Refractory and Relapsed Neuroblastoma: Exploring New Treatment Methods to Improve Outcomes

Neuroblastoma (NBL) is a highly malignant neuroectodermal tumor. It is the most common childhood extracranial solid tumor. The tumor mainly affects children 1-4 years of age. The estimated incidence is around 1:10,000 children per year. The International NBL Risk Group classification system categorized the disease into very low-risk, low-risk, intermediate-risk, and high-risk (HR) groups. HR NBL is diagnosed in approximately 40% of patients > 18 months of age and is associated with very aggressive clinical behavior. Treatment strategies for HR NBL involve the use of an intensive multi-model therapy plan; however, the outcome is still poor, with event-free survival and overall survival of 30% and 40% at 3 years, respectively. HR NBL causes approximately 15% of pediatric cancer deaths. Most mortalities are caused by disease relapse (50%) and refractoriness to therapy (20%). Refractory and relapsed (R&R) NBL is commonly diagnosed in the HR NBL group and is challenging to treat. Despite the use of chemotherapy (CTR), radiotherapy, high-dose CTR with hematopoietic stem cell support, and HD I¹³¹ metaiodobenzyl guanidine therapy, the treatment outcomes are still inferior with EFS and OS of 8% and 15% at 3 years. Total change or significant modification of the current treatment strategies is urgently needed to improve outcomes. Recent developments in cell biology and molecular genetics of NBL tissue have led to the discovery of several potential molecular targets that may improve the treatment results. This review discusses the various clinical aspects of HR and R&R NBL, newer treatment interventions, targeted and immunotherapies, and applicability.