Improving Outcomes in Children With High-Risk Neuroblastoma: The Role of Randomized Trials
Mené sur 630 patients pédiatriques atteints d'un neuroblastome à haut risque de récidive (âge : 1-20 ans), cet essai randomisé compare l'efficacité, du point de vue du taux de réponse complète et de la survie sans événement à 3 ans, de deux protocoles thérapeutiques d'induction, l'un de type MSKCC-N5 (protocole N5 développé par le "Memorial Sloan Kettering Cancer Center") et l'autre de type COJEC (cisplatine, vincristine, carboplatine, étoposide et cyclophosphamide)
Résumé en anglais
Outcomes for children with newly diagnosed high-risk neuroblastoma have improved significantly over the past 20 years, but despite intensive multimodality therapy, survival rates remain just over 50%.1 Modern-era therapy for high-risk patients with this embryonal malignancy in higher-income countries is composed of induction therapy that includes multiagent chemotherapy and surgery, consolidation therapy consisting of high-dose chemotherapy with autologous stem-cell rescue and external beam radiotherapy, and postconsolidation immunotherapy to address minimal residual disease.2 Neuroblastoma predominantly affects young children, and late effects of therapy place a heavy burden on those who survive.
Investigators around the world have long been intrigued by the challenges posed by this disease, and international collaborative efforts have resulted in key insights into the biologic basis of neuroblastoma and in major advancements in its treatment. In the article that accompanies this editorial, Garaventa et al3 describe the results of the HR-NBL1.5 trial conducted by the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN), a cooperative group that is committed to conducting randomized trials to address important questions that affect the care of patients with neuroblastoma. This large, multicenter study was conducted over nearly 16 years in total and included five randomizations that have addressed important questions related to all three phases of high-risk neuroblastoma therapy (induction, consolidation, and postconsolidation).
The current manuscript addresses a question regarding induction therapy, the phase of treatment designed to maximally reduce the burden of disease before subsequent therapy. In previous cooperative group studies, approximately 7%-15% of patients experienced early disease progression,1,4,5 highlighting the importance of identifying the most effective initial treatment for high-risk patients. Furthermore, it has been shown that subsequent survival outcomes are superior in patients who experience a partial response or better during induction therapy compared with those who have stable or progressive disease initially.6 In the HR-NBL1.5 trial, the European regimen associated with the best reported end-induction outcomes (known as rapid cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide [COJEC]4) was compared with the North American regimen associated with the best reported end-induction outcomes (the N5 regimen developed by investigators at Memorial Sloan Kettering Cancer Center, or MSKCC N5).7 The response rate associated with the MSKCC N5 regimen was initially reported in the context of a single-arm trial conducted at a single North American center and was not replicated in other contexts.8-10 Therefore, one might have argued that the preferred comparator would have been the induction regimen studied in multicenter cooperative group trials conducted by the Children's Oncology Group (COG) or another large consortium, given the greater expected generalizability of the results from multicenter trials compared with single-center studies. Nonetheless, the more important decision made by the SIOPEN team was the decision to commit to conducting a randomized clinical trial (RCT).
