Monosialotetrahexosylganglioside in the treatment of chronic oxaliplatin-induced peripheral neurotoxicity: TJMUCH-GI-001, a randomised controlled trial

Likun Zhou, Rui Liu, Dingzhi Huang, Hongli Li, Tao Ning, Le Zhang, Shaohua Ge, Ming Bai, Xia Wang, Yuchong Yang, XinYi Wang, Xingyun Chen, Zhiying Gao, Laizhi Luo, Yuanquan Yang, Xi Wu, Ting Deng, Yi Ba, Likun Zhou, Rui Liu, Dingzhi Huang, Hongli Li, Tao Ning, Le Zhang, Shaohua Ge, Ming Bai, Xia Wang, Yuchong Yang, XinYi Wang, Xingyun Chen, Zhiying Gao, Laizhi Luo, Yuanquan Yang, Xi Wu, Ting Deng, Yi Ba

Abstract

Background: Chronic oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most troublesome and dose-limiting side effect of oxaliplatin. There is no effective treatment for chronic OIPN. We conducted a randomised controlled trial to investigate the efficacy of monosialotetrahexosylganglioside (GM1) in treating chronic OIPN.

Methods: In this single-centre, double-blind, phase Ⅲ trial, gastrointestinal cancer patients with persistent chronic OIPN were randomised in 1:1 ratio to receive either GM1 or placebo at Tianjin Medical University Cancer Institute and Hospital, China. GM1 was dosed at 60 mg daily for every 3 weeks or 40 mg daily for every 2 weeks. Seven- and fourteen- day infusions were administered to concurrent oxaliplatin users and oxaliplatin discontinuation patients, respectively. The primary endpoint was the relief of neurotoxicity (≥30% improvement), measured by a newly developed patient reported outcome measure (MCIPN) based on prior questionnaires including the European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy Induced Peripheral Neuropathy Questionnaire twenty-item scale. Visual analogue score (VAS) was used as another instrument for patients to evaluate the total Chronic OIPN treatment effect. VAS responders (≥30% improvement), double responders (≥30% improvement in both MCIPN and VAS), and high responders (≥50% improvement in the MCIPN total score) were also calculated. The secondary endpoints were safety and quality of life. The additional endpoints are progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and tumour response. (Trial registration number: NCT02486198 at ClinicalTrials.gov).

Findings: Between May 2015 to December 2017, 145 patients were randomly assigned to receive either GM1 (n=73) and placebo (n=72). Majority of the patients in both arms (90% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. More patients responded in the GM1 group than in the placebo group (MCIPN responders: 53% vs 14%, VAS responders: 49% vs 22%, double responders: 41% vs 7%, and high responders: 32% vs 13%, all P < ·01). Analyses were also performed in concurrent oxaliplatin users. The results were consistent with those of the whole group. No deleterious effects of GM1 on survival or tumour response were found. There were no ≥G3 GM1-related adverse events.

Interpretation: In patients with chronic OIPN, the use of GM1 reduces the severity of chronic OIPN compared with placebo.

Funding: This work was supported by clinical trial development fund of Tianjin Medical University Cancer Institute and Hospital (No.C1706).

Keywords: CIPN; GM1; OIPN; monosialotetrahexosylganglioside; neurotoxicity; oxaliplatin.

Conflict of interest statement

All authors declare no competing interests.

© 2021 The Authors.

Figures

Fig. 1
Fig. 1
Study flow-chart. OIPN, oxaliplatin-induced peripheral neurotoxicity; GM1, monosialotetrahexosylganglioside.
Fig. 2
Fig. 2
MCIPN item analysis MCIPN, modified chemotherapy induced peripheal neuropathy questionaire; GM1, monosialotetrahexosylganglioside; CI, confidence interval. Responders were defined as patients who had ≥ 30% improvement in corresponding MCIPN item scores.
Fig. 3
Fig. 3
Survival and quality of life (a) DFS; (b) PFS; (c) OS; (d) SF-36 DFS, disease-free survival refers to the percentage of participants who have not experienced a recurrence of tumour or mortality at any given time; PFS, progression-free survival refers to the percentage of participants who have not experienced a progression of tumour or mortality at any given time; OS, overall survival refers to the percentage of participants who have not experienced a mortality at any given time; GM1, monosialotetrahexosylganglioside; HR, hazard ratio; CI, confidence interval; SF-36, the medical outcomes study item short from health survey; NS, not statistically significant. # denotes censured individual numbers were listed in brackets and * P

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