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Originally published as JCO Early Release 10.1200/JCO.2008.20.2739 on January 26 2009 © 2009 American Society of Clinical Oncology.
Progress in Defining and Treating High-Risk Neuroblastoma: Lessons From the Bench and BedsideDepartment of Pediatrics, the University of Chicago, Chicago, IL Neuroblastoma (NB) is remarkable for its biologic heterogeneity and broad range of clinical behavior.(1) 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.(2–5) 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.(6,7) 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.(8) 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,(1) 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.(9) 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(2) 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 follow-up, 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,(10,11) 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(3) 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 low- or 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.(12) 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.(9) This new age cutoff will shift approximately 10% of patients previously classified as high risk to a lower-risk group. Newly designed intermediate-risk clinical trials will need to be closely monitored to verify that high survival rates are maintained in this cohort of patients, despite therapy reduction. Janoueix-Lerosey et al(4) investigated the value of using a genetic approach to risk-stratify patients more precisely. In this study, the prognostic significance of genomic profiles was initially evaluated in 224 NB samples using array-based comparative genomic hybridization and then validated on a second series of 269 patients. In both cohorts, no disease-related death was observed in patients with whole chromosome copy number variations, whereas segmental chromosome alterations were associated with significantly worse outcome. In this series, genomic classification was found to be more powerful for predicting relapse than individual genetic markers. In addition, patients classified as low or intermediate risk with segmental alterations had significantly worse outcome than those lacking genetic aberrations. Similar results have been seen in other array-based studies.(1) Although genetic profiling is not routinely performed by the large cooperative groups at the present time, it is likely that global genetic data will replace individual genetic markers in future risk-stratification schemas. All four NB studies published in this issue of Journal of Clinical Oncology stress the need for new therapeutic approaches for high-risk NB. Building on the promising response rates in refractory NB with iodine-131-metaiodobenzylguanidine (131I-MIBG), Matthay et al(5) conducted a phase I study using double-infusion 131I-MIBG with autologous peripheral stem-cell rescue. The therapy was tolerated well and activity of 131I-MIBG was demonstrated. A randomized study will be required to determine if outcome is improved with double-infusion versus single-infusion 131I-MIBG. In an effort to further increase response rates, studies testing the combination of chemotherapy and 131I-MIBG in refractory NB are ongoing. COG is also developing a pilot study that will test 131I-MIBG in combination with myeloablative therapy and hematopoietic stem cell rescue in newly diagnosed high-risk patients. Although the studies in this issue of Journal of Clinical Oncology highlight the progress that has been made in stratifying and treating children with high-risk NB, outcomes remain dismal for this cohort of patients. To further improve survival, it is evident that novel treatment strategies targeting the biologic pathways responsible for driving the high-risk NB phenotype will be needed. Genomic studies have led to the discovery of a number of putative molecular targets. Recently, germline mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in patients with familial neuroblastoma,(13) and somatic ALK mutations have been detected in a subset of primary NBs and cell lines.(14–16) Functional studies show that many of the ALK mutations represent gain-of-function alleles that can sustain key signaling pathways and are therefore likely to be valid therapeutic targets for ALK inhibitors. Therapies, like ALK inhibitors, that are tailored to individual patients are now emerging, and early-phase pediatric clinical trials incorporating targeted therapies are ongoing. This approach may herald a paradigm shift in how patients with high-risk NB are treated, and, hopefully, will also lead to higher rates of cure. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Samuel L. Volchenboum, Susan L. Cohn Manuscript writing: Samuel L. Volchenboum, Susan L. Cohn Final approval of manuscript: Samuel L. Volchenboum, Susan L. Cohn REFERENCES 1. Maris JM, Hogarty MD, Bagatell R, et al: Neuroblastoma. Lancet 369:2106–2120, 2007.[CrossRef][Medline] 2. Matthay KK, Reynolds CP, Seeger RC, et al: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: A Children's Oncology Group Study. J Clin Oncol 27:1007–1013, 2009. 3. Canete A, Gerrard M, Rubie H, et al: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: The International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27:1014–1019, 2009. 4. Janoueix-Lerosey I, Schleiermacher G, Michels E, et al: Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol 27:1026–1033, 2009. 5. Matthay KK, Quach A, Huberty J, et al: Iodine-131-metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: A New Approaches to Neuroblastoma Therapy phase I study. J Clin Oncol 27:1020–1025, 2009. 6. Breslow N, McCann B: Statistical estimation of prognosis for children with neuroblastoma. Cancer Res 31:2098–2103, 1971. 7. Evans AE, D'Angio GJ, Randolph J: A proposed staging for children with neuroblastoma: Children's Cancer Study Group A. Cancer 27:374–378, 1971.[CrossRef][Medline] 8. Brodeur GM: Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer 3:203–216, 2003.[CrossRef][Medline] 9. Cohn SL, Pearson ADJ, London WB, et al: The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report. J Clin Oncol 27:289–297, 2009. 10. Berthold F, Boos J, Burdach S, et al: Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: A randomised controlled trial. Lancet Oncol 6:649–658, 2005.[Medline] 11. Pritchard J, Cotterill SJ, Germond SM, et al: High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 44:348–357, 2005.[CrossRef][Medline] 12. London WB, Castleberry RP, Matthay KK, et al: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23:6459–6465, 2005. 13. Mossé YP, Laudenslager M, Longo L, et al: Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455:930–935, 2008.[CrossRef][Medline] 14. Chen Y, Takita J, Choi YL, et al: Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455:971–974, 2008.[CrossRef][Medline] 15. Janoueix-Lerosey I, Lequin D, Brugieres L, et al: Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455:967–970, 2008.[CrossRef][Medline] 16. George RE, Sanda T, Hanna M, et al: Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455:975–978, 2008.[CrossRef][Medline]
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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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