Neuroprotection and prevention of oxaliplatin-induced neuropathy with Huangqi Guizhi Wuwu Decoction: a 12-center randomized, double-blind trial with mechanistic validation.

BACKGROUND

Oxaliplatin-induced peripheral neuropathy (OIPN) affects up to 80% of patients receiving oxaliplatin-based chemotherapy, and effective preventive strategies remain limited. Huangqi Guizhi Wuwu Decoction (HQGZWWD), a traditional Chinese herbal formula included in China's National Classic Famous Formulas, is widely used for OIPN in clinical practice, but high-quality clinical evidence remains lacking.

PURPOSE: This study evaluated the efficacy and safety of HQGZWWD for OIPN prevention and explored its neuroprotective mechanisms.

METHODS

We conducted a multicenter, randomized, double-blind, placebo-controlled trial at 12 tertiary hospitals in China. Adults with colorectal cancer scheduled to receive XELOX chemotherapy were randomly assigned (1:1) to oral HQGZWWD granules or placebo (47.5 g per sachet, twice daily) throughout chemotherapy. Participants, outcome assessors, and statisticians were blinded. The primary outcome was the incidence of grade ≥2 chronic OIPN in the modified intention-to-treat population, analyzed using logistic regression with multiple imputation for missing data.

RESULTS

A total of 360 participants were enrolled, and 354 were included in the modified intention-to-treat analysis. Grade ≥2 chronic OIPN occurred in 21.3% of patients receiving HQGZWWD group and 38.6% in the placebo group (OR, 0.43; 95% CI, 0.27-0.69; P<0.001). Adverse events were comparable between groups (OR, 1.27; 95% CI, 0.68-2.39; P=0.524). In animal models, HQGZWWD increased pain thresholds, preserved dorsal root ganglia, reduced IL-1β, MCP-1, and MDA levels, and enhanced SOD activity. Consistently, clinical serum enzyme-linked immunosorbent assay (ELISA) analyses further validated these mechanisms, demonstrating that HQGZWWD significantly attenuated chemotherapy-induced elevations of pro-inflammatory cytokines (IL-1β, MCP-1) and oxidative stress marker (MDA), while preserving antioxidant enzyme (SOD) activity in CRC patients receiving XELOX chemotherapy.

CONCLUSION

HQGZWWD significantly reduced the incidence of OIPN without increasing toxicity. Preclinical findings suggest that these effects may involve reduced oxidative stress and improved mitophagy. These findings support HQGZWWD as a promising preventive strategy for OIPN.

TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov (NCT04913376).