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Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of typical chemotherapeutics among cancer survivors. Despite the recent progress, the effective prevention and treatment strategies for CIPN remain limited. Better understanding of the pathogenesis of CIPN may provide new niches for developing a new ideal therapeutic strategy. This review summarizes the current understanding of CIPN and current recommendations along with completed/active clinical trials and aims to foster translational research to improve the development of effective strategies for managing CIPN.


Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) often occurs in cancer patients receiving neurotoxic chemotherapies. It often affects sensory neurons resulting in severe pain, which may lead to long-term morbidity in cancer survivors. Owing to the improvement in cancer survival rate, an increase in the prevalence and burden of CIPN is expected. Forty-seven percent of cancer survivors presented persistent neuropathy up to 6 years after chemotherapy completion. They exhibited altered gait patterns with slower and shorter steps, and had a 1.8-fold increase in fall risk than those without CIPN [1]. Additionally, it was reported that 12% of cancer survivors with CIPN fell within three months [2]. These observations highlight the need for an effective treatment for CIPN to improve the quality of life and safety among cancer survivors.
Currently, no treatments have been recommended to prevent CIPN. The lack of a specific target for chemotherapies is a significant challenge in CIPN management. A deeper understanding of the underlying mechanisms of how CIPN develops and progresses may help in developing novel effective strategies for prevention and treatment [3][4][5][6][7][8]. Additionally, a better way to translate the mechanistic understandings into clinical interventions, which will promote the development of new effective strategies, remains a challenge [9]. Nevertheless, an ideal study design based on known mechanisms will help in addressing the unmet medical need. This review summarizes the current understanding of CIPN and current recommendations based on completed/active clinical trials in Western medicine and alternative and complimentary medicines. Because of the absence of the blood-brain barrier and excellent lymphatic drainage, the peripheral nervous system (PNS) develops CIPN much easily than the central nervous system [11,25]. Moreover, it is much easier to penetrate sensory neurons than motor neurons owing to the lesser myelination [10]. The mechanisms are complex with peripheral, spinal, and supraspinal changes, ranging from the alternation of ion channel activity to intracellular signaling systems [26,27]. Common pathological mechanisms may include mitochondrial dysfunction, imbalance in redox homeostasis, inflammation leading to apoptosis, and nerve degeneration [28]. However, drug type, cumulative dosage, clinical features, and the time course of neuropathic symptoms vary among patients. The way of administration may affect the development of CIPN. Methotrexate will be associated with neurotoxicity only with intrathecal administration [29]. Bortezomib-induced CIPN can be reduced using subcutaneous administration [22]. Genetic variations may also set a role in the gene-environment interaction, which may act as predictive CIPN biomarkers [30][31][32][33][34][35][36][37][38][39][40][41][42][43], and are one of the risk factors for developing CIPN. It is recognized that the PNS damage triggers the migration of macrophages and Schwann cells into the lesions to clean up debris, followed by the release of neurotrophic factors by Schwann cells to promote neuroregeneration. Recently, the stimulator of interferon genes-interferon type I (STING-IFN-I) signaling axis was recognized as a critical regulator of physiological nociception and a promising target for treating CIPN [44]. Galactin-3 released by Schwann cells was also reported as a critical factor to cause CIPN [45].
Specific mechanisms of neurotoxic chemotherapies vary but may highly associate with their primary roles in anticancer effects. Platinum agents, such as cisplatin and oxaliplatin, exert damage via DNA cross-linking or oxidative stress, leading to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglia [46][47][48][49]. Moreover, oxalate metabolized from oxaliplatin prolongs the open state of the voltage-gated sodium channel, extending neuron depolarization and hyperexcitability [50]. It is noted that, unlike cancer cells, cells affected by CIPN are non-dividing. The distinct responses between the high-dividing cancer cells and non-dividing neuronal cells includes the imbalance of protepstasis, pointed a direction to simutaneously prolong neuronal cell survival via improving protein refolding by which to get chance to remove DNA adducts via DNA repair process.
Taxanes inhibit microtubule depolymerization via stabilizing GDP-bound tubulin, leading to mitotic arrest during the cell cycle G2/M phase [51]. Additionally, taxanes disrupt axonal energy supply by targeting mitochondria complexes I and II in primary afferent neurons [52,53]. Furthermore, paclitaxel induces the upregulation of toll-like receptor 4 and monocyte chemotactic protein 1 in the dorsal root ganglion, which triggers macrophage infiltration and corresponding inflammation [54]. Nevertheless, the upregulation of transient receptor potential cation channel subfamily V member 4 in the dorsal root ganglion has been linked to paclitaxel-induced neuropathic pain [55].
Unlike taxanes, vinca alkaloids prevent microtubule polymerization by binding and inhibiting tubulin-dependent GTP hydrolysis [56,57]. Vincristine-induced CIPN has been linked to the reduction of endomorphin-2 levels, thus disrupting its analgesic effect on muopioid receptors and subsequently leading to hypersensitivity and CIPN [58]. Additionally, chemotherapeutics-induced reactive oxygen species affect serine protease activity and afferent pain pathways [59,60]. Improved understanding of the underlying mechanisms will help in the development of new therapeutic/preventive approaches for CIPN. However, a better translation of those mechanisms into clinical benefits remains a challenge.

