Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating complication of several anti-neoplastic agents, including taxanes (paclitaxel, docetaxel), platinum derivatives (carboplatin, cisplatin, oxaliplatin), vinca alkaloids (vincristine, vinblastine), and proteasome inhibitors (bortezomib) [1, 2]. Taxanes and vinca alkaloids belong to a class of microtubule inhibitors [3]. Taxanes stabilize microtubules, so they cannot depolymerize and function properly, leading to cell cycle arrest, whereas vinca alkaloids inhibit β-tubulin polymerization, preventing mitotic spindle formation, leading to mitotic arrest and cell death by apoptosis [3]. A recent study demonstrated that integrins, cell surface receptors that mediate cell-extracellular matrix interaction, protect against paclitaxel-induced neuropathy. Paclitaxel exposure altered the branching pattern of nociceptive neurons in Drosophila — integrin overexpression rescued compromised interaction between sensory neurons and the extracellular matrix and restored lost nocifensive escape behavior to thermal noxious stimuli [4].

Platinum-based chemotherapies, or “alkylating-like agents” due to their similarity in mechanism to classical alkylating agents, cross-link DNA and form interstrand DNA-platinum adducts, leading to non-specific cell cycle arrest [5]. Bortezomib, a proteasome inhibitor and first-line treatment for multiple myeloma, inhibits the proteasome-ubiquitination pathway, preventing degradation of pro-apoptotic proteins [5, 6]. At clinically relevant doses, bortezomib alters microtubule stabilization by increasing tubulin polymerization, disrupting axonal transport of mitochondria, and promoting cytotoxicity [7]. In line with the sensory axonopathy associated with bortezomib treatment, multiple studies have shown that bortezomib significantly increases polymerized α-tubulin in the sciatic nerve and dorsal root ganglia of rats [8, 9]. A recent study highlighted the role of delta 2 tubulin, a marker of hyperstable microtubules, in bortezomib-induced axonopathy/loss of axonal transport of mitochondria and found D2 accumulation to be sufficient and necessary in driving this process [10]. For these anti-neoplastic agents, especially vincristine which has the greatest affinity for tubulin among vinca alkaloids, neurotoxicity is a major dose-limiting complication.

While CIPN pathophysiology is complex and should not be extrapolated from other peripheral neuropathies (e.g., diabetic neuropathy), signs and symptoms typically manifest in a “glove and stocking” anatomical distribution, simultaneously affecting hands and feet bilaterally, with distal-to-proximal symptom progression [11]. CIPN most commonly presents through sensory changes but motor and autonomic deficits can ensue. Signs and symptoms include evoked or spontaneous pain that ranges from tingling (“pins and needles” sensation) to stabbing or burning pain. Mechanical and cold allodynia (pain from pressure and cold temperature, otherwise innocuous), numbness, and weakness are common characteristics of CIPN [12].

CIPN is sometimes mild and reversible, whereas in other cases, it can be severe and irreversible, interfering with daily activities. CIPN prevalence depends on the chemotherapeutic agent, dosage, and duration. In one meta-analysis, it was found that 68.1% of patients experience CIPN within the first month after chemotherapy, 60.0% at 3 months, and 30.0% at 6 months and beyond (considered chronic CIPN) [13]. However, given the heterogeneity of CIPN risk with no validated clinical biomarkers, it is important to identify risk and protective factors for CIPN to better predict outcomes, understand its etiology and underlying mechanisms, and develop a personalized approach to CIPN prevention and treatment.

Clinical risk factors for develo** CIPN include a history of pre-existing neuropathy, comorbidities such as diabetes mellitus, lifestyle factors like smoking, and decreased creatinine clearance [13]. Interestingly, a history of autoimmune disease was found to be associated with reduced risk of CIPN [14]. Predisposing genetic factors include single nucleotide polymorphisms (SNPs) in FGD4, a gene associated with hereditary peripheral neuropathy in Charcot-Marie-Tooth disease, and genes involved in dysfunctional receptor activity resulting in neuronal apoptosis and prolonged muscle contraction in patients with CIPN treated with platinum drugs for breast and colon cancer, respectively [15, 16]. These CIPN-associated genetic markers may partly explain common symptoms that patients experience, including altered sensation due to apoptosis in dorsal root ganglion (DRG) sensory neurons and muscle ataxia. Cumulative dosing and infusion timing of the chemotherapeutic agent and SNPs in genes coding for voltage-gated sodium channels and myelinating Schwann cell-associated proteins are additional contributing risk factors related to CIPN mechanisms [17].

