Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence

Oxaliplatin is an essential drug in the chemotherapy of colorectal, gastric, and pancreatic cancers, but it frequently causes peripheral neuropathy as a dose-limiting factor. So far, animal models of oxaliplatin-induced peripheral neuropathy have been established. The mechanisms of development of neuropathy induced by oxaliplatin have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory effects on neuropathy. In this review, we summarize the basic and clinical evidence for the therapeutic effects of oxaliplatin. In basic research, there are many reports of neuropathy inhibitors that target oxidative stress, inflammatory response, sodium channel, transient receptor potential (TRP) channel, glutamate nervous system, and monoamine nervous system. Alternatively, very few drugs have clearly demonstrated the efficacy for oxaliplatin-induced peripheral neuropathy in clinical trials. It is important to activate translational research in order to translate basic research into clinical research.


Introduction
Oxaliplatin is a platinum-based chemotherapeutic agent that is widely used as a standard treatment for colorectal, gastric, and pancreatic cancers, usually combined with other therapeutic agents such as fluorouracil, irinotecan, capecitabine, or tegafur, gimeracil and oteracil, however it often causes severe peripheral neuropathy. Within a few hours to a few days after oxaliplatin administration, acute neuropathy, such as cold sensory disturbance in the limbs and perioral region, appears. In most cases, cold-related acute neuropathy is transient and reversible [1,2]. In addition, sensory deficits as chronic neuropathy, a dose-limiting factor, occur after repeated oxaliplatin administration [2,3]. These neuropathies remain a significant clinical problem with oxaliplatin chemotherapy because they can affect quality of life and lead to drug reductions or discontinuation. Previous reports have suggested that voltage-gated ion channels and transient receptor potential channels are involved in oxaliplatin-induced acute neuropathy [4][5][6]. Chronic neuropathy is thought to be caused by morphological changes in neurons, such as axonal degeneration and damage to neuronal cell bodies [7][8][9]. However, no drugs have been recommended to prevent chemotherapy-induced peripheral neuropathy [10]. Since around 2000, animal models of chemotherapy-induced peripheral neuropathy, including oxaliplatin-induced neuropathy, have been established and reported [11][12][13]. In this study, we reviewed the preclinical and clinical evidence for oxaliplatin-induced peripheral neuropathy.

Therapeutic Agents in Preclinical Evidence
All articles found in PubMed with the search term "oxaliplatin neuropathy or oxaliplatin neurotoxicity" were surveyed. The last search date was 1 August 2020. Reports that did not include information on therapeutic agents for oxaliplatin-induced peripheral neuropathy and clinical studies were excluded from the analysis. From the surveyed papers, we extracted information on the name and dosage of the drugs that showed statistically significant improvement, their mechanism of action, and the animal species in which they were used.
There were 1657 articles in PubMed for the search term "oxaliplatin neuropathy or oxaliplatin neurotoxicity". Of these, 127 articles reported on drugs that inhibit oxaliplatininduced peripheral neuropathy in animal studies. The following is a summary of the drugs had therapeutic effects on oxaliplatin-induced peripheral neuropathy in these basic studies (Table 1).  [14] Acetyl L-carnitine 50-100 mg/kg Rats Mechanical, thermal and cold allodynia Antioxidant effect [15] Acetyl L-carnitine 100 mg/kg Rats Mechanical allodynia Prevention of deficits in mitochondrial function [16] Alpha-lipoic acid 50-100 mg/kg Rats Mechanical, thermal and cold allodynia Antioxidant effect [15] Calmangafodipir (PledOx ® ) 2.

Antioxidants
Many previous preclinical reports support that oxidative stress plays a role in oxaliplatinrelated peripheral neuropathy [27, 140,141]. Vitamin C, vitamin E, acetyl L-carnitine, alphalipoic acid, and glutathione, which are widely known for their antioxidant effects, have been reported to alleviate the peripheral neuropathy of oxaliplatin in rodents [14-16,

Anti-Inflammatory Agents
Inflammatory cytokines such as IL-1β, IL-6, and TNF-α were elevated in the dorsal root ganglion (DRG) and spinal cord of oxaliplatin-treated animals, and some agents reduced the peripheral neuropathy symptoms via their anti-inflammatory effects [39, 41,42]. Activations of astrocytes and microglia were also observed in the spinal dorsal horn after oxaliplatin administrations, and minocycline, rapamycin, and fluorocitrate inhibited these spinal changes and prevented neurological damage [40,43,44].

Sodium Channel Inhibitors
Oxaliplatin-induced acute neuropathy is termed a 'channelopathy', as oxaliplatin and oxalate modulated voltage-gated Na + and K + channels in several types of neurons [3,142,143]. For example, oxaliplatin increases the amplitude and duration of compound action potentials interacting with voltage-gated Na + channels in rat sensory neurons [142]. Furthermore, oxaliplatin prolongs the duration of the A-fiber compound action potential related to K + channels [3]. Thus, the effect of oxaliplatin on Na + and K + channels is thought to be involved in acute neuropathy [4]. Many Na + channel inhibitors, such as lidocaine, mexiletine, and lamotrigine have been reported to ameliorate the neuropathic symptoms of oxaliplatin, especially the acute neuropathy [11,[45][46][47][48][49].