Current Treatment of CIPN-In the View of Western Medicine
There are no preventative treatments for CIPN [61,62]. The current primary recommended therapy for CIPN focuses on pain relief and symptom management with analgesics, antidepressants, and antiepileptics in clinical practice [63]. The first-tier choices include duloxetine, pregabalin/gabapentin, or amitriptyline [64]. Pregabalin or gabapentin structurally mimic gamma aminobutyric acid with recognized efficacy in the treatment of both epilepsy and neuropathic pain. However, unsteadiness, dizziness, edema, somnolence, and loss of concentration are the main problems [7]. Although tricyclic antidepressant amitriptyline is the gold standard for neuropathic pain, urinary retention or severe dizziness may occur in patients with benign prostate hyperplasia or elderly patients [65]. Opioids, such as tramadol or lidocaine patch, used as the second-tier choices only partially relieved neuropathic pain. The adverse effects such as nausea, dizziness, and somnolence have been observed [66,67]. Vitamin B [68,69] or vitamin E [70][71][72][73][74][75], often prescribed for neuropathic pain or diabetic polyneuropathy, showed no significant improvement in pain management. Other agents have been studied in clinical trials based on postulated effects on underlying mechanisms [7,61,66,67,[76][77][78]. State-of-the-art therapies such as cryotherapy [79] or induced pluripotent stem cells or fibroblast-derived neuronal subtypes, including dorsal root ganglion neurons [80,81], remain to be evaluated. Exercises such as yoga also show benefit for alleviating CIPN [82][83][84][85]. Understanding the underlying mechanisms of dual targets of rapidly dividing cancer cells and non-dividing, post-mitotic neurons remain challenging. The current recommendations or completed/active clinical trials for CIPN are summarized in Table 2. In particular, trial specifically for plantinum-especially cisplatin alone-is rare. Lack of obvious study end point may be one reason. In addition, difficulties for specific patient enrollment may be taken into account. Breakthrough for understanding the underlying mechanisms how those plantinum drugs causes neuronal cell death, and a niche for prolonging neuron survival will help to find the critical regulatory target.

Alternative and Complementary Treatment and Prevention of CIPN
In traditional Chinese medicine (TCM), the primary pathogenesis of CIPN is related to spleen deficiency (Pi xu 脾虛), qi deficiency (Qi xu 氣虛), toxicity (Du 毒), stagnation (Yu 瘀), dampness (Shi 濕), and kidney deficiency (Shen xu 腎虛) [86]. Some herbal medicines, acupuncture, and pharmacopuncture have shown benefits in managing the disease as described below.