Status of Treatments for CIPN

The American Society of Clinical Oncology (ASCO) recently updated their guidelines on CIPN preventive and treatment practices [18]. Several agents that have been investigated lack evidence to support their use as potential therapies. Acetyl-L-carnitine was strongly discouraged for prevention of CIPN. Other “natural” approaches such as all trans retinoic acid (vitamin A metabolite) and antioxidants like vitamin E and glutathione, omega-3 fatty acids, and calcium magnesium infusions were not recommended as no benefits for CIPN prevention were found. Calmangafodipir, an intravenous contrast agent for magnetic resonance imaging, explored for its superoxide dismutase-like (anti-oxidant) activity, was not recommended [19]. Other chemoprotectants such as nimodipine, a calcium channel blocker, and amifostine, a cytoprotective agent against cisplatin-induced nephrotoxicity, have shown mixed results and are currently not recommended for CIPN [20, 21]. RhuLIF (human recombinant leukemia-inhibiting factor), a member of the cytokine family that includes IL-6, proposed to be neuroprotective against peripheral neuropathy, was ineffective against CIPN in a randomized, double-blind, placebo-controlled phase II clinical trial [22].

Established neuropathic pain treatments include tricyclic antidepressants (TCAs), dual serotonin and norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, and opioid agonists [23]. Of these, only the SNRI duloxetine, which is US Food and Drug Administration (FDA)-approved for treating major depressive disorder and diabetic neuropathy, exhibits moderate efficacy in treating CIPN and is often used clinically at doses from 60 to 120 mg/day [24]. No other intervention in this drug class has shown comparable therapeutic effects with a favorable risk/benefit ratio. The TCA nortriptyline has a good safety profile but did not significantly relieve paresthesia or pain in a phase III randomized, double-blind, crossover trial [25, 26]. However, one clinical advantage to using antidepressants is improvement in mood which can help with overall treatment. Anticonvulsants like gabapentin and pregabalin that block voltage-gated calcium channels and decrease excitatory neurotransmission have conflicting efficacy data, and side effects including somnolence and dizziness. Opioids have many adverse side effects with chronic use and are not considered first-line treatment for neuropathic pain.

In general, a safer and more effective therapeutic approach may involve combination therapy. For example, the combination of morphine and gabapentin reduced neuropathic pain significantly more than either agent alone in a randomized controlled trial [27]. Combination therapy with nortriptyline and gabapentin led to a synergistic effect [28]. More clinical trials investigating combination therapy specific for CIPN are needed. A compounded topical analgesic gel consisting of baclofen (γ-amino-butyric acid [GABA]-B receptor agonist), amitriptyline (TCA), and ketamine (N-methyl-D-aspartate [NMDA] receptor antagonist) has shown mild benefit in treating CIPN symptoms with no signs of systemic toxicity; however, existing data are inconclusive and further research is required [29].

Drug-repositioning studies can help identify new or secondary actions of already-approved drugs, which may prove more efficient than de novo drug development [30]. Many drug candidates for CIPN prevention and treatment can be re-purposed based on their mechanism (e.g., neuronal damage) or by screening chemical libraries to test drugs with unclear actions to identify the mechanism, while also investigating the safety profile of these drugs to prevent further CIPN progression [30].

Proposed Mechanisms of CIPN

Mechanisms by which chemotherapy-induced neurotoxicity translates to CIPN are complex and multi-factorial. Suggested mechanisms include transporter-mediated uptake of chemotherapy drug, oxidative stress secondary to mitochondrial damage, microtubule disruption and subsequent loss of axonal transport, axonal degeneration, damage to DRG sensory neurons, abnormal discharge of pain fibers (A \(\delta\) and C fibers), upregulation of proinflammatory cytokines, changes to ion conductance, and inhibition of growth factors [31, 133]. Finally, we note that because of our limited understanding of CIPN pathophysiology and its heterogenous presentation, early patient education and discussion with clinicians is needed to alleviate the burden of CIPN and improve quality of life in cancer patients and survivors.