High-Risk and Relapsed Neuroblastoma: Toward More Cures and Better Outcomes

Abstract

Approximately half of the patients diagnosed with neuroblastoma are classified as having high-risk disease. This group continues to have inadequate cure rates despite multiagent chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, and immunotherapy directed against GD2. We review current efforts to try to improve outcomes in patients with newly diagnosed disease by integrating novel targeted therapies earlier in the course of the disease. We further examine a growing list of options available for patients with relapsed or refractory high-risk disease, with an eye toward graduating successful strategies from a relapsed/refractory setting to the frontline setting. Last, we review efforts to study and potentially mitigate the array of late effects faced by survivors of high-risk neuroblastoma.

MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

“…Current NB therapy in the majority of countries is constituted by three phases: induction, consolidation and maintenance therapies ( Figure 1 ), and lasts approximately 18 months, varying by the patient risk [ 50 , 51 ]. Treatment strategies for each phase may include chemotherapy, surgical resection, high-dose chemotherapy with autologous stem cell rescue, radiation therapy, immunotherapy and isotretinoin, but the modality of the administration of the single procedures mostly depends on patient risk status [ 52 ].…”

“…Multimodal chemotherapies treatment strategies for HR-NB patients may vary from place to place, but they always involve a combination of chemotherapy and both high dose and frequent administration strategies. The most used North American model, for example, involves the use of a five-cycle strategy consisting in the administration of topotecan/cyclophosphamide for cycles 1 and 2, cisplatin/etoposide for cycles 3 and 5, and vincristine/doxorubicin/cyclophosphamide for cycle 4 [ 51 ], while the well-established COJEC system (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E] and cyclophosphamide [C]) uses another mix of chemotherapy rapidly administered every 21 or 10 days [ 71 , 72 ]. Of course, the use of chemotherapy at a high concentration and frequency inevitably leads to a broad spectrum of side effects, and although the community effort is focused on increasing patient compliance, long-term toxicity still remains a major issue in HR patients [ 73 ].…”

Combined analysis of PHOX2B at two time points and its value for further risk stratification in high‐risk neuroblastoma

“…Patients with relapsed or refractory (R/R) disease had the worst cure rate due to the existence of drug-resistant minimal residual disease (MRD). 7 MRD is considered as residual cancer cells that persistently reside in patients despite multimodal treatment. 8 A larger part of patients with high-risk NB have MRD, which causes tumor relapse or progression.…”

Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants

“…However, it is associated with short and/or long-term side effects; these include neurological symptoms, renal, pancreatic, and thyroid dysfunction, poor growth, abnormal pubertal progression, infertility, and, for long-term survivors, increased risk of secondary solid or hematological malignancies. Moreover, approximately half of HR-NB patients do not respond to therapy and relapse [ 6 , 7 ]. Treatment of relapsing patients includes additional chemotherapeutic drugs, ALK inhibitors in the case of ALK-positive NB, and the use of Iodine-131 labeled MIBG, a molecule similar to noradrenaline avidly captured by NB through the noradrenaline transporter.…”