Autologous Stem-Cell Transplantation for High-Risk Neuroblastoma: Historical and Critical Review

SIMPLE SUMMARY: The original idea that providing higher doses of cytotoxic agents will result in higher rates of tumor cell killing was proposed in the 1980s. Preclinical data supported clinical testing. Advancements in bone marrow and peripheral stem-cell support technologies during the 1980s and 1990s allowed for clinical developments that permitted testing the higher dose hypothesis in oncology patients. The results of almost 20 years of clinical trials proved the linear relationship between dosing and clinical outcome to be mostly inaccurate. As a consequence, the adult oncology field abandoned high-dose chemotherapy strategies by the turn of the 21st century. Neuroblastoma is the only pediatric extracranial solid tumor where high-dose chemotherapy has remained part of the standard management for high-risk cases. This systematic review aims to understand the historical reason for such an exception and analyzes data challenging the benefit of high-dose chemotherapy and autologous stem-cell transplants in the era of anti-GD2 immunotherapy. ABSTRACT: Curing high-risk neuroblastoma (HR-NB) is a challenging endeavor, which involves the optimal application of several therapeutic modalities. Treatment intensity for cancer became highly appealing in the 1990s. Investigative trials assumed that tumor response correlated with the dosage or intensity of drug(s) administered, and that this response would translate into improved survival. It was postulated that, if myelotoxicity could be reversed by stem-cell rescue, cure might be possible by increasing the dose intensity of treatment. The principle supported autologous stem-cell transplant (ASCT) strategies. High-dose therapy transformed clinical practice, legislation, and public health policy, and it drove a two-decade period of entrepreneurial oncology. However, today, no ASCT strategies remain for any solid tumor indication in adults. As with most solid malignancies, higher dosing of cytotoxic agents has not resulted in a clear benefit in survival for HR-NB patients, whereas the long-term toxicity has been well defined. Fortunately, novel approaches such as anti-GD2 immunotherapy have demonstrated a significant survival benefit with a much less adverse impact on the patient’s wellbeing. On the basis of extensive experience, persisting with administering myeloablative chemotherapy as the standard to treat children with HR-NB is not consistent with the overall aim in pediatric oncology of curing with as little toxicity as possible.