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

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

doi:10.1016/j.eclinm.2021.101157

Abstract

BackgroundChronic 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.MethodsIn 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).FindingsBetween 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.InterpretationIn patients with chronic OIPN, the use of GM1 reduces the severity of chronic OIPN compared with placebo.FundingThis work was supported by clinical trial development fund of Tianjin Medical University Cancer Institute and Hospital (No.C1706).

Highlights

Oxaliplatin is a third-generation platinum complex which combined with other chemotherapy agents such as irinotecan, docetaxel, fluorouracil (5-FU), and 5-FU analogues, has become a central component of treatment regimen for gastrointestinal (GI) cancers in almost all disease phases in the neoadjuvant, adjuvant, perioperative, and palliative settings [1À8].Oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most severe and dose-limiting toxicity of oxaliplatin-containing chemotherapy
In the age of no effective drugs for chronic oxaliplatin-induced peripheral neurotoxicity (OIPN), medical decision has to balance the benefit of oxaliplatin continuation and the risk of neuropathy
“Stop and go” strategy and reducing chemotherapy cycles were the most widely investigated nonpharmacological approaches to reduce chronic OIPN. Both the approaches are of limited success. While both these approaches have been studied in colorectal cancer (CRC), whether they can be likewise applied to other cancers remains unclear

Summary

Introduction

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most severe and dose-limiting toxicity of oxaliplatin-containing chemotherapy. Chronic oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most troublesome and doselimiting side effect of oxaliplatin. 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. 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.

Methods

Results

Conclusion