Excellent Early Outcomes of Combined Chemotherapy With Arsenic Trioxide for Stage 4/M Neuroblastoma in Children: A Multicenter Nonrandomized Controlled Trial

Abstract

This nonrandomized, multi center cohort, open label clinical trial evaluated theefficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in childrenwith stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosedwith NB and assessed as stage 4/M and received either traditional chemotherapy or ATOcombined with chemotherapy according to their own wishes. Twenty two patients wereenrolled i n the trial group (ATO combined with chemotherapy) and thirteen patientswere enrolled in the control group (traditional chemotherapy). Objective response rate(ORR) at 4 weeks after completing induction chemotherapy was defined as the mainoutcome and adv erse events were monitored and graded in the meantime. Data cutoffdate was Dec. 31, 2019. Finally, we found that p patients who received ATO combined with chemotherapy had a significantly higher response rate than those who treated with traditional chemotherapy (ORR: 86.36% vs 46.16%, P=0.020). Reversible cardiotoxicity was just observed in 3 patients who treated with ATO and no other differential adverse events were observed between two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk neuroblastoma and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with arsenic trioxide, which creates new opportunity for prolonging survival. Besides, this treatment protocol furthest minimizes therapeutic costs compared with anti-GD2 therapy, MIBG and proton therapy, and can decrease the burden to families and society. However, we also need to bring into more cases to consolidate our conclusion.

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

“…Preliminary results are encouraging. 36 Of the 22 patients in the trial group and 13 in the control group, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who treated with traditional chemotherapy (objective response rate (ORR): 86.36% vs 46.16%, P = .020). Reversible cardiotoxicity was just observed in 3 patients who were treated with ATO and no other differential adverse events were observed between 2 groups.…”

Arsenic trioxide induces ferroptosis in neuroblastoma by mediating GPX4 transcriptional inhibition

“…revealed that the combination of ATO and (131)I‐MIBG for the treatment of relapsed or refractory stage 4 NB or metastatic pheochromocytoma did not yield a higher response rate compared to the use of single‐agent (131)I‐MIBG, despite the patients' favorable tolerance of the therapy 36 . In contrast, our multicenter non‐randomized controlled clinical study has provided evidence that the combination of ATO and chemotherapy, in comparison to conventional chemotherapy, could significantly enhance the objective remission rate (89.74% vs. 46.15%) and CR (69.23% vs. 23.08%) in patients with HR‐NB, while also being well‐tolerated 29 …”

“…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.…”

“…36 In contrast, our multicenter non-randomized controlled clinical study has provided evidence that the combination of ATO and chemotherapy, in comparison to conventional chemotherapy, could significantly enhance the objective remission rate (89.74% vs. 46.15%) and CR (69.23% vs. 23.08%) in patients with HR-NB, while also being well-tolerated. 29 In this study, we initially discovered ATO, a natural small molecule, as a novel GPX4 inhibitor showed a notable cytotoxic effect on NB cells, including SH-SY5Y and RA-resistant cell lines SK-N-AS, which may potentially serve as a promising therapeutic approach for patients with HR-NB. Our study confirmed that ATO significantly inhibited the proliferation and migration ability of NB cells, and induced ferroptosis.…”