Longitudinal plasma phosphorylated neurofilament-heavy chain levels in oxaliplatin-induced peripheral neuropathy: a prospective multi-institutional exploratory study

Purpose: Reliable circulating biomarkers for chemotherapy-induced peripheral neuropathy (CIPN) remain lacking. Phosphorylated neurofilament-heavy chain (pNF-H) is an axon-oriented biomarker of neuroaxonal injury, but its clinical relevance in oxaliplatin-induced peripheral neuropathy has not been established. We evaluated the feasibility and longitudinal behavior of plasma pNF-H in patients receiving oxaliplatin-based chemotherapy. Methods: This prospective multi-institutional exploratory study included patients with unresectable or recurrent colorectal cancer receiving CapeOX plus bevacizumab as part of the NYX study, a randomised trial of ninjin’yoeito (NYT; TJ-108, Tsumura & Co., Tokyo, Japan), a twelve-ingredient Kampo herbal extract, at 9.0 g/day for 24 weeks in the NYT arm. Plasma samples were collected at baseline, at clinically assessed CIPN onset (follow-up 1), and at the time of neuropathy resolution, at cycle 9, or at discontinuation, whichever came first (follow-up 2). Plasma pNF-H concentrations were measured by enzyme-linked immunosorbent assay. CIPN was assessed using CTCAE version 5.0. Results: Thirty patients with evaluable plasma samples were included. Plasma pNF-H levels showed substantial inter-individual variability without a consistent temporal pattern. Compared with baseline and CIPN onset, plasma pNF-H levels at follow-up 2 were modestly but significantly increased. However, plasma pNF-H levels were not associated with the onset, severity, or persistence of clinically assessed CIPN. Conclusions: Although longitudinal plasma pNF-H measurement was technically feasible, pNF-H did not function as a clinically meaningful biomarker for oxaliplatin-induced peripheral neuropathy. These findings may reflect a pathophysiological mismatch between dorsal root ganglion neuronal cell body injury and the axon-oriented biological specificity of pNF-H.