myeloablative therapy plus autologous bone marrow transplant [ABMT]) versus a less intensive arm (continued conventional-dose chemotherapy). All patients without evidence of disease after consolidation were then eligible for a second randomization to 13-cis-retinoic acid (cis-RA) versus no additional therapy. The initial results of the study, reported almost 10 years ago, demonstrated significantly better 3-year event-free survival (EFS) for the group randomly assigned to myeloablative therapy and ABMT and for patients randomly assigned to cis-RA. With additional followup, patients randomly assigned to the more intensive arm (myeloablative therapy and ABMT) continue to have significantly higher 5-year EFS. Similar results have been reported by European groups, although survival still remains poor. In the COG study, 30% SE 4% of the patients randomly assigned to the superior arm of therapy were event-free at 5 years. Although overall survival (OS) in the COG study was found to be significantly higher for each randomization at 5 years using a test of the log( log(.)) transformation, a significant advantage for OS was not observed in the European studies. Thus, the majority of the patients are not cured with intensive treatment strategies that include myeloablative therapy and stem-cell rescue. Furthermore, long-term follow-up studies have demonstrated that many survivors have serious late effects of therapy, including delays in growth and development, hearing loss, renal and cardiac dysfunction, learning problems, and treatment-related leukemia and second cancers. The study by Canete et al focuses on the outcome of infants younger than 12 months of age with high-risk disease treated on a International Society of Paediatric Oncology European Neuroblastoma (SIOPEN) clinical trial. In this cohort of 35 infants, 2-year EFS was 29% (SE 0.07) and OS was 30% (SE 0.08) after treatment with intensive multimodality therapy, including high-dose busulfan and melphalan with peripheral stem-cell support and cis-RA. Many of the tumors were resistant to chemotherapy, with 30% progressing or failing to respond to induction therapy. In the COG, infants with high-risk NB are treated on the same clinical trial as older patients with high-risk disease. Because of small numbers, international collaboration will likely be needed to determine if the clinical behavior of high-risk tumors diagnosed in infancy differs from high-risk tumors in older children. To ensure that patients with a lowor intermediate-risk clinical phenotype are spared toxic, dose-intensive, high-risk treatment regimens, accurate risk-group classification is critical. Historically, an age cutoff of 12 months has been used for risk stratification. However, recent analysis of a large series of 3,666 patients has demonstrated statistical evidence for increasing the age cutoff to 15 to 19 months. On the basis of these results, COG has modified eligibility criteria for its intermediate-risk clinical study to include toddlers, age 12 to 18 months, with favorable biology tumors. Similarly, an age cutoff of 18 months has been included in the INRG classification system. This new age cutoff will shift approximately 10% of patients previously classified as high risk to a lower-risk group. Newly designed JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 7 MARCH 1 2009