Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose limiting adverse effect of neurotoxic anticancer drugs. In addition to the limited option of management, there is also still no gold standard for the screening of CIPN in patients, except to the association of clinicians and patients reported outcome measures, which remain time consuming during the oncological follow-up. Circulating blood biomarkers of neurotoxicity, such as neurofilament light chain (NfL), gained interest for the screening of CIPN, both in animals and patients. But for instance and even if these blood biomarkers represent innovative strategies to detect risk patients, no biomarker can be recommended for a routine application. The aim of this pilot study was to screen a panel of blood biomarkers in rat models of CIPN, and in relation with the neuropathic pain.

Four rat models of CIPN (oxaliplatin, paclitaxel, bortezomib, and vincristine ; n=12 rats for each anticancer drug, and n=12 rats for each anticancer drug vehicle) were used for the study. After the end of anticancer drug injections, serum samples were obtained in order to monitored a panel of serum biomarkers (serum glial fibrillary acidic protein (GFAP), nerve growth factor (NGF), NfL, osteopontin (OPN) and cytokines (EGF, Eotaxin/CCL11, Fractalkine, G-CSF, GM-CSF, GRO/KC, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17A, IL-18, IP-10, Leptin, LIX, MCP-1, MIP-1α, MIP-2, RANTES, TNF-α and VEGF)). Neuropathic pain was assessed with the electronic von Frey test (tactile allodynia).

Several serum concentrations of biomarkers were modified between control and anticancer-treated animals. For oxaliplatin, MCP-1 and RANTES concentrations were higher in anticancer drug-treated animals than in control ones (effect size and 95 confidence interval: 1.42 [0.39 ; 2.41] p=0.01 and 1.29 [0.28 ; 2.26] p=0.02, respectively). NfL concentrations were lower in anticancer drug-treated animals than in control ones (-1.36 [-2.34 ; -0.34] p= 0.01). For paclitaxel, only NfL concentrations were higher in anticancer drug-treated animals than in control ones (0.63 [-0.31 ; 1.55] p= 0.03). For bortezomib, only LIX concentrations were lower in anticancer drug-treated animals than in control ones (-1.72 [-2.82 ; -0.58] p=0.003). For vincristine, fractalkine, IL18, IP-10, LIX, MCP-1, MIP-1 alpha, NfL, RANTES, and VEGF concentrations were higher in anticancer drug-treated animals than in control ones (1.42 [0.49 ; 2.33] p=0.003, 1.17 [0.27 ; 2.04] p =0.01, 1.79 [0.80 ; 2.75] p=0.001, 3.93 [2.46 ; 5.37] p<0.001, 3.77 [2.34 ; 5.17] p<0.001, 4.88 [3.16 ; 6.57] p<0.001, and 4.79 [3.10; 6.46] p<0.001, respectively). For the vincristine model, strong correlations (Spearman coefficient) were reported between LIX (-0.73), MCP-1 (-0.75), NfL (-0.81) and VEGF (-0.70) concentrations and tactile allodynia thresholds, and moderate correlations for fractalkine (-0.52), MIP-1 alpha (-0.66), and RANTES (-0.69) concentrations. For the bortezomib model, a moderate correlation (0.54) was reported between LIX concentrations and tactile allodynia thresholds. For oxaliplatin and paclitaxel models, no significant correlation was reported between biomarker concentrations and tactile allodynia thresholds. 

Finally, none of the biomarker assessed presented similar variation (increase or decrease) between all animal models of CIPN. Only, MCP-1 and RANTES concentrations showed an increase in anticancer drug-treated animals both for oxaliplatin and vincristine models, and as well as, NfL for paclitaxel and vincristine models. Noteworthy, blood concentrations of MCP-1 and RANTES may represent biomarkers of neuroinflammation in these animal models, and those of NfL may represent a biomarker of nervous system lesions. Finally, none of these biomarkers can be recommended as a unique circulating biomarker of CIPN-related neuropathic pain (and for every anticancer drugs). Further studies should be undertaken to define the kinetic of these serum biomarkers (MCP-1, RANTES, and NfL) in order to identify their occurrence earliness during the injections of anticancer drugs.