High-risk neuroblastoma presents a continuing therapeutic challenge. Progress thus far in combination chemotherapy, local control, myeloablative consolidation therapy, and treatment with differentiating agents for microscopic residual disease has improved the overall prognosis. Although the 3-year event-free survival for children with stage-4 disease has improved from <10 to >40% in the past two decades, late relapses continue to be a challenge such that the overall cure rate for stage-4 patients diagnosed at age greater than 18 months with neuroblastoma remained less than 25 %.
Dose-intensive induction protocols coupled with gross total resection are expected to achieve near complete remission (CR or VGPR) rates in excess of 70% of patients. In addition, primary site recurrence can now be effectively reduced with surgery combined with ~20Gy hyperfractionated radiation. Although tumors cannot be detected by histologic examinations or functional nuclear imaging, MRD remains the final hurdle. Myeloablative therapy while prolonging progression-free survival may only have a small effect on the long-term cure rate. Relapses in the CNS plus secondary leukemia can be other serious adverse events. Although their prevalence is <10% among survivors, these late effects of intensive chemotherapy and radiation therapy are expected to surface as patients live longer.
The challenges therefore are multiple. Since treatment induced cancer (e.g., leukemia) is a function of dose (Le Deley et al. 2003), can CR/VGPR rates be maintained by reducing dose without sacrificing dose intensity for subsets of patients? Can new cyto-toxic drugs be incorporated into induction therapy for the subset of patients whose tumors are resistant to standard agents? Should myeloablative therapy be applied to only those at higher risk for relapse? New methods to detect MRD suggest that this often persists even when patients are in clinical complete re mission, and may predict relapse. Can MRD measurement provide surrogate markers of disease such that different consolidation strategies can be objectively compared, and earlier treatment intervention be initiated? Finally, other approaches to eliminate MRD need to be explored urgently. Novel strategies to overcome drug resistance and to attack sanctuary sites of disease are necessary. Such approaches may include targeted radiotherapy, differentiating agents, immunologic therapies, agents to inhibit important transduction pathways, or drugs to inhibit tumor an-giogenesis and invasion.
Was this article helpful?