Phase III randomized, placebo‐controlled, double‐blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin‐induced peripheral neurotoxicity in stage II/III colorectal cancer

Abstract

BackgroundMonosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin‐based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin‐induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin‐based chemotherapy.MethodsIn total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI‐CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ‐CIPN20), time to grade 2 neurotoxicity (NCI‐CTCAE or the oxaliplatin‐specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3‐year disease‐free survival (DFS) and adverse events.ResultsThere were no significant differences between the arms in the rate of NCI‐CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ‐CIPN20 or time to grade 2 neurotoxicity using NCI‐CTCAE and the oxaliplatin‐specific neuropathy scale. GM1 substantially decreased participant‐reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3‐year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms.ConclusionPatients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

“…In a clinical trial conducted in colon cancer patients on FOLFOX therapy (Table 2), GM1 attenuated symptoms of acute neuropathy (cold sensitivity, throat discomfort, muscle cramps), but its use to prevent the neurotoxicity of oxaliplatin is currently not recommended, and additional placebocontrolled studies are needed to better assess the utility of this agent in this clinical condition [4,67].…”

Ganglioside Monosialic Acid Alleviates Peripheral Neuropathy Induced by Utidelone Plus Capecitabine in Metastatic Breast Cancer From a Phase III Clinical Trial

“…No substantial differences in permanent discontinuation of chemotherapy and effects on survival were noted between GM1 and control. In a phase III randomized, placebo-controlled, double-blind study, there were no significant differences between the GM1 and control arms with regard to the prevention of chronic neurotoxicity based on all the evaluation endpoints in patients with CRC (14). Interestingly, the trial showed that patients in the GM1 group were less troubled by acute neuropathy, with fewer patients in the GM1 group than in the placebo group reporting cold sensitivity and muscle cramps in patients with breast cancer (15).…”

Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development

“…GM1 attenuated the symptoms of acute neuropathy in a clinical trial conducted in colon cancer patients treated with FOLFOX therapy; however, its use in preventing neurotoxicity of OHP is currently not recommended. The utility of this agent in this clinical condition requires additional placebo-controlled studies [ 198 ].…”