Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects

Simple Summary Tumor differentiation therapy using retinoids has a long history of clinical development and an established role as a part of the standard treatment for high-risk neuroblastoma. However, basic and clinical science related to this treatment is still immature in multiple respects. In the present review, we systematically expand on the basic and clinical science of retinoids for neuroblastoma treatment, off-label issues related to the treatment and possible countermeasures, and finally, prospects for this therapy.Abstract Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.