Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development 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 PIPN effects. This review summarizes the basic and clinical evidence for therapeutic or prophylactic effects for PIPN. In pre-clinical research, many reports exist of neuropathy inhibitors that target oxidative stress, inflammatory response, ion channels, transient receptor potential (TRP) channels, cannabinoid receptors, and the monoamine nervous system. Alternatively, very few drugs have demonstrated PIPN efficacy in clinical trials. Thus, enhancing translational research to translate pre-clinical research into clinical research is important.

In paclitaxel-induced peripheral neuropathy (PIPN), many patients develop sensory abnormalities (e.g., numbness, pain, and burning sensation in the hands and feet) [12]. PIPN is a dose-limiting factor that causes difficulty in continuing cancer chemotherapy [13]. However, no evidence-based prophylactic agents for PIPN were noted [14]. Since the late 1990s, many studies on the mechanism and therapeutic or prophylactic agents using PIPN animal models have been reported [15][16][17]. In addition, the mechanisms of PIPN development have been gradually clarified [18]. This study reviewed the preclinical and clinical evidence of therapeutic or prophylactic agents for PIPN.

Preclinical Evidence
All articles found in PubMed with the search term "paclitaxel neuropathy or paclitaxel neurotoxicity" were surveyed. The last search date was 30 April 2021. Clinical studies and Siwei Jianbu decoction 5-10 g/kg, i.g.

Ion Channel Inhibitors and Activators
Some activators of potassium channels, especially Kv7, have been shown to suppress PIPN [57,58]. Focusing on calcium channels, T-type calcium channel blockers have been reported to alleviate PIPN symptoms [54,59].

Modulators of Monoamine Nervous System
Monoamines, including noradrenaline and serotonin, play an important role in the descending pain inhibitory system [110]. Some drugs and agents (e.g., quetiapine, reboxetine, venlafaxine, and bee venom) also showed analgesic effects by modulating the monoamine nervous system in the PIPN animal models [73][74][75][76].

Therapeutic Agents in Clinical Evidence
In PubMed, 1175 articles were found when using the search term "paclitaxel neuropathy or paclitaxel neurotoxicity" limited to "Randomized Controlled Trial" and "Meta-Analysis". After excluding reports other than about PIPN, the authors found 19 reports considered to be clinically important. A summarized list of the representative randomized controlled trials and meta-analyses on prophylactic and therapeutic agents for PIPN is shown below in Table 2.   Duloxetine was tested in a randomized, double-blind, placebo-controlled, crossover trial, for its ability to treat neuropathy in patients with taxane or platinum [115]. In this study, relative risks (RRs) (95% confidence interval (95% CI)) of experiencing 30% and 50% pain reduction were 1.96 (1.15-3.35) and 2.43 (1.11-5.30), respectively. However, in a subanalysis in taxane-treated patients, RRs (95% CI) of experiencing 30% and 50% pain reduction were 0.97 (0.41-2.32) and 1.22 (0. 35-4.18), respectively (not significant). Duloxetine significantly improved numbness and pain compared with vitamin B12 in a randomized, open-label, crossover study of patients who received chemotherapy including other anticancer drugs, as well as paclitaxel [114].
Pregabalin significantly improved the grade and score of taxane-related neuropathy compared with duloxetine in a randomized, double-blind, controlled study [125]. Moreover, pregabalin did not improve treatment-related pain and neuropathy scores related to paclitaxel in a randomized, double-blind, placebo-controlled, multicenter study [126]. Gabapentin was reported to significantly reduce the incidence of grade ≥2 PIPN and changes in nerve conduction velocity (NCV) in a randomized, double-blind, placebocontrolled study [122].
Omega-3 fatty acids significantly improved the incidence of peripheral neuropathy associated with paclitaxel administration in a randomized, double-blind, placebo-controlled study [122]. In a meta-analysis that included not only paclitaxel-treated patients but also oxaliplatin-treated patients, the suppressive effects of omega-3 fatty acids on neuropathy were significant [121]. Vitamin E significantly improved the incidence and scores of neuropathies in both a randomized, controlled study of patients with paclitaxel [128] and patients with paclitaxel or cisplatin [129]. Amifostine significantly improved paresthesia and sensory motor impairment in a randomized controlled study of paclitaxel/carboplatintreated patients [112]. However, it did not significantly improve neuropathy in a randomized controlled study of paclitaxel-treated patients [113]. Additionally, minocycline, N-acetylcysteine, and eicosapentenoic acid (EPA) have been reported to improve peripheral neuropathy associated with paclitaxel [119,120,123]. Moreover, glutamate, glutathione, poly ADP-ribose polymerase (PARP) inhibitors, and human leukemia inhibitory factor (LIF) did not show any significant effect on PIPN in randomized controlled trials or metaanalyses [117,118,124,127]. Long-term administration of acetyl-L-carnitine significantly worsened taxane-related peripheral neuropathy in a randomized, double-blind, placebocontrolled, multicenter study [111].
As described above, few drugs have shown clear therapeutic PIPN effects 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 [14].

Discussion
The PIPN mechanism has been recently elucidated in basic studies, and many drugs and agents targeting this mechanism have been explored and identified for PIPN therapy or prophylaxis [18]. In particular, many inhibitors of neuropathy targeting oxidative stress, inflammatory response, ion channels, TRP channels, cannabinoid receptor, and monoamine nervous system have been identified as candidates for inhibiting PIPN in animal research. In particular, more reports of inhibitors targeting peripheral and central inflammatory responses, TRP channels, and cannabinoid receptors were noted compared with pre-clinical research reports on oxaliplatin-induced peripheral neuropathy [130]. Targeting these may be useful in the search for PIPN-specific therapeutics.
Alternatively, very few drugs have shown the efficacy for PIPN in clinical trials. The American Society of Clinical Oncology's clinical practice guideline states that only duloxetine can be used for the treatment of chemotherapy-induced peripheral neuropathy [14]. In a randomized double-blind placebo-controlled crossover study, duloxetine has been reported to improve neuropathic pain caused by taxanes and platinum [115]. However, a subanalysis of that study also showed a weak inhibitory effect of duloxetine on taxanes in neuropathic pain [115]. Thus, few evidence-based treatments for PIPN were noted.
Most clinical studies examined the preventive rather than curative effects on PIPN. Meanwhile, pre-clinical studies have explored many therapeutic targets for PIPN. Of these, agents on the therapeutic targets that inhibit pain or sensory abnormalities, such as K channel, Ca channel, TRP channels, glutamate, cannabinoid receptors, opioid receptors, and monoamine nervous system, may have curative effects on PIPN that has already developed. More information on the clinical studies of these agents will make it possible to approach PIPN from both a preventive and curative perspective.
While many drugs have been reported in pre-clinical research as having the potential to inhibit the PIPN, few drugs have developed sufficient evidence in clinical studies. The valley of death between basic studies and clinical applications is 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. Thus, promoting translational research, that is, to bridge pre-clinical research to clinical research is important.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.

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