Therapeutic Agents in Clinical Evidence
We analyzed the articles found in PubMed with the search term "oxaliplatin neuropathy or oxaliplatin neurotoxicity" limited to "clinical trials". The last search date was 25 June 2020. Reports other than randomized trials and meta-analyses were excluded. Moreover, Information such as the investigational drug and its dosage, chemotherapy received by the patient, study design, number of patients, and results was collected.
There were 533 articles in PubMed for the search term "oxaliplatin neuropathy or oxaliplatin neurotoxicity" limited to "clinical trials". Of these, 127 articles reported on drugs that inhibit oxaliplatin-induced peripheral neuropathy in animal studies. After excluding reports other than randomized trials and meta-analyses, the authors found 16 reports that they considered to be clinically important. A summarized list of the representative randomized controlled trials and meta-analyses on prophylactic and therapeutic agents for oxaliplatin-induced peripheral neuropathy is shown below in Table 2.  No significant differences compared to placebo group in pain score [162] Minocycline 200 mg/day Oxaliplatin Randomized 66 No significant differences compared to control group [163] Abbreviations: 95% CI, 95% confidence interval; FACT/GOG-NTx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; RR, relative risk.
Duloxetine was tested in a randomized, double-blind, placebo-controlled, cross-over trial, for its ability to treat neuropathy in patients with taxane or platinum [148]. In this study, relative risks (RRs) (95% confidence interval (CI)) of experiencing 30% and 50% pain reduction were 1.96 (1.15-3.35) and 2.43 (1.11-5.30), respectively. A sub-analysis of this study indicates that duloxetine is more effective than taxanes in treating platinuminduced neuropathy.
Intravenous injection of calcium and magnesium is thought to chelate oxalate, and the preventive effects for oxaliplatin-induced peripheral neurotoxicity have been investigated since before [149][150][151][152]. Some studies reported significant inhibitory effects on oxaliplatinrelated neuropathy [149,150], some studies did not confirm significant effects [151,152]. The results of a meta-analysis including five studies showed that calcium and magnesium had no significant effect on neuropathy (relative risks (RRs) (95% CI) of incidence of ≥Grade 2 neuropathy and ≥Grade 1 chronic neuropathy were 0.81 (0.60-1.11) and 0.95 (0.69-1.32), respectively.) [153].
Goshajinkigan, a Japanese herbal medicine, has been studied in several clinical trials [154][155][156]. In a randomized controlled trial, goshajinkigan significantly reduced the incidence of Grade 2 or higher neuropathy [154]. In goshajinkigan oxaliplatin neurotoxicity evaluation (GONE) study, the incidence of Grade 2 or higher neuropathy until the 8th cycle was 39 and 51% in goshajinkigan and placebo groups, respectively, which was not statistically significant [155]. This study concluded that goshajinkigan appears to have an acceptable safety margin and a promising effect in delaying the onset of Grade 2 or greater peripheral neuropathy [155]. However, in the interim analysis of goshajinkigan effect for oxaliplatin neurotoxicity inhibition using mFOLFOX6 regimen (GENIUS) study, a multicenter randomized, double-blind, placebo-controlled trial, goshajinkigan significantly increased the incidence of neuropathy [156].
Alpha-lipoic acid and vitamin E, both of which have antioxidant properties, were also examined in clinical trials for their effects on neuropathy in patients using oxaliplatin [157][158][159]. However, neither has been reported to significantly improve neuropathy. Beside, glutathione and calmangafordipir, which also have antioxidant effects, were found to significantly improve neuropathy related oxaliplatin treatment in randomized trials [160,161]. However, the dose of glutathione used in this clinical trial was high (1.5 g/m 2 ), and calmangafodipir is undergoing Phase III trials and not approved as a drug at this time. Other drugs such as pregabalin, a general-purpose drug for neuropathic pain, and minocycline, a glial attenuator, have also been tested in clinical trials, but no significant inhibitory effects have been reported [162,163].
As described above, few drugs have shown clear therapeutic effects on oxaliplatininduced peripheral neuropathy in clinical trials. Thus, according to the clinical practice guideline updated by the American Society of Clinical Oncology in 2020, no agents have yet to be recommended for preventing chemotherapy-induced peripheral neuropathy and only duloxetine may be used as a treatment for neuropathy [10].

Discussion
Recently, the mechanism of oxaliplatin-induced peripheral neuropathy has been elucidated in basic studies, and many drugs and agents targeting this mechanism have been explored and identified for therapy for oxaliplatin-induced peripheral neuropathy. In particular, many inhibitors of neuropathy targeting oxidative stress, inflammatory response, sodium channel, TRP channel, glutamate nervous system, and monoamine nervous system have been identified as candidates for inhibiting oxaliplatin-induced neuropathy in animal research.
Alternatively, very few drugs have shown the efficacy of oxaliplatin for peripheral neuropathy in clinical trials. The American Society of Clinical Oncology's clinical practice guideline states that only duloxetine can be used for the treatment of chemotherapyinduced peripheral neuropathy [10]. Since duloxetine has been shown to improve pain in clinical trials [148], its use in patients with pain may be beneficial. However, consideration should be given to side effects such as drowsiness, headache, and dizziness. Goshajinkigan and glutathione are drugs that have few side effects, thus they can be considered easy to treat in patients. Goshajinkigan has been reported both to have therapeutic effects on oxaliplatin-induced peripheral neuropathy and not to have the effects [154][155][156]. In an animal study, it has been reported that goshajinkigan does not inhibit the progression of chronic neuropathy, but rather relieves neuropathic symptoms [124]. Therefore, it may be used to relieve symptoms in patients with oxaliplatin-induce neuropathy.
While many drugs have been reported in basic research as having the potential to inhibit the neuropathy by oxaliplatin, few drugs have developed sufficient evidence in clinical studies. The "valley of death" between basic researches and clinical applications is considered caused by many issues, including the difference between clinical symptoms and animal assessment methods, the cost and time of conducting clinical research, safety considerations in clinical application, and the lack of collaboration between basic and clinical researchers. It is important to promote translational research, that is, to bridge basic research to clinical research.

Funding: This research received no external funding
Acknowledgments: This work was partly supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (JP20K07198).

Conflicts of Interest:
The authors declare that they have no conflicts of interest to this work.