Acupuncture
Acupuncture significantly reduces CIPN, such as neuropathic symptoms (pain, tingling, and numbness), quality of life, and nerve conduction, and is considered for treat-ment/prevention of CIPN. However, the evidence remains to be accumulated [103][104][105]. Acupuncture might help nerve repair by increasing the limbs' blood flow [106,107]. A sixweek acupuncture course improves pain, numbness, and tingling in patients with grade II CIPN [108]. A randomized controlled trial showed that acupuncture plus methylcobalamin was superior to methylcobalamin alone in providing pain relief and improving the quality of life [109].

Electroacupuncture
The effects of electroacupuncture on CIPN remain to be evaluated. In a four-arm randomized trial, a comparison of four different treatments, including electro-acupuncture, hydroelectric baths, Vitamin B1/B6 capsules, and placebo groups, in patients with CIPN showed no therapeutic effect of electroacupuncture [14]. Although a randomized controlled trial revealed that an eight-week course of electro-acupuncture relieves CIPN symptoms [110,111], a trial focused on preventing the symptoms of CIPN by electroacupuncture was not as good as expected [112]. Transcutaneous electrical nerve stimulation (TENS) has become an alternative for CIPN treatment; however, it requires empirical clinical evidence. Although some studies have shown efficacy in nerve regeneration and a wireless, home-based TENS may be a feasible device to relieve the symptoms of CIPN such as tingling, numbness, cramping, and pain [113], valid results were not found in a preliminary case-controlled study in clinical conditions [114]. A new approach, acupuncture-like transcutaneous nerve stimulation, applies TENS to the acupoints based on TCM theory and has shown significant improvement in neuropathic pain and numbness [115]. Scrambler therapy, another type of electrical stimulation, showed its benefit for acute or chronic CIPN [116] and quality of life [117,118]. Although a randomized phase II pilot study revealed a superior effect of TENS when compared with scrambler therapy [119], the benefit for the pain score remains to be evaluated [120]. Current completed or active acupuncture clinical trials for CIPN are summarized in Table 3.

Challenges of TCM for CIPN
Several challenges remain for applying TCM for CIPN management. TCM syndrome plays a vital role in TCM fundamental theories. The main limit is the high difficulty of comparing alternative medicines with respect to the principles of evidence-based medicine. A precise scientific method to identify specific TCM syndrome and to consider and evaluate clinical trials will be essential. Additionally, the source, process methods, active component identification, and quality control of herbal medicine remain to be standardized. Furthermore, TCM techniques such as acupuncture, concise practitioner training, acupoint selection, deep of needle insertion, and practical protocols will be crucial. Nevertheless, TCM syndrome-specific animal models, effective chemotherapeutic agents, mode of delivery (intravenous rather than intraperitoneal injection), and adequately randomized and blinded studies are needed to represent real clinical situations [4].

Conclusions and Future Perspectives
CIPN is a common and persistent side effect of common chemotherapeutics. Currently, there is no intervention available for its prevention, although duloxetine has shown moderate treatment efficacy.
Study details of biological mechanisms attributing to CIPN will be required for finding the therapeutic niches. Additionally, an ideal preclinical model will be needed to better mimic individual differences, age-and gender-dependent phenotypes of interest, and the use of standardized behavioral tests for adequately powered study designs, including appropriate controls and randomization, is needed.
Clinical studies provide additional challenges. The intervention design, eligibility criteria selection, outcome measures and study endpoints, potential effects of an intervention on chemotherapy efficacy, and sample sizes of randomized groups based on anticipated effect size and variability are critical for research success. Systemic and multidisciplinary collaborative research ensure the development of next-generation strategies for CIPN treatment/prevention and provide benefits and better quality of life for cancer survivors suffering from CIPN.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.