Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series

Abstract

Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations.

Arsenic trioxide induces ferroptosis in neuroblastoma by mediating GPX4 transcriptional inhibition

“…Moreover, subsequent clinical trials have provided further evidence that the combination of ATO and chemotherapy substantially improves complete response (CR) rates for patients with HR-NB, whereas concurrently maintaining a favorable safety profile. 28,29 Additionally, a previous study by our research team uncovered a substantial enrichment of differential proteins within the ferroptosis pathway subsequent to the administration of ATO to NB cell lines, as evidenced by off-label quantitative proteomics methodologies. Notably, the expression of GPX4, a crucial rate-limiting enzyme closely associated with the ferroptosis pathway, was markedly reduced.…”

“…The findings from our prior investigations have established that the administration of ATO exhibits a notable capacity to augment the cytotoxic effects on NB cells. Moreover, subsequent clinical trials have provided further evidence that the combination of ATO and chemotherapy substantially improves complete response (CR) rates for patients with HR‐NB, whereas concurrently maintaining a favorable safety profile 28,29 . Additionally, a previous study by our research team uncovered a substantial enrichment of differential proteins within the ferroptosis pathway subsequent to the administration of ATO to NB cell lines, as evidenced by off‐label quantitative proteomics methodologies.…”

Arsenic Prodrug-Mediated Tumor Microenvironment Modulation Platform for Synergetic Glioblastoma Therapy

“…However, the respective and synergetic effect of ATO is still confined to preclinical trials owing to the higher dose limit toxicity . Hence, several combinational chemotherapies were developed to reduce the higher dose toxicity effect and improve the efficacy of ATO treatment . However, the current complementary synergetic strategies are costly, time-consuming, and insufficient.…”

“…35 Hence, several combinational chemotherapies were developed to reduce the higher dose toxicity effect and improve the efficacy of ATO treatment. 40 However, the current complementary synergetic strategies are costly, time-consuming, and insufficient. Recently, some efforts have been made as an alternative to the ATO-based system to overcome the high dose-related issues to treating the solid tumor.…”