Chemotherapy‐induced neuropathies—a growing problem for patients and health care providers

Abstract Introduction Chemotherapy‐induced neuropathies are one of the most common side effects of cancer treatment, surpassing bone marrow suppression and kidney dysfunction. Chemotherapy effects on the nervous system vary between different classes of drugs and depend on specific chemical and physical properties of the drug used. The three most neurotoxic classes of anti‐cancer drugs are: platinum‐based drugs, taxanes, and thalidomide and its analogs; other, less neurotoxic but also commonly used drugs are: bortezomib, ixabepilone, and vinca alkaloids. Methods Here, in this paper, based on our experience and current knowledge, we provide a short review of the most common, neuropathy‐inducing anti‐cancer drugs, describe the most prevalent neuropathy symptoms produced by each of them, and outline preventive measures and treatment guidelines for cancer patients suffering from neuropathy and for their health care providers. Results Patients should be encouraged to report any signs of neuropathic pain, alteration in sensory perception, tingling, numbness, burning, increased hot/cold sensitivity and motor dysfunctions as early as possible. If known neurotoxic chemotherapeutics are used, a neurological examination with electrophysiological evaluation should be implemented early in the course of treatment so, both patients and physicians would be better prepared to cope with possible neurotoxic effects. Conclusions The use of neurotoxic chemotherapeutics should be closely monitored and if clinically permitted, that is, if a patient shows signs of cancer regression, drug doses should be reduced or combined with other less neurotoxic anti‐cancer medication. If not counteractive, the use of over the counter antineuropathic supplements such as calcium or magnesium might be encouraged. If physically possible, patients should also be encouraged to exercise regularly and avoid factors that might increase nerve damage such as excessive drinking, smoking, or sitting in a cramped position.

Chemotherapy-induced polyneuropathies are one of the most common side effects of cancer treatment, surpassing bone marrow suppression and kidney dysfunction. The effects of chemotherapy on the nervous system vary between different classes of drugs and depend on specific chemical and physical properties of the drug used. Observed symptoms range from acute, transient thermal sensation to permanent, accumulative changes in peripheral nerves accompanied by chronic pain and irreversible nerve damage. These symptoms affect patient motor ability, often requiring extensive physical therapy and posing a heavy burden for health care providers (Lema, Foley, & Hausheer, 2010).
Chemotherapeutics exerting neurotoxic effects on the peripheral nervous system are often the ones that are also most commonly used, often listed as a standard, routine medication for most common types of cancer (WHO, 2014). Among them, the three most neurotoxic classes of anti-cancer drugs are: platinum-based drugs, taxanes, and thalidomide and its analogs; other, less neurotoxic but also commonly used drugs are: bortezomib, ixabepilone, and vinca alkaloids (Table 1).
Here, in this paper, we aim to provide a short review of the most common, neuropathy-inducing anti-cancer drugs, describe the most prevalent neuropathy symptoms produced by each of them, and outline preventive measures and treatment guidelines for cancer patients suffering from neuropathy and for their health care providers.

