单唾液酸四己糖神经节苷脂治疗慢性奥沙利铂诱导的周围神经毒性：TJMUCH-GI-001，一项随机对照试验。

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

作者信息

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

机构信息

Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University, Tianjin, China.

Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

出版信息

EClinicalMedicine. 2021 Oct 29;41:101157. doi: 10.1016/j.eclinm.2021.101157. eCollection 2021 Nov.

DOI:10.1016/j.eclinm.2021.101157

PMID:34765950

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8569480/

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 < ·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).

摘要

背景

慢性奥沙利铂诱导的周围神经毒性（OIPN）是奥沙利铂最棘手且限制剂量的副作用。目前尚无针对慢性OIPN的有效治疗方法。我们开展了一项随机对照试验，以研究单唾液酸四己糖神经节苷脂（GM1）治疗慢性OIPN的疗效。

方法

在这项单中心、双盲、Ⅲ期试验中，中国天津医科大学肿瘤医院将患有持续性慢性OIPN的胃肠道癌患者按1:1比例随机分组，分别接受GM1或安慰剂治疗。GM1的给药方案为每3周每日60mg或每2周每日40mg。正在接受奥沙利铂治疗的患者和已停用奥沙利铂的患者分别进行7天和14天的输注。主要终点是神经毒性的缓解（改善≥30%），通过一种新开发的基于先前问卷（包括欧洲癌症研究与治疗组织生活质量化疗所致周围神经病变问卷20项量表）的患者报告结局指标（MCIPN）来衡量。视觉模拟评分（VAS）用作患者评估慢性OIPN总体治疗效果的另一工具。还计算了VAS缓解者（改善≥30%）、双重缓解者（MCIPN和VAS均改善≥30%）和高度缓解者（MCIPN总分改善≥50%）。次要终点是安全性和生活质量。额外终点是无进展生存期（PFS）、无病生存期（DFS）、总生存期（OS）和肿瘤反应。（试验注册号：ClinicalTrials.gov上的NCT02486198）。

研究结果

2015年5月至2017年12月期间，145例患者被随机分配接受GM1（n = 73）或安慰剂（n = 72）治疗。两组中的大多数患者（GM1组为90%，安慰剂组为83%）在试验期间继续接受奥沙利铂治疗。GM1组的缓解患者多于安慰剂组（MCIPN缓解者：53%对14%，VAS缓解者：49%对22%，双重缓解者：41%对7%，高度缓解者：32%对13%，均P < 0.01）。对正在接受奥沙利铂治疗的患者也进行了分析。结果与全组一致。未发现GM1对生存期或肿瘤反应有有害影响。未发生≥G3级与GM1相关的不良事件。