Acute lymphoblastic leukemia (ALL) is the most common disease in pediatric oncology. The history of developmental therapeutics for ALL began in the 1960s with the repetition of “unreliable” medical interventions against this lethal disease. By the 1990s, the development of multi-agent chemotherapy and various types of supportive care rendered ALL treatable. Highly sophisticated, molecular, diagnostic techniques have enabled highly accurate prediction of the relapse risk, and the application of risk-adapted treatments has increased the survival rate in the standard-risk group to nearly 100% in most European nations and North America. Incorporation of state-of-the-art, molecularly targeted agents and novel treatments, including cell and immunotherapy, is further improving outcomes even in the high-risk group. On the other hand, the financial burden of treating children with ALL has increased, imperiling the availability of these diagnostic and treatment strategies to patients in low- and middle-income countries (LMICs). The fundamental treatment strategy, consisting of corticosteroid and classical cytotoxic therapy, has achieved fairly good outcomes and should be feasible in LMICs as well. The present review will discuss the history of developmental therapeutics for childhood ALL in various countries through an extensive literature review with the aim of proposing a model for a treatment backbone for pediatric ALL. The discussion will hopefully benefit LMICs and be useful as a base for future clinical trials of novel treatments.

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.

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma in children, but can also develop in adolescents and young adults (AYA). The mainstay of treatment is multi-agent chemotherapy, ideally with concomitant local treatment, including surgical resection and/or radiation therapy. Although most treatment decisions for RMS in AYA are based on scientific evidence accumulated through clinical studies of pediatric RMS, treatment outcomes are significantly inferior in AYA patients than in children. Factors responsible for the significantly poor outcomes in AYA are tumor biology, the physiology specific to the age group concerned, refractoriness to multimodal treatments, and various psychosocial and medical care issues. The present review aims to examine the various issues involved in the treatment and care of AYA patients with RMS, discuss possible solutions, and provide an overview of the literature on the topic with several observations from the author’s own experience. Clinical trials for RMS in AYA are the best way to develop an optimal treatment. However, a well-designed clinical trial requires a great deal of time and resources, especially when targeting such a rare population. Until clinical trials are designed and implemented, and their findings duly analyzed, we must provide the best possible practice for RMS treatment in AYA patients based on our own expertise in manipulating the dosage schedules of various chemotherapeutic agents and administering local treatments in a manner appropriate for each patient. Precision medicine based on state-of-the-art cancer genomics will also form an integral part of this personalized approach. In the current situation, the only way to realize such a holistic treatment approach is to integrate new developments and findings, such as gene-based diagnostics and treatments, with older, fundamental evidence that can be selectively applied to individual cases.