| PLATINUM-BASED DRUGS
Platinum-based drugs, sometimes referred as to platins, such as oxaliplatin, cisplatin, and carboplatin belong to a large class of synthetic anti-cancer drugs whose main antineoplastic action is triggered by DNA-cross-linking-inhibiting cancer cell DNA synthesis and repair (Kelland & Farrell, 2000). Platinum-based drugs are enlisted on the WHO Model List of Essential Medicines which represents the most important medications in a basic health system (WHO, 2014) and are used in the treatment of a variety of tumors, from lung and ovarian cancers to bladder, germ cell, testicular, and colorectal cancers.
Neurotoxicity is their main dose-limiting side effect and affects a large number of platin-treated patients, with neuropathy incidence rate ranging from 70% to 100% of all treated patients (McWhinney, Goldberg, & McLeod, 2009). These numbers make platinum-based drugs the most neurotoxic anti-cancer drugs available on market. Among platins, oxaliplatin evokes the most varied and unique neurotoxic effects, making it detrimental among available classes of anti-cancer drugs.
Platin-induced neurotoxic effects include dysesthesias, tingling, and burning sensation and neuropathic pain. Using electrophysiological techniques, peripheral nerve changes are diagnosed as mononeuropathies such as carpal tunnel syndrome or mild to severe sensory and sensorimotor polyneuropathies of axonal origin. Studies suggest that the neurotoxic effects are triggered by drug accumulation in the dorsal root ganglia, causing neuronal dysfunction and apoptosis, thus leading to long-term, often, irreversible changes in the peripheral nervous system (Avan et al., 2015;Park et al., 2015).
In case of oxaliplatin, additional transient post IV infusion neurotoxic effects have also been observed, which have often been described as jaw tightening, eye pain, leg cramps, pseudolaryngospasm, and cold hypersensitivity. These symptoms usually occur 30-60 min post infusion and resolve within a couple of days (Argyriou et al., 2013;Avan et al., 2015). The mechanisms underlying these transient neurotoxic effects remain unclear; however, recent studies indicate that they might be a direct result of structural properties of oxaliplatin. An oxalate, as part of the oxaliplatin chemical compound, released during oxaliplatin metabolism, binds to calcium through chelation, blocking calcium channels and altering neuronal signal transduction (Avan et al., 2015;McWhinney et al., 2009).

| TAXANES
Taxanes are a class of diterpenoids and include: paclitaxel (Taxol), docetaxel (Taxotere), and cabazitaxel (Jevtana) that act on microtubules, effectively preventing cancer cell division (Abal, Andreu, & Barasoain, 2003). Taxanes have been approved for use in a number of different types of cancer including, but not limited to: breast cancer, ovarian cancer, lung cancer, pancreatic cancer, and recently prostate cancer (cabazitaxel). Within that group, paclitaxel received the status of essential medicine on the WHO Model List of Essential Medicines (WHO, 2014). Despite their widespread use in cancer treatment, taxanes have a number of side effects, one of them being chemotherapyinduced polyneuropathy. Depending on the taxane used, neuropathy T A B L E 1 Summarized characteristics of neurotoxicity-inducing drugs routinely used in cancer treatment. List of cancers treated is by no means exclusive, rather we point out to the most frequently treated cancers assigned to a given drug or a group of drugs incidence ranges from 11% to 87%, the highest rates of which are reported for paclitaxel (Park et al., 2014;Scripture, Figg, & Sparreboom, 2006). Neurological symptoms include paresthesias and dysesthesias of toes, finger numbness, and loss of dexterity (Pace et al., 1997).
Using electrophysiological techniques, patients were predominately diagnosed with moderate axonal sensory neuropathy; however, rare cases of sensorimotor polyneuropathy and carpal tunnel syndrome were observed as well (Vahdat et al., 2001). The mechanism of taxane-induced neurotoxicity remains elusive; however, growing evidence indicates that a disturbance of axonal transport and neuronal oxidative stress might be the leading factors resulting in neuropathic changes in taxane-treated cancer patients (Shemesh & Spira, 2010).

| THALIDOMIDE AND ITS ANALOGS
Thalidomide (sold as Immunoprin, Talidex, Talizer, or Thalomid) and its synthetic analogs such as lenalidomide, pomalidomide, and apremilast belong to the family of antiangiogenic and immunomodulatory drugs used in multiple myeloma treatment (Hideshima et al., 2000).
Neurotoxic effects of thalidomide are predominately observed in lower extremities neuropathies, such as foot and leg dysesthesia, sensory loss, tingling, impaired reflexes, and painful muscle cramps. Using electrophysiological techniques, thalidomide-induced neurotoxicity is observed as impaired nerve conduction velocity, altered amplitude, and H reflex absence and in the vast majority of patients is diagnosed as sensory or sensorimotor polyneuropathy of primarily axonal origin.
The mechanism of thalidomide-induced neurotoxicity is not completely clear; however, studies suggest that it might be prompted by nuclear factor-kappaB-related dysregulation of neurotrophins that are critical for sensory neuron survival . Furthermore, growing evidence indicates that old age and pre-existing predisposition to nerve diseases resulting from a polymorphism of genes involved in nerve repair might play a crucial role in developing a thalidomide-induced polyneuropathy .

