Lecithinized superoxide dismutase prevents oxaliplatin-induced peripheral neuropathy: a double-blind, placebo-controlled, randomized phase II study

Background: Oxaliplatin-based adjuvant chemotherapy improves recurrence-free survival in stage II/III colorectal cancer (CRC) patients. However, oxaliplatin treatment is frequently limited by chemotherapy-induced peripheral neuropathy (CIPN). Oxidative stress is implicated in CIPN pathogenesis. Lecithinized superoxide dismutase (PC-SOD) is a long-circulating antioxidant enzyme that has demonstrated favorable pharmacokinetics and safety in prior studies. This study aimed to evaluate the efficacy of PC-SOD in preventing oxaliplatin-induced CIPN. Materials and methods: In this double-blind, placebo-controlled, randomized trial, patients with stage II/III CRC scheduled to receive 12 cycles of mFOLFOX6 were randomly assigned to receive intravenous PC-SOD (80 mg) or placebo before each oxaliplatin dose. The primary endpoint was the number of cycles until National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade ≥2 CIPN occurred. Secondary endpoints included time to Neurotoxicity Criteria of DEBIOPHARM (DEB-NTC) grade ≥2 CIPN. Post hoc exploratory analyses evaluated time to NCI-CTCAE grade ≥1 CIPN and infusion-related reaction (IRR). Results: Ninety patients were enrolled (PC-SOD: n = 43; placebo: n = 47). The primary endpoint was not met [hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.44-1.78, P = 0.72]. However, the PC-SOD group experienced delayed onset of DEB-NTC grade ≥2 CIPN (HR 0.73, 95% CI 0.48-1.12, P = 0.08) and NCI-CTCAE grade ≥1 CIPN (HR 0.62, 95% CI 0.40-0.96, P = 0.01, post hoc). The incidence of IRRs (post hoc) was notably lower in the PC-SOD group (7.0%) compared with placebo (23.4%). Conclusions: This trial did not meet its primary endpoint, maybe due to underpowered sample size. PC-SOD showed a potential to delay the onset of oxaliplatin-induced CIPN and reduced IRR. A confirmatory study on a large scale and with adequate statistical power is needed.