| BORTEZOMIB
Bortezomib ( suggesting that its neurotoxicity might be a side effect of blocking NF-kB activation and subsequent inhibition of nerve growth factors required for neuronal survival. Finally, there is a body of evidence suggesting that bortezomib neurotoxicity might be triggered by inflammatory processes concomitant with neoplastic growth (Argyriou, Iconomou, & Kalofonos, 2008;Meregalli, 2015). Surprisingly, studies showed that cancer therapy involving both bortezomib and thalidomide reduced incidence of  (Vahdat et al., 2012). As with other chemotherapeutics, the mechanisms underlying ixabepilone neurotoxicity remain unclear. Limited available evidence shows that ixabepilone neurotoxicity might be due to increased deposits of the drug in peripheral neurons, triggering mitochondrial dysfunction and increased oxidative stress in affected neurons (Ebenezer et al., 2014).  (Ness et al., 2013). Mechanisms underlying neurotoxicity of vinca alkaloids remain unclear; however, available evidence suggests that genetic polymorphism of genes crucial for microtubule formation might play a role in developing neuropathy in cancer patients (Diouf et al., 2015).
A standard skin punch biopsy 3 mm in diameter can be taken 10 cm proximal to the lateral malleolus (Lauria et al., 2010). Morphometric examination of epidermal and dermal nerves is very helpful, especially for investigating small nerve fiber abnormalities, inaccessible to neurophysiological tests. Using immunohistochemical or immunofluorescent techniques, unmyelinated fibers innervating the epidermis and large myelinated fibers and autonomic fibers can be observed (Lauria, Lombardi, Camozzi, & Devigili, 2009).
Conventional nerve conduction velocity studies include the examination of large myelinated fibers; however, the main limitation of this method is its inability to detect changes in small fibers (Themistocleous et al., 2014).
Quantitative sensory testing is another noninvasive, standardized technique for psychophysical threshold evaluation of cold and warm sensations-thermal detection, pain thresholds, and stimuli-response function (Devigili et al., 2008;Themistocleous et al., 2014). Furthermore, this kind of testing can assess the function of thin and unmyelinated nerve fibers (Verberne, Wiggers, Vermeulen, & de Jong, 2013).
Furthermore, there are new diagnostic techniques such as the measurement of nerve fiber density using corneal confocal microscopy and nociceptive evoked potentials (Hoeijmakers, Faber, Lauria, Merkies, & Waxman, 2012). Nerve morphology can be assessed using in vivo corneal confocal microscopy, including corneal nerve fiber density, that is, the number of nerve fibers/mm 2 , corneal nerve branch density-the number of branch points in the main nerves/mm 2 and corneal fiber length-the total length of nerves mm/mm 2 (Ferdousi et al., 2015). In patients with chemotherapy-induced peripheral neuropathy, using in vivo corneal confocal microscopy revealed an increase in corneal nerve fiber length. This observation correlated with nerve regeneration (Ferdousi et al., 2015).

| CHEMOTHERAPY-INDUCED NEUROPATHIES-WHAT CAN WE DO?
As discussed here, a large body of evidence suggests that chemotherapy-induced neuropathies are highly prevalent among cancer patients, constituting a major problem both for cancer patients and survivors as well as for their health care providers. The important question arises-is it possible to prevent and/or alleviate chemotherapy-induced neuropathy symptoms without jeopardizing cancer treatment regimens and incurring additional treatment costs?
The answer should be affirmative. It is possible to reduce the number of chemotherapy-induced neuropathies and lower their financial burden on patients and health care provides, but in order to do so efficiently, we would need to revise patient examination and treatment protocols. Revised protocols should reflect our knowledge of chemotherapeutic neurotoxicity and encourage larger involvement of primary care physicians and neurologists in cancer treatment protocols.
T A B L E 2 Randomized controlled trials concerning prevention and treatment of chemotherapy-induced peripheral neuropathy according to Brami, Bao, and Deng (2016), with modifications should also be encouraged to exercise regularly and avoid factors that might increase nerve damage such as excessive drinking, smoking, or sitting in a cramped position.

CONFLICT OF INTEREST
None declared.